| WO2017132474A1 | 2017-08-03 | |||
| WO2019040573A1 | 2019-02-28 | |||
| WO2005049593A2 | 2005-06-02 | |||
| WO2005049594A1 | 2005-06-02 | |||
| WO2009064938A1 | 2009-05-22 | |||
| WO2017132474A1 | 2017-08-03 | |||
| WO2019040550A1 | 2019-02-28 | |||
| WO2019040573A1 | 2019-02-28 | |||
| WO2014113413A1 | 2014-07-24 |
| US20040036770W | 2004-11-03 | |||
| US20040037911W | 2004-11-12 | |||
| US20080182845A1 | 2008-07-31 | |||
| US4522811A | 1985-06-11 | |||
| US9018381B2 | 2015-04-28 | |||
| US20120189539A1 | 2012-07-26 |
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CHEMICAL ABSTRACTS, Columbus, Ohio, US; abstract no. 1375325-77-1
| WHAT IS CLAIMED IS: 1. A compound of Formula (A), or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug of said compound of Formula (A) or N-oxide thereof: Formula (A) wherein V is N or P(O); Qi is 6 membered heterocycloalkyl, 6 membered heterocycloalkenyl, or 6 membered heteroaryl; Q2 is 6-membered heterocycloalkyl, 6-membered heterocycloalkenyl, 6- membered aryl, or 6-membered heteroaryl; Q3 is cycloalkyl, cycloalkenyl, bridged cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl; Q4 is cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl; Q5 is 6-membered heterocycloalkyl, or 6-membered heterocycloalkenyl; Q6 is 6-membered aryl, or 5-6 membered heteroaryl; Q7 is 6-membered aryl or 5-6 membered heteroaryl, each of which is optionally fused with a benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane, or heterocycloalkene; each of Ri, R2, R3, R4, R5, R6, R7, R8, Rio, and Rn, independently, is H, D, alkyl, spiroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, halo, nitro, oxo, cyano, ORa, SRa, alkyl-Ra, NH(CH2)pRa, C(0)Ra, S(0)Ra, S02Ra, C(0)0Ra, 0C(0)Ra, NRbRc, C(0)N(Rb)Rc, N(Rb)C(0)Rc, -P(0)RbRc, -alkyl-P(0)RbRc, -S(0)(=N(Rb))Rc, -N=S(0)RbRc, =NRb, S02N(Rb)Rc, or N(Rb)S02Rc, in which said cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl is optionally subsitiuted with one or more R4; R9 is R9A OG R9B; R9A is H, D, alkyl, spiroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, halo, nitro, oxo, cyano, ORa, SRa, alkyl-Ra, NH(CH2)pRa, C(0)Ra, S(0)Ra, S02Ra, C(0)0Ra, 0C(0)Ra, NRbRc, C(0)N(Rb)Rc, N(Rb)C(0)Rc, -P(0)RbRc, -alkyl- P(0)RbRc, -S(0)(=N(Rb))Rc, -N=S(0)RbRc, =NRb, S02N(Rb)Rc, or N(Rb)S02Rc, in which said cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl is optionally subsitiuted with one or more Rd; Rgs is a small molecule E3 ubiquitin ligase binding moiety that binds an E3 ubiquitin ligase; Rd, independently, is H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, =0, -P(0)RbbRcc, -alkyl-P(0)RbbRcc, -S(0)(=N(Rbb))Rcc, -N=S(0)RbbRcc, =NRbb, C(0)NHOH, C(0)OH, C(0)NH2, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, halo- alky lamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, in which said alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl is optionally subsitiuted with one or more Re; Ra, Rb, Rc, Rbb and Rcc, independently, is H, D, alkyl, spiroalkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, in which said alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl is optionally subsitiuted with one or more Re; Re, independently, is H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, =0, C(0)NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, halo -alkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl; Zi is a bond, (CH2)P, N(H), O, S, C(O), S(02), OC(O), C(0)0, OS02, S(02)0, C(0)S, SC(O), C(0)C(0), C(0)N(H), N(H)C(0), S(02)N(H), N(H)S(02), 0C(0)0, OC(0)S, OC(0)N(H), N(H)C(0)0, N(H)C(0)S, N(H)C(0)N(H), (CH2)pN(H)(CH2)q, (CH2)pN(H)C(0)(CH2)q, (CH2)pC(0)N(H)(CH2)q, 0C(0)N(H)(CH2)p+iN(H)(CH2)q, a bivalent alkenyl group, or a bivalent alkynyl group; L is Li or L2; Li is bond, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, in which said alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl is optionally subsitiuted with one or more Rd; L2 is an alkyl in which one or more -L,- are optionally inserted between any two adjacent carbon atoms; -Li- is -N(Ra)-, -0-, -S-, -C(O)-, -S(02)-, -OC(O)-, -C(0)0-, -OS02-, -S(02)0-, -C(0)S-, -SC(O)-, -C(0)C(0)-, -C(0)N(Ra)-, -N(Ra)C(0)-, -S(02)N(Ra)-, -N(Ra)S(02)-, -0C(0)0-, -OC(0)S-, -OC(0)N(Ra)-, -N(Ra)C(0)0-, -N(Ra)C(0)S-, -N(Ra)C(0)N(Ra)-, a bivalent alkenyl group, a bivalent alkynyl group, a bivalent cycloalkyl group, a bivalent heterocycloalkyl group, a bivalent aryl group, a bivalent heteroaryl group; W is O or N(Ra); two of Ri group, taken together with the atoms to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl, in which said cycloalkyl or heterocycloalkyl of Ri, is optionally subsitiuted with one or more R ; two of R2 group, taken together with the atom(s) to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl, in which said cycloalkyl or heterocycloalkyl of R2, is optionally subsitiuted with one or more Rd; R3 and R4 group, taken together with the atom to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl, in which said cycloalkyl or heterocycloalkyl of R3 and R4, is optionally subsitiuted with one or more Rd; two of R5 group, taken together with the atom(s) to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl, in which said cycloalkyl or heterocycloalkyl of R5, is optionally subsitiuted with one or more Rd; two of R6 group, taken together with the atoms to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl, in which said cycloalkyl or heterocycloalkyl of R6, is optionally subsitiuted with one or more Rd; two of R7 group, taken together with the atoms to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl, in which said cycloalkyl or heterocycloalkyl of R7, is optionally subsitiuted with one or more Rd; two of Rio group, taken together with the atom(s) to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl, in which said cycloalkyl or heterocycloalkyl of Rio, is optionally subsitiuted with one or more Rd; two of Rn group, taken together with the atom(s) to which they are attached, may optionally form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, in which said cycloalkyl, heterocyclo alkyl, aryl, or heteroaryl of Rn, is optionally subsitiuted with one or more Rd; R2 and R5 group, taken together with the atoms to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl, in which said cycloalkyl or heterocycloalkyl of R2 and R5, is optionally subsitiuted with one or more R ; R3 and R5 group, taken together with the atoms to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl, in which said cycloalkyl or heterocycloalkyl of R3 and R5, is optionally subsitiuted with one or more Rd; Rb and Rc group, taken together with the atom to which they are attached, may optionally form a cycloalkyl, or heterocycloalkyl, in which said cycloalkyl or heterocycloalkyl of Rb and Rc, is optionally subsitiuted with one or more Re; two of Rd group, taken together with the atom(s) to which they are attached, may optionally form a cycloalkyl, or heterocycloalkyl, in which said cycloalkyl or heterocycloalkyl of Rd, is optionally subsitiuted with one or more Re; two of Re group, taken together with the atom(s) to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl, in which said cycloalkyl or heterocycloalkyl of Re is optionally subsitiuted with one or more groups selected from H, D, alkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, C(0)NH0H, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, halo- alky lamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl; each of g and j is, independently, 0, 1, 2, or 3; each of n, v and k is, independently, 0, 1, 2, 3, 4, 5, 6, 7, or 8; s is 0 or 1 ; and each of h, m, p, and q is, independently, 0, 1, 2, 3, 4, or 5. 2. The compound according to claim 1, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein the compound is represented by Formula (A-l): Formula (A-l) The compound according to claim 2 or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein the compound is represented by Formula (A-2): Formula (A-2) The compound according to claim 3 or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein the compound is represented by Formula (A-3): Formula (A-3) wherein“ -” is absent or a bond; Wi is N or CH; and W2 is N or C or CH. The compound according to claim 4 or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein the compound is represented by Formula (A-4): Formula (A-4) The compound according to claim 5 or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein the compound is represented by Formula (A-5): Formula (A-5) The compound according to any one of claims 1-6, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein which Qg is 5-7 membered heterocycloalkyl, 5-7 membered heterocycloalkenyl, phenyl, or 5-7 membered heteroaryl; and gg is 0, 1, 2, 3, or 4. The compound according to any one of claims 1-7, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein which each Za and Zb is independently -0-, -CH2-, -C(O)-, -N(Ra)-, -S-, -S(O)-, -S(02)-, -S(0)(=N(Ra))-, -P(0)(Ra)-; wherein Ra of Za and Zb, independently, is H, D, Ci-C6alkyl, C2-C6alkenyl, Ci-C6alkylcarbonyl, Ci-C6alkoxycarbonyl, C3-C6cycloalkyl, 5-8 membered monocyclic heterocycloalkyl, Ce-C aryl, or 5-8 membered monocyclic heteroaryl, in which said Ci-C6alkyl, C3-C6cycloalk l, 5-8 membered monocyclic heterocycloalkyl, C6-Cl4aryl, 5-8 membered monocyclic heteroaryl is optionally substituted with one or more Re. The compound according to any one of claims 1-8, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein 10. The compound according to any one of claims 1-9, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein Zi is absent or (CH2)P; L is Li and Li is bond, and R9 is 5-7 membered heterocyclyl or 7-10 membered bridged heterocyclyl, each of which is optionally substituted with 1-3 groups selected from halo, -OH, -CN, -COOH, -NH2, -N(CH3)2, -(Ci-C4)alkyl, and -(Ci-C4)alkoxy. 11. The compound according to any one of claims 1-10, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein 12. The compound according to any one of claims 1-10, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein h is 0, 1, or 2; each of mi and m2, independently, is 0, 1, or 2; and each of Z3, Z4, Z5 and Z6, independently, is a bond, (CH2)P, N(H), O, S, C(O), S(02), OC(O), C(0)0, OS02, S(02)0, C(0)S, SC(O), C(0)C(0), C(0)N(H), N(H)C(0), S(02)N(H), N(H)S(02), 0C(0)0, OC(0)S, OC(0)N(H), N(H)C(0)0, N(H)C(0)S, N(H)C(0)N(H), (CH2)pN(H)(CH2)q, (CH2)pN(H)C(0)(CH2)q, (CH2)pC(0)N(H)(CH2)q, 0C(0)N(H)(CH2)p+1N(H)(CH2)q, a bivalent alkenyl group, or a bivalent alkynyl group. 13. The compound according to claim 12 or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein 14. The compound according to claim 13 or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein wherein Z2 is -0-, -CH2-, -Geo)-, -N(Ra)-, -S-, -S(O)-, -S(02)-, -S(0)(=N(Ra))-, -P(0)(Ra)-; wherein Ra of Z2, independently, is H, D, Ci-C6alkyl, C2-C6alkenyl, Ci- Cealkylcarhonyl, Ci-C6alkoxycarbonyl, C3-C6cycloalkyl, 5-8 membered monocyclic heterocycloalkyl, Ce-C aryl, or 5-8 membered monocyclic heteroaryl, in which said Ci-C6alkyl, C3-C6cycloalkyl, 5-8 membered monocyclic heterocycloalkyl, Ce-Cuaryl, 5-8 membered monocyclic heteroaryl is optionally subsitiuted with one or more Re; k is 0, 1, 2, 3, or 4; and f is 0. 15. The compound according to claim 14 or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein 16. The compound according to any one of claims 1-15, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an i-)- RM isotopic form, or a prodrug thereof, wherein Rio is aryl, heteroaryl, or R12 ; R12 is H, D, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, halo, nitro, oxo, cyano, ORa, SRa, alkyl-Ra, NH(CH2)pRa, C(0)Ra, S(0)Ra, S02Ra, C(0)ORa, OC(0)Ra, NRbRc, P(0)RbRc, alkyl- P(0)RbRc, C(0)N(Rb)Rc, N(Rb)C(0)Rc, S(0)(=N(Rb))Rc, -N=S(0)RbRc, S02N(Rb)Rc, or N(Rb)S02Rc, in which said cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl is optionally substituted with one or more Rd; and each of R13, and R14, independently, is H, D, alkyl, halo-alkyl, or R13 and R^ taken together with the atom to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl, in which said cycloalkyl or heterocycloalkyl is optionally substituted with one or more R . The compound according to claim 15, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein which (¾ is a C4-C6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl; and w is 0, 1, 2, 3, or 4. 18. The compound according to claim 17, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein Q9 is C5-C6 cycloalkyl, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; each of which is optionally substituted with 1 to 3 groups selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, -OH, CN, and NH2. 19. The compound according to any one of claims 1-9 and 11-18, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein R9 is R9B. 20. The compound according to claim 19 or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein said E3 ubiquitin ligase is Von Hippel-Lindau (VLM), cereblon (CLM), mouse double-minute homolog2 (MLM), and IAP (ILM). 21. The compound according to claim 19 or 20, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein wherein Za is a bond, (CH2)P, N(H), O, S, C(O), S(02), OC(O), C(0)0, 0S02, S(02)0, C(0)S, SC(O), C(0)C(0), C(0)N(H), N(H)C(0), S(02)N(H), N(H)S(02), 0C(0)0, 0C(0)S, 0C(0)N(H), N(H)C(0)0, N(H)C(0)S, N(H)C(0)N(H), (CH2)pN(H)(CH2)q, (CH2)pN(H)C(0)(CH2)q, (CH2)pC(0)N(H)(CH2)q, 0C(0)N(H)(CH2)p+iN(H)(CH2)q, a bivalent alkenyl group, or a bivalent alkynyl group. 22. The compound according to claim 19 or 20, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein wherein Zb is a bond, (CH2)P, N(H), O, S, C(O), S(02), OC(O), C(0)0, OS02, S(02)0, C(0)S, SC(O), C(0)C(0), C(0)N(H), N(H)C(0), S(02)N(H), N(H)S(02), 0C(0)0, OC(0)S, OC(0)N(H), N(H)C(0)0, N(H)C(0)S, N(H)C(0)N(H), (CH2)pN(H)(CH2)q, (CH2)pN(H)C(0)(CH2)q, (CH2)pC(0)N(H)(CH2)q, 0C(0)N(H)(CH2)p+iN(H)(CH2)q, a bivalent alkenyl group, or a bivalent alkynyl group. 23. The compound according to any one of claims 1-9 and 11-22, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein L is L2, and L2 is 11111 mp , wherein each of mn and mp is independently an integer of 0 to 12; and each of L3 and L4 independently, is a bond, (CH2)P, N(H), O, S, C(O), S(02), OC(O), C(0)0, 0S02, S(02)0, C(0)S, SC(O), C(0)C(0), C(0)N(H), N(H)C(0), S(02)N(H), N(H)S(02), 0C(0)0, 0C(0)S, 0C(0)N(H), N(H)C(0)0, N(H)C(0)S, N(H)C(0)N(H), (CH2)pN(H)(CH2)q, (CH2)pN(H)C(0)(CH2)q, (CH2)pC(0)N(H)(CH2)q, 0C(0)N(H)(CH2)p+iN(H)(CH2)q, a bivalent alkenyl group, or a bivalent alkynyl group. 24. The compound according to claim 23 or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein said L2 is 11111 11111 11111 25. The compound according to any one of claims 1-24 or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein 26. The compound according to any one of claims 1-25 or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein Rg is N02. 27. The compound according to claim 1 or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein the compound is (S)-N-((4-(((l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4’- chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2-yl)methyl)piperazin-l-yl)-2- (2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]thiazin-l(6H)-yl)benzamide, (R)-N-((4-(((l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4- ((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2-yl)methyl)piperazin-l- yl)-2-(2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]thiazin-l(6H)-yl)benzamide, N-((4-((((S)-l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4’- chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2-yl)methyl)piperazin-l-yl)-2- ((S)-3-methyl-2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]thiazin-l(6H)- yl)benzamide, N-((4-((((R)-l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4- ((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2-yl)methyl)piperazin-l- yl)-2-((R)-3-methyl-2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]thiazin-l(6H)- yl)benzamide, N-((4-((((S)-l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4’- chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2-yl)methyl)piperazin-l-yl)-2- ((R)-3-(trifluoromethyl)-2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]thiazin- l(6H)-yl)benzamide, or N-((4-((((R)-l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4- ((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2-yl)methyl)piperazin-l- yl)-2-((S)-3-(trifluoromethyl)-2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]thiazin- l(6H)-yl)benzamide, 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2- yl)methyl)piperazin-l-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4- yl)methyl)amino)phenyl)sulfonyl)-2-(3-(pyridin-3-yl)-2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)benzamide, (R)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(3-(2-fluoropropan-2-yl)-2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)-N-((3-nitro-4- (((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide, 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(3-(l-(2-(dimethylamino)ethoxy)-2-methylpropan-2-yl)- 2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin-l(6H)-yl)-N-((3-nitro-4- (((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide, 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(3-(l-(4,4-difluoropiperidin-l-yl)-2-methylpropan-2-yl)- 2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin-l(6H)-yl)-N-((3-nitro-4- (((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide, 4-(4-((4’-chloro-[l, -biphenyl]-2-yl)(hydroxy)methyl)piperidin-l-yl)-2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)-N-((3-nitro-4- (((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide, N-(((S)-3-((S)-l,4-dioxan-2-yl)-5-nitro-3,4-dihydro-2H-benzo[b][l,4]oxazin- 7-yl)sulfonyl)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3- b] [ 1 ,4]oxazin- 1 (6H)-yl)benzamide, N-(((S)-3-((R)-l,4-dioxan-2-yl)-5-nitro-3,4-dihydro-2H-benzo[b][l,4]oxazin- 7-yl)sulfonyl)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3- b] [ 1 ,4]oxazin- 1 (6H)-yl)benzamide, N-(((R)-3-((S)-l,4-dioxan-2-yl)-5-nitro-3,4-dihydro-2H-benzo[b][l,4]oxazin- 7-yl)sulfonyl)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3- b] [ 1 ,4]oxazin- 1 (6H)-yl)benzamide, N-(((R)-3-((R)-l,4-dioxan-2-yl)-5-nitro-3,4-dihydro-2H-benzo[b][l,4]oxazin- 7-yl)sulfonyl)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3- b] [ 1 ,4]oxazin- 1 (6H)-yl)benzamide, 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-(((S)-5-nitro-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro- 2H-benzo[b][l,4]oxazin-7-yl)sulfonyl)benzamide, 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-(((R)-5-nitro-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro- 2H-benzo[b][l,4]oxazin-7-yl)sulfonyl)benzamide, 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-(((S)-3-(morpholinomethyl)-5-nitro-3,4-dihydro-2H- benzo[b][l,4]oxazin-7-yl)sulfonyl)benzamide, 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-(((R)-3-(morpholinomethyl)-5-nitro-3,4-dihydro-2H- benzo[b][l,4]oxazin-7-yl)sulfonyl)benzamide, N-(((S)-3-(((lS,4S)-2-oxa-5-azabicyclo[2.2.l]heptan-5-yl)methyl)-5-nitro-3,4- dihydro-2H-benzo[b][l,4]oxazin-7-yl)sulfonyl)-4-(4-((4’-chloro-5,5-dimethyl- 3,4,5,6-tetrahydro-[l,r-biphenyl]-2-yl)methyl)piperazin-l-yl)-2-((R)-3-methyl-2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin-l(6H)-yl)benzamide, N-(((S)-3-(((lR,4R)-2-oxa-5-azabicyclo[2.2.l]heptan-5-yl)methyl)-5-nitro- 3,4-dihydro-2H-benzo[b][l,4]oxazin-7-yl)sulfonyl)-4-(4-((4’-chloro-5,5-dimethyl- 3,4,5,6-tetrahydro-[l,r-biphenyl]-2-yl)methyl)piperazin-l-yl)-2-((R)-3-methyl-2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin-l(6H)-yl)benzamide, N-(((R)-3-(((lS,4S)-2-oxa-5-azabicyclo[2.2.l]heptan-5-yl)methyl)-5-nitro- 3, 4-dihydro-2H-benzo[b][l,4]oxazin-7-yl)sulfonyl)-4-(4-((4’-chloro-5, 5-dimethyl- 3,4,5,6-tetrahydro-[l,r-biphenyl]-2-yl)methyl)piperazin-l-yl)-2-((R)-3-methyl-2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin-l(6H)-yl)benzamide, N-(((R)-3-(((lR,4R)-2-oxa-5-azabicyclo[2.2.l]heptan-5-yl)methyl)-5-nitro- 3,4-dihydro-2H-benzo[b][l,4]oxazin-7-yl)sulfonyl)-4-(4-((4’-chloro-5,5-dimethyl- 3,4,5,6-tetrahydro-[l,r-biphenyl]-2-yl)methyl)piperazin-l-yl)-2-((R)-3-methyl-2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin-l(6H)-yl)benzamide, 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l’-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-(((S)-3-((4-methylpiperazin-l-yl)methyl)-5-nitro-3,4- dihydro-2H-benzo[b][l,4]oxazin-7-yl)sulfonyl)benzamide, or 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-(((R)-3-((4-methylpiperazin-l-yl)methyl)-5-nitro-3,4- dihydro-2H-benzo[b][l,4]oxazin-7-yl)sulfonyl)benzamide, 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2- yl)methyl)piperazin-l-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4- yl)methyl)amino)phenyl)sulfonyl)-2-(4-oxo-4,6-dihydro-lH-pyrrolo[2,3- b] [ 1 ,5]naphthyridin- 1 -yl)benzamide, 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2- yl)methyl)piperazin-l-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4- yl)methyl)amino)phenyl)sulfonyl)-2-(4-oxo-4,6-dihydro-lH- pyrrolo[3’,2’:5,6]pyrido[3,2-d]pyrimidin-l-yl)benzamide, 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,2-dioxido-3H-pyrrolo[3’,2’:5,6]pyrido[3,2- e][l,3,4]oxathiazin-l(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide, 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l’-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(l,l-dioxido-2,3-dihydropyrrolo[3’,2’:5,6]pyrido[3,2- e][l,2,4]thiadiazin-4(8H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide, 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l’-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(l,l-dioxidopyrrolo[3’,2’:5,6]pyrido[3,2- e][l,2,4]thiadiazin-4(8H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide, or 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l’-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(4,4-dimethyl-2-oxo-4,6- dihydropyrrolo[3’,2’:5,6]pyrido[3,2-d][l,3]oxazin- l(2H)-yl)-N-((3-nitro-4- (((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide, N-((4-((((S)-l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4’- chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2-yl)methyl)piperazin-l-yl)-2- ((5aS,8aS)-5a,6,8,8a-tetrahydrofuro[3,4-b]pyrrolo[3’,2’:5,6]pyrido[3,2-e][l,4]oxazin- 5(lH)-yl)benzamide, N-((4-((((S)-l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4’- chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l’-biphenyl]-2-yl)methyl)piperazin-l-yl)-2- ((5aS,8aR)-5a,6,8,8a-tetrahydrofuro[3,4-b]pyrrolo[3’,2’:5,6]pyrido[3,2-e][l,4]oxazin- 5(lH)-yl)benzamide, N-((4-((((S)-l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4’- chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l’-biphenyl]-2-yl)methyl)piperazin-l-yl)-2- ((5aR,8aR)-5a,6,8,8a-tetrahydrofuro[3,4-b]pyrrolo[3’,2’:5,6]pyrido[3,2-e][l,4]oxazin- 5(lH)-yl)benzamide, or N-((4-((((S)-l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4’- chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l’-biphenyl]-2-yl)methyl)piperazin-l-yl)-2- ((5aR,8aS)-5a,6,8,8a-tetrahydrofuro[3,4-b]pyrrolo[3’,2’:5,6]pyrido[3,2-e][l,4]oxazin- 5(lH)-yl)benzamide. 28. A pharmaceutical composition comprising a compound of Formula (A) or an N-oxide thereof as defined in any one of claims 1-27, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug of said compound of Formula (A) or an N-oxide thereof, and a pharmaceutically acceptable diluent or carrier. 29. A method of treating a neoplastic disease, an autoimmune disease, or a neorodegenerative disease, comprising administering to a subject in need thereof an effective amount of a compound of Formula (A) or an N-oxide thereof as defined in any one of claims 1-27, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug of said compound of Formula (A) or an N-oxide thereof. 30. The method of claim 29, wherein the neoplastic disease, the autoimmune disease, or the neorodegenerative disease is characterized by abnormal (e.g., enhanced or increased) BCL-2 activity, such as a hematological malignancy / cancer, type I diabetes, or schizophrenia. 31. The method of claim 30, wherein the neoplastic disease is myeloma, multiple myeloma, lymphoma, follicular lymphoma (FL), non- Hodgkin’ s lymphoma, leukemia, acute leukemia, acute lymphoblastic leukemia (ALL) (such as BCL-2- dependent ALL and pediatric ALL), chronic lymphoblastic leukemia (CLL) (such as relapsed/refractory CLL, del(l7p) CLL), chronic myeloid leukemia (CML) (such as blast-crisis CML), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma, lung cancer such as small cell lung cancer (SCLC), melanoma, breast cancer, or prostate cancer, including drug-resistant cancer thereof. 32. The method of claim 31, further comprising administering one or more further treatment(s) effective to treat the neoplastic disease, such as surgery, radiation therapy, a chemotherapeutic agent (such as bendamustine, NL-101, cisplatin, carboplatin, etoposide, topotecan), a target therapy (such as rituximab, ibrutinib, ACP-196, idelalisib); an antibody-drug conjugate or ADC (such as brentuximab vedotin), an immunotherapy (such as pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab), or a CAR-T thearpy (such as tisagenlecleucel, axicabtagene ciloleucel). |
REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of the filing dates of U.S. Provisional Application Nos. 62/721,203, filed on August 22, 2018; 62/721,596, filed on August 22, 2018;
62/721,769, filed on August 23, 2018; 62/721,858, filed on August 23, 2018; 62/722,326, filed on August 24, 2018; 62/722,377, filed on August 24, 2018; 62/771,055, filed on November 24, 2018; 62/791,840, filed on January 13, 2019; 62/846,500, filed on May 10, 2019; and 62/846,754, filed on May 13, 2019, the entire contents of each of the above referenced applications are hereby incorporated herein by reference.
BACKGROUND OF THE INVENTION
Apoptosis, or programmed cell death, is a conserved and regulated process that is the primary mechanism for the removal of aged, damaged and unnecessary cells. The ability to block apoptotic signaling is a key hallmark of cancer and is thus important for oncogenesis, tumor maintenance and chemoresistance [Hanahan, D. & Weinberg, R.A. The hallmarks of cancer. Cell 100, 57-70 (2000).]. Dynamic binding interactions between prodeath (for example, BCL-2-associated X protein (BAX), BCL-2 antagonist/killer 1 (BAK), BCL- 2- associated agonist of cell death (BAD), BCL- 2-like 11 (BIM), NOXA and BCL-2 binding component 3 (PUMA)) and prosurvival (BCL-2, BCL- XL, BCL- 2-like 2 (BCL-W), myeloid cell leukemia sequence 1 (MCL-l) and BCL-2-related protein Al (BFL-l)) proteins in the BCL-2 family control commitment to programmed cell death. Altering the balance among these opposing factions provides one means by which cancer cells undermine normal apoptosis and gain a survival advantage [Youle, R.J. & Strasser, A. The BCL-2 protein family: opposing activities that mediate cell death. Nat. Rev. Mol. Cell Biol. 9, 47-59 (2008)].
BCL-2, the first identified apoptotic regulator, was originally cloned from the breakpoint of a t( 14; 18) translocation present in human B cell lymphomas [Tsujimoto, Y., et al. Science 228, 1440-1443 (1985); Cleary, M.L., et al Cell 47, 19-28 (1986); Boise, L.H. et al. Cell 74, 597-608 (1993)]. This protein has since been shown to have a dominant role in the survival of multiple lymphoid malignancies [Vaux, D.L., et al pre-B cells. Nature 335, 440-442 (1988)]. Overexpression of BCL-2 proteins correlates with resistance to chemotherapy, clinical outcome, disease progression, overall prognosis or a combination thereof in various cancers and disorders of the immune system. Involvement of BCL-2 proteins in bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, spleen cancer, and the like is described in PCT/US2004/36770, published as WO 2005/049593, and PCT/US2004/37911, published as WO/2005/049594. Involvement of BCL-2 proteins in immune and autoimmune diseases is described in Current Allergy and Asthma Reports 2003, 3, 378-384; British Journal of Hematology 2000, 110(3), 584-90; Blood 2000, 95(4), 1283-92; and New England Journal of Medicine 2004, 351(14), 1409-1418. Involvement of BCL-2 proteins in arthritis is disclosed in WO 2009/064938. Involvement of BCL-2 proteins in bone marrow transplant rejection is disclosed in US 2008-0182845 Al. All incorporated herein by reference.
In the last decade, several BCL-2 inhibitors such as ABT-737, ABT-263, and ABT- 199 as shown below have been identified and entered human clinical trials for cancers treatment.
ABT-737 is discovered by nuclear magnetic resonance (NMR)-based screening, parallel synthesis and structure based fragment drug design [Tillman Oltersdorf, et al, Nature, Vol 435, 2005, p 677]. ABT-737 a small-molecule inhibitor of the anti- apopto tic proteins BCL-2, Bcl-XL and Bcl-w, with an affinity two to three orders of magnitude more potent than previously reported compounds. Mechanistic studies reveal that ABT-737 does not directly initiate the apoptotic process, but enhances the effects of death signals, displaying synergistic cytotoxicity with chemotherapeutic s and radiation. ABT-737 exhibits single- agent-mechanism-based killing of cells from lymphoma and small-cell lung carcinoma lines, as well as primary patient-derived cells, and in animal models, ABT-737 improves survival, causes regression of established tumors, and produces cures in a high percentage of the mice. Unfortunately, ABT-737 is not orally bioavailable, and its formulation for intravenous delivery is hampered by its low aqueous solubility.
After extensive MedChem effort, an orally bioavailable BCL-2 inhibitor ABT-263 (Navitoclax) has been developed [Cheol-Min Park, et al J. Med. Chem. 2008, 51, 6902- 6915]. ABT-263 is a potent inhibitor of Bcl-xL, BCL-2 and Bcl-w with Ki of < 0.5 nM, < 1 nM and < 1 nM. ABT-263 has an IC50 of 110 nM against SCLC H146 cell line. When ABT- 263 is administered at 100 mg/kg/day in the H345 xenograft model, significant antitumor efficacy is observed with 80% TGI and 20% of treated tumors indicating at least a 50% reduction in tumor volume. Oral administration of ABT-263 alone causes complete tumor regressions in xenograft models of small-cell lung cancer and acute lymphoblastic leukemia [Tse C, et al. Cancer Res. 2008, 68(9), 3421-3428]. In the clinical trial, however, the inhibition of BCL-XL by ABT-263 (navitoclax) induces a rapid, concentration-dependent decrease in the number of circulating platelets. This mechanism-based thrombocytopenia is the dose-limiting toxicity of single-agent navitoclax treatment in patients and limits the ability to drive drug concentrations into a highly efficacious range.
Thus, a BCL-2 selective (BCL-XL sparing) inhibitor would culminate in substantially reduced thrombocytopenia while maintaining efficacy in lymphoid malignancies. The resulting increase in the therapeutic window should allow for greater BCL-2 suppression and clinical efficacy in BCL- 2-dependent tumor types. After extensive MedChem, ABT-199 (GDC-0199) has been successfully developed [Andrew J Souers, et al, Nature Medicine, Volume 19, 22, p202, 2013]. ABT-199 is a BCL-2-selective inhibitor with Ki of <0.01 nM, >4800-fold more selective versus Bcl-xL and Bcl-w, and no activity to Mcl-l. ABT-199 potently inhibits RS4;l 1 cells with EC50 of 8 nM. In addition, ABT-199 induces a rapid apoptosis in RS4;l l cells with cytochrome c release, caspase activation, and the
accumulation of sub-GO/Gl DNA. Quantitative immunoblotting reveals that sensitivity to ABT-199 correlated strongly with the expression of BCL-2, including NHL, DLBCL, MCL, AML and ALL cell lines. ABT-199 also induces apoptosis in CLL with an average EC50 of 3.0 nM. A single dose of 100 mg/kg of ABT-199 causes a maximal tumor growth inhibition of 95% and tumor growth delay of 152% in RS4;l 1 xenografts. ABT-199 also inhibits xenograft growth (DoHH2, Granta-5l9) as a single agent or in combination with
Bendamustine and other agents. Human Phase I and II data showed that ABT-199 is highly efficacious for CLL who have 17r deletion, and was approved by FDA in 2016.
WO/2017/132474, WO/2019/040550, and WO/2019/040573 disclosed a novel class of BCL-2 inhibitors. However, there is still a strong need for continuing search in this field of art for more potent BCL-2 inhibitor.
SUMMARY OF THE INVENTION
Described herein are compounds of Formulae (A), (A-l), (A-2), (A-3), (A-4), and (A- 5), and the compounds of the examples (collectively referred to herein as“the compounds of the invention”), that inhibit the activity of BCL-2 family proteins, such as Bcl-2, and pharmaceutically acceptable salts, solvates, polymorphs, tautomers, stereoisomers, isotopic forms, or prodrugs thereof.
In one aspect, the invention provides a compound represented by structural formula (A):
Formula (A) or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug of the compound of Formula (A) or N-oxide thereof. The definition of each variable is recited herein.
A modified compound of any one of such compounds including a modification having an improved ( e.g ., enhanced, greater) pharmaceutical solubility, stability, bio availability, and/or therapeutic index as compared to the unmodified compound is also contemplated. Exemplary modifications include (but are not limited to) applicable prodrug derivatives, and deuterium-enriched compounds.
Also within the scope of this invention is a pharmaceutical composition containing one or more of the compounds (such as any one of those in Formulae (A), (A-l), (A-2), (A- 3), (A-4), and (A-5), or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof or an N-oxide thereof), modifications, and/or salts thereof described herein, and a pharmaceutically acceptable diluent or carrier, for use in treating a neoplastic disease, therapeutic uses thereof, and use of the compounds for the manufacture of a medicament for treating the disease / disorder.
This invention also relates to a method of treating a disease treatable by inhibiting the activity of one or more Bcl-2 family member proteins, such as a neoplastic disease, an autoimmune disease, or a neorodegenerative disease, comprising administering to a subject in need thereof an effective amount of one or more compounds of the invention, modifications, and/or salts thereof described herein, or a pharmaceutical composition comprising the compound(s) of the invention.
In certain embodiments, the neoplastic disease, autoimmune disease, or
neorodegenerative disease is characterized by abnormal ( e.g ., enhanced or increased) BCL-2 family protein (such as Bcl-2) activity. For example, the neoplastic disease can be a hematological malignancy or cancer including solid tumor; the autoimmune disease can be type I diabetes; and the neorodegenerative disease can be schizophrenia.
In certain embodiments, the neoplastic disease is myeloma, multiple myeloma, lymphoma, follicular lymphoma (FL), non- Hodgkin’s lymphoma, leukemia, acute leukemia, acute lymphoblastic leukemia (ALL) (such as BCL- 2-dependent ALL and pediatric ALL), chronic lymphoblastic leukemia (CLL) (such as relapsed/refractory CLL, del(l7p) CLL), chronic myeloid leukemia (CML) (such as blast-crisis CML), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma, lung cancer such as small cell lung cancer (SCLC), melanoma, breast cancer, or prostate cancer, including drug-resistant cancer thereof.
In certain embodiments, the method further comprises administering one or more further treatment(s) effective to treat the neoplastic disease, such as surgery, radiation therapy, a chemotherapeutic agent (such as bendamustine, NL-101 (7-(5-(bis(2- chloroethyl)amino)- l-methyl- lH-benzo[d]imidazol-2-yl)-N-hydroxyheptanamide), cisplatin, carboplatin, etoposide, topotecan), a target thearpy (e.g., an anti-CD20 antibody such as rituximab, a Bruton’s tyrosine kinase inhibitor such as ibrutinib and acalabrutinib (ACP-196), a PI3K5 inhibitor such as idelalisib); an antibody-drug conjugate or ADC (such as anti-CD30 ADC brentuximab vedotin), an immunotherapy (such as an anti- PD- 1 antibody including pembrolizumab and nivolumab, or an anti-PD-Ll antibody including atezolizumab, durvalumab, and avelumab), or a CAR-T thearpy (such as tisagenlecleucel, axicabtagene ciloleucel).
Also provided herein is the use of one or more compounds of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one or more compounds of the invention, for the preparation of a medicament for the treatment of the above-referenced diseases or conditions.
In another embodiment, provided herein the compounds of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one or more of the disclosed compounds are for use in treating the above-referenced diseases or conditions.
The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. It should be understood that all mebodiments / features of the invention (compounds, pharmaceutical compositions, methods of make / use, etc ) described herein, including any specific features described in the examples and original claims, can combine with one another unless not applicable or explicitly disclaimed.
DETAILED DESCRIPTION OF THE INVENTION
In a first embodiment, the invention provides compounds of the Formula (A) or an N- oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug of said compound of Formula (A) or N-oxide thereof:
Formula (A)
wherein
V is N or P(O);
Qi is 6-membered heterocycloalkyl, 6-membered heterocycloalkenyl, or 6-membered heteroaryl;
Q 2 is 6-membered heterocycloalkyl, 6-membered heterocycloalkenyl, 6-membered aryl, or 6-membered heteroaryl;
Q 3 is cycloalkyl, cycloalkenyl, bridged cycloalkyl, heterocycloalkyl,
heterocycloalkenyl, aryl or heteroaryl;
Q 4 is cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl;
Q 5 is 6-membered heterocycloalkyl, or 6-membered heterocycloalkenyl;
Q 6 is 6-membered aryl, or 5-6 membered heteroaryl;
Q 7 is 6-membered aryl or 5-6 membered heteroaryl, each of which is optionally fused with a benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane, or
heterocycloalkene; each of Ri, R 2 , R 3 , R4, R5, R 6, R 7 , R 8 , Rio, and Rn, independently, is H, D, alkyl, spiroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,
spiroheterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, halo, nitro, oxo, cyano, OR a , SR a , alkyl-R a , NH(CH 2 ) p R a , C(0)R a , S(0)R a , S0 2 R a , C(0)0R a , 0C(0)R a , NR b R c , C(0)N(R b )R c , N(R b )C(0)R c , -P(0)R b R c , -alkyl-P(0)R b R c , -S(0)(=N(R b ))R c , -N=S(0)R b R c , =NR b ,
S0 2 N(R b )R c , or N(R b )S0 2 R c , in which said cycloalkyl, cycloalkenyl, heterocyclo alkyl, heterocycloalkenyl, aryl, heteroaryl is optionally subsitiuted with one or more R d ;
R9 is R 9A or R9 B ;
R9 A is H, D, alkyl, spiroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, halo, nitro, oxo, cyano, OR a , SR a , alkyl-R a , NH(CH 2 ) p R a , C(0)R a , S(0)R a , S0 2 R a , C(0)0R a , 0C(0)R a , NR b R c , C(0)N(R b )R c , N(R b )C(0)R c , -P(0)R b R c , -alkyl-P(0)R b R c , -S(0)(=N(R b ))R c , - N=S(0)R b R c , =NR b , S0 2 N(R b )R c , or N(R b )S0 2 R c , in which said cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl is optionally subsitiuted with one or more R ;
Rgs is a small molecule E3 ubiquitin ligase binding moiety that binds an E3 ubiquitin ligase;
each R d , independently, is H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, =0, -P(0)R bb R cc , -alkyl-P(0)R bb R cc , -S(0)(=N(R bb ))R cc ,
-N=S(0)R bb R cc , =NR bb , C(0)NHOH, C(0)OH, C(0)NH 2 , alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, halo -alkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, in which said alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl is optionally subsitiuted with one or more R e ;
R a , R b , R c , R bb and R cc , independently, is H, D, alkyl, spiroalkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, in which said alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl is optionally subsitiuted with one or more R e ;
each R e , independently, is H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, =0, C(0)NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, halo- alkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl;
Zi is a bond, (CH 2 ) P , N(H), O, S, C(O), S(0 2 ), OC(O), C(0)0, 0S0 2 , S(0 2 )0, C(0)S, SC(O), C(0)C(0), C(0)N(H), N(H)C(0), S(0 2 )N(H), N(H)S(0 2 ), 0C(0)0, 0C(0)S, 0C(0)N(H), N(H)C(0)0, N(H)C(0)S, N(H)C(0)N(H), (CH 2 ) p N(H)(CH 2 ) q ,
(CH 2 ) p N(H)C(0)(CH 2 ) q , (CH 2 ) p C(0)N(H)(CH 2 ) q , 0C(0)N(H)(CH 2 ) p+i N(H)(CH 2 ) q , a bivalent alkenyl group, or a bivalent alkynyl group;
L is Li or L 2 ;
Li is bond, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,
heterocycloalkenyl, aryl, or heteroaryl, in which said alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl is optionally subsitiuted with one or more R d ;
L 2 is an alkyl in which one or more -L,- are optionally inserted between any two adjacent carbon atoms;
-Li- is -N(R a )-, -0-, -S-, -C(O)-, -S(0 2 )-, -OC(O)-, -C(0)0-, -OS0 2 -, -S(0 2 )0-, - C(0)S-, -SC(O)-, -C(0)C(0)-, -C(0)N(R a )-, -N(R a )C(0)-, -S(0 2 )N(R a )-, -N(R a )S(0 2 )-, - 0C(0)0-, -OC(0)S-, -OC(0)N(R a )-, -N(R a )C(0)0-, -N(R a )C(0)S-, -N(R a )C(0)N(R a )-, a bivalent alkenyl group, a bivalent alkynyl group, a bivalent cycloalkyl group, a bivalent heterocycloalkyl group, a bivalent aryl group, a bivalent heteroaryl group;
W is O or N(R a );
two of Ri group, taken together with the atoms to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl, in which said cycloalkyl or heterocycloalkyl of Ri, is optionally subsitiuted with one or more Ra;
two of R 2 group, taken together with the atom(s) to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl, in which said cycloalkyl or heterocycloalkyl of R 2 , is optionally subsitiuted with one or more Ra;
R 3 and R4 group, taken together with the atom to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl, in which said cycloalkyl or heterocycloalkyl of R 3 and R4, is optionally subsitiuted with one or more Ra;
two of R5 group, taken together with the atom(s) to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl, in which said cycloalkyl or heterocycloalkyl of R5, is optionally subsitiuted with one or more Ra;
two of R 6 group, taken together with the atoms to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl, in which said cycloalkyl or heterocycloalkyl of R 6 , is optionally subsitiuted with one or more Ra; two of R 7 group, taken together with the atoms to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl, in which said cycloalkyl or heterocycloalkyl of R 7 , is optionally subsitiuted with one or more R i ;
two of Rio group, taken together with the atom(s) to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl, in which said cycloalkyl or heterocycloalkyl of Rio, is optionally subsitiuted with one or more R d ;
two of Rn group, taken together with the atom(s) to which they are attached, may optionally form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, in which said cycloalkyl, heterocycloalkyl, aryl, or heteroaryl of Rn, is optionally subsitiuted with one or more R d ;
R 2 and R 5 group, taken together with the atoms to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl, in which said cycloalkyl or heterocycloalkyl of R 2 and R 5 , is optionally subsitiuted with one or more R ;
R 3 and R 5 group, taken together with the atoms to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl, in which said cycloalkyl or heterocycloalkyl of R 3 and R 5 , is optionally subsitiuted with one or more R d ;
R b and R c group, taken together with the atom to which they are attached, may optionally form a cycloalkyl, or heterocycloalkyl, in which said cycloalkyl or
heterocycloalkyl of R b and R c , is optionally subsitiuted with one or more R e ;
two of R d group, taken together with the atom(s) to which they are attached, may optionally form a cycloalkyl, or heterocycloalkyl, in which said cycloalkyl or
heterocycloalkyl of R d , is optionally subsitiuted with one or more R e ;
two of R e group, taken together with the atom(s) to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl, in which said cycloalkyl or heterocycloalkyl of R e is optionally subsitiuted with one or more groups selected from H, D, alkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, C(0)NH0H, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, halo -alkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl;
each of g and j is, independently, 0, 1, 2, or 3;
each of n, v and k is, independently, 0, 1, 2, 3, 4, 5, 6, 7, or 8;
s is 0 or 1 ; and
each of h, m, p, and q is, independently, 0, 1, 2, 3, 4, or 5; optionally, the compound of Formula (A) is not
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l’-b iphenyl]-2-yl)methyl)piperazin-l-yl)- 2-(2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin -l(6H)-yl)-N-((3-nitro-4- (((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)ben zamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2-yl)methyl)piperazin-l-yl)- 2-(2,3-dihydro-[l,4]oxazino[3,2-f]indol-l(6H)-yl)-N-((3-nitr o-4-(((tetrahydro-2H-pyran-4- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biph enyl]-2-yl)methyl)piperazin-l-yl)- 2-(6,7-dihydroimidazo[4’,5’:4,5]benzo[l,2-b][l,4]oxazin- 8(3H)-yl)-N-((3-nitro-4- (((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)ben zamide, and
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2-yl)methyl)piperazin-l-yl)- 2-(6,7-dihydro-[l,4]oxazino[3,2-f]indazol-5(lH)-yl)-N-((3-ni tro-4-(((tetrahydro-2H-pyran-4- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide .
In a second embodiment, the invention provides the compound of the first
embodiment, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein Formula (A) does not include Formula (A’):
Formula (A 1 )
wherein:
Qr is a 6-membered heterocycloalkyl, 6-membered heterocycloalkenyl, or 6- membered heteroaryl;
Q 2’ is an aryl or heteroaryl;
Q 3’ is a cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl;
each of Rr, R 2’ , R 3’ , R 4 , R 5’ , R 6\ R 7’ , Rss R 9’ , Rio ’ , Rir, and R I2 , independently, is H,
D, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, halo, nitro, oxo, cyano, OR a’ , SR a’ , alkyl-R a· , NH(CH 2 ) p R a’ , C(0)R , S(0)Ra , S0 2 Ra ’ , C(0)0Ra , 0C(0)Ra , NRb Rc , P(0)Rb Rc , alkyl-P(0)R b R c , C(0)N(R b )R C’ , N(R b )C(0)R c , S(0)(=N(R a ))R b , -N=S(0)R b R C’ , S0 2 N(R b )R C’ , or N(R b )S0 2 R C’ , in which said cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl is optionally subsitiuted with one or more R d ;
R a’ , R b’ , R c’ and R d’ , independently, is H, D, alkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, C(0)NH0H, C(0)0H, C(0)NH 2 , alkoxy, alkoxyalkyl, halo alkyl, hydroxyalkyl, amino alkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, halo -alkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, in which said alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,
heterocycloalkenyl, aryl, heteroaryl is optionally subsitiuted with one or more R e ;
R e’ is H, D, alkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, C(0)NHOH, alkoxy, alkoxyalkyl, halo alkyl, hydroxyalkyl, amino alkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, halo -alkylamino, cycloalkyl, cycloalkenyl,
heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl;
Zr is a bond, (CH 2 ) P , N(H), O, S, C(O), S(0 2 ), OC(O), C(0)0, OS0 2 , S(0 2 )0, C(0)S, SC(O), C(0)C(0), C(0)N(H), N(H)C(0), S(0 2 )N(H), N(H)S(0 2 ), 0C(0)0, OC(0)S, OC(0)N(H), N(H)C(0)0, N(H)C(0)S, N(H)C(0)N(H), (CH 2 ) p N(H)(CH 2 ) q ,
(CH 2 ) P’ N(H)C(0)(CH 2 ) q’ , (CH 2 ) P’ C(0)N(H)(CH 2 ) q’ , 0C(0)N(H)(CH 2 ) P’+i N(H)(CH 2 ) q’ , a bivalent alkenyl group, or a bivalent alkynyl group;
L’ is a bond, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo alkyl, heterocycloalkenyl, aryl, or heteroaryl, in which said alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl is optionally subsitiuted with one or more R ’ ;
each of Y’, W\ Wr, and W 2 \ independently, is CH or N, except that Wr is N when Qi ’ is 6-membered;
W 3 is O or N(R a ;
V’ is N, C, or CH;
two of Rc;· group, taken together with the atom to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl, in which said cycloalkyl or heterocycloalkyl of R 9’ is optionally subsitiuted with one or more R d· ;
two of R 2’ group, taken together with the atom to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl, in which said cycloalkyl or heterocycloalkyl of R 2’ is optionally subsitiuted with one or more R d’ ; two of Rio ’ group, taken together with the atom to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl, in which said cycloalkyl or heterocycloalkyl of Rio ’ is optionally subsitiuted with one or more R ;
Ri i and R I2 group, taken together with the atom to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl, in which said cycloalkyl or heterocycloalkyl of Rir or R I2 is optionally subsitiuted with one or more R ;
Rio ’ and R 2 group, taken together with the atom to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl, in which said cycloalkyl or heterocycloalkyl of Rio ’ or R 2 is optionally subsitiuted with one or more R ;
R 4 - and -Z I -L-R 6’ group, taken together with the atom to which they are attached, may optionally form a cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, in which said cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl of R 4’ is optionally subsitiuted with one or more R^ ;
R b’ and R t group, taken together with the atom to which they are attached, may optionally form a cycloalkyl, or heterocycloalkyl, in which said cycloalkyl or
heterocycloalkyl of R b’ and R c , is optionally subsitiuted with one or more R c ;
two of R d’ group, taken together with the atom to which they are attached, may optionally form a cycloalkyl, or heterocycloalkyl, in which said cycloalkyl or
heterocycloalkyl of R ’ is optionally subsitiuted with one or more R c ;
two of R e’ group, taken together with the atom to which they are attached, may optionally form a cycloalkyl, or heterocycloalkyl;
each of j’ and k’, independently, is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and
each of m’, n’, p’, q’, and r’, independently, is 0, 1, 2, 3, or 4.
In an alternative second embodiment, the compounds of Formula (A) do not include the compounds explicitly / expressly disclosed in International Application Publication No. WO2019/040573, incorporated herein by reference. Some of these previously disclosed compounds are listed below and are incorporated herein.
In a third embodiment, the invention provides a compound according to the first or second (hereinafter including the alternative second) embodiment, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug of said compound or N-oxide thereof, wherein the compound is represented by Formula (A-l):
Formula (A-l)
In a fourth embodiment, the invention provides a compound according to the first, second, or third embodiment, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug of said compound or N-oxide thereof, wherein the compound is represented by Formula (A-2) :
Formula (A-2)
In a fifth embodiment, the invention provides a compound according to the first, second, third, or fourth embodiment, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug of said compound or N-oxide thereof, wherein the compound is represented by Formula (A-3):
Formula (A-3)
wherein“ -” is absent or a bond; Wi is N or CH; and W 2 is N or C or CH.
In a six embodiment, the invention provides a compound according to the first, second, third, fourth, or fifth embodiment, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug of said compound or N-oxide thereof, wherein the compound is represented by Formula (A-4):
Formula (A-4) In a seventh embodiment, the invention provides a compound according to the first, second, third, fourth, fifth, or sixth embodiment, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug of said compound or N-oxide thereof, wherein the compound is represented by Formula (A-5):
Formula (A-5)
In an eighth embodiment, the invention provides a compound according to the first, second, third, fourth, fifth, sixth, or seventh embodiment, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic
form, or a prodrug of said compound or N-oxide thereof, wherein IS which Qg is 5-7 membered heterocycloalkyl, 5-7 membered heterocycloalkenyl, phenyl, or 5-7 membered heteroaryl; and gg is 0, 1, 2, 3, or 4.
In a ninth embodiment, the invention provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, or eighth embodiment, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic
form, or a prodrug of said compound of Formula or N-oxide thereof, wherein
which each Z a and Z b is independently -O-, -CH 2 -, -C(O)-, -N(R a )-, -S-,
-S(O)-, -S(0 2 )-, -S(0)(=N(R a ))-, -P(0)(R a )-; wherein R a of Z a and Z b , independently, is H, D, Ci-C 6 alkyl, C 2 -C 6 alkenyl, Ci-C 6 alkylcarbonyl, Ci-C 6 alkoxycarbonyl, C3-C6cycloalkyl,
5-8 membered monocyclic heterocycloalkyl, Ce-C aryl, or 5-8 membered monocyclic heteroaryl, in which said Ci-C 6 alkyl, C3-C6cycloalkyl, 5-8 membered monocyclic
heterocycloalkyl, Ce-C aryl, 5-8 membered monocyclic heteroaryl is optionally substituted with one or more R e .
In a tenth embodiment, the invention provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic
form, or a prodrug of said compound or N-oxide thereof, wherein
In an eleventh embodiment, the invention provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug of said compound or N-oxide thereof, wherein Zi is absent or (CH 2 ) p ; L is Li and Li is bond, and Rg is 5-7 membered heterocyclyl or 7-10 membered bridged heterocyclyl, each of which is optionally substituted with 1-3 groups selected from halo, -OH, -CN, -COOH, -NH 2 , -N(CH 3 ) 2 , -(Ci-C 4 )alkyl, and -(Ci-C 4 )alkoxy.
In a twelfth embodiment, the invention provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug of said compound or N-oxide thereof, wherein
In a thirteenth embodiment, the invention provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug of said compound or N-oxide thereof, wherein
h is 0, 1, or 2;
each of mi and m 2 , independently, is 0, 1, or 2; and
each of Z 3 , Z 4 , Z 5 and Z 6 , independently, is a bond, (CH 2 ) P , N(H), O, S, C(O), S(0 2 ), OC(O), C(0)0, OS0 2 , S(0 2 )0, C(0)S, SC(O), C(0)C(0), C(0)N(H), N(H)C(0),
S(0 2 )N(H), N(H)S(0 2 ), 0C(0)0, OC(0)S, OC(0)N(H), N(H)C(0)0, N(H)C(0)S, N(H)C(0)N(H), (CH 2 ) p N(H)(CH 2 ) q , (CH 2 ) p N(H)C(0)(CH 2 ) q , (CH 2 ) p C(0)N(H)(CH 2 ) q , 0C(0)N(H)(CH 2 ) p+i N(H)(CH 2 ) q , a bivalent alkenyl group, or a bivalent alkynyl group. In
one specific embodiment,
more specific embodiment,
-S-, -S(O)-, -S(0 2 )-, -S(0)(=N(R a )K -P(0)(R a )-; wherein R a of Z 2 , independently, is H, D, Ci-C 6 alkyl, C 2 -C 6 alkenyl, Ci-C 6 alkylcarbonyl, Ci-C 6 alkoxycarbonyl, C3-C6cycloalkyl, 5-8 membered monocyclic heterocyclo alkyl, Ce-C aryl, or 5-8 membered monocyclic heteroaryl, in which said Ci-C 6 alkyl, C3-C6cycloalkyl, 5-8 membered monocyclic
heterocycloalkyl, C 6 -C l4 aryl, 5-8 membered monocyclic heteroaryl is optionally subsitiuted with one or more R e ; k is 0, 1, 2, 3, or 4; and f is 0. In one specific embodiment,
, wherein f=0.
In a fourteenth embodiment, the invention provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiment, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug of said compound or N-
oxide thereof, wherein Rio is aryl, heteroaryl, or R 12 ; R 12 is H, D, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, halo, nitro, oxo, cyano, OR a , SR a , alkyl-R a , NH(CH 2 ) p R a , C(0)R a , S(0)R a , S0 2 R a , C(0)OR a , OC(0)R a , NR b R c , P(0)R b R c , alkyl-P(0)R b R c , C(0)N(R b )R c , N(R b )C(0)R c , S(0)(=N(R b ))R c ,
-N=S(0)R b R c , S0 2 N(R b )R c , or N(R b )S0 2 R c , in which said cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl is optionally substituted with one or more R 4 ; and each of R^, and R I4 , independently, is H, D, alkyl, halo-alkyl, or R13 and R l4 taken together with the atom to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl, in which said cycloalkyl or heterocycloalkyl is optionally substituted with one or more R 4 ; and the remaining variables are as defined ins.
In a fifteenth embodiment, the invention provides a compound according to the thirteenth embodiment, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug of said compound or N-
oxide thereof, wherein which Qg is a C 4 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl; f=0; and w is 0, 1, 2, 3, or 4. In one specific embodiment, Qg is C 5 -C 6 cycloalkyl, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; each of which is optionally substituted with 1 to 3 groups selected from halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, -OH, CN, and
NH 2 .
In a sixteenth embodiment, the invention provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, twelfth, thirteenth, fourteenth, or fifteenth embodiment, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug of said compound or N-oxide thereof, wherein Rg is Rgu. In one specific embodiment, wherein Rgu is a small molecule E3 ubiquitin ligase binding moiety that binds an E3 ubiquitin ligase; said E3 ubiquitin ligase is Von Hippel-Lindau (VLM), cereblon (CLM), mouse double-minute homolog2 (MLM), and IAP (ILM).
In a seventeenth embodiment, the invention provides a compound according to the sixteenth embodiment, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug of said compound or N-
oxide thereof, wherein
wherein Z a is a bond, (CH 2 ) P , N(H), O, S, C(O), S(0 2 ), OC(O), C(0)0, OS0 2 , S(0 2 )0, C(0)S, SC(O), C(0)C(0), C(0)N(H), N(H)C(0), S(0 2 )N(H), N(H)S(0 2 ), 0C(0)0, OC(0)S, OC(0)N(H), N(H)C(0)0, N(H)C(0)S, N(H)C(0)N(H), (CH 2 ) p N(H)(CH 2 ) q ,
(CH 2 ) p N(H)C(0)(CH 2 ) q , (CH 2 ) p C(0)N(H)(CH 2 ) q , 0C(0)N(H)(CH 2 ) p+i N(H)(CH 2 ) q , a bivalent alkenyl group, or a bivalent alkynyl group.
In an eighteenth embodiment, the invention provides a compound according to the sixteenth embodiment, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug of said compound or N- oxide thereof, wherein , wherein Z b is a bond, (CH 2 ) P , N(H), O, S, C(O), S(0 2 ), OC(O), C(0)0, 0S0 2 , S(0 2 )0, C(0)S, SC(O), C(0)C(0), C(0)N(H), N(H)C(0), S(0 2 )N(H), N(H)S(0 2 ), 0C(0)0, 0C(0)S, 0C(0)N(H), N(H)C(0)0, N(H)C(0)S, N(H)C(0)N(H), (CH 2 ) p N(H)(CH 2 ) q , (CH 2 ) p N(H)C(0)(CH 2 ) q , (CH 2 ) p C(0)N(H)(CH 2 ) q , 0C(0)N(H)(CH 2 ) p+1 N(H)(CH 2 ) q , a bivalent alkenyl group, or a bivalent alkynyl group.
In a nineteenth embodiment, the invention provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, or eighteenth embodiment, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic
form, or a prodrug thereof, wherein L is L 2 , and L 2 is 11111 111 P , wherein each of mn and mp is independently an integer of 0 to 12; and each of L 3 and L 4 independently, is a bond, (CH 2 ) P , N(H), O, S, C(O), S(0 2 ), OC(O), C(0)0, 0S0 2 , S(0 2 )0, C(0)S, SC(O), C(0)C(0), C(0)N(H), N(H)C(0), S(0 2 )N(H), N(H)S(0 2 ), 0C(0)0, 0C(0)S, 0C(0)N(H), N(H)C(0)0, N(H)C(0)S, N(H)C(0)N(H), (CH 2 ) p N(H)(CH 2 ) q , (CH 2 ) p N(H)C(0)(CH 2 ) q , (CH 2 ) p C(0)N(H)(CH 2 ) q , 0C(0)N(H)(CH 2 ) p+1 N(H)(CH 2 ) q , a bivalent alkenyl group, or a
bivalent alkynyl group. In one specific embodiment, wherein said L 2 is mn
which mn is 0 to 12.
In a twentieth embodiment, the invention provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, or nineteenth embodiment, or an N- oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein
In a twenty first embodiment, the invention provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, or twentieth embodiment, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein Rg is N0 2 .
Exemplary compounds described herein include, but are not limited to, the following:
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)-yl- 2,2,3,3-d4)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l’-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(3-methyl-2,3-dihydropyrrolo[3 ,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran -4- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l’-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(3,3-dimethyl-2,3-dihydropyrrolo [3’,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran -4- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide,
(R)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2-methyl-2,3-dihydropyrrolo[3 ,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran -4- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide,
(S)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(3-methyl-2,3-dihydropyrrolo[3 ,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran -4- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide, 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biph enyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]thiazin-l(6H)- yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)p henyl)sulfonyl)benzamide,
(R)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l , -biphenyl]-2- yl)methyl)piperazin-l-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyr an-4- yl)methyl)amino)phenyl)sulfonyl)-2-(3-(trifluoromethyl)-2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)benzamide,
(R)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l , -biphenyl]-2- yl)methyl)piperazin-l-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyr an-4- yl)methyl)amino)phenyl)sulfonyl)-2-(3-(trifluoromethyl)-2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]thiazin-l(6H) -yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)- 3- nitrophenyl) sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-N-((4-(((4-fluorotetrahydro-2H-pyr an-4-yl)methyl)amino)-3- nitrophenyl)sulfonyl)-2-(2-methyl-2,3-dihydropyrrolo[3’,2 :5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)benzamide,
(S)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l ,r-biphenyl]-2- yl)methyl)piperazin-l-yl)-N-((4-(((4-fluorotetrahydro-2H-pyr an-4-yl)methyl)amino)-3- nitrophenyl)sulfonyl)-2-(3-methyl-2,3-dihydropyrrolo[3’,2 :5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,2-dimethyl-2,3-dihydropyrrolo [3’,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran -4-yl)methyl)amino)-3- nitrophenyl) sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-N-((4-(((4-fluorotetrahydro-2H-pyr an-4-yl)methyl)amino)-3- nitrophenyl)sulfonyl)-2-(2’H-spiro[cyclopropane- l,3’-pyrrolo[3’,2’:5,6]pyrido[2,3- b] [ 1 ,4]oxazin] - 1’ (6’H)-yl)benzamide, 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biph enyl]-2- yl)methyl)piperazin-l-yl)-N-((4-(((4-fluorotetrahydro-2H-pyr an-4-yl)methyl)amino)-3- nitrophenyl)sulfonyl)-2-(2,3,4,6-tetrahydro-lH-pyrrolo[2,3-b ][l,5]naphthyridin-l- yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-N-((4-(((4-fluorotetrahydro-2H-pyr an-4-yl)methyl)amino)-3- nitrophenyl)sulfonyl)-2-(2-oxo-2,3,4,6-tetrahydro-lH-pyrrolo [2,3-b][l,5]naphthyridin-l- yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-N-((4-(((4-fluorotetrahydro-2H-pyr an-4-yl)methyl)amino)-3- nitrophenyl)sulfonyl)-2-(3-oxo-2,3-dihydropyrrolo[3’,2’: 5,6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-N-((4-(((4-fluorotetrahydro-2H-pyr an-4-yl)methyl)amino)-3- nitrophenyl)sulfonyl)-2-(4-oxo-2,3,4,6-tetrahydro-lH-pyrrolo [2,3-b][l,5]naphthyridin-l- yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biph enyl]-2- yl)methyl)piperazin-l-yl)-N-((4-(((4-fluorotetrahydro-2H-pyr an-4-yl)methyl)amino)-3- nitrophenyl)sulfonyl)-2-(2,3,4,6-tetrahydro-lH-pyrrolo[3’, 2’:5,6]pyrido[2,3-b]pyrazin-l- yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(4,4-dioxido-2,3-dihydropyrrolo[ 3’,2’:5,6]pyrido[2,3- b][l,4]thiazin-l(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyra n-4-yl)methyl)amino)-3- nitrophenyl) sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-N-((4-(((4-fluorotetrahydro-2H-pyr an-4-yl)methyl)amino)-3- nitrophenyl)sulfonyl)-2-(4-(methylimino)-4-oxido-2,3,4,6-tet rahydro-lH-4 4- pyrrolo [3’ ,2’ :5,6]pyrido [2,3-b] [ 1 ,4]thiazin- 1 -yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biph enyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-3-yl)methyl)amino)p henyl)sulfonyl)benzamide, 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biph enyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-((2-morpholinoethyl)amino)-3-nitrophenyl)sulfonyl) benzamide,
(R)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l , -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((4-methylmorpholin-2-yl)methyl)amino)-3-nitrophe nyl)sulfonyl)benzamide,
(R)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l , -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-nitro-4-(((4-(oxetan-3-yl)morpholin-2-yl)methyl)am ino)phenyl)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((4-hydroxycyclohexyl)methyl)amino)-3-nitrophenyl )sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-((((lr,4r)-4-methoxycyclohexyl)methyl)amino)-3-nit rophenyl)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-((((ls,4s)-4-hydroxy-4-methylcyclohexyl)methyl)ami no)-3- nitrophenyl) sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-((((ls,4s)-4-ethyl-4-hydroxycyclohexyl)methyl)amin o)-3- nitrophenyl) sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-nitro-4-((l-(tetrahydro-2H-pyran-4-yl)piperidin-4- yl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((ls,4s)-4-morpholinocyclohexyl)amino)-3-nitrophe nyl)sulfonyl)benzamide, 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biph enyl]-2- yl)methyl)piperazin-l-yl)-N-((4-((4-(cyclopropylamino)cycloh exyl)amino)-3- nitrophenyl)sulfonyl)-2-(2,3-dihydropyrrolo[3’,2’:5,6]py rido[2,3-b][l,4]oxazin-l(6H)- yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-N-((4-(((4,4-difluorocyclohexyl)me thyl)amino)-3- nitrophenyl)sulfonyl)-2-(2,3-dihydropyrrolo[3’,2’:5,6]py rido[2,3-b][l,4]oxazin-l(6H)- yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl) sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-3-yl)methoxy)phenyl) sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(2-morpholinoethoxy)-3-nitrophenyl)sulfonyl)benzam ide,
(S)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l , -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-((4-methylmorpholin-2-yl)methoxy)-3-nitrophenyl)su lfonyl)benzamide,
(S)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l , -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-nitro-4-((4-(oxetan-3-yl)morpholin-2-yl)methoxy)ph enyl)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-((4-hydroxycyclohexyl)methoxy)-3-nitrophenyl)sulfo nyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((lr,4r)-4-methoxycyclohexyl)methoxy)-3-nitrophen yl)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((ls,4s)-4-hydroxy-4-methylcyclohexyl)methoxy)-3- nitrophenyl) sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((ls,4s)-4-ethyl-4-hydroxycyclohexyl)methoxy)-3- nitrophenyl) sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-nitro-4-((l-(tetrahydro-2H-pyran-4-yl)piperidin-4- yl)oxy)phenyl)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((ls,4s)-4-morpholinocyclohexyl)oxy)-3-nitropheny l)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-N-((4-((4-(cyclopropylamino)cycloh exyl)oxy)-3- nitrophenyl)sulfonyl)-2-(2,3-dihydropyrrolo[3’,2’:5,6]py rido[2,3-b][l,4]oxazin-l(6H)- yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-N-((4-((4,4-difluorocyclohexyl)met hoxy)-3-nitrophenyl)sulfonyl)-
2-(2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxa zin-l(6H)-yl)benzamide,
4-(4-((2-(4-chlorophenyl)cyclopent-l-en-l-yl)methyl)piper azin-l-yl)-2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H- pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((2-(4-chlorophenyl)cyclohept-l-en-l-yl)methyl)piper azin-l-yl)-2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H- pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyr an-3-yl)methyl)piperazin- l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4] oxazin-l(6H)-yl)-N-((4-(((4- fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)s ulfonyl)benzamide,
4-(4-((4’-chloro-4-(methoxymethyl)-4-methyl-3,4,5,6-tet rahydro-[l,r-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((4-fluorotetra ydro-2H-pyran-4-yl)methyl)amino)-3- nitrophenyl) sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methy l)amino)-3- nitrophenyl) sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((6-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)- 5-nitropyridin-3- yl)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)- 3-
((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(6,7-dIhydroimidazo[4’,5’:5, 6]pyrido[2,3-b][l,4]oxazin-8(3H)- yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)p henyl)sulfonyl)benzamide,
4-(4-((9-(4-chlorophenyl)-3-methyl-3-azaspiro[5.5]undec-8 -en-8-yl)methyl)piperazin- l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4] oxazin-l(6H)-yl)-N-((4-(((4- fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)s ulfonyl)benzamide,
4-(4-((9-(4-chlorophenyl)-3-(l,3-difluoropropan-2-yl)-3-a zaspiro[5.5]undec-8-en-8- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)- 3- nitrophenyl) sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-difluoro-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)- 3- nitrophenyl) sulfonyl)benzamide,
4-(4-((5-(4-chlorophenyl)spiro[2.5]oct-5-en-6-yl)methyl)p iperazin-l-yl)-2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)-N-((4-(((4-fluorotetraliydro-2H- pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide, 4-(4-((7-(4-chlorophenyl)spiro[3.5]non-6-en-6-yl)methyl)pipe razin-l-yl)-2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H- pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4’-chloro-3’-fluoro-5,5-dimethyl-3,4,5,6-tetra hydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)p henyl)sulfonyl)benzamide,
4-(4-((4’-chloro-3’,5,5-trimethyl-3,4,5,6-tetrahydro- [l,r-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)p henyl)sulfonyl)benzamide,
2-(2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxa zin-l(6H)-yl)-4-(4-((4,4- dimethyl-2-(pyridin-3-yl)cyclohex- l-en- l-yl)methyl)piperazin- l-yl)-N-((3-nitro-4- (((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)ben zamide,
4-(4-((2-(lH-indol-5-yl)-4,4-dimethylcyclohex-l-en-l-yl)m ethyl)piperazin-l-yl)-2-
(2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazi n-l(6H)-yl)-N-((3-nitro-4-(((tetrahydro-
2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
(R)-N-((4-(((l,4-dioxan-2-yl)methyl)amino)-3-fluoro-5-nit rophenyl)sulfonyl)-4-(4-
((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)pipera zin-l-yl)-2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)benzamide,
(R)-N-((4-(((l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl) sulfonyl)-4-(4-((6-(4- chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-l-yl)- 2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)benzamide,
(R)-N-((4-(((l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl) sulfonyl)-4-(4-((6-(4- chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methyl)piperazin- l-yl)-2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)benzamide,
(R)-N-((4-(((l,4-dioxan-2-yl)methyl)amino)-3-fluoro-5-nit rophenyl)sulfonyl)-4-(4-
((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphen yl]-2-yl)methyl)piperazin-l-yl)-2-
(2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazi n-l(6H)-yl)benzamide,
4-(4-((6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)me thyl)piperazin-l-yl)-2-
(2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazi n-l(6H)-yl)-N-((3-nitro-4-(((tetrahydro-
2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide, 4-(4-((6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methy l)piperazin-l-yl)-2-
(2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazi n-l(6H)-yl)-N-((4-(((4- fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)s ulfonyl)benzamide,
(S)-N-((4-(((l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sul fonyl)-4-(4-((6-(4- chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-l-yl)- 2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-6-fluorobenzamide,
(S)-N-((4-(((l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sul fonyl)-4-(4-((6-(4- chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-l-yl)- 2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-5-fluorobenzamide,
4-(4-((4’-chloro-5,5-bis(methyl-d3)-3,4,5,6-tetrahydro-[l, -biphenyl]-2-yl)methyl)- 2-methylpiperazin-l-yl-2,3,3,5,5,6,6-d7)-2-(2,3-dihydropyrro lo[3’,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran -4- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide,
diethyl ((2-(((4-(N-(4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahy dro-[l,l’-biphenyl]- 2-yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’: 5,6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)benzoyl)sulfamoyl)-2-nitrophenyl)amino)methyl)morpholino) methyl)phosphonate,
diethyl (((3-((4-(N-(4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahy dro-[l,l’-biphenyl]- 2-yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’: 5,6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)benzoyl)sulfamoyl)-2-nitrophenyl)amino)propyl)(methyl)ami no)methyl)phosphonate,
2-(((2-((4-(N-(4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-te trahydro-[l,l’-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)benzoyl)sulfamoyl)-2- nitrophenyl)amino)ethyl)((pivaloyloxy)methoxy)phosphoryl)oxy )ethyl pivalate,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l’-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((l-methyl-l-oxidophosphinan-4-yl)methyl)amino)-3 - nitrophenyl) sulfo nyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l’-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((l-hydroxy-l-oxidophosphinan-4-yl)methyl)amino)- 3- nitrophenyl) sulfo nyl)benzamide, ((4-(((4-(N-(4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahy dro-[l,r-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)benzoyl)sulfamoyl)-2-nitrophenyl)amino)methyl)-l-oxidopho sphinan-l-yl)oxy)methyl pivalate,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((2-methyl-2-oxido-l,3,2-oxazaphosphinan-5-yl)met hyl)amino)-3- nitrophenyl) sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-((2-(2-methyl-2-oxido-l,3,2-oxazaphosphinan-3-yl)e thyl)amino)-3- nitrophenyl) sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((l-(dimethylphosphoryl)piperidin-4-yl)methyl)ami no)-3- nitrophenyl) sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-(dimethylphosphoryl)-4-(((tetrahydro-2H-pyran-4- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide,
N-((4-(((l,4-dioxaspiro[4.5]decan-8-yl)methyl)amino)-3-ni trophenyl)sulfonyl)-4-(4-
((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2-yl)methyl)piperazin-l-yl)-2-
(2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazi n-l(6H)-yl)benzamide,
N-((4-(((2-oxaspiro[3.5]nonan-7-yl)methyl)amino)-3-nitrop henyl)sulfonyl)-4-(4-((4’- chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2-yl)methyl)piperazin-l-yl)-2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-((2-(hexahydrofuro[3,4-c]pyridin-5(3H)-yl)ethyl)am ino)-3- nitrophenyl) sulfo nyl)benzamide, (R)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r- biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-nitro-4-((2-(3-oxooctahydro-7H-imidazo[l,5-d][l,4] diazepin-7- yl)ethyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-nitro-4-((2-(3-oxooctahydro-5H-pyrrolo[3,4-c]pyrid in-5- yl)ethyl)amino)phenyl)sulfonyl)benzamide,
N-((4-((2-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)ethyl)amin o)-3-nitrophenyl)sulfonyl)-
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2-yl)methyl)piperazin-l-yl)-
2-(2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxa zin-l(6H)-yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((3-hydroxy-3-methylbicyclo[3. l. l]heptan-6-yl)methyl)amino)-3- nitrophenyl) sulfonyl)benzamide,
N-((4-((2-(2-oxa-5-azabicyclo[2.2. l]heptan-5-yl)ethyl)amino)-3- nitrophenyl)sulfonyl)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5, 6-tetrahydro-[l,r-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)benzamide,
2-((3R)-8-(2-((4-(N-(4-(4-((4’-chloro-5,5-dimethyl-3,4, 5,6-tetrahydro-[l, - biphenyl]-2-yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[ 3’,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)benzoyl)sulfamoyl)-2-nitrophenyl)amin o)ethyl)-6,6-difluoro-8- azabicyclo[3.2. l]octan-3-yl)acetic acid,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-N-((4-((2-(6,6-difluoro-8-azabicyc lo[3.2. l]octan-8- yl)ethyl)amino)-3-nitrophenyl)sulfonyl)-2-(2,3-dihydropyrrol o[3’,2’:5,6]pyrido[2,3- b] [ 1 ,4]oxazin- 1 (6H)-yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-nitro-4-((2-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[ 3.3]heptan-6- yl)amino)phenyl)sulfonyl)benzamide, 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biph enyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-nitro-4-(((tetrahydro-2H-thiopyran-4-yl)methyl)ami no)phenyl)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((l-imino-l-oxidohexahydro-H6-thiopyran-4-yl)meth yl)amino)-3- nitrophenyl) sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((4-(methylsulfonyl)morpholin-2-yl)methyl)amino)- 3- nitrophenyl) sulfonyl)benzamide,
N-((4-(((4-aminotetrahydro-2H-pyran-4-yl)methyl)amino)-3- nitrophenyl)sulfonyl)-4-
(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2-yl)methyl)piperazin-l-yl)-2-
(2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazi n-l(6H)-yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-nitro-4-((l-(tetrahydro-2H-pyran-4- yl)cyclopropyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-N-((4-((2-(5,6-dihydroimidazo[l,2- a]pyrazin-7(8H)- yl)ethyl)amino)-3-nitrophenyl)sulfonyl)-2-(2,3-dihydropyrrol o[3’,2’:5,6]pyrido[2,3- b] [ 1 ,4]oxazin- 1 (6H)-yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-nitro-4-(((5,6,7,8-tetrahydroimidazo[l,2-a]pyridin -6- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l -biphenyl]-2- yl)methyl)piperazin-l-yl)-N-((4-((3-(difluoromethoxy)benzyl) amino)-3- nitrophenyl)sulfonyl)-2-(2,3-dihydropyrrolo[3’,2’:5,6]py rido[2,3-b][l,4]oxazin-l(6H)- yl)benzamide, 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biph enyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-nitro-4-(((3, 4, 5-trihydro xytetrahydrofuran-2- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-nitro-4-(((3,4,5,6-tetrahydroxytetrahydro-2H-pyran -2- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((4, 5-dihydro xy-6,6-dimethyltetrahydro-2H-pyran-2-yl)methyl)amino)-3- nitrophenyl) sulfo nyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-nitro-4-(((2, 3, 5-trihydro xy-6-(hydroxymethyl)tetrahydro-2H-pyran-4- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-nitro-4-(((2,3,4,5,6- pentahydroxycyclohexyl)methyl)amino)phenyl)sulfonyl)benzamid e
(R)-N-((4-(((l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl) sulfonyl)-4-(l-((4’-chloro-
5.5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2-yl)methy l)-l,2,3,6-tetrahydropyridin-4-yl)- 2-(2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin -l(6H)-yl)benzamide,
4-(l-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)- l,2,3,6-tetrahydropyridin-
4-yl)-2-(2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l ,4]oxazin-l(6H)-yl)-N-((3-nitro-4-
(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl) benzamide,
(R)-N-((4-(((l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl) sulfonyl)-4-(l-((4’-chloro-
5.5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2-yl)methy l)piperidin-4-yl)-2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)benzamide,
(S)-N-((4-(((l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl) sulfonyl)-5-(4-((6-(4- chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-l-yl)- 3-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)picolinamide,
(S)-N-((4-(((l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl) sulfonyl)-6-(4-((6-(4- chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-l-yl)- 2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)nicotinamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2-methyl-2,3-dihydropyrrolo[3 ,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran -4- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,2-dimethyl-2,3-dihydropyrrolo [3’,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran -4- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(3-(hydroxymethyl)-2,3-dihydropy rrolo[3’,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran -4- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide,
(S)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l ,l’-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2-methyl-2,3-dihydropyrrolo[3 ,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran -4- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide,
(R)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l ,l’-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(3-methyl-2,3-dihydropyrrolo[3 ,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran -4- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(4,4-dioxido-2,3-dihydropyrrolo[ 3’,2’:5,6]pyrido[2,3- b][l,4]thiazin-l(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyra n-4- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide,
(S)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l ,l’-biphenyl]-2- yl)methyl)piperazin-l-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyr an-4- yl)methyl)amino)phenyl)sulfonyl)-2-(3-(trifluoromethyl)-2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)benzamide,
(S)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l , -biphenyl]-2- yl)methyl)piperazin-l-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyr an-4- yl)methyl)amino)phenyl)sulfonyl)-2-(3-(trifluoromethyl)-2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]thiazin-l(6H) -yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)-yl- 2,2,3,3-d4)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl )amino)-3- nitrophenyl) sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-N-((4-(((4-fluorotetrahydro-2H-pyr an-4-yl)methyl)amino)-3- nitrophenyl)sulfonyl)-2-(3-methyl-2,3-dihydropyrrolo[3’,2 :5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)benzamide,
(R)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l , -biphenyl]-2- yl)methyl)piperazin-l-yl)-N-((4-(((4-fluorotetrahydro-2H-pyr an-4-yl)methyl)amino)-3- nitrophenyl)sulfonyl)-2-(3-methyl-2,3-dihydropyrrolo[3’,2 :5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(3,3-dimethyl-2,3-dihydropyrrolo [3’,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran -4-yl)methyl)amino)-3- nitrophenyl) sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-N-((4-(((4-fluorotetrahydro-2H-pyr an-4-yl)methyl)amino)-3- nitrophenyl)sulfonyl)-2-(3’H-spiro[cyclopropane- l,2’-pyrrolo[3’,2’:5,6]pyrido[2,3- b] [ 1 ,4]oxazin] - 1’ (6’H)-yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]thiazin-l(6H)- yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)- 3- nitrophenyl) sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-N-((4-(((4-fluorotetrahydro-2H-pyr an-4-yl)methyl)amino)-3- nitrophenyl)sulfonyl)-2-(2-oxo-2,3-dihydropyrrolo[3’,2’: 5,6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-N-((4-(((4-fluorotetrahydro-2H-pyr an-4-yl)methyl)amino)-3- nitrophenyl)sulfonyl)-2-(3-oxo-2,3,4,6-tetrahydro-lH-pyrrolo [3’,2’:5,6]pyrido[2,3-b]pyrazin- l-yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-N-((4-(((4-fluorotetrahydro-2H-pyr an-4-yl)methyl)amino)-3- nitrophenyl)sulfonyl)-2-(4-oxo-4,6-dihydro-lH-pyrrolo[2,3-b] [l,5]naphthyridin-l- yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-N-((4-(((4-fluorotetrahydro-2H-pyr an-4-yl)methyl)amino)-3- nitrophenyl)sulfonyl)-2-(4-methyl-2,3,4,6-tetrahydro-lH-pyrr olo[3’,2’:5,6]pyrido[2,3- b]pyrazin- l-yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-N-((4-(((4-fluorotetrahydro-2H-pyr an-4-yl)methyl)amino)-3- nitrophenyl)sulfonyl)-2-(4-imino-4-oxido-2,3,4,6-tetrahydro- lH-4 4- pyrrolo [3’ ,2’ :5,6]pyrido [2,3-b] [ 1 ,4]thiazin- 1 -yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-N-((4-(((4-fluorotetrahydro-2H-pyr an-4-yl)methyl)amino)-3- nitrophenyl)sulfonyl)-2-(4-methyl-4-oxido-2,3,6-trihydropyrr olo[3’,2’:5,6]pyrido[3,2- b] [ 1 ,4] azapho sphinin- 1 -yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((3-fluorotetrahydro-2H-pyran-3-yl)methyl)amino)- 3- nitrophenyl) sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-((3-morpholinopropyl)amino)-3-nitrophenyl)sulfonyl )benzamide,
(S)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l , -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((4-methylmorpholin-2-yl)methyl)amino)-3-nitrophe nyl)sulfonyl)benzamide,
(S)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l , -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-nitro-4-(((4-(oxetan-3-yl)morpholin-2-yl)methyl)am ino)phenyl)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((4-hydroxy-4-methylcyclohexyl)methyl)amino)-3- nitrophenyl) sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-((((ls,4s)-4-methoxycyclohexyl)methyl)amino)-3-nit rophenyl)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-((((lr,4r)-4-hydroxy-4-methylcyclohexyl)methyl)ami no)-3- nitrophenyl) sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-((((lr,4r)-4-ethyl-4-hydroxycyclohexyl)methyl)amin o)-3- nitrophenyl) sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-nitro-4-((l-(oxetan-3-yl)piperidin-4-yl)amino)phen yl)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((lr,4r)-4-morpholinocyclohexyl)amino)-3-nitrophe nyl)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-((4-(methyl(oxetan-3-yl)amino)cyclohexyl)amino)-3- nitrophenyl) sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-nitro-4-(((l,4,4-trifluorocyclohexyl)methyl)amino) phenyl)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-3-nitr ophenyl)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-((3-fluorotetrahydro-2H-pyran-3-yl)methoxy)-3-nitr ophenyl)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(3-morpholinopropoxy)-3-nitrophenyl)sulfonyl)benza mide,
(R)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l , -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-((4-methylmorpholin-2-yl)methoxy)-3-nitrophenyl)su lfonyl)benzamide,
(R)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l , -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-nitro-4-((4-(oxetan-3-yl)morpholin-2-yl)methoxy)ph enyl)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-((4-hydroxy-4-methylcyclohexyl)methoxy)-3-nitrophe nyl)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((ls,4s)-4-methoxycyclohexyl)methoxy)-3-nitrophen yl)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((lr,4r)-4-hydroxy-4-methylcyclohexyl)methoxy)-3- nitrophenyl) sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((lr,4r)-4-ethyl-4-hydroxycyclohexyl)methoxy)-3-n itrophenyl)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-nitro-4-((l-(oxetan-3-yl)piperidin-4-yl)oxy)phenyl )sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((lr,4r)-4-morpholinocyclohexyl)oxy)-3-nitropheny l)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-((4-(methyl(oxetan-3-yl)amino)cyclohexyl)oxy)-3-ni trophenyl)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-nitro-4-((l,4,4-trifluorocyclohexyl)methoxy)phenyl )sulfonyl)benzamide,
4-(4-((4-(4-chlorophenyl)-5,6-dihydro-2H-pyran-3-yl)methy l)piperazin-l-yl)-2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H- pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
(Z)-4-(4-((2-(4-chlorophenyl)cyclooct-l-en-l-yl)methyl)pi perazin-l-yl)-2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H- pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4’-chloro-4-methoxy-4-methyl-3,4,5,6-tetrahydro- [l,r-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)- 3- nitrophenyl) sulfonyl)benzamide,
4-(5-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2-yl)methyl)-2,5- diazabicyclo[2.2.2]octan-2-yl)-2-(2,3-dihydropyrrolo[3’,2 :5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)a mino)-3- nitrophenyl) sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-(4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3 - nitrophenylsulfonimidoyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-N-((5-chloro-6-((tetrahydro-2H-pyr an-4-yl)methoxy)pyridin-3- yl)sulfonyl)-2-(2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)benzamide, 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biph enyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)- 3-(S-
(trifluoromethyl)sulfonimidoyl)phenyl)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydro-[l,4]oxazino[3,2-f] indol-l(6H)-yl)-N-((3-nitro-4-
(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl) benzamide,
4-(4-((9-(4-chlorophenyl)-3-isopropyl-3-azaspiro[5.5]unde c-8-en-8- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)- 3- nitrophenyl) sulfonyl)benzamide,
4-(4-((9-(4-chlorophenyl)-3-(oxetan-3-yl)-3-azaspiro[5.5] undec-8-en-8- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)- 3- nitrophenyl) sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-bis(fluoromethyl)-3,4,5,6-tetrahyd ro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)- 3- nitrophenyl) sulfonyl)benzamide,
4-(4-(l-(4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)cyclopropyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2 :5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)a mino)-3- nitrophenyl) sulfonyl)benzamide,
4-(4-((6-(4-chlorophenyl)spiro[2.5]oct-5-en-5-yl)methyl)p iperazin-l-yl)-2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H- pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
4-(4-((4’-chloro-2’-fluoro-5,5-dimethyl-3,4,5,6-tetra hydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)p henyl)sulfonyl)benzamide,
4-(4-((4’-chloro-2’,5,5-trimethyl-3,4,5,6-tetrahydro- [l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-nitro-4-(((tetra ydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
2-(2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxa zin-l(6H)-yl)-4-(4-((4,4- dimethyl-2-(pyridin-2-yl)cyclohex- l-en- l-yl)methyl)piperazin- l-yl)-N-((3-nitro-4- (((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)ben zamide,
2-(2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxa zin-l(6H)-yl)-4-(4-((4,4- dimethyl-2-( lH-pyrrolo[2,3-b]pyridin-5-yl)cyclo hex- l-en- l-yl)methyl)piperazin-l-yl)-N-((3- nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulf onyl)benzamide,
(S)-N-((4-(((l,4-dioxan-2-yl)methyl)amino)-3-fluoro-5-nit rophenyl)sulfonyl)-4-(4-
((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)pipera zin-l-yl)-2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)benzamide,
(S)-N-((4-(((l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl) sulfonyl)-4-(4-((6-(4- chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-l-yl)- 2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)benzamide,
(S)-N-((4-(((l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl) sulfonyl)-4-(4-((6-(4- chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methyl)piperazin- l-yl)-2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)benzamide,
(S)-N-((4-(((l,4-dioxan-2-yl)methyl)amino)-3-fluoro-5-nit rophenyl)sulfonyl)-4-(4-
((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2-yl)methyl)piperazin-l-yl)-2-
(2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazi n-l(6H)-yl)benzamide,
4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)p iperazin-l-yl)-2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H- pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)p iperazin-l-yl)-2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H- pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,
(S)-N-((4-(((l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl) sulfonyl)-4-(4-((6-(4- chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-l-yl)- 2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)-3-fluorobenzamide,
(S)-N-((4-(((l,4-dioxan-2-yl)methyl)amino)-3-fluoro-5-nit rophenyl)sulfonyl)-4-(4-
((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)pipera zin-l-yl)-2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)-6-fluorobenzamide, 4-(4-((4’-chloro-5,5-bis(methyl-d3)-3,4,5,6-tetrahydro-[l, r-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)-yl- 2,2,3,3-d4)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide,
((2-(((4-(N-(4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahy dro-[l,l’-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)benzoyl)sulfamoyl)-2-nitrophenyl)amino)methyl)morpholino) methyl)phosphonic acid, diethyl (2-((2-((4-(N-(4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetra hydro-[l,l’- biphenyl]-2-yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[ 3’,2’:5,6]pyrido[2,3- b] [ 1 ,4]oxazin- 1 (6H)-yl)benzoyl)sulfamoyl)-2- nitrophenyl)amino)ethyl)(methyl)amino)ethyl)phosphonate,
ethyl P-(2-((4-(N-(4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahy dro-[l,l’-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)benzoyl)sulfamoyl)-2-nitrophenyl)amino)ethyl)-N,N-dimethy lphosphonamidate,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l’-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((l-(dimethylamino)-l-oxidophosphinan-4-yl)methyl )amino)-3- nitrophenyl) sulfo nyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l’-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((l-ethoxy-l-oxidophosphinan-4-yl)methyl)amino)-3 - nitrophenyl) sulfo nyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l’-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((l-isopropoxy-l-oxidophosphinan-4-yl)methyl)amin o)-3- nitrophenyl) sulfo nyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l’-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-nitro-4-(((l,2,3-trimethyl-2-oxido-l,3,2-diazaphos phinan-5- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide, 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biph enyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-((2-(2-methyl-2-oxido-l,3,2-diazaphosphinan-l-yl)e thyl)amino)-3- nitrophenyl) sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((4-(dimethylphosphoryl)morpholin-2-yl)methyl)ami no)-3- nitrophenyl) sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(dimethylphosphoryl)-3-nitrophenyl)sulfonyl)benzam ide,
N-((4-(((l,4-dithiaspiro[4.5]decan-8-yl)methyl)amino)-3-n itrophenyl)sulfonyl)-4-(4-
((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2-yl)methyl)piperazin-l-yl)-2-
(2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazi n-l(6H)-yl)benzamide,
N-((4-((2-(6-azaspiro[2.5]octan-6-yl)ethyl)amino)-3-nitro phenyl)sulfonyl)-4-(4-((4’- chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2-yl)methyl)piperazin-l-yl)-2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-N-((4-((2-(2,2-difluoro-7-azaspiro [3.5]nonan-7-yl)ethyl)amino)-3- nitrophenyl)sulfonyl)-2-(2,3-dihydropyrrolo[3’,2’:5,6]py rido[2,3-b][l,4]oxazin-l(6H)- yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-nitro-4-((2-(2-(oxetan-3-yl)octahydro-5H-pyrrolo[3 ,4-c]pyridin-5- yl)ethyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-nitro-4-((2-(l-oxooctahydro-5H-pyrrolo[3,4-c]pyrid in-5- yl)ethyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((3-hydroxybicyclo[3. l. l]heptan-6-yl)methyl)amino)-3- nitrophenyl) sulfonyl)benzamide,
N-((4-(((3-amino-3-methylbicyclo[3. l. l]heptan-6-yl)methyl)amino)-3- nitrophenyl)sulfonyl)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5, 6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-nitro-4-((2-(5-(oxetan-3-yl)-2,5-diazabicyclo[2.2. l]heptan-2- yl)ethyl)amino)phenyl)sulfonyl)benzamide,
2-((3S)-8-(2-((4-(N-(4-(4-((4’-chloro-5,5-dimethyl-3,4, 5,6-tetrahydro-[l, -biphenyl]- 2-yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’: 5,6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)benzoyl)sulfamoyl)-2-nitrophenyl)amino)ethyl)-6,6-difluor o-8-azabicyclo[3.2. l]octan-3- yl)acetic acid,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-N-((4-((2-(6,6-difluoro-8-azabicyc lo[3.2. l]octan-8- yl)ethyl)amino)-3-nitrophenyl)sulfonyl)-2-(2,3-dihydropyrrol o[3’,2’:5,6]pyrido[2,3- b] [ 1 ,4]oxazin- 1 (6H)-yl)benzamide,
N-((4-((7-oxaspiro[3.5]nonan-2-yl)amino)-3-nitrophenyl)su lfonyl)-4-(4-((4’-chloro-
5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2-yl)methyl)piperazin-l-yl)-2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((l,l-dioxidotetrahydro-2H-thiopyran-4-yl)methyl) amino)-3- nitrophenyl) sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((l-(isopropylimino)-l-oxidohexahydro-H6-thiopyra n-4-yl)methyl)amino)-3- nitrophenyl) sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((4-(S-methylsulfonimidoyl)morpholin-2-yl)methyl) amino)-3- nitrophenyl) sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-N-((4-(((4-cyanotetrahydro-2H-pyra n-4-yl)methyl)amino)-3- nitrophenyl)sulfonyl)-2-(2,3-dihydropyrrolo[3’,2’:5,6]py rido[2,3-b][l,4]oxazin-l(6H)- yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-nitro-4-((2-(tetrahydro-2H-pyran-4-yl)propan-2- yl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-N-((4-((2-(5,6-dihydro-[l,2,4]tria zolo[l,5-a]pyrazin-7(8H)- yl)ethyl)amino)-3-nitrophenyl)sulfonyl)-2-(2,3-dihydropyrrol o[3’,2’:5,6]pyrido[2,3- b] [ 1 ,4]oxazin- 1 (6H)-yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-nitro-4-(((l-(thiazol-2-yl)piperidin-4-yl)methyl)a mino)phenyl)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-N-((4-((4-(difluoromethoxy)benzyl) amino)-3- nitrophenyl)sulfonyl)-2-(2,3-dihydropyrrolo[3’,2’:5,6]py rido[2,3-b][l,4]oxazin-l(6H)- yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((3,5-dihydroxytetrahydrofuran-2-yl)methyl)amino) -3- nitrophenyl) sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-nitro-4-(((3,4,5-trihydroxy-6,6-dimethyltetrahydro -2H-pyran-2- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-nitro-4-(((2, 3, 5-trihydro xytetrahydro-2H-pyran-4- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-nitro-4-(((3, 4, 5-trihydro xy-6-(methylthio)tetrahydro-2H-pyran-2- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-nitro-4-(((3, 4, 5-trihydro xy-6-(((4, 5, 6-trihydro xy-2-(hydroxymethyl)tetrahydro-2H- pyran- 3 - yl) methoxy) methy 1) tetrahydro -2H-pyran- 2- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide,
N-((4-(((l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulf onyl)-4-(l-((6-(4- chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methyl)-l,2,3,6-t etrahydropyridin-4-yl)-2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)benzamide,
4-(l-((6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)me thyl)-l,2,3,6- tetrahydropyridin-4-yl)-2-(2,3-dihydropyrrolo[3’,2’:5,6] pyrido[2,3-b][l,4]oxazin-l(6H)-yl)-
N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)ph enyl)sulfonyl)benzamide,
(R)-4-(l-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l ,l’-biphenyl]-2- yl)methyl)piperidin-4-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-3-yl)methyl)amino)p henyl)sulfonyl)benzamide,
(S)-6-(4-((6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-y l)methyl)piperazin-l-yl)-4- (2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin-l (6H)-yl)-N-((3-nitro-4-(((tetrahydro- 2H-pyran- 3 - yl) methyl) amino )pheny 1) sulfo ny 1) nicotinamide,
(S)-N-((4-(((l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl) sulfonyl)-6-(4-((4’-chloro-
5.5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2-yl)methy l)piperazin-l-yl)-2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)nicotinamide,
N-((4-((((R)-l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl) sulfonyl)-4-(4-((4’-chloro-
5.5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2-yl)methy l)piperazin-l-yl)-2-((S)-3-methyl- 2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin-l( 6H)-yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l -biphenyl]-2- yl)methyl)piperazin-l-yl)-N-((4-((((S)-2-fluoro-l,4-dioxan-2 -yl)methyl)amino)-3- nitrophenyl)sulfonyl)-2-((S)-3-methyl-2,3-dihydropyrrolo[3 ,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)benzamide,
(R)-N-((4-(((l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl) sulfonyl)-4-(4-((4’-chloro-
5.5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2-yl)methyl)piperazin-l-yl)-2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)benzamide,
(S)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l , -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((2-fluoro-l,4-dioxan-2-yl)methyl)amino)-3-nitrop henyl)sulfonyl)benzamide,
(R)-N-((4-(((l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl) sulfonyl)-4-(4-((4’-chloro-
5.5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2-yl)methy l)piperazin-l-yl)-2-(3,3-difluoro- 2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin-l( 6H)-yl)benzamide,
(S)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l ,r-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(3,3-difluoro-2,3-dihydropyrrolo [3’,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-((4-(((2-fluoro-l,4-dioxan-2-yl)me thyl)amino)-3- nitrophenyl) sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(3,3-difluoro-2,3-dihydropyrrolo [3’,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran -4- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide,
N-((4-((((S)-l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl) sulfonyl)-4-(4-((4’-chloro-
5.5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2-yl)methy l)piperazin-l-yl)-2-((S)-3-methyl- 2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin-l( 6H)-yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l -biphenyl]-2- yl)methyl)piperazin-l-yl)-N-((4-((((R)-2-fluoro-l,4-dioxan-2 -yl)methyl)amino)-3- nitrophenyl)sulfonyl)-2-((S)-3-methyl-2,3-dihydropyrrolo[3 ,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)benzamide,
(S)-N-((4-(((l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl) sulfonyl)-4-(4-((4’-chloro-
5.5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2-yl)methy l)piperazin-l-yl)-2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)benzamide,
(R)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l ,l’-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((2-fluoro-l,4-dioxan-2-yl)methyl)amino)-3-nitrop henyl)sulfonyl)benzamide,
(S)-N-((4-(((l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl) sulfonyl)-4-(4-((4’-chloro-
5.5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2-yl)methyl)piperazin-l-yl)-2-(3,3-difluoro- 2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin-l( 6H)-yl)benzamide,
(R)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l , -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(3,3-difluoro-2,3-dihydropyrrolo [3’,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-((4-(((2-fluoro-l,4-dioxan-2-yl)me thyl)amino)-3- nitrophenyl) sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(3,3-difluoro-2,3-dihydropyrrolo [3’,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran -4-yl)methyl)amino)-3- nitrophenyl) sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((4-((dimethyl(oxo)-l6-sulfaneylidene)amino)cyclo hexyl)methyl)amino)-3- nitrophenyl) sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-((2-(4-((dimethyl(oxo)-l6-sulfaneylidene)amino)pip eridin-l-yl)ethyl)amino)-3- nitrophenyl) sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-nitro-4-(((4-((l-oxidotetrahydro-H6-thiophen-l- ylidene)amino)cyclohexyl)methyl)amino)phenyl)sulfonyl)benzam ide, or
(S)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l , -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-((l-(4-((dimethyl(oxo)-l6-sulfaneylidene)amino)pip eridin-l-yl)propan-2-yl)amino)- 3-nitrophenyl)sulfonyl)benzamide.
N-((4-((((S)-l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl) sulfonyl)-4-(4-((4’-chloro-
5.5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2-yl)methyl)piperazin-l-yl)-2-((R)-3-methyl- 2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin-l( 6H)-yl)benzamide, N-((4-((((S)-l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sul fonyl)-4-(4-((4’-chloro-
5.5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2-yl)methyl)piperazin-l-yl)-2-((R)-3-methyl- 2-oxo-2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxa zin-l(6H)-yl)benzamide,
(S)-N-((4-(((l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl) sulfonyl)-4-(4-((4’-chloro-
5.5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2-yl)methyl)piperazin-l-yl)-2-(3,3-dimethyl- 2-oxo-2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxa zin-l(6H)-yl)benzamide,
(S)-N-((4-(((l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl) sulfonyl)-4-(4-((4’-chloro-
5.5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2-yl)methyl)piperazin-l-yl)-2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]thiazin-l(6H) -yl)benzamide,
(R)-N-((4-(((l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl) sulfonyl)-4-(4-((4’-chloro-
5.5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2-yl)methy l)piperazin-l-yl)-2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]thiazin-l(6H) -yl)benzamide,
N-((4-((((S)-l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl) sulfonyl)-4-(4-((4’-chloro-
5.5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2-yl)methy l)piperazin-l-yl)-2-((S)-3-methyl- 2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]thiazin-l (6H)-yl)benzamide,
N-((4-((((R)-l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl) sulfonyl)-4-(4-((4’-chloro-
5.5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2-yl)methy l)piperazin-l-yl)-2-((R)-3-methyl- 2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]thiazin-l (6H)-yl)benzamide,
N-((4-((((S)-l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl) sulfonyl)-4-(4-((4’-chloro-
5.5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2-yl)methy l)piperazin-l-yl)-2-((R)-3- (trifluoromethyl)-2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2, 3-b][l,4]thiazin-l(6H)-yl)benzamide,
N-((4-((((R)-l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl) sulfonyl)-4-(4-((4’-chloro-
5.5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2-yl)methy l)piperazin-l-yl)-2-((S)-3- (trifluoromethyl)-2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2, 3-b][l,4]thiazin-l(6H)-yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo [3’,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-((3-nitro-4-(((S)-l-(tetrahydro-2H -pyran-4- yl)ethyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo [3’,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-((3-nitro-4-(((R)-l-(tetrahydro-2H -pyran-4- yl)ethyl)amino)phenyl)sulfonyl)benzamide,
N-((4-((((5r,8r)-l-oxaspiro[4.5]decan-8-yl)methyl)amino)- 3-nitrophenyl)sulfonyl)-4-
(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2-yl)methyl)piperazin-l-yl)-2-
((R)-3-methyl-2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3 -b][l,4]oxazin-l(6H)-yl)benzamide,
N-((4-((((5s,8s)-l-oxaspiro[4.5]decan-8-yl)methyl)amino)- 3-nitrophenyl)sulfonyl)-4-
(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2-yl)methyl)piperazin-l-yl)-2-
((R)-3-methyl-2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3 -b][l,4]oxazin-l(6H)-yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyr an-4- yl)methyl)amino)phenyl)sulfonyl)-2-(3-(pyridin-3-yl)-2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)benzamide,
(R)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l ,r-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(3-(2-fluoropropan-2-yl)-2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H- pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(3-(l-(2-(dimethylamino)ethoxy)- 2-methylpropan-2-yl)-2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H- pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(3-(l-(4,4-difluoropiperidin-l-y l)-2-methylpropan-2-yl)-2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H- pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyr an-4- yl)methyl)amino)phenyl)sulfonyl)-2-(4-oxo-4,6-dihydro-lH-pyr rolo[2,3-b][l,5]naphthyridin- l-yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyr an-4- yl)methyl)amino)phenyl)sulfonyl)-2-(4-oxo-4,6-dihydro-lH-pyr rolo[3’,2’:5,6]pyrido[3,2- d]pyrimidin- 1 -yl)benzamide, 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biph enyl]-2- yl)methyl)piperazin-l-yl)-2-(2,2-dioxido-3H-pyrrolo[3’,2 :5,6]pyrido[3,2- e][l,3,4]oxathiazin-l(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H -pyran-4- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(l,l-dioxido-2,3-dihydropyrrolo[ 3’,2’:5,6]pyrido[3,2- e][l,2,4]thiadiazin-4(8H)-yl)-N-((3-nitro-4-(((tetrahydro-2H -pyran-4- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(l,l-dioxidopyrrolo[3’,2’:5, 6]pyrido[3,2-e][l,2,4]thiadiazin- 4(8H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(4,4-dimethyl-2-oxo-4,6-dihydrop yrrolo[3’,2’:5,6]pyrido[3,2- d][l,3]oxazin-l(2H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran -4- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide,
(S)-N-((4-(((l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl) sulfonyl)-4-(4-((4’-chloro-
5.5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2-yl)methyl)piperazin-l-yl)-2-(4-methyl-3- oxo-2,3,4,6-tetrahydro-lH-pyrrolo[3’,2’:5,6]pyrido[2,3-b ]pyrazin-l-yl)benzamide,
(S)-N-((4-(((l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl) sulfonyl)-4-(4-((4’-chloro-
5.5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2-yl)methyl)piperazin-l-yl)-2-(4-oxo-4H- pyrrolo[l,2-a]pyrrolo[3’,2’:5,6]pyrido[3,2-e]pyrazin-5(9 H)-yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(7,7-difluoro-6,7,8,8a-tetrahydr o-lH- cyclopenta[b]pyrrolo[3’,2’:5,6]pyrido[3,2-e][l,4]oxazin- 5(5aH)-yl)-N-((3-nitro-4-
(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl) benzamide,
N-((4-((((S)-l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl) sulfonyl)-4-(4-((4’-chloro-
5.5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2-yl)methyl)piperazin-l-yl)-2-((5aS,8aS)- 6,7,8,8a-tetrahydro-lH-cyclopenta[b]pyrrolo[3’,2’:5,6]py rido[3,2-e][l,4]oxazin-5(5aH)- yl)benzamide, N-((4-((((S)-l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sul fonyl)-4-(4-((4’-chloro-
5.5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2-yl)methyl)piperazin-l-yl)-2-((5aS,8aS)- 5a,6,8,8a-tetrahydrofuro[3,4-b]pyrrolo[3’,2’:5,6]pyrido[ 3,2-e][l,4]oxazin-5(lH)- yl)benzamide,
N-((4-((((S)-l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl) sulfonyl)-4-(4-((4’-chloro-
5.5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2-yl)methyl)piperazin-l-yl)-2-((5aS,8aR)- 5a,6,8,8a-tetrahydrofuro[3,4-b]pyrrolo[3’,2’:5,6]pyrido[ 3,2-e][l,4]oxazin-5(lH)- yl)benzamide,
N-((4-((((S)-l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl) sulfonyl)-4-(4-((4’-chloro-
5.5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2-yl)methyl)piperazin-l-yl)-2-((5aR,8aR)- 5a,6,8,8a-tetrahydrofuro[3,4-b]pyrrolo[3’,2’:5,6]pyrido[ 3,2-e][l,4]oxazin-5(lH)- yl)benzamide,
N-((4-((((S)-l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl) sulfonyl)-4-(4-((4’-chloro-
5.5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2-yl)methy l)piperazin-l-yl)-2-((5aR,8aS)- 5a,6,8,8a-tetrahydrofuro[3,4-b]pyrrolo[3’,2’:5,6]pyrido[ 3,2-e][l,4]oxazin-5(lH)- yl)benzamide,
N-((4-((((S)-l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl) sulfonyl)-4-(4-((4’-chloro-
5.5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2-yl)methy l)piperazin-l-yl)-2-((5aR,8aR)- 6,7,8,8a-tetrahydro-lH-cyclopenta[b]pyrrolo[3’,2’:5,6]py rido[3,2-e][l,4]oxazin-5(5aH)- yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyr an-4- yl)methyl)amino)phenyl)sulfonyl)-2-(6,7,9,9a-tetrahydro-lH-p yrano[3,4- b]pyrrolo[3’,2’:5,6]pyrido[3,2-e][l,4]oxazin-5(5aH)-yl)b enzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydro-4H-benzo[b][l,4]oxa zin-4-yl)-N-((3-nitro-4-
(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl) benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydro-4H-pyrido[3,2-b][l, 4]oxazin-4-yl)-N-((3-nitro-4-
(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl) benzamide, 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biph enyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydro-lH-pyrido[3,4-b][l, 4]oxazin-l-yl)-N-((3-nitro-4-
(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl) benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydro-4H-pyrido[4,3-b][l, 4]oxazin-4-yl)-N-((3-nitro-4-
(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl) benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydro-lH-pyrido[2,3-b][l, 4]oxazin-l-yl)-N-((3-nitro-4-
(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl) benzamide,4-(4-((4’-chloro-
[l, -biphenyl]-2-yl)(hydroxy)methyl)piperidin-l-yl)-2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H- pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
N-((4-((((S)-l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl) sulfonyl)-4-(4-((R)-(4’- chloro-[l, -biphenyl]-2-yl)(hydroxy)methyl)piperidin-l-yl)-2-((R)-3-met hyl-2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)benzamide,
N-((4-((((S)-l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl) sulfonyl)-4-(4-((R)-(4’- chloro-[l,r-biphenyl]-2-yl)(hydroxy)methyl)piperidin-l-yl)-2 -((S)-3-methyl-2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)benzamide,
N-((4-((((R)-l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl) sulfonyl)-4-(4-((R)-(4’- chloro-[l,r-biphenyl]-2-yl)(hydroxy)methyl)piperidin-l-yl)-2 -((R)-3-methyl-2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)benzamide,
N-((4-((((R)-l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl) sulfonyl)-4-(4-((R)-(4’- chloro-[l,r-biphenyl]-2-yl)(hydroxy)methyl)piperidin-l-yl)-2 -((S)-3-methyl-2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)benzamide,
N-((4-((((R)-l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl) sulfonyl)-4-(4-((R)-(4’- chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2-yl)( hydroxy)methyl)piperidin-l-yl)-
2-((R)-3-methyl-2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2 ,3-b][l,4]oxazin-l(6H)-yl)benzamide,
N-((4-((((R)-l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl) sulfonyl)-4-(4-((R)-(6-(4- chlorophenyl)spiro[3.5]non-6-en-7-yl)(hydroxy)methyl)piperid in-l-yl)-2-((R)-3-methyl-2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)benzamide, N-((4-((((R)-l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sul fonyl)-4-(4-((R)-(6-(4- chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)(hydroxy)methyl)p iperidin-l-yl)-2-((R)-3- methyl-2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]ox azin-l(6H)-yl)benzamide,
N-(((S)-3-((S)-l,4-dioxan-2-yl)-5-nitro-3,4-dihydro-2H-be nzo[b][l,4]oxazin-7- yl)sulfonyl)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahy dro-[l,r-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo [3’,2’:5,6]pyrido[2,3- b] [ 1 ,4]oxazin- 1 (6H)-yl)benzamide,
N-(((S)-3-((R)-l,4-dioxan-2-yl)-5-nitro-3,4-dihydro-2H-be nzo[b][l,4]oxazin-7- yl)sulfonyl)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahy dro-[l,r-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo [3’,2’:5,6]pyrido[2,3- b] [ 1 ,4]oxazin- 1 (6H)-yl)benzamide,
N-(((R)-3-((S)-l,4-dioxan-2-yl)-5-nitro-3,4-dihydro-2H-be nzo[b][l,4]oxazin-7- yl)sulfonyl)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahy dro-[l,r-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo [3’,2’:5,6]pyrido[2,3- b] [ 1 ,4]oxazin- 1 (6H)-yl)benzamide,
N-(((R)-3-((R)-l,4-dioxan-2-yl)-5-nitro-3,4-dihydro-2H-be nzo[b][l,4]oxazin-7- yl)sulfonyl)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahy dro-[l,r-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo [3’,2’:5,6]pyrido[2,3- b] [ 1 ,4]oxazin- 1 (6H)-yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo [3’,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-(((S)-5-nitro-3-(tetrahydro-2H-pyr an-4-yl)-3,4-dihydro-2H- benzo[b][l,4]oxazin-7-yl)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo [3’,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-(((R)-5-nitro-3-(tetrahydro-2H-pyr an-4-yl)-3,4-dihydro-2H- benzo[b][l,4]oxazin-7-yl)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo [3’,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-(((S)-3-(morpholinomethyl)-5-nitro -3,4-dihydro-2H- benzo[b][l,4]oxazin-7-yl)sulfonyl)benzamide, 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biph enyl]-2- yl)methyl)piperazin-l-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo [3’,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-(((R)-3-(morpholinomethyl)-5-nitro -3,4-dihydro-2H- benzo[b][l,4]oxazin-7-yl)sulfonyl)benzamide,
N-(((S)-3-(((lS,4S)-2-oxa-5-azabicyclo[2.2.l]heptan-5-yl)met hyl)-5-nitro-3,4- dihydro-2H-benzo[b][l,4]oxazin-7-yl)sulfonyl)-4-(4-((4’-ch loro-5,5-dimethyl-3,4,5,6- tetrahydro-[l,r-biphenyl]-2-yl)methyl)piperazin-l-yl)-2-((R) -3-methyl-2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)benzamide,
N-(((S)-3-(((lR,4R)-2-oxa-5-azabicyclo[2.2.l]heptan-5-yl)met hyl)-5-nitro-3,4- dihydro-2H-benzo[b][l,4]oxazin-7-yl)sulfonyl)-4-(4-((4’-ch loro-5,5-dimethyl-3,4,5,6- tetrahydro-[l,r-biphenyl]-2-yl)methyl)piperazin-l-yl)-2-((R) -3-methyl-2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)benzamide,
N-(((R)-3-(((lS,4S)-2-oxa-5-azabicyclo[2.2.l]heptan-5-yl)met hyl)-5-nitro-3,4- dihydro-2H-benzo[b][l,4]oxazin-7-yl)sulfonyl)-4-(4-((4’-ch loro-5,5-dimethyl-3,4,5,6- tetrahydro-[l,r-biphenyl]-2-yl)methyl)piperazin-l-yl)-2-((R) -3-methyl-2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)benzamide,
N-(((R)-3-(((lR,4R)-2-oxa-5-azabicyclo[2.2.l]heptan-5-yl)met hyl)-5-nitro-3,4- dihydro-2H-benzo[b][l,4]oxazin-7-yl)sulfonyl)-4-(4-((4’-ch loro-5,5-dimethyl-3,4,5,6- tetrahydro-[l,r-biphenyl]-2-yl)methyl)piperazin-l-yl)-2-((R) -3-methyl-2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biph enyl]-2- yl)methyl)piperazin-l-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo [3’,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-(((S)-3-((4-methylpiperazin-l-yl)m ethyl)-5-nitro-3,4-dihydro-2H- benzo[b][l,4]oxazin-7-yl)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biph enyl]-2- yl)methyl)piperazin-l-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo [3’,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-(((R)-3-((4-methylpiperazin-l-yl)m ethyl)-5-nitro-3,4-dihydro-2H- benzo[b][l,4]oxazin-7-yl)sulfonyl)benzamide,
N-(((S)-3-((S)-l,4-dioxan-2-yl)-5-nitro-3,4-dihydro-2H-benzo [b][l,4]oxazin-7- yl)sulfonyl)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahy dro-[l,r-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-((S)-3-(trifluoromethyl)-2,3-dih ydropyrrolo[3’,2’:5,6]pyrido[2,3- b] [ 1 ,4]oxazin- 1 (6H)-yl)benzamide, N-(((S)-3-((R)-l,4-dioxan-2-yl)-5-nitro-3,4-dihydro-2H-benzo [b][l,4]oxazin-7- yl)sulfonyl)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahy dro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-((S)-3-(trifluoromethyl)-2,3-dih ydropyrrolo[3’,2’:5,6]pyrido[2,3- b] [ 1 ,4]oxazin- 1 (6H)-yl)benzamide,
N-(((R)-3-((S)-l,4-dioxan-2-yl)-5-nitro-3,4-dihydro-2H-be nzo[b][l,4]oxazin-7- yl)sulfonyl)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahy dro-[l,r-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-((S)-3-(trifluoromethyl)-2,3-dih ydropyrrolo[3’,2’:5,6]pyrido[2,3- b] [ 1 ,4]oxazin- 1 (6H)-yl)benzamide,
N-(((R)-3-((R)-l,4-dioxan-2-yl)-5-nitro-3,4-dihydro-2H-be nzo[b][l,4]oxazin-7- yl)sulfonyl)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahy dro-[l,r-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-((S)-3-(trifluoromethyl)-2,3-dih ydropyrrolo[3’,2’:5,6]pyrido[2,3- b] [ 1 ,4]oxazin- 1 (6H)-yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-N-(((S)-5-nitro-3-(tetrahydro-2H-p yran-4-yl)-3,4-dihydro-2H- benzo[b][l,4]oxazin-7-yl)sulfonyl)-2-((S)-3-(trifluoromethyl )-2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-N-(((R)-5-nitro-3-(tetrahydro-2H-p yran-4-yl)-3,4-dihydro-2H- benzo[b][l,4]oxazin-7-yl)sulfonyl)-2-((S)-3-(trifluoromethyl )-2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-N-(((R)-3-(morpholinomethyl)-5-nit ro-3,4-dihydro-2H- benzo[b][l,4]oxazin-7-yl)sulfonyl)-2-((S)-3-(trifluoromethyl )-2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)benzamide,
N-(((R)-3-(((lS,4S)-2-oxa-5-azabicyclo[2.2. l]heptan-5-yl)methyl)-5-nitro-3,4- dihydro-2H-benzo[b][l,4]oxazin-7-yl)sulfonyl)-4-(4-((4’-ch loro-5,5-dimethyl-3,4,5,6- tetrahydro-[l,r-biphenyl]-2-yl)methyl)piperazin-l-yl)-2-((S) -3-(trifluoromethyl)-2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-N-(((S)-3-((4-methylpiperazin-l-yl )methyl)-5-nitro-3,4-dihydro-
2H-benzo[b][l,4]oxazin-7-yl)sulfonyl)-2-((S)-3-(trifluoro methyl)-2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)benzamide, N-(((S)-3-((S)-l,4-dioxan-2-yl)-5-nitro-3,4-dihydro-2H-benzo [b][l,4]oxazin-7- yl)sulfonyl)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahy dro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)benzamide,
N-(((S)-3-((R)-l,4-dioxan-2-yl)-5-nitro-3,4-dihydro-2H-be nzo[b][l,4]oxazin-7- yl)sulfonyl)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahy dro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)benzamide,
N-(((R)-3-((S)-l,4-dioxan-2-yl)-5-nitro-3,4-dihydro-2H-be nzo[b][l,4]oxazin-7- yl)sulfonyl)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahy dro-[l,r-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)benzamide,
N-(((R)-3-((R)-l,4-dioxan-2-yl)-5-nitro-3,4-dihydro-2H-be nzo[b][l,4]oxazin-7- yl)sulfonyl)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahy dro-[l,r-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)benzamide,
(S)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l ,r-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((5-nitro-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-2H- benzo[b][l,4]oxazin-7- yl)sulfonyl)benzamide,
(R)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l ,r-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((5-nitro-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-2H- benzo[b][l,4]oxazin-7- yl)sulfonyl)benzamide,
(S)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l ,r-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-(morpholinomethyl)-5-nitro-3,4-dihydro-2H-benzo[b] [l,4]oxazin-7- yl)sulfonyl)benzamide,
(R)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l ,r-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-(morpholinomethyl)-5-nitro-3,4-dihydro-2H-benzo[b] [l,4]oxazin-7- yl)sulfonyl)benzamide, N-(((S)-3-(((lS,4S)-2-oxa-5-azabicyclo[2.2.l]heptan-5-yl)met hyl)-5-nitro-3,4- dihydro-2H-benzo[b][l,4]oxazin-7-yl)sulfonyl)-4-(4-((4’-ch loro-5,5-dimethyl-3,4,5,6- tetrahydro-[l, -biphenyl]-2-yl)methyl)piperazin-l-yl)-2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)benzamide,
N-(((R)-3-(((lS,4S)-2-oxa-5-azabicyclo[2.2.l]heptan-5-yl)met hyl)-5-nitro-3,4- dihydro-2H-benzo[b][l,4]oxazin-7-yl)sulfonyl)-4-(4-((4’-ch loro-5,5-dimethyl-3,4,5,6- tetrahydro-[l, -biphenyl]-2-yl)methyl)piperazin-l-yl)-2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)benzamide,
(S)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-((4-methylpiperazin-l-yl)methyl)-5-nitro-3,4-dihyd ro-2H-benzo[b][l,4]oxazin-7- yl)sulfonyl)benzamide,
(R)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-((4-methylpiperazin-l-yl)methyl)-5-nitro-3,4-dihyd ro-2H-benzo[b][l,4]oxazin-7- yl)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biph enyl]-2- yl)methyl)piperazin-l-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo [3’,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-(((R)-3-(2-morpholinoethyl)-5-nitr o-3,4-dihydro-2H- benzo[b][l,4]oxazin-7-yl)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biph enyl]-2- yl)methyl)piperazin-l-yl)-N-(((R)-3-(4-hydroxy-4-methylcyclo hexyl)-5-nitro-3,4-dihydro-
2H-benzo[b][l,4]oxazin-7-yl)sulfonyl)-2-((R)-3-methyl-2,3 - dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biph enyl]-2- yl)methyl)piperazin-l-yl)-N-(((R)-3-((4-hydroxy-4-methylpipe ridin-l-yl)methyl)-5-nitro-3,4- dihydro-2H-benzo[b][l,4]oxazin-7-yl)sulfonyl)-2-((R)-3-methy l-2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biph enyl]-2- yl)methyl)piperazin-l-yl)-N-(((S)-3-cyclopropyl-5-nitro-3,4- dihydro-2H- benzo[b][l,4]oxazin-7-yl)sulfonyl)-2-((R)-3-methyl-2,3-dihyd ropyrrolo[3’,2’:5,6]pyrido[2,3- b] [ 1 ,4]oxazin- 1 (6H)-yl)benzamide, 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biph enyl]-2- yl)methyl)piperazin-l-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo [3’,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-(((S)-5-nitro-3-(pyridin-2-ylmethy l)-3,4-dihydro-2H- benzo[b][l,4]oxazin-7-yl)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo [3’,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-((3-((4-methylpiperazin-l-yl)methy l)-5-nitro-3,4-dihydro-2H- benzo[b][l,4]thiazin-7-yl)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo [3’,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-((2-(morpholinomethyl)-8-nitro-2,3 -dihydrobenzo[b][l,4]dioxin-
6-yl)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo [3’,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-(((R)-2-((4-methylpiperazin-l-yl)m ethyl)-7-nitroindolin-5- yl)sulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo [3’,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-(((R)-2-(morpholinomethyl)-7-nitro indolin-5- yl)sulfonyl)benzamide,
(R)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l ,r-biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(3-methyl-2,3-dihydropyrrolo[3 ,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-((2-(morpholinomethyl)-7-nitro-lH- indol-5- yl)sulfonyl)benzamide,
4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)p iperazin-l-yl)-2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)-N-((5-nitro-4-((tetrahydro-2H- pyran-4-yl)methyl)-3,4-dihydro-2H-benzo[b][l,4]oxazin-7-yl)s ulfonyl)benzamide,
4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((7-nitro-2-(oxetan-3-yl)isoindolin-5-yl)sulfonyl)benz amide, 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biph enyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((7-nitro-3-oxoisoindolin-5-yl)sulfonyl)benzamide,
4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)p iperazin-l-yl)-2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)-N-((7-nitro-3-oxo-2-
((tetrahydro-2H-pyran-4-yl)methyl)isoindolin-5-yl)sulfony l)benzamide,
4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)p iperazin-l-yl)-N-((2- cyclopropyl-7-nitro-lH-benzo[d]imidazol-5-yl)sulfonyl)-2-(2, 3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)benzamide, 4-(4-((6-(4- chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-l-yl)- 2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)-N-((7-nitro-2-((tetrahydro-2H- pyran-4-yl)methyl)-2H-indazol-5-yl)sulfonyl)benzamide,
4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)p iperazin-l-yl)-2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)-N-((7-nitro-l-((tetrahydro-2H- pyran-4-yl)methyl)-lH-indazol-5-yl)sulfonyl)benzamide,4-(4-( (6-(4- chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-l-yl)- 2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)-N-((4-nitro-l-((tetrahydro-2H- pyran-4-yl)methyl)-lH-indazol-6-yl)sulfonyl)benzamide,
4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)p iperazin-l-yl)-2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)-N-((4-nitro-l-(tetrahydro-2H- pyran-4-yl)-lH-indazol-6-yl)sulfonyl)benzamide,
4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)p iperazin-l-yl)-2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)-N-((2-isopropyl-7-nitro-lH- benzo [d] imidazol-5-yl) sulfonyl)benzamide,
4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)p iperazin-l-yl)-2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)-N-((4-nitro-2-(tetrahydro-2H- pyran-4-yl)-2H-indazol-6-yl)sulfonyl)benzamide,
4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)p iperazin-l-yl)-2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)-N-((3-fluoro-2-(2- methoxyethyl)-4-nitro-2H-indazol-6-yl)sulfonyl)benzamide, 4-(4-(3-(2-(4-chlorophenyl)-l-isopropyl-5-methyl-4-(methylsu lfonyl)-lH-pyrrol-3- yl)-5-fluorophenyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3 ,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide,
(S)-N-((4-(((l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl) sulfonyl)-4-(4-(3-(2-(4- chlorophenyl)-l-isopropyl-5-methyl-4-(methylsulfonyl)-lH-pyr rol-3-yl)-5- fluorophenyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’ :5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)benzamide,
(R)-N-((4-(((l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl) sulfonyl)-4-(4-(3-(2-(4- chlorophenyl)-l-isopropyl-5-methyl-4-(methylsulfonyl)-lH-pyr rol-3-yl)-5- fluorophenyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’ :5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)benzamide,
4-(4-(3-(2-(4-chlorophenyl)-l-isopropyl-5-methyl-4-(methy lsulfonyl)-lH-pyrrol-3- yl)-5-fluorophenyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3 ,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)-N-((5-nitro-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihyd ro-2H-benzo[b][l,4]oxazin-7- yl)sulfonyl)benzamide,
5-(4-chlorophenyl)-4-(3-(4-(3-(2,3-dihydropyrrolo[3’,2 :5,6]pyrido[2,3- b] [ 1 ,4]oxazin- 1 (6H)-yl)-4-(((3-nitro-4-(((tetrahydro-2H-pyran-4- yl) methyl) amino )pheny 1) sulfo nyl)carbamoyl)phenyl)piperazin-l-yl)phenyl)-l,2-dimethyl- lH-pyrrole-3-carboxylic acid,
5-(4-chlorophenyl)-4-(3-(4-(3-(2,3-dihydropyrrolo[3’,2 :5,6]pyrido[2,3- b] [ 1 ,4]oxazin- 1 (6H)-yl)-4-(((3-nitro-4-(((tetrahydro-2H-pyran-4- yl)methyl)amino)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-l -yl)phenyl)-l -ethyl-2- methyl- lH-pyrrole-3-carboxylic acid,
2-(2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxa zin-l(6H)-yl)-4-(4-(3-(l-ethyl-
2-(4-fluorophenyl)-5-methyl-4-(methylsulfonyl)-lH-pyrrol- 3-yl)-5-fluorophenyl)piperazin-l- yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)p henyl)sulfonyl)benzamide,
2-(2,3-dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxa zin-l(6H)-yl)-4-(4-(3-fluoro-5- (2-(4-fluorophenyl)-l-isopropyl-5-methyl-4-(methylsulfonyl)- lH-pyrrol-3- yl)phenyl)piperazin-l-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyr an-4- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide, 5-(4-chlorophenyl)-4-(3-(4-(3-(2,3-dihydropyrrolo[3’,2’: 5,6]pyrido[2,3- b] [ 1 ,4]oxazin- 1 (6H)-yl)-4-(((3-nitro-4-(((tetrahydro-2H-pyran-4- yl)methyl)amino)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-l -yl)phenyl)-l -isopropyl-2- methyl- lH-pyrrole-3-carboxylic acid,
5-(4-chlorophenyl)-4-(3-(4-(3-(2,3-dihydropyrrolo[3’,2 :5,6]pyrido[2,3- b] [ 1 ,4]oxazin- 1 (6H)-yl)-4-(((3-nitro-4-(((tetrahydro-2H-pyran-4- yl)methyl)amino)phenyl) sulfo nyl)carbamoyl)phenyl)piperazin-l-yl)phenyl)-l-isopropyl-2- methyl-N-(methylsulfonyl)-lH-pyrrole-3-carboxamide,
4-(4-(3-(2-(4-chlorophenyl)-l-isopropyl-5-methyl-4-(morph oline-4-carbonyl)-lH- pyrrol-3-yl)phenyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3 ,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide,
5-(4-chlorophenyl)-4-(3-(4-(3-(2,3-dihydropyrrolo[3’,2 :5,6]pyrido[2,3- b] [ 1 ,4]oxazin- 1 (6H)-yl)-4-(((3-nitro-4-(((tetrahydro-2H-pyran-4- yl)methyl)amino)phenyl) sulfo nyl)carbamoyl)phenyl)piperazin-l-yl)phenyl)-l-isopropyl- N, N, 2-trimethyl- lH-pyrrole-3-carboxamide,
N-((4-((((S)-l,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl) sulfonyl)-4-(4-((4’-chloro-
5,5-dimethyl-3,4,5,6-tetrahydro-[l, -biphenyl]-2-yl)methyl)piperazin-l-yl)-2-(l-oxido-
2,3,6-trihydro-[l,4]oxaphosphinino[2,3-b]pyrrolo[3,2-e]py ridin-l-yl)benzamide,
4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex- l-en- l-yl]methyl]piperaz in- l-yl)-N- (4-[[(2S)-l,4-dioxan-2-ylmethyl] amino]-3-nitrobenzenesulfonyl)-2-[l l-oxo-l3-oxa-2,4,l0-tr iazatricyclo[7.4.0. 0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzamide,
(R)-4-(4-((2-(3-chlorobicyclo[l. l. l]pentan-l-yl)-4,4-dimethylcyclohex-l-en-l- yl)methyl)piperazin-l-yl)-2-(3-methyl-2,3-dihydropyrrolo[3 ,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran -4- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide,
(R)-4-(4-((4,4-dimethyl-2-(3-methylbicyclo[l. l. l]pentan-l-yl)cyclo hex- l-en- 1- yl)methyl)piperazin-l-yl)-2-(3-methyl-2,3-dihydropyrrolo[3 ,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran -4- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide, (R)-4-(4-((2-(3-(tert-butyl)bicyclo[l. l. l]pentan-l-yl)-4,4-dimethylcyclohex-l-en-l- yl)methyl)piperazin-l-yl)-2-(3-methyl-2,3-dihydropyrrolo[3 ,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran -4- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide,
(R)-4-(4-((4,4-dimethyl-2-(3-(trifluoromethyl)bicyclo[l .1. l]pentan-l-yl)cyclohex-l- en-l-yl)methyl)piperazin-l-yl)-2-(3-methyl-2,3-dihydropyrrol o[3’,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran -4- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide,
(R)-4-(4-((4,4-dimethyl-2-(3-(l,l,l-trifluoro-2-methylpro pan-2- yl)bicyclo[l .1. l]pentan- l-yl)cyclohex- l-en- l-yl)methyl)piperazin- l-yl)-2-(3-methyl-2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H- pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,
(R)-4-(4-((4,4-dimethyl-2-(3-phenylbicyclo[l. l. l]pentan-l-yl)cyclo hex- l-en- 1- yl)methyl)piperazin-l-yl)-2-(3-methyl-2,3-dihydropyrrolo[3 ,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran -4- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide,
(R)-4-(4-((4,4-dimethyl-2-(3-morpholinobicyclo[l .1. l]pentan-l-yl)cyclohex-l-en-l- yl)methyl)piperazin-l-yl)-2-(3-methyl-2,3-dihydropyrrolo[3 ,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran -4- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide,
(R)-4-(4-((2-(3-(2-aminopropan-2-yl)bicyclo[l. l. l]pentan-l-yl)-4,4- dimethylcyclohex- l-en- l-yl)methyl)piperazin- l-yl)-2-(3-methyl-2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H- pyran-4-yl)methyl)amino)phenyl) sulfo nyl)benzamide, and,
(R)-4-(4-((2-(3-(2-cyanopropan-2-yl)bicyclo[l. l. l]pentan-l-yl)-4,4- dimethylcyclohex-l-en-l-yl)methyl)piperazin-l-yl)-2-(3-methy l-2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H- pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide.
Compounds of the invention may contain one or more asymmetric carbon atoms. Accordingly, the compounds may exist as diastereomers, enantiomers or mixtures thereof. The syntheses of the compounds may employ racemates, diastereomers or enantiomers as starting materials or as intermediates. Diastereomeric compounds may be separated by chromatographic or crystallization methods. Similarly, enantiomeric mixtures may be separated using the same techniques or others known in the art. Each of the asymmetric carbon atoms may be in the R or S configuration, and both of these configurations are within the scope of the invention.
Compounds having one or more chiral centers can exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement.
Stereoisomers include all diastereomeric, enantiomeric, and epimeric forms as well as racemates and mixtures thereof.
The term“geometric isomer” refers to cyclic compounds having at least two substituents, wherein the two substituents are both on the same side of the ring ( cis ) or wherein the substituents are each on opposite sides of the ring ( trans ). When a disclosed compound is named or depicted by structure without indicating stereochemistry, it is understood that the name or the structure encompasses one or more of the possible stereoisomers, or geometric isomers, or a mixture of the encompassed stereoisomers or geometric isomers.
When a geometric isomer is depicted by name or structure, it is to be understood that the named or depicted isomer exists to a greater degree than another isomer, that is that the geometric isomeric purity of the named or depicted geometric isomer is greater than 50%, such as at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight. Geometric isomeric purity is determined by dividing the weight of the named or depicted geometric isomer in the mixture by the total weight of all of the geomeric isomers in the mixture.
Racemic mixture means 50% of one enantiomer and 50% of is corresponding enantiomer. When a compound with one chiral center is named or depicted without indicating the stereochemistry of the chiral center, it is understood that the name or structure encompasses both possible enantiomeric forms (e.g., both enantiomerically-pure, enantiomerically-enriched or racemic ) of the compound. When a compound with two or more chiral centers is named or depicted without indicating the stereochemistry of the chiral centers, it is understood that the name or structure encompasses all possible diasteriomeric forms (e.g., diastereomerically pure, diastereomerically enriched and equimolar mixtures of one or more diastereomers (e.g., racemic mixtures) of the compound.
Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral-phase gas
chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Enantiomers and diastereomers also can be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.
When a compound is designated by a name or structure that indicates a single enantiomer, unless indicated otherwise, the compound is at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as“enantiomerically pure”). Optical purity is the weight in the mixture of the named or depicted enantiomer divided by the total weight in the mixture of both enantiomers.
When the stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer ( e.g ., as in a diastereomeric pair), it is to be understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers is included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomers at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers.
A modified compound of any one of such compounds including a modification having an improved (e.g., enhanced, greater) pharmaceutical solubility, stability, bio availability and/or therapeutic index as compared to the unmodified compound is also contemplated. The examples of modifications include but not limited to the prodrug derivatives, and the deuterium-enriched compounds. For example:
• Prodrug derivatives: prodrugs, upon administration to a subject, will converted in vivo into active compounds of the present invention [. Nature Reviews of Drug Discovery, 2008, Volume 7, p255] . It is noted that in many instances, the prodrugs themselves also fall within the scope of the range of compounds according to the present invention. The prodrugs of the compounds of the present invention can be prepared by starndard organic reaction, for example, by reacting with a carbamylating agent (e.g., l,l-acyloxyalkylcarbonochloridate, para-nitrophenyl carbonate, or the like) or an acylating agent. Further examples of methods and strategies of making prodrugs are described in Bioorganic and Medicinal Chemistry Letters, 1994, Vol. 4, p. 1985.
• Deuterium-enriched compounds: deuterium (D or H) is a stable, non-radioactive isotope of hydrogen and has an atomic weight of 2.0144. Hydrogen naturally occurs as a mixture of the isotopes H (hydrogen or protium), D ( H or deuterium), and T ( H or tritium). The natural abundance of deuterium is 0.015%. One of ordinary skill in the art recognizes that in all chemical compounds with a H atom, the H atom actually represents a mixture of H and D, with about 0.015% being D. Thus, compounds with a level of deuterium that has been enriched to be greater than its natural abundance of 0.015%, should be considered unnatural and, as a result, novel over their nonenriched counterparts.
It should be recognized that the compounds of the present invention may be present and optionally administered in the form of salts, and solvates. The invention encompasses any pharmaceutically acceptable salts and solvates of any one of the above-described compounds and modifications thereof. For example, it is within the scope of the present invention to convert the compounds of the present invention into and use them in the form of their pharmaceutically acceptable salts derived from various organic and inorganic acids and bases in accordance with procedures well known in the art.
When the compounds of the present invention possess a free base form, the compounds can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, e.g., hydrohalides such as hydrochloride, hydrobromide, hydroiodide; other mineral acids such as sulfate, nitrate, phosphate, etc.; and alkyl and monoarylsulfonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate; and other organic acids and their corresponding salts such as acetate, tartrate, maleate, succinate, citrate, benzoate, salicylate and ascorbate. Further acid addition salts of the present invention include, but are not limited to: adipate, alginate, arginate, aspartate, bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, cyclopentanepropionate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, fumarate, galacterate (from mucic acid), galacturonate, glucoheptaoate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, 2-hydroxyethanesulfonate, iodide, isethionate, iso-butyrate, lactate, lactobionate, malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate, monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, oxalate, oleate, pamoate, pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphonate and phthalate. It should be recognized that the free base forms will typically differ from their respective salt forms somewhat in physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base forms for the purposes of the present invention. When the compounds of the present invention possess a free acid form, a pharmaceutically acceptable base addition salt can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base. Examples of such bases are alkali metal hydroxides including potassium, sodium and lithium hydroxides; alkaline earth metal hydroxides such as barium and calcium hydroxides; alkali metal alkoxides, e.g., potassium ethano late and sodium propano late; and various organic bases such as ammonium hydroxide, piperidine, diethanolamine and N-methylglutamine. Also included are the aluminum salts of the compounds of the present invention. Further base salts of the present invention include, but are not limited to: copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium and zinc salts. Organic base salts include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, e.g., arginine, betaine, caffeine, chloroprocaine, choline, N,N’-dibenzylethylenediamine
(benzathine), dicyclohexylamine, diethanolamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N- ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, iso-propylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine and tris-(hydroxymethyl)-methylamine (tromethamine). It should be recognized that the free acid forms will typically differ from their respective salt forms somewhat in physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid forms for the purposes of the present invention.
In one aspect, a pharmaceutically acceptable salt is a hydrochloride salt,
hydrobromide salt, methanesulfonate, toluenesulfonate, acetate, fumarate, sulfate, bisulfate, succinate, citrate, phosphate, maleate, nitrate, tartrate, benzoate, biocarbonate, carbonate, sodium hydroxide salt, calcium hydroxide salt, potassium hydroxide salt, tromethamine salt, or mixtures thereof.
Compounds of the present invention that comprise tertiary nitrogen-containing groups may be quaternized with such agents as (Ci -4 ) alkyl halides, e.g., methyl, ethyl, iso-propyl and tert-butyl chlorides, bromides and iodides; di-(Ci -4 ) alkyl sulfates, e.g., dimethyl, diethyl and diamyl sulfates; alkyl halides, e.g., decyl, dodecyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aryl (Ci -4 ) alkyl halides, e.g., benzyl chloride and phenethyl bromide. Such salts permit the preparation of both water- and oil- soluble compounds of the invention. Amine oxides, also known as amine-A-oxide and A-oxide, of anti-cancer agents with tertiary nitrogen atoms have been developed as prodrugs [Mol Cancer Therapy. 2004 Mar; 3(3):233-44]. Compounds of the present invention that comprise tertiary nitrogen atoms may be oxidized by such agents as hydrogen peroxide (H 2 0 2 ), Caro’s acid or peracids like inela- Chloroperoxybenzoic acid (mCPBA) to from amine oxide.
The compounds disclosed therein are inhibitors for Bcl-2 family proteins, such as Bcl- 2. For simplicity, the term“Bcl-2 inhibitor” includes compounds that inhibits one activity of at least one Bcl-2 family member, especially Bcl-2 family member with anti- apopto tic activity, such as Bcl-2.
Bcl-2 family proteins have a general structure that consists of a hydrophobic a-helix surrounded by amphipathic a-helices. Some members of the family have transmembrane domains at their c-terminus, which primarily function to localize them to the mitochondrion. For example, Bcl-x(L) has 233 residues and exhibits a single highly hydrophobic putative transmembrane a-helical segment (residues 210-226) when in the membrane. Related family members include Bax and Bak, which also influence apoptosis.
All members of the Bcl-2 family share one or more of the four characteristic domains of homology entitled the Bcl-2 homology (BH) domains (named BH1, BH2, BH3 and BH4). The BH domains are known to be crucial for function, as deletion of these domains via molecular cloning affects survival/apoptosis rates. The anti- apopto tic Bcl-2 proteins, such as Bcl-2 and Bcl-xL, conserve all four BH domains. Structural homology suggests that Bcl-2 family members that contain the BH1 and BH2 domains (Bcl-X(L), Bcl-2, and Bax) function similarly. On the other hand, the BH domains also serve to subdivide the pro-apoptotic Bcl-2 proteins into those with several BH domains (e.g. Bax and Bak) or those proteins that have only the BH3 domain (e.g., Bim, Bid, and BAD).
All anti- apopto tic Bcl-2 family proteins (such as Bcl-2, Bcl-xL, Bcl-w, Mcl-l, CED-9, Al, and Bfl-l) contain BH1 and BH2 domains, some of them contain an additional N- terminal BH4 domain (Bcl-2, Bcl-x(L) and Bcl-w), which is also seen in some pro-apoptotic proteins like Bcl-x(S), Diva, Bok-L and Bok-S. On the other hand, all pro-apoptotic Bcl-2 family proteins (such as Bcl-xS, Bax, Bak, Diva, Bik, Bim, BAD, Bid, and Egl-l) contain a BH3 domain necessary for dimerization with other proteins of Bcl-2 family and crucial for their killing activity, some of them also contain BH1 and BH2 domains (e.g., Diva, Bax and Bak). The BH3 domain is also present in some anti- apopto tic protein, such as Bcl-2 or Bcl- x(L). The three functionally important Bcl-2 homology regions (BH1, BH2 and BH3) are in close spatial proximity. They form an elongated cleft that may provide the binding site for other Bcl-2 family members.
In certain embodiments, the compounds of the invention function as BH3 mimetic to inhibit the function of one or more Bcl-2 family members that are anti- apopto tic, such as Bcl- 2, Bcl-x(L), and/or Bcl-w, thus enhancing apoptosis ( e.g ., enhances an apoptotic signal).
The pharmaceutical composition of the present invention comprises one or more BCL-2 inhibitors, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
“Pharmaceutically acceptable carrier” and“pharmaceutically acceptable diluent” refer to a substance that aids the formulation and/or administration of an active agent to and/or absorption by a subject and can be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the subject. Non- limiting examples of pharmaceutically acceptable carriers and/or diluents include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydro xymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the compounds provided herein. One of ordinary skill in the art will recognize that other pharmaceutical excipients are suitable for use with disclosed compounds.
The pharmaceutical compositions of the present invention optionally include one or more pharmaceutically acceptable carriers and/or diluents therefor, such as lactose, starch, cellulose and dextrose. Other excipients, such as flavoring agents; sweeteners; and preservatives, such as methyl, ethyl, propyl and butyl parabens, can also be included. More complete listings of suitable excipients can be found in the Handbook of Pharmaceutical Excipients (5 th Ed., Pharmaceutical Press (2005)). A person skilled in the art would know how to prepare formulations suitable for various types of administration routes.
Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington’s Pharmaceutical Sciences (2003 - 20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999. The carriers, diluents and/or excipients are“acceptable” in the sense of being compatible with the other ingredients of the pharmaceutical composition and not deleterious to the recipient thereof.
The pharmaceutical compositions of the present invention may further comprise other conventional pharmaceutically inactive agents. Any inert excipient that is commonly used as a carrier or diluent may be used in compositions of the present invention, such as sugars, polyalcohols, soluble polymers, salts and lipids. Sugars and polyalcohols which may be employed include, without limitation, lactose, sucrose, mannitol, and sorbitol. Illustrative of the soluble polymers which may be employed are polyoxyethylene, poloxamers,
polyvinylpyrrolidone, and dextran. Useful salts include, without limitation, sodium chloride, magnesium chloride, and calcium chloride. Lipids which may be employed include, without limitation, fatty acids, glycerol fatty acid esters, glycolipids, and phospholipids.
In addition, the pharmaceutical compositions of the present invention may further comprise binders ( e.g ., acacia, cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydro xypropyl cellulose, hydro xypropyl methyl cellulose, povidone), disintegrating agents (e.g., cornstarch, potato starch, alginic acid, silicon dioxide, croscarmellose sodium, crospovidone, guar gum, sodium starch glycolate, Primogel), buffers (e.g., tris-HCL, acetate, phosphate) of various pH and ionic strength, additives such as albumin or gelatin to prevent absorption to surfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts), protease inhibitors, surfactants (e.g., sodium lauryl sulfate), permeation enhancers, solubilizing agents (e.g., glycerol, polyethylene glycerol, cyclodextrins), a glidant (e.g., colloidal silicon dioxide), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite, butylated hydro xyanisole), stabilizers (e.g., hydro xypropyl cellulose, hydro xypropylmethyl cellulose), viscosity increasing agents (e.g., carbomer, colloidal silicon dioxide, ethyl cellulose, guar gum), sweeteners (e.g., sucrose, aspartame, citric acid), flavoring agents (e.g., peppermint, methyl salicylate, or orange flavoring), preservatives (e.g., Thimerosal, benzyl alcohol, parabens), lubricants (e.g., stearic acid, magnesium stearate, polyethylene glycol, sodium lauryl sulfate), flow-aids (e.g., colloidal silicon dioxide), plasticizers (e.g., diethyl phthalate, triethyl citrate), emulsifiers (e.g., carbomer, hydroxypropyl cellulose, sodium lauryl sulfate, methyl cellulose, hydroxyethyl cellulose, carboxymethylcellulose sodium), polymer coatings (e.g., poloxamers or poloxamines), coating and film forming agents (e.g., ethyl cellulose, acrylates, polymethacrylates) and/or adjuvants.
In one embodiment, the pharmaceutical compositions are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.
Additionally, the invention encompasses pharmaceutical compositions comprising any solid or liquid physical form of the compound of the invention. For example, the compounds can be in a crystalline form, in amorphous form, and have any particle size. The particles may be micronized, or may be agglomerated, particulate granules, powders, oils, oily suspensions or any other form of solid or liquid physical form.
When compounds according to the present invention exhibit insufficient solubility, methods for solubilizing the compounds may be used. Such methods are known to those of skill in this art, and include, but are not limited to, pH adjustment and salt formation, using co-solvents, such as ethanol, propylene glycol, polyethylene glycol (PEG) 300, PEG 400, DMA (10-30%), DMSO (10-20%), NMP (10-20%), using surfactants, such as polysorbate 80, polysorbate 20 (1-10%), cremophor EL, Cremophor RH40, Cremophor RH60 (5-10%), Pluronic F68/Poloxamer 188 (20-50%), Solutol HS15 (20-50%), Vitamin E TPGS, and d-a- tocopheryl PEG 1000 succinate (20-50%), using complexation such as HPpCD and SBEpCD (10-40%), and using advanced approaches such as micelle, addition of a polymer, nanoparticle suspensions, and liposome formation.
A wide variety of administration methods may be used in conjunction with the compounds of the present invention. Compounds of the present invention may be
administered or coadministered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent), subcutaneously, intraadipo sally, intraarticularly, or
intrathecally. The compounds according to the invention may also be administered or coadministered in slow release dosage forms. Compounds may be in gaseous, liquid, semi liquid or solid form, formulated in a manner suitable for the route of administration to be used. For oral administration, suitable solid oral formulations include tablets, capsules, pills, granules, pellets, sachets and effervescent, powders, and the like. Suitable liquid oral formulations include solutions, suspensions, dispersions, emulsions, oils and the like. For parenteral administration, reconstitution of a lyophilized powder is typically used.
As used herein,“acyl” means a carbonyl containing substituent represented by the formula -C(0)-R in which R is H, alkyl, a carbocycle, a heterocycle, carbocycle- substituted alkyl or heterocycle-substituted alkyl wherein the alkyl, alkoxy, carbocycle and heterocycle are as defined herein. Acyl groups include alkanoyl (e.g. acetyl), aroyl (e.g. benzoyl), and heteroaroyl.
“Aliphatic” means a moiety characterized by a straight or branched chain arrangement of constituent carbon atoms and may be saturated or partially unsaturated with one or more double or triple bonds.
The term“alkyl” refers to a straight or branched hydrocarbon containing 1-20 carbon atoms (e.g., Ci-Cio, Ci-C 6 ). Examples of alkyl include, but are not limited to, methyl, methylene, ethyl, ethylene, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl. Preferably, the alkyl group has one to ten carbon atoms. More preferably, the alkyl group has one to four carbon atoms.
The term“alkenyl” refers to a straight or branched hydrocarbon containing 2-20 carbon atoms (e.g., C 2 -Cio, C2-C 6 ) and one or more double bonds. Examples of alkenyl include, but are not limited to, ethenyl, propenyl, and allyl. Preferably, the alkylene group has two to ten carbon atoms. More preferably, the alkylene group has two to four carbon atoms.
The term“alkynyl” refers to a straight or branched hydrocarbon containing 2-20 carbon atoms (e.g., C 2 -Cio, C 2 -C 6 ) and one or more triple bonds. Examples of alkynyl include, but are not limited to, ethynyl, l-propynyl, 1- and 2-butynyl, and l-methyl-2- butynyl. Preferably, the alkynyl group has two to ten carbon atoms. More preferably, the alkynyl group has two to four carbon atoms.
The term“alkylamino” refers to an -N(R)-alkyl in which R can be H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl.
“Alkoxy” means an oxygen moiety having a further alkyl substituent.
“Alkoxycarbonyl” means an alkoxy group attached to a carbonyl group.
“Oxoalkyl” means an alkyl, further substituted with a carbonyl group. The carbonyl group may be an aldehyde, ketone, ester, amide, acid or acid chloride.
The term“cycloalkyl” refers to a saturated hydrocarbon ring system having 3 to 30 carbon atoms (e.g., C 3 -C l2 C3-C8, C3-C6). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The term “cycloalkenyl” refers to a non-aromatic hydrocarbon ring system having 3 to 30 carbons ( e.g ., C 3 -C 12 ) and one or more double bonds. Examples include cyclopentenyl, cyclohexenyl, and cycloheptenyl.
The term“heterocycloalkyl” refers to a saturated or unsaturated nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1 to 4 heteroatoms (such as O, N, S, B, P, Si, or Se), which may be the same or different. Examples of heterocycloalkyl groups include, but are not limited to, piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, and tetrahydrofuranyl.
The term“heterocycloafkenyl” refers to a nonaromatic 5-8 membered monocyclic, 8- 12 membered bicyclic, or 11-14 membered tricyclic ring system having one or more heteroatoms (such as O, N, S, P, B, Si, or Se) and one or more double bonds.
The term“aryl” refers to a 6-carbon monocyclic, lO-carbon bicyclic, l4-carbon tricyclic aromatic ring system. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.
The term“heteroaryl” refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having one or more
heteroatoms (such as O, N, S, P, or Se). Examples of heteroaryl groups include pyridyl, furyl, imidazolyl, benzimidazolyl, pyrimidinyl, thienyl, quinolinyl, indolyl, and thiazolyl.
Alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl,
heterocycloafkenyl, alkylamino, aryl, and heteroaryl mentioned above include both substituted and unsubstituted moieties. Possible substituents on alkylamino, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloafkenyl, aryl, and heteroaryl include, but are not limited to, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 20 cycloalkyl, C 3 -C 20 cycloalkenyl, C 1 -C 20 heterocycloalkyl, C 1 -C 20 heterocycloafkenyl, C 1 -C 10 alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C 1 -C 10 alkylamino, arylamino, hydroxy, halo, oxo (0=), thioxo (S=), thio, silyl, C 1 -C 10 alkylthio, arylthio, C 1 -C 10 alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, amidino, mercapto, amido, thioureido, thiocyanato, sulfonamido, guanidine, ureido, cyano, nitro, acyl, thioacyl, acyloxy, carbamido, carbamyl, carboxyl, and carboxylic ester. On the other hand, possible substituents on alkyl, alkenyl, or alkynyl include all of the above-recited substituents except C 1 -C 10 alkyl. Cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloafkenyl, aryl, and heteroaryl can also be fused with each other.
“Amino” means a nitrogen moiety having two further substituents where each substituent has a hydrogen or carbon atom alpha bonded to the nitrogen. Unless indicated otherwise, the compounds of the invention containing amino moieties may include protected derivatives thereof. Suitable protecting groups for amino moieties include acetyl, tert- butoxycarbonyl, benzyloxycarbonyl, and the like.
“Aromatic” means a moiety wherein the constituent atoms make up an unsaturated ring system, all atoms in the ring system are sp2 hybridized and the total number of pi electrons is equal to 4n+2. An aromatic ring may be such that the ring atoms are only carbon atoms or may include carbon and non-carbon atoms (see Heteroaryl).
“Carbamoyl” means the radical -0C(0)NR a R b where R a and R b are each
independently two further substituents where a hydrogen or carbon atom is alpha to the nitrogen. It is noted that carbamoyl moieties may include protected derivatives thereof. Examples of suitable protecting groups for carbamoyl moieties include acetyl, tert- butoxycarbonyl, benzyloxycarbonyl, and the like. It is noted that both the unprotected and protected derivatives fall within the scope of the invention.
“Carbonyl” means the radical -C(O)-. It is noted that the carbonyl radical may be further substituted with a variety of substituents to form different carbonyl groups including acids, acid halides, amides, esters, and ketones.
“Carboxy” means the radical -C(0)0-. It is noted that compounds of the invention containing carboxy moieties may include protected derivatives thereof, i.e., where the oxygen is substituted with a protecting group. Suitable protecting groups for carboxy moieties include benzyl, tert-butyl, and the like.
“Cyano” means the radical -CN.
“Formyl” means the radical -CH=0.
“Formimino” means the radical -HC=NH.
“Halo” means fluoro, chloro, bromo or iodo.
“Halo -substituted alkyl”, as an isolated group or part of a larger group, means“alkyl” substituted by one or more“halo” atoms, as such terms are defined in this Application. Halo- substituted alkyl includes haloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl and the like.
“Hydroxy” means the radical -OH.
“Imine derivative” means a derivative comprising the moiety -C(=NR)-, wherein R comprises a hydrogen or carbon atom alpha to the nitrogen.
“Isomers” mean any compound having identical molecular formulae but differing in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed
“stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereomers” and stereoisomers that are nonsuperimpo sable mirror images are termed “enantiomers” or sometimes“optical isomers.” A carbon atom bonded to four nonidentical substituents is termed a“chiral center.” A compound with one chiral center has two enantiomeric forms of opposite chirality. A mixture of the two enantiomeric forms is termed a“racemic mixture.”
“Nitro” means the radical -N0 2 .
“Protected derivatives” means derivatives of compounds in which a reactive site are blocked with protecting groups. Protected derivatives are useful in the preparation of pharmaceuticals or in themselves may be active as inhibitors. A comprehensive list of suitable protecting groups can be found in T.W.Greene, Protecting Groups in Organic Synthesis, 3rd edition, Wiley & Sons, 1999.
The term“substituted” means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group. For aryl and heteroaryl groups, the term “substituted” refers to any level of substitution, namely mono-, di-, tri-, tetra-, or penta- substitution, where such substitution is permitted. The substituents are independently selected, and substitution may be at any chemically accessible position. The term
“unsubstituted” means that a given moiety may consist of only hydrogen substituents through available valencies (unsubstituted).
If a functional group is described as being“optionally substituted,” the function group may be either (1) not substituted, or (2) substituted. If a carbon of a functional group is described as being optionally substituted with one or more of a list of substituents, one or more of the hydrogen atoms on the carbon (to the extent there are any) may separately and/or together be replaced with an independently selected optional substituent.
“Sulfide” means -S-R wherein R is H, alkyl, carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl. Particular sulfide groups are mercapto, alkylsulfide, for example methylsulfide (-S-Me); arylsulfide, e.g., phenylsulfide; aralkylsulfide, e.g., benzylsulfide.
“Sulfinyl” means the radical -S(O)-. It is noted that the sulfinyl radical may be further substituted with a variety of substituents to form different sulfinyl groups including sulfinic acids, sulfinamides, sulfinyl esters, and sulfoxides.
“Sulfonyl” means the radical -S(0)(0)-. It is noted that the sulfonyl radical may be further substituted with a variety of substituents to form different sulfonyl groups including sulfonic acids, sulfonamides, sulfonate esters, and sulfones.
“Thiocarbonyl” means the radical -C(S)-. It is noted that the thiocarbonyl radical may be further substituted with a variety of substituents to form different thiocarbonyl groups including thioacids, thioamides, thioesters, and thioketones. “Animal” includes humans, non- human mammals ( e.g ., non-human primates, rodents, mice, rats, hamsters, dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, and the like) and non-mammals (e.g., birds, and the like).
“Bio availability” as used herein is the fraction or percentage of an administered dose of a drug or pharmaceutical composition that reaches the systemic circulation intact. In general, when a medication is administered intravenously, its bio availability is 100%.
However, when a medication is administered via other routes (e.g., orally), its bio availability decreases (e.g., due to incomplete absorption and first-pass metabolism). Methods to improve the bio availability include prodrug approach, salt synthesis, particle size reduction, complexation, change in physical form, solid dispersions, spray drying, and hot-melt extrusion.
“Disease” specifically includes any unhealthy condition of an animal or part thereof and includes an unhealthy condition that may be caused by, or incident to, medical or veterinary therapy applied to that animal, i.e., the“side effects” of such therapy.
“Pharmaceutically acceptable” means that which is useful in preparing a
pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use.
“Pharmaceutically acceptable salts” means organic or inorganic salts of compounds of the present invention which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids, or with organic acids. Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate“mesylate,” ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate (i.e., l,l’-methylene-bis-(2-hydroxy-3- naphthoate)) salts, alkali metal (e.g., sodium and potassium) salts, alkaline earth metal (e.g., magnesium) salts, and ammonium salts. A pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion.
The counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counter ions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counter ion.
“Pharmacophore,” as defined by The International Union of Pure and Applied
Chemistry, is an ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biological target and to trigger (or block) its biological response. For example, Camptothecin is the pharmacophore of the well known drug topotecan and irinotecan. Mechlorethamine is the pharmacophore of a list of widely used nitrogen mustard drugs like Melphalan, Cyclophosphamide, Bendamustine, and so on.
“Prodrug” means a compound that is convertible in vivo metabolically into an active pharmaceutical according to the present invention. For example, an inhibitor comprising a hydroxyl group may be administered as an ester that is converted by hydrolysis in vivo to the hydroxyl compound.
“Stability” in general refers to the length of time a drug retains its properties without loss of potency. Sometimes this is referred to as shelf life. Factors affecting drug stability include, among other things, the chemical structure of the drug, impurity in the formulation, pH, moisture content, as well as environmental factors such as temperature, oxidization, light, and relative humidity. Stability can be improved by providing suitable chemical and/or crystal modifications (e.g., surface modifications that can change hydration kinetics; different crystals that can have different properties), excipients (e.g., anything other than the active substance in the dosage form), packaging conditions, storage conditions, etc.
“Therapeutically effective amount” of a composition described herein is meant an amount of the composition which confers a therapeutic effect on the treated subject, at a reasonable benefit/risk ratio applicable to any medical treatment. The therapeutic effect may be objective ( i.e ., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect). An effective amount of the composition described above may range from about 0.1 mg/kg to about 500 mg/kg, preferably from about 0.2 to about 50 mg/kg. Effective doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents. It will be understood, however, that the total daily usage of the compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or contemporaneously with the specific compound employed; and like factors well known in the medical arts.
As used herein, the term“treating” refers to administering a compound to a subject that has a neoplastic or immune disorder, or has a symptom of or a predisposition toward it, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect the disorder, the symptoms of or the predisposition toward the disorder. The term“an effective amount” refers to the amount of the active agent that is required to confer the intended therapeutic effect in the subject. Effective amounts may vary, as recognized by those skilled in the art, depending on route of administration, excipient usage, and the possibility of co-usage with other agents.
A“subject” refers to a human and a non-human animal. Examples of a non-human animal include all vertebrates, e.g., mammals, such as non-human primates (particularly higher primates), dog, rodent (e.g., mouse or rat), guinea pig, cat, and non- mammals, such as birds, amphibians, reptiles, etc. In a preferred embodiment, the subject is a human. In another embodiment, the subject is an experimental animal or animal suitable as a disease model.
“Combination therapy” includes the administration of the subject compounds of the present invention in further combination with other biologically active ingredients (such as, but not limited to, a second and different antineoplastic agent) and non-drug therapies (such as, but not limited to, surgery or radiation treatment). For instance, the compounds of the invention can be used in combination with other pharmaceutically active compounds, or non drug therapies, preferably compounds that are able to enhance the effect of the compounds of the invention. The compounds of the invention can be administered simultaneously (as a single preparation or separate preparation) or sequentially to the other therapies. In general, a combination therapy envisions administration of two or more drugs/treatments during a single cycle or course of therapy.
In one embodiment, the compounds of the invention are administered in combination with one or more of traditional chemotherapeutic agents. The traditional chemotherapeutic agents encompass a wide range of therapeutic treatments in the field of oncology. These agents are administered at various stages of the disease for the purposes of shrinking tumors, destroying remaining cancer cells left over after surgery, inducing remission, maintaining remission and/or alleviating symptoms relating to the cancer or its treatment. Examples of such agents include, but are not limited to, alkylating agents such as Nitrogen Mustards (e.g., Bendamustine, Cyclophosphamide, Melphalan, Chlorambucil, Isofosfamide), Nitrosureas (e.g., Carmustine, Lomustine and Streptozocin), ethylenimines (e.g., thiotepa,
hexamethylmelanine), Alkylsulfonates (e.g., Busulfan), Hydrazines and Triazines (e.g., Altretamine, Procarbazine, Dacarbazine and Temozolomide), and platinum based agents (e.g., Carboplatin, Cisplatin, and Oxaliplatin); plant alkaloids such as Podophyllotoxins (e.g., Etoposide and Tenisopide), Taxanes (e.g., Paclitaxel and Docetaxel), Vinca alkaloids (e.g., Vincristine, Vinblastine and Vinorelbine); anti-tumor antibiotics such as Chromomycins (e.g., Dactinomycin and Plicamycin), Anthracyc lines (e.g., Doxorubicin, Daunorubicin, Epirubicin, Mitoxantrone, and Idarubicin), and miscellaneous antibiotics such as Mitomycin and Bleomycin; anti- metabolites such as folic acid antagonists (e.g., Methotrexate), pyrimidine antagonists (e.g., 5-Fluoro uracil, Foxuridine, Cytarabine, Capecitabine, and Gemcitabine), purine antagonists (e.g., 6-Mercaptopurine and 6-Thioguanine) and adenosine deaminase inhibitors (e.g., Cladribine, Fludarabine, Nelarabine and Pentostatin);
topoisomerase inhibitors such as topoisomerase I inhibitors(Topotecan, Irinotecan), topoisomerase II inhibitors (e.g., Amsacrine, Etoposide, Etoposide phosphate, Teniposide), and miscellaneous anti-neoplastics such as ribonucleotide reductase inhibitors
(Hydroxyurea), adrenocortical steroid inhibitor (Mitotane), anti-microtubule agents
(Estramu stine), and retinoids (Bexarotene, Isotretinoin, Tretinoin (ATRA).
In one aspect of the invention, the compounds may be administered in combination with one or more targeted anti-cancer agents that modulate protein kinases involved in various disease states. Examples of such kinases may include, but are not limited ABL1, ABL2/ARG, ACK1, AKT1, AKT2, AKT3, ALK, ALK1/ACVRL1, ALK2/ACVR1,
ALK4/ACVR1B, ALK5/TGFBR1, ALK6/BMPR1B, AMPK(Al/Bl/Gl),
AMPK(Al/B 1/G2), AMPK(Al/B 1/G3), AMPK(Al/B2/Gl), AMPK(A2/B 1/G1),
AMPK(A2/B2/Gl), AMPK(A2/B2/G2), ARAF, ARK5/NUAK1, ASK1/MAP3K5, ATM, Aurora A, Aurora B , Aurora C , AXL, BLK, BMPR2, BMX/ETK, BRAF, BRK, BRSK1, BRSK2, BTK, CAMKla , CAMKlb, CAMKld, CAMKlg , CAMKIIa , CAMKIIb , CAMKIId , CAMKIIg , CAMK4, CAMKK1, CAMKK2, CDC7-DBF4, CDKl-cyclin A, CDKl-cyclin B, CDKl-cyclin E, CDK2-cyclin A, CDK2-cyclin Al, CDK2-cyclin E, CDK3- cyclin E, CDK4-cyclin Dl, CDK4-cyclin D3, CDK5-p25, CDK5-p35, CDK6-cyclin Dl, CDK6-cyclin D3, CDK7-cyclin H, CDK9-cyclin K, CDK9-cyclin Tl, CHK1, CHK2,
CKlal, CKld , CKlepsilon , CKlgl , CKlg2, CKlg3 , CK2a , CK2a2, c-KIT, CLK1,
CLK2, CLK3, CLK4, c-MER, c-MET, COT1/MAP3K8, CSK, c-SRC, CSF1R, CTK/MATK, DAPK1, DAPK2, DCAMKL1, DCAMKL2, DDR1, DDR2, DLK/MAP3K12, DMPK, DMPK2/CDC42BPG, DNA-PK, DRAK1/STK17A, DYRK1/DYRK1A, DYRK1B, DYRK2, DYRK3, DYRK4, EEF2K, EGFR, EIF2AK1, EIF2AK2, EIF2AK3, EIF2AK4/GCN2, EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHB 1, EPHB2, EPHB3, EPHB4, ERBB2/HER2, ERBB4/HER4, ERK1/MAPK3, ERK2/MAPK1,
ERK5/MAPK7, FAK/PTK2, FER, FES/FPS, FGFR1, FGFR2, FGFR3, FGFR4, FGR, FFT1/VEGFR1, FFT3, FFT4/VEGFR3, FMS, FRK/PTK5, FYN, GCK/MAP4K2, GRK1, GRK2, GRK3, GRK4, GRK5, GRK6, GRK7, GSK3a, GSK3b, Haspin, HCK,
HGK/MAP4K4, HIPK1, HIPK2, HIPK3, HIPK4, HPK1/MAP4K1, IGF1R, IKKa/CHUK , IKKb/IKBKB, IKKe/IKBKE, IR, IRAK1, IRAK4, IRR/INSRR, ITK, JAK1, JAK2, JAK3, JNK1 , JNK2 , JNK3, KDR/VEGFR2, KHS/MAP4K5, FATS 1, FATS2, FCK, FCK2/ICK, FKB 1 , FIMK1, FOK/STK10, FRRK2, FYN, FYNB, MAPKAPK2, MAPKAPK3,
MAPKAPK5/PRAK, MARK1, M ARK2/P AR- 1 B a, MARK3, MARK4, MEK1, MEK2, MEKK1, MEKK2, MEKK3, MEEK, MINK/MINK1, MKK4, MKK6, MFCK/MYFK, MFCK2/MYFK2, MFK1/MAP3K9, MFK2/MAP3K10, MFK3/MAP3K11, MNK1, MNK2, MRCKa/, CDC42BPA, MRCKb/, CDC42BPB, MSK1/RPS6KA5, MSK2/RPS6KA4, MSSK1/STK23, MST1/STK4, MST2/STK3, MST3/STK24, MST4, mTOR/FRAPl, MUSK, MYFK3, MY03b, NEK1, NEK2, NEK3, NEK4, NEK6, NEK7, NEK9, NEK11,
NIK/MAP3K14, NEK, OSR1/OXSR1, P38a/MAPKl4, P38b/MAPKl l, P38d/MAPKl3 , P38g/MAPKl2 , P70S6K/RPS6KB 1, p70S6Kb/, RPS6KB2, PAK1, PAK2, PAK3, PAK4, PAK5, PAK6, PASK, PBK/TOPK, PDGFRa, PDGFRb, PDK1/PDPK1, PDK1/PDHK1, PDK2/PDHK2 , PDK3/PDHK3, PDK4/PDHK4, PHKgl , PHKg2 , PI3Ka, (pl l0a/p85a), PI3Kb, (pl l0b/p85a), PI3Kd, (pl l0d/p85a), PI3Kg(pl20g), PIM1, PIM2, PIM3, PKA, PKAcb, PKAcg , PKCa , PKCbl , PKCb2 , PKCd , PKCepsilon, PKCeta, PKCg , PKCiota, PKCmu/PRKDl, PKCnu/PRKD3, PKCtheta, PKCzeta, PKD2/PRKD2, PKGla , PKGlb , PKG2/PRKG2, PKN1/PRK1, PKN2/PRK2, PKN3/PRK3, PLK1, PLK2, PLK3, PLK4/SAK, PRKX, PYK2, RAF1, RET, RIPK2, RIPK3, RIPK5, ROCK1, ROCK2, RON/MST1R, ROS/ROS 1, RSK1, RSK2, RSK3, RSK4, SGK1, SGK2, SGK3/SGKL, SIK1, SIK2,
SLK/STK2, SNARK/NUAK2, SRMS, SSTK/TSSK6, STK16, STK22D/TSSK1,
STK25/YSK1, STK32b/Y ANK2, STK32c/YANK3, STK33, STK38/NDR1, STK38L/NDR2, STK39/STLK3, SRPK1, SRPK2, SYK, TAK1, TAOK1, TA0K2/TA01, TAOK3/JIK, TBK1, TEC, TESK1, TGFBR2, TIE2/TEK, TLK1, TLK2, TNIK, TNK1, TRKA, TRKB, TRKC, TRPM7/CHAK1 , TSSK2, TSSK3/STK22C, TTBK1, TTBK2, TTK, TXK,
TYK1/LTK, TYK2, TYR03/SKY, ULK1, ULK2, ULK3, VRK1, VRK2, WEE1, WNK1, WNK2, WNK3, YES/YES 1, ZAK/MLTK, ZAP70, ZIPK/DAPK3, KINASE, MUTANTS, ABLl(E255K), ABLl(F3l7I), ABLl(G250E), ABLl(H396P), ABLl(M35lT),
ABLl(Q252H), ABLl(T3l5I), ABLl(Y253F), ALK (C1156Y), ALK(Ll l96M), ALK (F1174L), ALK (R1275Q), BRAF(V599E), BTK(E4lK), CHK2(Il57T), c-Kit(A829P), c- KIT(D8l6H), c-KIT(D8l6V), c-Kit(D820E), c-Kit(N822K), C-Kit (T670I), c-Kit(V559D), c-Kit(V559D/V654A), c-Kit(V559D/T670I), C-Kit (V560G), c-KIT(V654A), C- MET(Dl228H), C-MET(Dl228N), C-MET(F 12001), c-MET(Ml250T), C-MET(Y 1230A), C-MET(Y 1230C), C-MET(Y 1230D), C-MET(Y 1230H), c-Src(T34lM), EGFR(G7l9C), EGFR(G7l9S), EGFR(L858R), EGFR(L86lQ), EGFR(T790M), EGFR, (L858R,T790M) , EGFR(d746-750/T790M) , EGFR(d746-750), EGFR(d747-749/A750P), EGFR(d747- 752/P753S), EGFR(d752-759), FGFRl(V56lM), FGFR2(N549H), FGFR3(G697C), FGFR3(K650E), FGFR3(K650M), FGFR4(N535K), FGFR4(V550E), FGFR4(V550L), FLT3(D835Y), FLT3(ITD), JAK2 (V617F), LRRK2 (G2019S), LRRK2 (I2020T), LRRK2 (R1441C), p38a(Tl06M), PDGFRa(D842V), PDGFRa(T674I), PDGFRa(V56lD),
RET(E762Q), RET(G69lS), RET(M9l8T), RET(R749T), RET(R8l3Q), RET(V804L), RET(V804M), RET(Y79lF), TIF2(R849W), TIF2(Y897S), and TIF2(Yl l08F).
In another aspect of the invention, the subject compounds may be administered in combination with one or more targeted anti-cancer agents that modulate non-kinase biological targets, pathway, or processes. Such targets pathways, or processes include but not limited to heat shock proteins (e.g.HSP90), poly-ADP (adenosine diphosphate) -ribose polymerase (PARP), hypoxia-inducible factors(HIF), proteasome, Wnt/Hedgehog/Notch signaling proteins, TNF-alpha, matrix metalloproteinase, farnesyl transferase, apoptosis pathway (e.g Bcl-xL, BCL-2, Bcl-w), histone deacetylases (HD AC), histone
acetyltransferases (HAT), and methyltransferase (e.g., histone lysine methyltransferases, histone arginine methyltransferase, DNA methyltransferase, etc), and other
immunotherapies(e.g anti-PDl, anti-PDLl, anti-CTLA4, CAR-T, IDO, A2A antagonist etc).
In another aspect of the invention, the compounds of the invention are administered in combination with one or more of other anti-cancer agents that include, but are not limited to, gene therapy, RNAi cancer therapy, chemoprotective agents (e.g., amfostine, mesna, and dexrazoxane), antibody conjugate(e.g brentuximab vedotin, ibritumomab tioxetan), cancer immunotherapy such as Interleukin-2, cancer vaccines//?.#., sipuleucel-T) or monoclonal antibodies (e.g., Bevacizumab, Alemtuzumab, Rituximab, Trastuzumab, etc).
In another aspect of the invention, the subject compounds are administered in combination with radiation therapy or surgeries. Radiation is commonly delivered internally (implantation of radioactive material near cancer site) or externally from a machine that employs photon (x-ray or gamma-ray) or particle radiation. Where the combination therapy further comprises radiation treatment, the radiation treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and radiation treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the radiation treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.
In certain embodiments, the compounds of the invention are administered in combination with one or more of radiation therapy, surgery, or anti-cancer agents that include, but are not limited to, DNA damaging agents, anti-metabolites, topoisomerase inhibitors, anti-microtubule agents, kinase inhibitors, epigenetic agents, HSP90 inhibitors, PARP inhibitors, and antibodies targeting VEGF, HER2, EGFR, CD50, CD20, CD30, CD33, etc.
In certain embodiments, the compounds of the invention are administered in combination with one or more of abarelix, abiraterone acetate, aldesleukin, alemtuzumab, altretamine, anastrozole, asparaginase, bendamu stine, bevacizumab, bexarotene,
bicalutamide, bleomycin, bortezombi, brentuximab vedotin, busulfan, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, clomifene, crizotinib, cyclophosphamide, dasatinib, daunorubicin liposomal, decitabine, degarelix, denileukin diftitox, denileukin diftitox, denosumab, docetaxel, doxorubicin, doxorubicin liposomal, epirubicin, eribulin mesylate, erlotinib, estramustine, etoposide phosphate, everolimus, exemestane, fludarabine, fluorouracil, fotemustine, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, hydroxyurea, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alfa 2a, ipilimumab, ixabepilone, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, mechlorethamine, melphalan, methotrexate, mitomycin C, mitoxantrone, nelarabine, nilotinib, oxaliplatin, paclitaxel, paclitaxel protein- bound particle, pamidronate, panitumumab, pegaspargase, peginterferon alfa- 2b, pemetrexed disodium, pentostatin, raloxifene, rituximab, sorafenib, streptozocin, sunitinib maleate, tamoxifen, temsirolimus, teniposide, thalidomide, toremifene, tositumomab, trastuzumab, tretinoin, uramustine, vandetanib, vemurafenib, vinorelbine, zoledronate, pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab , as tisagenlecleucel, axicabtagene ciloleucel, radiation therapy, or surgery. The invention further provides methods for the prevention or treatment of a neoplastic disease or autoimmune disease. In one embodiment, the invention relates to a method of treating a neoplastic disease or autoimmune disease, in a subject in need of treatment comprising administering to said subject a therapeutically effective amount of a compound of the invention. In one embodiment, the invention further provides for the use of a compound of the invention in the manufacture of a medicament for halting or decreasing a neoplastic disease or autoimmune disease.
In certain embodiments, the neoplastic disease is a lung cancer, head and neck cancer, central nervous system cancer, prostate cancer, testicular cancer, colorectal cancer, pancreatic cancer, liver cancer, stomach cancer, biliary tract cancer, esophageal cancer, gastrointestinal stromal tumor, breast cancer, cervical cancer, ovarian cancer, uterine cancer, leukemia, lymphomas, multiple myeloma, melanoma, basal cell carcinoma, squamous cell carcinoma, bladder cancer, renal cancer, sarcoma, mesothelioma, thymoma, myelodysplastic syndrome, or myeloproliferative disease.
The autoimmune diseases that can be affected using compounds and compositions according to the invention include, but are not limited to allergy, Alzheimer’ s disease, acute disseminated encephalomyelitis, Addison’s disease, ankylosing spondylitis, antiphospholipid antibody syndrome, asthma, atherosclerosis, autoimmune hemolytic anemia, autoimmune hemolytic and thrombocytopenic states, autoimmune hepatitis, autoimmune inner ear disease, bullous pemphigoid, coeliac disease, chagas disease, chronic obstructive pulmonary disease, chronic Idiopathic thrombocytopenic purpura (ITP), churg-strauss syndrome, Crohn’s disease, dermatomyositis, diabetes mellitus type 1, endometriosis, Goodpasture’s syndrome (and associated glomerulonephritis and pulmonary hemorrhage), graves’ disease, guillain- barre syndrome, hashimoto’s disease, hidradenitis suppurativa, idiopathic thrombocytopenic purpura, interstitial cystitis, irritable bowel syndrome, lupus erythematosus, morphea, multiple sclerosis, myasthenia gravis, narcolepsy, neuromyotonia, Parkinson’s disease, pemphigus vulgaris, pernicious anaemia, polymyositis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, schizophrenia, septic shock, scleroderma, Sjogren’s disease, systemic lupus erythematosus (and associated glomerulonephritis), temporal arteritis, tissue graft rejection and hyperacute rejection of transplanted organs, vasculitis (ANCA- associated and other vasculitides), vitiligo, and wegener’s granulomatosis.
It should be understood that the invention is not limited to the particular embodiments shown and described herein, but that various changes and modifications may be made without departing from the spirit and scope of the invention as defined by the claims. The compounds according to the present invention may be synthesized according to a variety of schemes. Necessary starting materials may be obtained by standard procedures of organic chemistry. The compounds and processes of the present invention will be better understood in connection with the following representative synthetic schemes and examples, which are intended as an illustration only and not limiting of the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and such changes and modifications including, without limitation, those relating to the chemical structures, substituents, derivatives, and/or methods of the invention may be made without departing from the spirit of the invention and the scope of the appended claims.
A typical approach to synthesize of the intermediate
described in Scheme 1-1 below: Ri, R 2 , m, and n, in general Scheme 1-1 are the same as those described in the Summary section above.
In Scheme 1-1, the appropriate ketone starting material 1-1-1 can react with tribromophosphine to form the aldehyde intermediate 1-1-2, which can couple with Boc- protected piperazine to form the intermediate 1-1-3. After that, 1-1-3 will couple with appropriate phenylboronic acid via a Suzuki reaction to form intermediate 1-1-4, followed by a de-boc process to yield key intermediate 1-1-5.
A typical approach to synthesize of the intermediate was described in US9,0l8,38l (e.g Scheme 2, Scheme 3, Scheme 5, Scheme 6).
The intermediate can be prepared by the method similar to the Scheme 1-1, and those described in US9,0l8,38lby using appropriate staring materials and intermediates.
A typical approach to synthesize of the intermediate H H 9 in which R 8 is N0 2 is described in Scheme 2-1 below. R 7 , R 8 , L, and Rg, in general Scheme 2-1 are the same as those described in the Summary section above.
In Scheme 2-1, the starting material 2-1-1 reacts with appropriate alcohol or amine will yield 2-1-2.
A typical approach to synthesize of the intermediate which
R 8 is N0 2 is described in Scheme 2-2 below. R 8 , Zi, L, and R 9 , in general Scheme 2-2 are the same as those described in the Summary section above.
In Scheme 2-2, the bromination of the commercially available 2-2-1 results in 2-2-2, and then the reaction of 2-2-2 with appropriate amine provides 2-2-3. Intramolecular cycliation of 2-2-3 using metal catalyzed coupling condition such as Buchwald reaction or other coupling reaction known in the literature give 2-2-4. Alternatively, 2-2-4 can be obtained via a 3 step sequence of mesylation of the hydroxyl group of 2-2-3, SN2 reaction and intramolecular cyclization.
Similarly, the intermediate different Z a and Z b can be prepared by the method similar to the Scheme 2-2 by using appropriate staring materials intermediates, and intramolecular cylization.
Similarly, the intermediate different Qg can be prepared by the method similar to the Scheme 2-2 by using appropriate staring materials, intermediates, and intramolecular cylization.
Similarly, the intermediate different R 7 and Q 7 can be prepared by the method similar to the Scheme 2-1 and 2-2 by using appropriate staring materials, intermediates, and intramolecular cylization.
A typical approach to synthesize of the intermediate
described in Scheme 2-3 below. The mn in general Scheme 2-3 are the same as those described in the Summary section above.
In Scheme 2-3, the appropriate staring material 2-3-1 can react with 4-fluoro-3- nitrobenzenesulfonamide to form the intermediate 2-3-2, which can be easily converted into carboxylic acid intermeidate 2-3-3. Finally, 2-3-3 can react with the commercially available reagent (2S,4R)-l-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4- (4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide to form the target intermediate 2-3-4.
Similarly, the intermediate which R Q is
can be prepared by the method similar to the Scheme 2-3 by using appropriate staring materials, and intermediates.
A typical approach to synthesize of the intermediate
described in Scheme 2-4 below. The mn in general Scheme 2-4 are the same as those described in the Summary section above.
In Scheme 2-4, the appropriate staring material 2-4-1 can react with 4-fluoro-3- nitrobenzenesulfonamide to form the intermediate 2-4-2, which can be easily converted into amine intermeidate 2-4-3. Finally, 2-4-3 can react with the commercially available reagent 2- (2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-l,3-dione to form the target intermediate 2-4-4.
Similarly, the intermediate which R is , can be prepared by the method similar to the
Scheme 2-4 by using appropriate staring materials, and intermediates.
A typical approach to synthesize the intermediate
described in Scheme 3-1 below. R 2 , and n, in general Scheme 3-1 are the same as those described in the Summary section above.
In Scheme 3-1, the intermeidate 1-1-5 undergoes nucleophilic aromatic substitution with selected p-fluoro-2-bromo-benzoate to give 3-1-2.
A typical approach to synthesize of the intermediate
described in Scheme 3-2 below. Ri, R 2 , R 3 , and n, in general Scheme 3-2 are the same as those described in the Summary section above.
In Scheme 3-2, the intermeidate 3-2-1 undergoes nucleophilic aromatic substitution with selected p-fluoro-2-bromo-benzoate to give 3-2-2.
A typical approach to synthesize of the intermediate
described in Scheme 3-3 below. Ri, R 2 , R 3 , R4, R5, R 6 , Q 3 , Q4, Qs, Q 6 , m, n, v, s, and j, in general Scheme 3-3 are the same as those described in the Summary section above.
In Scheme 3-3, the intermeidate 3-3-1 undergoes nucleophilic aromatic substitution or metal catalyzed coupling condition such as Buchwald reaction or other coupling reaction known in the literature with appropriate intermediate 3-3-2 to give 3-3-3.
A typical approach to synthesize of target compounds (A-2), in which f=0, is described in Scheme A-2:
In Scheme A-2, the intermeidate A-2-1 can be prepared by standard organic reactions or by the methods similar to those described in International Application Publication No. WO2019/040573. The Buckwald coupling of A-2-1 with 3-1-2 yields A-2-2. A-2-2 is deprotected sequentially with TFA to remove SEM group and NaOH to remove ester group, producing free carboxylic acid intermediate A-2-4. Finally, the coupling of A-2-4 with 2-1-2 affords target compounds A-2.
A typical approach to synthesize target compounds of G-2, in which f=0, is described in Scheme G-2
In Scheme G-2, the intermeidate G-2-1 can be prepared by standard organic reactions. The Buckwald coupling of G-2-1 with 3-2 yields G-2-2. G-2-2 is deprotected sequentially with TFA to remove SEM group and NaOH to remove ester group, producing free carboxylic acid intermediate G-2-4. Finally, the coupling of G-2-4 with appropriate side chain affords target compounds of G-2.
Similarly, the compound which f=0, can be prepared by the method similar to the General Scheme II by using appropriate staring materials and intermediates.
A typical approach to synthesize of target compounds of E-2 is described in Scheme
E-2:
In Scheme E-2, the appropriate staring material E-2-1 are either commercially available or can be prepared by standard organic reactions, or by the methods similar to those described in International Application Publication No. WO2019/040573. The Buckwald coupling of E-2- 1 with 3-1-2 yields E-2-2, which is deprotected with NaOH to remove ester group, producing free carboxylic acid intermediate E-2-4. Finally, the coupling of E-2-4 with appropriate side chain affords target compounds of E-2.
A typical approach to synthesize of C-2 compounds, in which f=0, is described in Scheme C-2:
In Scheme C-2, the intermeidate C-2-1 can be prepared by standard organic reactions or by the methods similar to those described in International Application Publication No.
WO2019/040573. The Buckwald coupling of C-2-1 with 3-2-2 yields C-2-2. C-2-2 is deprotected sequentially with TFA to remove SEM group and NaOH to remove ester group, producing free carboxylic acid intermediate C-2-4. Finally, the coupling of C-2-4 with 2-1-2 affords target compound C-2.
Similarly, the compound of can be prepared by the method similar to Scheme C-2 by using appropriate staring materials and
intermediates.
A typical approach to synthesize of target compounds (D-4), in which f=0, is described in Scheme D-4
In Scheme D-4, the intermeidate D-4-1 can be prepared by standard organic reactions or by the methods similar to those described in International Application Publication No. WO2019/040573. The Buckwald coupling of D-4-1 with 3-1-2 yields D-4-2. D-4-2 is deprotected sequentially with TFA to remove SEM group and NaOH to remove ester group, producing free carboxylic acid intermediate D-4-4. Finally, the coupling of D-4-4 with appropriate side chain affords target compounds of D-4.
Similarly, the compound which f=0, can be prepared by the method similar to Scheme D-4 by using appropriate staring materials and intermediates.
Similarly, the compound which f=0, can be prepared by the method similar to Scheme D-4 by using appropriate staring materials and intermediates.
Similarly, the compound can be prepared by the method similar to Scheme D-4 by using appropriate staring materials and intermediates.
A typical approach to synthesize of Formula (B-l) compounds of is described in Scheme B-l:
In Scheme B-l, the appropriate staring material B-l-l can be prepared by the methods similar to those described in US/2012/0189539 and WO2014/113413. B-l-l undergoes nucleophilic aromatic substitution reaction to give B-l-2, which can react with appropriate amine to obtain B-l-3. After that B-l-3 can be reduced to the amine intermediate B-l-4, which can finally react with appropriate sulfuric aicd intermediate to afford the final product with Formula (B-l).
Similarly, the compounds of Formula (A-3) can |-, c prepared by the method similar to above Schemes by using appropriate staring materials and intermediates.
Similarly, the compounds of Formula (A-2) can | -, c prepared by the method similar to above the Schemes by using appropriate staring materials and intermediates.
Similarly, the compounds of Formula (A-l) can be prepared by the method similar to above Schemes by using appropriate staring materials and intermediates.
Similarly, the compounds of Formula (A) can be prepared by the method similar to above the Schemes by using appropriate staring materials and intermediates.
The compounds and processes of the present invention will be better understood in connection with the following examples, which are intended as an illustration only and not limiting of the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and such changes and modifications including, without limitation, those relating to the chemical structures, substituents, derivatives, formulations and/or methods of the invention may be made without departing from the spirit of the invention and the scope of the appended claims.
Where NMR data are presented, 1H spectra were obtained on XL400 (400 MHz) and are reported as ppm down field from Me 4 Si with number of protons, multiplicities, and coupling constants in Hertz indicated parenthetically. Where HPLC data are presented, analyses were performed using an Agilent 1100 system. Where LC/MS data are presented, analyses were performed using an Applied Biosystems API- 100 mass spectrometer and Shimadzu SCL-10A LC column:
Example INT-1: Preparation of l-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l’- biphenyl]-2-yl)methyl)piperazine
Synthesis of 2-bromo-4,4-dimethylcyclohex-l-enecarbaldehyde 2: A solution of anhydrous chloroform (57 ml) and anhydrous N,N-dimethylformamide (9 mL) were cooled to ~3 °C (internal temperature) under nitrogen before phosphorus tribromide (10 mL, 0.1 mol) was introduced dropwise at a rate so that the reaction was maintained at ~3 °C. After the addition was complete the reaction was allowed to warm slowly to -10 °C and then the temperature was raised to 70 °C where it was maintained for 30 min. The reaction was cooled to rt and 3,3-dimethylcyclohexanone 1 (5 g, 0.04 mol) was added slowly over 20 min. After the addition was complete the reaction was warmed to 70 °C and it was stirred for 1.5 h. The mixture was then cooled to 0 °C and a solution of 4M sodium acetate (53 ml) was added slowly. The pH of the resulting solution was adjusted to -7 using a solution of 5M NaOH and the mixture was then extracted with heptanes (100 mLx3). The combined organic fractions were dried (Na 2 S0 4 ), filtered and concentrated under reduced pressure to give 2-bromo-4,4- dimethylcyclohex-l-enecarbaldehyde 2 (4 g, 49%)as a yellow oil.
Synthesis of 2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-enecarbaldehyde 3: To a degassed solution of 2-bro mo-4, 4-dimethylcyclo hex- l-enecarbaldehyde 2 (5 g, 0.023 mol) and 4-chlorophenyl boronic acid (3.6 g, 0.023 mol) in l,4-dioxane (50 mL) at rt was added a solution of 2M Na 2 C0 3 (20.4 ml). Nitrogen was bubbled through the mixture for 2 min and then PdCl 2 (dppf) (0.5 g) was added. The reaction flask was heated to 120 °C where it was maintained for 3 h. After this time the suspension was cooled to rt and filtered through Celite. The collected solids were washed with additional dichloromethane and the combined filtrate and washings were concentrated under reduced pressure. Purification by column
chromatography on silica with PE: EA=20:l gave 2-(4-chlorophenyl)-4,4-dimethylcyclohex- l-enecarbaldehyde 3 (3 g, 53%) as a white solid. MS: 249[M+H] +
Synthesis of (2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-enyl)methanol 4: A solution of 2-(4-chlorophenyl)-4, 4-dimethylcyclo hex- l-enecarbaldehyde 3 (20 g, 80.6 mmol) in MeOH (100 mL) was cooled to 0 °C, NaBH 4 (3.lg, 80.6 mmol) was added portionwise to the reaction at a rate so that the reaction was maintained at 0-5 °C. After added, the mixture was stirred for 1 h at 0 °C. Water was added slowly to the mixture and extracted with EA (200 mL x3), the organic layer was washed with brine and dried Na 2 S0 4. filtered and concentrated under reduced pressure to give (2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-enyl)methanol 4 (15 g, 75%) as a white solid. MS: 233[M+H-H 2 0] +
Synthesis ofl-(2-(bromomethyl)-5,5-dimethylcyclohex-l-enyl)-4-chlorobe nzene 5: A solution of (2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-enyl)methanol 4 (15 g, 0.060 mol) and in Et 2 0 (300 ml) was cooled to 0 °C before phosphorus tribromide (7.5 mL) was added dropwise to the mixture, after added, the mixture was stirred for 1 h at 0 °C for 90 minutes. The reaction mixture was added H 2 0 before being extracted with EA. The organic layer was washed with a saturated NaHCCT solution and brine and dried Na 2 S0 4. filtered and concentrated under reduced pressure to give l-(2-(bromomethyl)-5,5-dimethylcyclohex-l- enyl)-4-chlorobenzene 5 (18 g, 96 %) as a colorless oil.
Synthesis of tert-butyl 4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-l- enyl)methyl)piperazine-l-carboxylate - To a solution of l-bromo-2-(bromomethyl)-5,5- dimethylcyclohex-l-ene 5 (21 g, 0.067 mol) and tert-butyl piperazine- l-carboxy late (12.4 g, 0.067 mol) in dichloro methane (200 ml) at rt was added TEA (12.2 g, 0.12 mol). The reaction was stirred for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product. Purification by column chromatography on silica with PE:EA=20:l provided tert-butyl 4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex- l-enyl)methyl)piperazine- 1- carboxylate 6 (21 g, 75%).
Synthesis of l-((2-(4-chlorophenyl)-4,4-dimethylcyclohex- l-enyl)methyl)piperazine hydrogen chloride: To a solution of tert-butyl 4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex- l-enyl)methyl)piperazine- l-carboxy late 6 (30 g, 0.072 mol) in MeOH (20 ml) was added cone. HC1 (50 mL). The reaction was stirred for 24 hours and then concentrated under reduced pressure. A saturated solution of Na 2 C0 3 was added to adjust the pH to -8-9 and the mixture was extracted with dichloro methane (x2). The combined extracts were washed with brine, dried (Na 2 S0 4 ), filtered and concentrated under reduced pressure. The oil product was treated with MeOH/HCl(g) (3M, 500 mL) and stirred for 1 hour, then concentrated under reduced pressure to get the product l-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-l- enyl)methyl)piperazine hydrogen chloride IM-14-1 (23 g, 83%). MS: 3l9[M+H] + 1H NMR (400 MHz, DMSO) d 11.51 (s, 1H), 9.60 (s, 1H), 9.18 (s, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 3.43 (s, 8H), 2.84 (s, 2H), 2.39 (s, 2H), 2.03 (s, 2H), 1.45 (t, J = 6.0 Hz, 2H), 0.96 (s, 6H).
Example INT-2: Preparation of 3-nitro-4-(((tetrahydro-2H-pyran-4- y 1) methyl) amino )benzene sulfo namide
To a 500 mL three-neck RB flask equipped with a mechanical stirrer were charged the 4-chloro-3-nitrobenzenesulfonamide (23.7 g, 100 mmol), DIPEA (12.9 g, 100 mmol), (tetrahydro-2H-pyran-4-yl)methanamine(l l.5 g, 100 mmol) and acetonitrile (200 mL). The reaction mixture was adjusted to an internal temperature of 80 °C and agitated for no less than 12 hours. The product solution was cooled down to 40 °C and agitated for no less than 1 hour until precipitation observed. The product slurry was further cooled to 20 °C. Water (80 mL) was slowly charged over no less than 1 hour, and the mixture cooled to 10 °C and agitated for no less than 2 hours before collected by filtration. The wet cake was washed with 1:1 mix of acetonitrile:water (40 mL). The wet cake was rinsed with water (80 mL) at 40 °C for no less than 1 hour before collected by filtration. The wet cake was rinsed with water (20 mL), and dried at 75° C under vacuum to give the 3-nitro-4-(((tetrahydro-2H-pyran-4- yl)methyl)amino)benzenesulfonamide (24.5 g, 78%) as an orange solid. 1H NMR (400 MHz, DMSO) d 8.60 (t, J = 5.9 Hz, 1H), 8.48 (d, J = 2.2 Hz, 1H), 7.84 (dd, J = 9.2, 2.0 Hz, 1H), 7.54 - 7.18 (m, 3H), 3.86 (dd, J = 11.3, 3.2 Hz, 2H), 3.35 (s, 2H), 3.27 (t, J = 10.9 Hz, 2H), 1.92 (ddd, J = 11.2, 7.4, 3.9 Hz, 1H), 1.62 (d, J = 11.4 Hz, 2H), 1.27 (qd, J = 12.3, 4.4 Hz, 2H).
Example INT-3: Preparation of 4-[[(4-fluorooxan-4-yl)methyl]amino]-3-nitrobenzene-l- sulfonamide
Into a 50-mL round-bottom flask, was placed (4-fluorooxan-4-yl)methanamine hydrochloride (500 mg, 2.95 mmol, 1.00 equiv), 4-fluoro-3-nitrobenzene-l-sulfonamide (650 mg, 2.95 mmol, 1.00 equiv), tetrahydrofuran (15 mL), CS 2 CO 3 (2.8 g, 8.59 mmol, 3.00 equiv). The resulting solution was stirred for 14 h at 50°C in an oil bath. The reaction mixture was cooled to room temperature. The resulting mixture was filtered and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (4: 1). This resulted in 650 mg (66%) of 4-[[(4-fluorooxan-4-yl)methyl]amino]-3- nitrobenzene-l-sulfonamide as a yellow solid. LCMS (ES, m/z): M+l: 334. H-NMR: (300 MHz, DMSO, ppm): 5 8.58 (t, 7=6.3 Hz, 1 H), 8.49 (d, 7=2.1 Hz, 1 H), 7.90 - 7.80 (m, 1 H), 7.44 (d, 7=9.3 Hz,l H), 7.34 (s, 2 H), 3.87 - 3.70 (m , 4 H), 3.61 - 3.50 (m, 2 H),l.95 - 1.70 (m, 4 H).
Example INT-4: Preparation of (S)-4-((l,4-dioxan-2-yl)methylamino)-3- nitrobenzene sulfo namide
Synthesis of (R)-l-chloro-3-(2-chloroethoxy)propan-2-ol : (R)-2- (chloromethyl)oxirane (500.0 g, 5.4 mol, 1.00 equiv) was slowly added to a stirred solution of 2-chloroethanol (870.0, 10.8 mol, 2.00 equiv) and BF 3 .Et 2 0 (38.0 g, 27 mmol, 0.05 equiv) at 45°C. The reaction mixture was heated on an oil bath for 3 h at 45°C. The reaction mixture was cooled to R,T and Diethyl ether (lOOmL) was added to this solution. The organic layer was washed with water (2 x 300 mL), dried over magnesium sulfate, and concentrated to yield a light brown liquid (R)-l-chloro-3-(2-chloroethoxy)propan-2-ol (800.0 g, quantitative). H-NMR: (300 MHz, DMSO -d 6, ppm) d: 3.85-3.47 (m, 9H). Synthesis of (R)-2-((2-chloroethoxy)methyl)oxirane. (R)-l-chloro-3-(2- chloroethoxy)propan-2-ol (800.0 g, crude, 4.7 mol, 1.0 eq) was added dropwise to a stirred solution of NaOH (465.0 g, 11.6 mol, 2.5 eq) in water (500 mL) on an ice-bath. The ice-bath was immediately removed after addition of (R)-l-chloro-3-(2-chloroethoxy)propan-2-ol.
After stirring 2 h at an ambient temperature, diethyl ether (1.5 L) and water (500 mL) were added. The organic layer was washed with water (1 x 50 mL), dried over sodium sulfate, and concentrated to give a light brown liquid (R)-2-((2-chloroethoxy)methyl)oxirane (400.0 g). H-NMR: (300 MHz, CDCL3 , ppm) d: 3.82-3.52 (m, 5H), 3.40-3.35 (m, 1H), 3.11-3.09 (m, 1H), 2.75-2.73.
Synthesis of (S)-(l,4-dioxan-2-yl)methanol. (R)-2-((2-chloroethoxy)methyl)oxirane (400.0 g, 2.94 mol, 1.0 eq) was added to a solution of NaOH (294.0 g, 7.35 mol, 2.5 eq) in water (2900 mL) at room temperature. The reaction mixture was heated on an oil bath for 2 h at 90 °C. The resulting solution was cooled to R,T and adjusted PH value to 5 by HC1 (6 M). The mixture was concentrated and the residue was distilled (90-95 °C, 0.1 kPa) under vacuum pump to give a colorless oil (S)-(l,4-dioxan-2-yl)methanol (110 g, 31.7%). H-NMR: (300 MHz, CDCL3 , ppm) d: 3.85-3.42 (m, 9H), 2.15 (bs, 1H).
Synthesis of (R)-(l,4-dioxan-2-yl)methyl methanesulfonate. A mixture of (S)-(l, 4- dioxan-2-yl)methanol (50.0 g, 0.42 mol, 1.0 eq), TEA (63.6 g, 0.63 mol, 1.5 eq) and DCM (500 mL) at ice-bath, MsCl (48.1 g, 0.42 mol, 1.0 eq) was added dropwise. And then, the ice-bath removed and the mixture was stirred at R,T for 2 hours. The reaction mixture was washed by water (2 x 50 mL) and the organic phase was dried over sodium sulfate, and concentrated to give a light brown oill (R)-(l,4-dioxan-2-yl)methyl methanesulfonate (71.0 g, 83%). H-NMR: (300 MHz, CDCL3 , ppm) d: 4.23-4.20 (m, 2H), 3.82-3.56 (m, 6H), 3.50- 3.40 (m, 1H), 3.02 (m, 3H).
Synthesis of (S)-(l,4-dioxan-2-yl)methanamine: In 1000 mL autoclave, to a solution of (R)-(l,4-dioxan-2-yl)methyl methanesulfonate (70.0 g, 0.36 mol, 1.0 eq) in NH ,.McOH (7 M, 500 mL) was stirred at 80°C for 12 hours, the reaction mixture was cooled to R,T and concentrated to give a light brown oil (S)-(l,4-dioxan-2-yl)methanamine (30.0 g, 73%).
NMR: (300 MHz, DMSO -d 6, ppm) d: 8.27 (bs, 2H), 3.82-3.42 (m, 6H), 3.24-3.20 (m, 1H), 2.98-2.62 (m, 2H).
Synthesis of (S)-4-((l,4-dioxan-2-yl)methylamino)-3-nitrobenzenesulfonami de: A mixture of (S)-(l, 4-dioxan-2-yl)methanamine (25.0 g, 0.21 mol, 1.0 eq), 4-fluoro-3- nitrobenzenesulfonamide (46.0 g, 0.21 mol, 1.0 eq) and CS 2 CO 3 (137.3 g, 0.42 mol, 2.0 eq) in THF (700 mL) was stirred at 50°C for 6 hours, LCMS showed material was consumed completely, the reaction mixture was cooled R,T and poured into water (3500 mL). The mixture was filtrated and collected filtrate cake and dried by oven to give a yellow solid (S)- 4-((l,4-dioxan-2-yl)methylamino)-3-nitrobenzenesulfonamide (60.0 g, 89.5%). H-NMR:
(300 MHz, DMSO -d 6, ppm) d: 8.52-8.47 (m, 2H), 7.86-7.83 (m, 1H), 7.28-7.00 (m, 3H), 3.82-3.29 (m, 9H).
Example INT-5: Preparation of methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4- dimethylcyclohex- 1 -en- 1 -yl] methyl]piperazin- 1 -yl)benzoate :
Into a 250-mL round-bottom flask, was placed a solution of Example 1-1, i.e, l-[[2- (4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl]piper azine (15.09 g, 47.32 mmol, 1.00 equiv) in DMA (150 mL), DIEA (12.9 g, 99.81 mmol, 2.00 equiv), methyl 2-bromo-4- fluorobenzoate (11.6 g, 49.78 mmol, 1.00 equiv). The resulting solution was stirred for 12 h at 100 degree. The reaction mixture was cooled to room temperature. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x100 mL of brine. The mixture was dried over anhydrous sodium sulfate, then filtered and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0:1- 1:5). This resulted in 7 g (crude) of methyl 2-bromo-4-(4-[[2-(4- chlorophenyl)-4,4-dimethylcyclo hex- l-en-l-yl]methyl]piperazin-l-yl) benzoate as yellow oil. LC-MS: (ES, m/z ): M+l=533, 531.
Example INT-6: Preparation of 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-l -enyl)methyl)piperazin-l-yl)-N-(3-nitro-4-((tetrahydro-2H-py ran-4- y 1) methylamino )pheny lsulfo ny l)benzamide
Synthesis of methyl 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex -1- enyl) methyl)piperazin-l-yl) benzoate Into a 20000-mL round-bottom flask, was placed l-((2- (4-chlorophenyl)-4, 4-dimethylcyclohex-l-enyl)methyl)piperazine dihydrochloride (600 g, 1.53 mol, 1 equiv), methyl 2-bromo-4-fluorobenzoate (357 g, 1.53 mol, 1 equiv), DBU (319 g, 6.12 mol, 4 equiv) and DMSO (8000 mL). The resulting solution was stirred for 20 h at 70 degrees C. LCMS showed material was completely consumed. The resulting mixture was cooled to R,T and poured into water (32 L). The mixture was filtrated, collection of filter cake and the filter cake was washed by water (3000 mL x 3) and dried by oven to give product 740 g (Y: 91%) methyl 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-l- enyl)methyl)piperazin-l-yl) benzoate as a white solid. H-NMR-PH-PHNW-4-55-400: (300 MHz, DMSO -άb , rrhi) d: 7.73 (d, 7=9.0 Hz, 1H), 7.42-7.39 (m, 2H), 7.18-7.12 (m, 3H), 6.97-6.94 (m, 1H), 4.00-3.84 (m, 2H), 3.76 (s, 2H), 3.57 (s, 3H), 3.51-3.33 (m, 4H), 2.79- 2.60 (m, 2H), 2.32-2.30 (m, 2H), 2.03-1.97 (m, 2H), 1.47-1.45 (m, 2H), 0.96 (s, 6H).
Synthesis of 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex- l-enyl) methyl)piperazin-l-yl) benzoic acid: Into a 20000-mL round-bottom flask, was placed methyl 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-eny l)methyl)piperazin-l- yl)benzoate (730 g, 1.37 mol, 1 equiv), LiOH (131.5 g, 5.48 mol, 4 equiv) and
MeOH/THF/water (4500mL/3000mL/l000 mL). The resulting solution was stirred for 16 h at 70 degrees C. LCMS showed material was completely consumed. The resulting mixture was cooled to R,T and concentrated. The residue was diluted with water (5000 mL) and the mixture was adjust PH to 3-5 with HC1 (6 M), followed by filtrated, collection of filter cake and dried by oven to give product 650 g (Y: 93%) 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4- dimethylcyclohex-l-enyl)methyl)piperazin-l-yl)benzoic acid as a white solid. H-NMR-PH- PHNW-4-55-400: (300 MHz, DMSO -d 6, ppm) d: 10.60 (bs, 1H), 7.73 (d, 7=8.4 Hz, 1H), 7.42-7.39 (m, 2H), 7.14-7.11 (m, 3H), 6.95-6.92 (m, 1H), 4.00-3.84 (m, 2H), 3.76 (s, 2H), 3.51-3.33 (m, 4H), 2.79-2.60 (m, 2H), 2.32-2.30 (m, 2H), 2.03-1.97 (m, 2H), 1.47-1.45 (m, 2H), 0.97 (s, 6H).
Synthesis of 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex- l-enyl) methyl)piperazin-l-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4- yl)methylamino)phenylsulfonyl)benzamide: Into a 20000-mL round-bottom flask, was placed 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-eny l)methyl)piperazin-l- yl)benzoic acid (583 g, 1.13 mol, 1 equiv), DCM (10 L), 3-nitro-4-[[(oxan-4- yl)methyl]amino]benzene-l-sulfonamide (338 g, 1.07 mol, 0.95 equiv), EDCI (326 g, 1.7 mol, 1.5 equiv), DMAP (551 g, 4.52 mol, 4 equiv). The resulting solution was stirred for overnight at 25 degrees C. LCMS showed material was completely consumed. The resulting mixture is followed by dilute hydrochloric acid (1.0 M) (1000 mL x 3), saturated sodium bicarbonate (1000 mL x 3) and brine (1000 mL x 1), and then the organic phase was dried by Na 2 S0 4 , filtrated. The filtrate was concentrated to give product 857 g (Y: 93%) as a light brown yellow solid 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-l - enyl)methyl)piperazin-l-yl)-N-(3-nitro-4-((tetrahydro-2H-pyr an-4- yl)methylamino)phenylsulfonyl)benzamide as a brown yellow solid. LC-MS: (ES, m/z): M+1=814/816/818, R,T=2.0l min. H-NMR-PH-PHNW-4-55-400: (300 MHz, DMSO-7 6, ppm) d: 8.63-8.61 (m, 2H), 7.94-7.92 (m, 1H), 7.37-7.35 (m, 3H), 7.27-7.24 (m, 1H), 7.05- 7.02 (m, 3H), 6.86-6.83 (m, 1H), 3.87-3.82 (m, 2H), 3.37-3.23 (m, 8H), 2.92 (s, 2H), 2.50- 2.38 (m, 4H), 2.22-2.20 (m, 2H), 2.00-1.97 (m, 2H), 1.64-1.60 (m, 2H), 1.48-1.46 (m, 2H), 1.26-1.20 (m, 2H), 0.97 (s, 6H).
Example 15: Preparation of 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l’- biphenyl]-2-yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[ 3’,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran -4- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide
Into a 250-mL round-bottom flask, was placed a solution of l-[[2-(4-chlorophenyl)- 4,4-dimethylcyclohex-l-en-l-yl]methyl]piperazine (15.09 g, 47.32 mmol, 1.00 equiv) in DMA (150 mL), DIEA (12.9 g, 99.81 mmol, 2.00 equiv), methyl 2-bromo-4-fluorobenzoate (11.6 g, 49.78 mmol, 1.00 equiv). The resulting solution was stirred for 12 h at 100 degree. The reaction mixture was cooled to room temperature. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x100 mL of brine. The mixture was dried over anhydrous sodium sulfate, then filtered and
concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0:1- 1:5). This resulted in 7 g (crude) of methyl 2-bromo-4-(4-[[2-(4- chlorophenyl)-4,4-dimethylcyclo hex- l-en-l-yl]methyl]piperazin-l-yl) benzoate as yellow oil. LC-MS (ES, m/z): M+l=533, 531.
Into a 40- mL round-bottom flask, was placed a solution of 4-[[2- (trimethylsilyl)ethoxy]methyl]-l3-oxa-2,4,l0-triazatricyclo[ 7.4.0.0 A [3,7]]trideca-l,3(7),5,8- tetraene (175 mg, 0.57 mmol, 1.00 equiv) in dioxane (10 mL), CS 2 CO 3 (560 mg, 1.72 mmol, 3.00 equiv), XantPhos Pd G2 (CAS: 1375325-77-1) (53 mg, 0.06 mmol, 0.10 equiv), methyl 2-bromo-4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohex- l-en- l-yl]methylpiperazin- 1- yl)benzoate (334.7 mg, 0.63 mmol, 1.10 equiv). The resulting solution was stirred for 2 h at 110 degee. The reaction mixture was cooled to room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0:1- 1:3). This resulted in 200 mg (46%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex- l-en- l-yl]methyl]piperazin- l-yl)-2- (4-[[2-(trimethylsilyl)ethoxy]methyl]-l3-oxa-2,4,l0-triazatr icyclo[7.4.0.0 A [3,7]]trideca- l,3(7),5,8-tetraen-l0-yl)benzoate as yellow oil. LC-MS: (ES, m/z): M+l=756, R,T= 1.252 min. The measurements of the retention were done with a reversed phase column (Cl 8). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microm; Eluent A: water (0.05 % TFA); Eluent B: Acetonitrile; linear gradient.
Into a 50-mL round-bottom flask, was placed a solution of methyl 4-(4-[[2-(4- chlorophenyl)-4,4-dimethylcyclohex- l-en- l-yl]methyl]piperazin- l-yl)-2-(4-[[2- (trimethylsilyl) ethoxy]methyl]-l3-oxa-2,4,l0-triazatricyclo[7.4.0.0 A [3,7]]trideca-l,3(7),5,8- tetraen-lO-yl)benzoate (200 mg, 0.26 mmol, 1.00 equiv) in tetrahydrofuran (20 mL), TBAF (3 mg, 0.01 mmol), ethane- 1, 2-diamine (3 mL). The resulting solution was stirred for 24 h at 60 degree. The reaction mixture was cooled to room temperature. The reaction was then quenched by the addition of 30 mL of water. The resulting solution was extracted with 2x30 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2x30 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0: 1-1:2). This resulted in 90 mg (54%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4- dimethylcyclohex-l-en-l-yl]methyl]piperazin-l-yl)-2-[l3-oxa- 2,4,l0- triazatricyclo[7.4.0.0 A [3,7]]trideca-l,3(7),5,8-tetraen-l0-yl]benzoate as a yellow solid. LC- MS(ES, m/z): M+l=626, R,T= 1.052 min. The measurements of the retention were done with a reversed phase column (C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18 , 2.6 microm; Eluent A: water (0.05 % TFA); Eluent B: Acetonitrile; linear gradient.
Into a 8-mL round-bottom flask, was placed a solution of methyl 4-(4-[[2-(4- chlorophenyl)-4,4-dimethylcyclohex- l-en- l-yl]methyl]piperazin- l-yl)-2-[l3-oxa-2,4, 10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l,3(7),5,8-tetraen-l0-yl]benzoate (90 mg, 0.14 mmol,
1.00 equiv) in tetrahydrofuran/MeOH/H 2 0 (2/2/2 mL), sodium hydroxide (23 mg, 0.57 mmol, 4.00 equiv). The resulting solution was stirred for overnight at 60 degree. The reaction mixture was cooled to room temperature. The reaction was then quenched by the addition of 5 mL of water. The pH value of the solution was adjusted to 6 with hydrogen chloride (1 mol/L). The resulting solution was extracted with 2x10 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x10 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0:1- 1:1). This resulted in 70 mg (80%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]met hyl]piperazin- l-yl)-2-[l3-oxa-2,4,l0-triazatricyclo[7.4.0.0 A [3,7]]trideca-l,3(7),5,8-tetraen-l0-yl]benzoic acid as a yellow solid.
LC-MS(ES, m/z): M+l=6l2, R,T= 1.005 min. The measurements of the retention were done with a reversed phase column (C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18 , 2.6 microm; Eluent A: water (0.05 % TFA); Eluent B: Acetonitrile; linear gradient.
Into a 8-mL round-bottom flask, was placed a solution of 4-(4-[[2-(4-chlorophenyl)- 4,4-dimethylcyclohex-l-en-l-yl]methyl]piperazin- l-yl)-2-[l3-oxa-2,4,l0- triazatricyclo[7.4.0.0 A [3,7]]trideca-l,3(7),5,8-tetraen-l0-yl]benzoic acid (35 mg, 0.06 mmol, 1.00 equiv) in dichloromethane (5 mL), 4-dimethylaminopyridine (27.8 mg, 0.23 mmol, 4.00 equiv), 3-nitro-4-[(oxan-4-ylmethyl)amino]benzene-l-sulfonamide (21.7 mg, 0.07 mmol,
1.20 equiv), EDCI (22 mg, 0.11 mmol, 2.00 equiv). The resulting solution was stirred for overnight at room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Waters-2767): Column, X-bridge RP18, 5um, l9* l00mm; mobile phase, 0.03% ammonia in water (0.03% NH4HC03 & NH40H ) and CH3CN (32% CH3CN up to 52% in 6 min); Detector, UV 254 nm. This resulted in 28.3 mg (54%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en- l-yl]methyl]piperazin-l-yl)-N-([3-nitro-4-[(oxan-4-ylmethyl) amino]benzene]sulfonyl)-2-[l3- oxa-2,4,l0-triazatricyclo[7.4.0.0 A [3,7]]trideca-l,3(7),5,8-tetraen-l0-yl]benzamide as a yellow solid. LC-MS-: (ES, m/z ): (ES, m/z): M+l=909, R.T= 1.52 min. The measurements of the retention were done with a reversed phase column (C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18 , 2.6 microm; Eluent A: water (0.05 % TFA); Eluent B: Acetonitrile; linear gradient. H-NMR: (CDCl 3 , 300 MHz) d: 8.70 (s, 1H), 8.46 (m, 2 H), 8.10-8.06 (m, 1 H), 7.89-7.60 (m, 1 H), 7.10 (s, 1 H), 6.94-6.71 (m, 5 H), 6.49 (s, 1 H), 6.16 (s, 1 H), 4.70- 4.65 (m, 2 H), 4.00-4.10 (m, 2 H), 3.67-3. l9(m, 7 H), 3.20-3.00(m, 4 H), 2.78(s, 1 H), 2.58- 2.52(m, 2 H), 2.27-2. l7(m, 3 H), 2.05-l.98(m, 4 H), 1.74-1.70 (m, 3 H), 1.55-1.40 (m, 3H), 0.98 (s, 6H).The measurements of the NMR spectra were done with BrukerAvancelll HD 300MHzwith a probe head of BBOF.
Example 16: Preparation of 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l’- biphenyl]-2-yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[ 3’,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran -4-yl)methyl)amino)-3- nitrophenyl) sulfonyl)benzamide
Into a 8-mL round-bottom flask, was placed a solution of 4-(4-[[2-(4-chlorophenyl)- 4,4-dimethylcyclohex-l-en-l-yl]methyl]piperazin- l-yl)-2-[l3-oxa-2,4,l0- triazatricyclo[7.4.0.0 A [3,7]]trideca-l,3(7),5,8-tetraen-l0-yl]benzoic acid (35 mg, 0.06 mmol, 1.00 equiv) in dichloromethane (5 mL), 4-dimethylaminopyridine (27.8 mg, 0.23 mmol, 4.00 equiv), EDCI (22 mg, 0.11 mmol, 2.00 equiv), 4-[(4-fluorooxan-4-yl)methyl]amino-3- nitrobenzene- l-sulfonamide (22.7 mg, 0.07 mmol, 1.20 equiv). The resulting solution was stirred for overnight at room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Waters-2767): Column, X-bridge RP18, 5um, l9* l00mm; mobile phase, 0.03% ammonia in water (0.03% NH4HCO3 & NH 4 OH ) and CH 3 CN (32% CH 3 CN up to 52% in 6 min);
Detector, UV 254 nm. This resulted in 26.2 mg (50%) of 4-(4-[[2-(4-chlorophenyl)-4,4- dimethylcyclohex- l-en- l-yl]methyl]piperazin- l-yl)-N-[(4-[[(4-fluorooxan-4- yl)methyl]amino]-3-nitrobenzene)sulfonyl]-2-[l3-oxa-2,4,l0- triazatricyclo[7.4.0.0 A [3,7]]trideca-l,3(7),5,8-tetraen-l0-yl]benzamide as a yellow solid. LC- MS: (ES, m/z ): (ES, m/z): M+l=927, R,T= 1.27 min. The measurements of the retention were done with a reversed phase column (C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18 , 2.6 microm; Eluent A: water (0.05 % TFA); Eluent B: Acetonitrile; linear gradient from 5 % acetonitrile to 100 % acetonitrile in 3.5 minutes; Oven temperature 40 °C;
flow: l.5mL/min. H-NMR: (CDCl 3 , 300 MHz) d: 12.38 (bs, 1H), 8.69 (d, J= 2.1 Hz, 1 H), 8.58 (t, /= 6.3 Hz, 1 H), 8.44 (s, 1H), 8.07 (d, /= 9.0 Hz,IH), 7.90-7.87 (m, 1H), 7.24-7.22 (m, 2H), 7.08 (s, 1H), 6.94(m, 2H), 6.85 (s, 1H), 6.80-6.77 (m, 2 H), 6.49 (s, 1H), 6.14 (s,
1H), 4.74-4.67 (m, 2H), 3.91-3.80 (m, 2H), 3.80-3.44 (m, 6H), 3.17 (m, 4H), 2.77(s, 1H), 2.22-2.10 (m, 6H), 2.00 (s, 2H), 1.98-1.75 (m, 3H), 1.80-1.60 (m, 2H), 1.55-1.40 (m, 2H), 0.94 (s, 6H). The measurements of the NMR spectra were done with BrukerAvancelll HD 300MHzwith a probe head of BBOF.
Example 17: Preparation of 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l’- biphenyl]-2-yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[ 3’,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl-2,2,3,3-d4)-N-((4-(((4-fluorotetrahyd ro-2H-pyran-4- y 1) methyl) amino ) - 3 -nitrophenyl) sulfo ny l)benzamide
Synthesis of 4-[[2-(trimethylsilyl)ethoxy]methyl](l2,l2-2H2)-l3-oxa-2,4,l 0- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l l-one: Into a 8-mL vial, was placed 4- [[2-(trimethylsilyl)ethoxy]methyl]-l3-oxa-2,4,l0-triazatricy clo[7.4.0.0 A [3,7]]trideca- l(9),2,5,7-tetraen-l l-one (90 mg, 0.28 mmol, 1 equiv), D 2 0 (1 mL), MeOD (1 mL), Na 2 C0 3 (89.6 mg, 0.85 mmol, 3.00 equiv). The resulting solution was stirred for 48 h at 60 °C in an oil bath. The resulting solution was extracted with 3x3 mL of dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 60 mg (66%) of 4-[[2-(trimethylsilyl)ethoxy]methyl](l2,l2-2H2)-l3-oxa-2,4,l 0- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l l-one as a yellow solid. LC-MS-PH- PHNW-4-34-1: (ES, m/z ): M+l=322,The measurements of the retention were done with a reversed phase column (C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18 , 2.6 microm; Eluent A: water (0.05 % TFA); Eluent B: Acetonitrile; linear gradient from 5 % acetonitrile to 100 % acetonitrile in 3.5 minutes; Oven temperature 40 °C; flow: l.5mL/min. H-NMR-PH-PHNW-4-34-2: (d-DMSO, 300 ppm): 7.44-7.41 (m, 2H), 6.43-6.42(d, /=6Hz, 1H), 5.46-5.41 (m, 2H), 3.5l-3.46(m, 2H), l.24(s, 1H), 0.86-0.79(m, 4H), -0.04-0.05(m,
9H).
Synthesis of 4-[[2-(trimethylsilyl)ethoxy]methyl](l l,l l,l2,l2-2H4)-l3-oxa-2,4,l0- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraene: Into a 8-mL vial, was placed 4-[[2- (trimethylsilyl)ethoxy]methyl](l2,l2-2H2)-l3-oxa-2,4,l0-tria zatricyclo[7.4.0.0 A [3,7]]trideca- l(9),2,5,7-tetraen-l l-one (60 mg, 0.19 mmol, 1 equiv), THF (3 mL). This was followed by the addition of LiAlD 4 (31.3 mg, 0.75 mmol, 3.99 equiv) in portions at 0 °C. The resulting solution was stirred for overnight at room temperature. The reaction was then quenched by the addition of 1 mL of D 2 0. The resulting solution was extracted with 3x5 mL of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 25 mg (43.28%) of 4-[[2- (trimethylsilyl)ethoxy]methyl](l l,l l,l2,l2-2H4)-l3-oxa-2,4,l0- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraene as a yellow solid. LC-MS-PH-PHNW- 4-34-2: (ES, m/z): M+l=93 l. H-NMR-PH-PHNW-4-34-2: (CDCl 3 , 300 ppm): 7.35(s, 1H), 7. l7-7. l5(d, /=6Hz, 1H), 6.35-6.34(d, /=3Hz, 1H), 5.56-5.53 (m, 2H), 3.58-3.52(m, 2H), 2.08(s, 1H), l.28(s, 1H), 0.93-0.88(m, 3H), -0.04-0.05(m, 9H).
Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin- l-yl)-2-(4-[[2-(trimethylsilyl)ethoxy]methyl](l 1, 11, 12, 12-2H4)- l3-oxa- 2,4,l0-triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7- tetraen-lO-yl)benzoate: Into a 8-mL vial, was placed 4-[[2-(trimethylsilyl)ethoxy]methyl]( 11,11 , 12, 12-2H4)- l3-oxa-2,4, 10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraene (25 mg, 0.08 mmol, 1 equiv), methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex- l-en- l-yl]methyl]piperazin- 1- yl)benzoate (55.9 mg, 0.11 mmol, 1.3 equiv), Dioxane (5 mL), CS 2 CO 3 (52.6 mg, 0.16 mmol,
2 equiv), Chloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene] [2-amino- l,l-biphenyl- 2-yl]palladium(II) (5 mg). The resulting solution was stirred for 2 h at 100 °C in an oil bath. After the reaction completed, the crude solution is concentrated and the residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0: 1- 1: 1). This resulted in 20 mg (32.56%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin- l-yl)-2-(4-[[2-(trimethylsilyl)ethoxy]methyl](l 1, 11, 12, 12-2H4)- l3-oxa- 2,4,l0-triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7- tetraen-lO-yl)benzoate as a yellow solid. The measurements of the retention were done with a reversed phase column (Cl 8). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18 , 2.6 microm; Eluent A: water (0.05 % TFA); Eluent B: Acetonitrile; linear gradient from 5 % acetonitrile to 100 % acetonitrile in 3.5 minutes; Oven temperature 40 °C; flow:l.5mL/min.
Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin- l-yl)-2-[( 11,11, 12, 12-2H4)- l3-oxa-2,4, 10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzoate. Into a 8-mL vial, was placed methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex- l-en- l-yl]methyl]piperazin- l-yl)-2-(4-[[2-(trimethylsilyl)ethoxy]methyl](l l,l l,l2,l2-2H4)-l3-oxa-2,4,l0- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9), (20 mg, 0.03 mmol, 1 equiv), THF (2 mL), TBAF (100 mg, 0.38 mmol, 14.54 equiv), ethane- 1, 2-diamine (1 mL, 0.02 mmol, 0.63 equiv). The resulting solution was stirred for overnight at 70 °C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0: 1-1: 1). This resulted in 12 mg (72.40%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4- dimethylcyclohex-l-en-l-yl]methyl]piperazin-l-yl)-2-[(l l,l l,l2,l2-2H4)-l3-oxa-2,4,l0- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzoate as a yellow solid. LC- MS-PH-PHNW-4-34-4: (ES, m/z): M+l=630. The measurements of the retention were done with a reversed phase column (C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB- C18 , 2.6 microm; Eluent A: water (0.05 % TFA); Eluent B: Acetonitrile; linear gradient from 5 % acetonitrile to 100 % acetonitrile in 3.5 minutes; Oven temperature 40 °C;
flow:l.5mL/min.
Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin- l-yl)-2-[( 11,11, 12, 12-2H4)- l3-oxa-2,4, 10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzoic acid: Into a 8-mL vial, was placed methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin- l-yl)-2-[( 11,11, 12, 12-2H4)- l3-oxa-2,4, 10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzoate (12 mg, 0.02 mmol, 1 equiv), MeOH (1 mL), H 2 0 (1 mL), THF (1 mL), NaOH (3.0 mg, 0.08 mmol, 3.94 equiv).
The resulting solution was stirred for overnight at 60 °C in an oil bath. The pH value of the solution was adjusted to 5 with HC1 (1 mol/L). The reaction mixture was concentrated under vacuum. The residue was applied on a silica gel column and eluted with PE/EA(l:0-2:3).
This resulted in 9 mg (76.71%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin- l-yl)-2-[( 11,11, 12, 12-2H4)- l3-oxa-2,4, 10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzoic acid as an off-white solid. LC-MS-PH-PHNW-4-34-5: (ES, m/z): M+l=6l6. The measurements of the retention were done with a reversed phase column (C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB- C18 , 2.6 microm; Eluent A: water (0.05 % TFA); Eluent B: Acetonitrile; linear gradient from 5 % acetonitrile to 100 % acetonitrile in 3.5 minutes; Oven temperature 40 °C;
flow: l.5mL/min.
Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-N-(4-[[(4-fluorooxan-4-yl)methyl]a mino]-3-nitrobenzenesulfonyl)- 2-[(l l,l l,l2,l2-2H4)-l3-oxa-2,4,l0-triazatricyclo[7.4.0.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen- lO-yl]benzamide: Into a 8-mL vial, was placed 4-(4-[[2-(4-chlorophenyl)-4,4- dimethylcyclohex-l-en-l-yl]methyl]piperazin-l-yl)-2-[(l l,l l,l2,l2-2H4)-l3-oxa-2,4,l0- triazatricyclo[7.4.0.0 A [3,7]]trideca-l,3(7),5,8-tetraen-l0-yl]benzoic acid (9 mg, 0.01 mmol, 1 equiv), 4-[[(4-fluorooxan-4-yl)methyl]amino]-3-nitrobenzene-l-sulfon amide (6.3 mg, 0.02 mmol, 1.3 equiv), DCM (2 mL), DMAP (7.1 mg, 0.06 mmol, 3.98 equiv), EDCI (5.6 mg,
0.03 mmol, 2 equiv). The resulting solution was stirred for overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloro methane/methanol (10: 1). This resulted in 6 mg (44.10%) of 4-(4- [[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl]p iperazin-l-yl)-N-(4-[[(4- fluorooxan-4-yl)methyl]amino]-3-nitrobenzenesulfonyl)-2-[(l 1, 11, 12, 12-2H4)- l3-oxa- 2,4,l0-triazatricyclo[7.4.0.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzamide as a yellow solid. LC-MS-PH-PHNW-4-34-0: (ES, m/z): M+l=93 l. The measurements of the retention were done with a reversed phase column (C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18 , 2.6 microm; Eluent A: water (0.05 % TFA); Eluent B: Acetonitrile; linear gradient from 5 % acetonitrile to 100 % acetonitrile in 3.5 minutes; Oven temperature 40 °C;
flow: l.5mL/min. H-NMR-PH-PHNW-4-34-0: (d-DMSO, 300 ppm): 8.57(s, 1H), 8.37(s, 1H), 7.58-7.55(m, 1H), 7.37-7.35 (m, 3H), 7.08-7.05(m, 3H), 6.87-6.76(m, 3H), 3.76-3.73(m, 6H), 3.57-3.53(m, 6H), 3.33(m, 3H), 2.76-2.73(m, 2H), 2.26-2.20(m, 6H), l.98(m, 2H), 1.81- l.76(m, 5H), l.4l-l.39(m, 5H), l.39(m, 4H), 0.9l-0.88(m, 6H).
Example 18: Preparation of 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l’- biphenyl]-2-yl)methyl)piperazin-l-yl)-N-((4-(((4-fluorotetra hydro-2H-pyran-4- yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(2-methyl-2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)benzamide Synthesis of tert-butyl l-(5-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- pyrrolo[2,3-b]pyridin-6-yloxy)propan-2-ylcarbamate. Into a 250mL round-bottom flask was placed tert-butyl 1 -hydro xypropan-2-ylcarbamate (2.28 g, 13.05 mmol, 1.50 equiv), DMF (30 mL), NaH (0.87 g, 21.75 mmol, 2.50 equiv) at 0 °C for 10 min. 5-bromo-6-fluoro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine (3.0 g, 8.70 mmol, 1.00 equiv) was added. The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 200 mL of H 2 0. The resulting solution was extracted with 3x300 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1x200 mL of H 2 0 and 1x200 mL sodium chloride(aq). The resulting mixture was
concentrated under vacuum. The residue was applied onto a silica gel column with PE/EA (5:1). This resulted in 2.2g (50%) of tert-butyl l-(5-bromo-l-((2-
(trimethylsilyl)ethoxy)methyl)- lH-pyrrolo[2,3-b]pyridin-6-yloxy)propan-2-ylcarbamate as a yellow oil. LC-MS-PH-PHNW-4-35-l(ES, m/z) LC-MS (M+l): 502; RT=L50 min.The measurements of the retention were done with a reversed phase column (Cl 8). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microm; Eluent A: water (0.05% TFA);
Eluent B: Acetonitrile; linear gradient from 5 % acetonitrile to 100 % acetonitrile in 2.0 minutes; Oven temperature 40 °C; flow: 1.5 mL/min.
Synthesis of tert-butyl 2-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazine-l(6H) -carboxylate. Into a lOOmL round- bottom flask was placed tert-butyl l-(5-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- pyrrolo[2,3-b]pyridin-6-yloxy)propan-2-ylcarbamate (2.2 g, 4.39 mmol, 1.00 equiv), dioxane (25 mL), Cs 2 C0 3 (4.30 g, 13.17 mmol, 3.00 equiv), X-phosPd 3G (1.04 g, 1.317 mmol, 0.30 equiv). The resulting solution was stirred overnight at l00°C under N 2 . The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with PE/EA (3:1). This resulted in 1.26 g (68%) of tert-butyl 2-methyl-6-((2- (trimethylsilyl)ethoxy)methyl)-2,3-dihydropyrrolo[3’,2’: 5,6]pyrido[2,3-b][l,4]oxazine- 1 (6H)-carboxylate as a yellow oil LC-MS-PH-PHNW-4-35-2(ES, m/z) LC-MS (M+l): 420; RT=L84 min.The measurements of the retention were done with a reversed phase column (C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-ODS, 2.6 microm; Eluent A: water (0.05% TFA); Eluent B: Acetonitrile; linear gradient from 5 % acetonitrile to 100 % acetonitrile in 2.6 minutes; Oven temperature 40 °C; flow: 1.0 mL/min.
Synthesis of 2-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)- 1 ,2,3,6-tetrahydropyrrolo [3’,2’:5,6] pyrido[2,3-b][l,4]oxazine: Into a 250mL round-bottom flask was placedtert-butyl 2-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydropyr rolo[3’,2’:5,6]pyrido[2,3- b][l,4]oxazine-l(6H)-carboxylate (1.26 g, 3.00 mmol, 1.00 equiv), DCM (15 mL), ZnBr 2 (10.0 g, 30 mmol, 10.0 equiv). The resulting solution was stirred at room temperature for 3 h. The resulting solution was diluted with 50 mL of NaHC0 3 . The resulting solution was extracted with 3x50 mL of DCM and the organic layers combined. The resulting mixture was washed with 1x50 mL of H 2 0 and 1x50 mL sodium chloride(aq). The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with PE/EA (1:1). This resulted in 800 mg (83%) of 2-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)- l,2,3,6-tetrahydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]ox azine as a yellow oil.LC-MS-PH- PHNW-4-35-3(ES, m/z ): LC-MS (M+l): 320; RT=l.54 min.The measurements of the retention were done with a reversed phase column (C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-ODS, 2.6 microm; Eluent A: water (0.05% TFA); Eluent B: Acetonitrile; linear gradient from 5 % acetonitrile to 100 % acetonitrile in 2.6 minutes; Oven temperature 40 °C; flow: 1.0 mL/min.
Synthesis of methyl 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l’-b iphenyl]- 2-yl)methyl) piperazin-l-yl)-2-(2-methyl-6-((2-(trimethylsilyl)ethoxy)met hyl)-2,3- dihydropyrrolo[3’,2’:5,6] pyrido [2, 3-b][l,4]oxazin-l(6H)-yl) benzoate: Into a lOOmL round- bottom flask was placed tert-butyl l-(5-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- pyrrolo[2,3-b]pyridin-6-yloxy)propan-2-ylcarbamate (300 mg, 0.94 mmol, 1.00 equiv), dioxane (15 mL), Cs 2 C0 3 (920 mg, 2.82 mmol, 3.00 equiv), XantphosPd 2G (83 mg, 0.094 mmol, 0.10 equiv), methyl 2-bromo-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[ l,l’- biphenyl]-2-yl)methyl)piperazin-l-yl)benzoate(l.O g, 1.88 mmol, 2.00equiv). The resulting solution was stirred overnight at H0°C under N 2 . The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with PE/EA (5:1). This resulted in 360 mg (50%) of methyl 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l’- biphenyl]-2-yl)methyl)piperazin-l-yl)-2-(2-methyl-6-((2-(tri methylsilyl)ethoxy)methyl)-2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)benzoate as a yellow oil . LC- MS-PH-PHNW-4-35-4(ES, m/z) LC-MS (M+l): 770; RT=l.56 min. The measurements of the retention were done with a reversed phase column (C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-ODS, 2.6 microm; Eluent A: water (0.05% TFA); Eluent B: Acetonitrile; linear gradient from 5 % acetonitrile to 100 % acetonitrile in 2.6 minutes; Oven temperature 40 °C; flow: 1.0 mL/min.
Synthesis of methyl 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l’-b iphenyl]- 2-yl)methyl) piperazin-l-yl)-2-(2-methyl-2,3-dihydropyrrolo[3’,2’:5,6 ]pyrido[2,3- b][l,4]oxazin-l(6H)-yl) benzoate Into a lOOmL round-bottom flask was placedtert-butyl methyl 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l’-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2-methyl-6-((2-(trimethylsilyl) ethoxy)methyl)-2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)benzoate (300 mg, 0.39 mmol, 1.00 equiv), THF (10 mL), TBAF(3.0 g), ethane- l,2-diamine(5mL). The resulting solution was stirred overnight at 60°C. The resulting mixture was concentrated under vacuum. The mixture was adjust PH<7 by 2N HC1. The resulting solution was extracted with 3x200 mL of EA and the organic layers combined. The resulting mixture was washed with 1x10 mL of H 2 0 and 1x10 mL sodium chloride(aq). The resulting mixture was concentrated under vacuum. This resulted in 120 mg (48%) of methyl 4-(4-((4’-chloro-5,5-dimethyl-3, 4,5,6- tetrahydro- [1,1’ -biphenyl] -2-yl)methyl)piperazin- 1 -yl) -2-(2-methyl-2,3 - dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)benzoate as a yellow oil. LC- MS-PH-PHNW-4-35-5(ES, m/z ): LC-MS (M+l): 640; RT=2.82 min. The measurements of the retention were done with a reversed phase column (C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u HPH-C18, 2.6 microm; Eluent A: water (0.05% NH4HCO3); Eluent B:
Methanol; linear gradient from 10 % acetonitrile to 98 % acetonitrile in 3.5 minutes; Oven temperature 40 °C; flow:0.8mL/min.
Synthesis of 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l’-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2-methyl-2,3-dihydropyrrolo[3 ,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl) benzoic acid. Into a 50mL round-bottom flask was methyl 4-(4-((4’- chloro-5,5-dimethyl-3, 4, 5, 6-tetrahydro-[ 1,1’-biphenyl] -2-yl)methyl)piperazin-l-yl)-2-(2- methyl-2, 3-dihydropyrrolo[3’, 2’ :5,6]pyrido[2,3-b][l,4]oxazin-l(6H)-yl)benzoate (70 mg, 0.11 mmol, 1.00 equiv), MeOH/H 2 0 (5/5 mL), NaOH (44 mg, 1.10 mmol, 10 equiv). The resulting solution was stirred at 60°C for 3h. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1). This resulted in 50 mg (73%) of 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [l,l’-biphenyl]-2-yl)methyl)piperazin-l-yl)-2-(2-methyl-2, 3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)benzoic acid as a white soild. LC-MS-PH-PHNW-4-35-6(ES, m/z) LC-MS (M+l): 626; RT=2.45 min. The measurements of the retention were done with a reversed phase column (Cl 8). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u HPH-C18, 2.6 microm; Eluent A: water (0.05% NH4HCO3); Eluent B: Methanol; linear gradient from 10 % acetonitrile to 98 % acetonitrile in 3.5 minutes; Oven temperature 40 °C; flow:0.8mL/min
Synthesis of 4-(4-((4’-chloro-5, 5-dimethyl-3, 4, 5, 6-tetrahydro-[ 1,1’-biphenyl] -2-yl) methy l)piperazin-l-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl) methyl)amino)-3- nitropheny l)sulfonyl)-2-(2-methyl-2,3-dihydropyrrolo[3’,2’:5,6]pyr ido[2,3-b][l,4]oxazin- l(6H)-yl)benzamide: Into a 50-mL l-necked round-bottom flask was placed 4-(4-((4’-chloro- 5,5-dimethyl-3,4,5,6-tetrahydro-[l,l’-biphenyl]-2-yl)methy l)piperazin-l-yl)-2-(2-methyl-2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)benzoic acid (40 mg, 0.064 mol, 1.00 equiv), DCM (4 mL), EDCI (49 mg, 0.256 mmol, 4.00 equiv), DMAP (16 mg, 0.128 mmol, 2.00 equiv), 4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3- nitrobenzenesulfonamide(28 mg, 0.0832 mol, 1.30 equiv). The resulting solution was stirred overnight at 40 °C. The resulting mixture was concentrated under vacuum. This resulted in 2.9 mg (70%) of 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l’-b iphenyl]-2- yl)methyl)piperazin-l-yl)-N-((4-(((4-fluorotetrahydro-2H-pyr an-4-yl)methyl)amino)-3- nitrophenyl)sulfonyl)-2-(2-methyl-2,3-dihydropyrrolo[3’,2 :5,6]pyrido[2,3-b][l,4]oxazin- 1 (6H)-yl)benzamide as a yellow soild.LC-MS-PH-PHNW-4-35-0A(ES, m/z) LC-MS (M+l):94l; RT=5.02 min. The measurements of the retention were done with a reversed phase column (C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u Ascends Express C18, 2.6 microm; Eluent A: water (0.05% TFA); Eluent B: Methanol; linear gradient from 5 % acetonitrile to 95 % acetonitrile in 7.0 minutes; Oven temperature 40 °C; flow:l.0mL/min.
Example 19: Preparation of (S)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l - biphenyl]-2-yl)methyl)piperazin-l-yl)-N-((4-(((4-fluorotetra hydro-2H-pyran-4- yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(3-methyl-2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)benzamide and (R)-4-(4-((4’- chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l’-biphenyl]-2-y l)methyl)piperazin-l-yl)-N-((4- (((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophe nyl)sulfonyl)-2-(3-methyl-2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)benzamide
Synthesis of l2-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-l3-oxa-2,4,l0 - triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l l-one: Into a 100- mL round-bottom flask, was placed 5-amino- l-[[2-(trimethylsilyl)ethoxy]methyl]-lH-pyrrolo[2,3-b]pyridi n-6- ol (1.5 g, 5.37 mmol, 1 equiv), DMF (50 mL), K 2 C0 3 (2.2 g, 16.11 mmol, 3 equiv). This was followed by the addition of 2-chloropropanoyl chloride (1.4 g, 10.74 mmol, 2 equiv) dropwise with stirring at 0 °C. The resulting solution was stirred for overnight at room temperature. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 2x50 mL of ethyl acetate. The resulting mixture was washed with 2 x50 mL of brine. The mixture was dried over anhydrous sodium sulfate and filtrate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0:1- 1:3). This resulted in 500 mg (27.93%) of l2-methyl- 4-[[2-(trimethylsilyl)ethoxy]methyl]-l3-oxa-2,4,l0-triazatri cyclo[7.4.0.0 A [3,7]]trideca- l(9),2,5,7-tetraen-l l-one as a yellow solid. LC-MS-PH-PHNW-4-37-1: (ES, m/z) M+l=334, R,T= 1.123 min. The measurements of the retention were done with a reversed phase column (C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18 , 2.6 microm; Eluent A: water (0.05 % TFA); Eluent B: Acetonitrile; linear gradient from 5 % acetonitrile to 100 % acetonitrile in 3.5 minutes; Oven temperature 40 °C; flow:l.5mL/min. H-NMR-PH-PHNW- 4-37-1: (CDC13, 300 ppm): 8.34 (s, 1H), 7.63 (d, J= 3 Hz, 1H), 7.42-7.28 (m, 1H), 6.46(d,
J= 3 Hz, 1H), 5.68(s, 2H), 4.92-4.85(m, 1H), 3.63-3.53(m, 2H), l.85-l.8l(d, J= 12 Hz, 3H), 0.94-0.89(m, 2H), -0.l54(s, 9H). The measurements of the NMR spectra were done with BrukerAvancelll HD 300MHzwith a probe head of BBOF.
Synthesis of l2-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-l3-oxa-2,4,l0 - triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraene & (12R or S)-l2-methyl-4-[[2- (trimethylsilyl)ethoxy]methyl]-l3-oxa-2,4,l0-triazatricyclo[ 7.4.0.0 A [3,7]]trideca-l(9),2,5,7- tetraen e(Assumed) & (12S or R)-l2-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-l3-oxa- 2,4,l0-triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraene(A55Mme < i): Into a lOO-mL 3- necked round-bottom flask, was placed l2-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-l3- oxa-2,4,l0-triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l l-one (500 mg, 1.50 mmol,
1 equiv), THF (20 mL). This was followed by the addition of LiAlH 4 (113.8 mg, 3.00 mmol,
2 equiv), in portions at 0 °C. The resulting solution was stirred for 1 overnight at room temperature. The reaction was then quenched by the addition of 20 mL of water. The solids were filtered out. The resulting solution was extracted with 2x20 mL of ethyl acetate. The resulting mixture was washed with 2 x20 mL of brine. The mixture was dried over anhydrous sodium sulfate and filtrate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0:1- 1:3). This resulted in 450 mg (93%) of l2-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-l3-oxa-2,4,l0 - triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraene as a yellow solid.
The crude l2-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-l3-oxa-2,4,l0 - triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraene (450 mg) was purified by Chiral-Prep- HPLC with the following conditions: (SHIMADZU LC-20AT): Column, CHIRALPAK IC; mobile phase A:n-hexane, Phase B:ethanol; Detector, 220 nm. This resulted in 200 mg (44%) of (12R or S)-l2-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-l3-oxa-2,4 ,l0- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraene as a yellow solid {Assumed). This resulted in 200 mg (44%) of (12S or R)-l2-methyl-4-[[2- (trimethylsilyl)ethoxy]methyl]-l3-oxa-2,4,l0-triazatricyclo[ 7.4.0.0 A [3,7]]trideca-l(9),2,5,7- tetraene as a yellow solid {Assumed).
LC-MS-PH-PHNW-4-37-2: (ES, m/z) M+l=320, R,T= 1.107 min.
The measurements of the retention were done with a reversed phase column (Cl 8). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18 , 2.6 microm; Eluent A: water (0.05 % TFA); Eluent B: Acetonitrile; linear gradient from 5 % acetonitrile to 100 % acetonitrile in 3.5 minutes; Oven temperature 40 °C; flow: l.5mL/min.
H-NMR-PH-PHNW-4-37-2: (CDC13, 300 ppm): 7.63 (s, 1H), 7.17 (s, 1H), 6.36-
6.35(d, J= 3 Hz, 1H), 5.57-5.52(m, 2H), 4.59-4.55(m, 1H), 3.62-3.46(m, 3H), 3. l8-3. l4(m, 1H), l.62-l.44(m, 3H), 0.93-0.88(m, 2H), -0. l7(s, 9H).
Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-2-[(l2R or S)-l2-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-l3- oxa-2,4,l0-triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,4,l0- triazatricyclo[7.4.0.0 A 3,7]trideca- 1(9), 2, 5, 7- tctracn- 10-ylJ bcn/oatc(As.sw/7; <¾ /): Into a 8-mL vial, was placed (l2R)-l2-methyl- 4-[[2-(trimethylsilyl)ethoxy]methyl]-l3-oxa-2,4,l0-triazatri cyclo[7.4.0.0 A [3,7]]trideca- l(9),2,5,7-tetraene (200 mg, 0.63 mmol, 1 equiv), methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)- 4, 4-dimethylcyclo hex- l-en-l-yl]methyl]piperazin- l-yl) benzoate (399.6 mg, 0.75 mmol, 1.2 equiv), CS 2 CO 3 (611.9 mg, 1.88 mmol, 3 equiv), Dioxane (5 mL), Chloro[9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene][2-amino-l,l-biphenyl-2-yl]pa lladium(II) (120 mg). The resulting solution was stirred for 2 hr at 110 °C in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0: 1-1: 10). This resulted in 250 mg (51.83%) of methyl 4-(4-[[2-(4- chlorophenyl)-4, 4-dimethylcyclo hex- l-en- l-yl]methyl]piperazin- l-yl)-2-[(l2R or S)- 12- methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]- l3-oxa-2,4, 10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,4,l0- triazatricyclo[7.4.0.0 A 3,7]trideca-l(9),2,5,7- tetraen-lO-yl]benzoate as a yellow solid(Assumed).
Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl] methyl]piperazin- 1 -yl)-2- [( 12R or S )- 12-methyl- 13 -oxa-2,4, 10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzoate(Assume d) Into a 100- mL round-bottom flask, was placed methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex- l-en-l-yl]methyl]piperazin-l-yl)-2-[(l2R or S)-l2-methyl-4-[[2-
(trimethylsilyl)ethoxy]methyl]-l3-oxa-2,4,l0-triazatricyc lo[7.4.0.0 A [3,7]]trideca-l(9),2 (250 mg, 0.32 mmol, 1 equiv), TBAF (3 g, 11.47 mmol, 35.36 equiv), THF (30 mL), ethane-l,2- diamine (2 g, 33.28 mmol, 102.56 equiv). The resulting solution was stirred for 12 h at 70 °C in an oil bath. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 2x50 mL of ethyl acetate. The resulting mixture was washed with 3 x50 mL of brine. The mixture was dried over anhydrous sodium sulfate and filtrate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0: 1- 1:3). This resulted in 90 mg (43%) of methyl 4-(4- [[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl]p iperazin-l-yl)-2-[(l2R or S)- l2-methyl-l3-oxa-2,4,l0-triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0- yl]benzoate as a yellow solid(Assumed).H-NMR-PH-PHNW-4-37-50: (CDC13, 300 ppm): 8.24(s, 1H), 7.89-7.86(d, /= 9 Hz, 1H), 7.32-7.24 (m, 6H), 7.14-7.01 (m, 1H), 6.97-6.94(m, 2H), 6.73-6.65(m, 2H), 6. l8(s, 1H), 3.67-3.53(m, 3H), 3.32-3. l8(m, 3H), 2.98-2.80(m, 1H), 2.30-2.04(m, 6H), l.99(s, 2H), l.56-l.50(m, 5H), 0.9l-0.88(m, 6H).
Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl] methyl]piperazin- 1 -yl)-2- [( 12R or S )- 12-methyl- 13 -oxa-2,4, 10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzoic acid( Assumed). Into a 8- mL vial, was placed methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl] methyl]piperazin- 1 -yl)-2- [( 12R or S )- 12-methyl- 13 -oxa-2,4, 10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzoate (90 mg, 0.14 mmol, 1 equiv), MeOH (1 mL), H 2 0 (1 mL), THF (1 mL), NaOH (22.5 mg, 0.56 mmol, 4 equiv). The resulting solution was stirred for overnight at 60 °C in an oil bath. The pH value of the solution was adjusted to 5 with HC1 (1 mol/L). The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (1:0-10: 1). This resulted in 80 mg (90%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
1-en-l-yl]methyl]piperazin-l-yl)-2-[(l2R or S)-l2-methyl-l3-oxa-2,4,l0- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzoic acid as a yellow solid(Assumed). LC-MS-PH-PHNW-4-37-60: (ES, m/z ): M+l=626, R,T= 1.035 min. vThe measurements of the retention were done with a reversed phase column (Cl 8). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18 , 2.6 microm; Eluent A: water (0.05 % TFA); Eluent B: Acetonitrile; linear gradient from 5 % acetonitrile to 100 % acetonitrile in 3.5 minutes; Oven temperature 40 °C; flow: l.5mL/min.
Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-N-(4-[[(4-fluorooxan-4-yl)methyl]a mino]-3-nitrobenzenesulfonyl)-
2-[(l2R or S)-l2-methyl-l3-oxa-2,4,l0-triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen- lO-yl]benzamide(Assumed): Into a 8-mL vial, was placed 4-(4-[[2-(4-chlorophenyl)-4,4- dimethylcyclohex- l-en- l-yl]methyl]piperazin- l-yl)-2-[(l2R or S)-l2-methyl-l3-oxa-2,4,l0- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzoic acid (90 mg, 0.14 mmol,
1 equiv), 4-[[(4-fluorooxan-4-yl)methyl]amino]-3-nitrobenzene-l-sulfon amide (57.5 mg,
0.17 mmol, 1.2 equiv), DCM (5 mL), DMAP (70.2 mg, 0.57 mmol, 4 equiv), EDCI (55.1 mg, 0.29 mmol, 2.00 equiv). The resulting solution was stirred for overnight at room
temperature. The resulting mixture was concentrated. The crude product was purified by Flash- Prep-HPLC with the following conditions (IntelFlash-l): Column, C18 silica gel;
mobile phase, Water(0. l%FA) and ACN (48.0% ACN up to 53.0% in 7 min, hold 95.0% in 1 min, down to 48.0% in 1 min, hold 48.0% in 1 min) within 5 min; Detector, UV 254 nm. This resulted in 28 mg (20%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-N-(4-[[(4-fluorooxan-4-yl)methyl]a mino]-3-nitrobenzenesulfonyl)- 2-[(l2R or S)-l2-methyl-l3-oxa-2,4,l0-triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen- l0-yl]benzamide as a yellow solid( Assumed). 19.8 mg product was submited(Assumed). LC- MS-PH-PHNW-4-37-0: (ES, m/z) M+l=94l, R,T= 3.04 min. The measurements of the retention were done with a reversed phase column (C18). Shimadzu FCMS 2020; 50*3.0 Kinetex 2.6u XB-C18 , 2.6 microm; Eluent A: water (0.05 % TFA); Eluent B: Acetonitrile; linear gradient from 5 % acetonitrile to 100 % acetonitrile in 3.5 minutes; Oven temperature 40 °C; flow: l.5mL/min. H-NMR-PH-PHNW-4-37-0: (d-DMSO, 300 ppm): 8.59(s, 1H), 8.54(s, 1H), 7.55-7.53(m, 1H), 7.36-7.29 (d, /=6Hz, 3H), 7.12-7.06 (m, 3H), 6.80-6.72(m, 3H), 5.95(m, 1H), 4.53-4.5l(m, 1H), 3.78-3.43(m, 7H), 3.2l-3.00(m, 5H), 2.22-2. l7(m, 5H), l.96-l.75(m, 6H), l.58-l.56(m, 5H), 0.93-0.88(m, 6H).
Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl] methyl]piperazin- 1 -yl)-2- [( 12S or R)- 12-methyl-4- [ [2-(trimethylsilyl)ethoxy] methyl] -13- oxa-2,4,l0-triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,2,5,7- tetraen-lO- yl]benzoate( Assumed): Into a 8-mL vial, was placed (12S or R)-l2-methyl-4-[[2- (trimethylsilyl)ethoxy]methyl]-l3-oxa-2,4,l0-triazatricyclo[ 7.4.0.0 A [3,7]]trideca-l(9),2,5,7- tetraene (200 mg, 0.63 mmol, 1 equiv), methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4- dimethylcyclohex-l-en-l-yl]methyl]piperazin-l-yl)benzoate (399.6 mg, 0.75 mmol, 1.2 equiv), CS 2 CO 3 (611.9 mg, 1.88 mmol, 3 equiv), Dioxane (5 mL), Chloro[9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene][2-amino-l,l-biphenyl-2-yl]pa lladium(II) (120 mg). The resulting solution was stirred for 2 h at 110 °C in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0: 1-1: 10). This resulted in 250 mg (51%) of methyl 4-(4-[[2-(4- chlorophenyl)-4, 4-dimethylcyclo hex- l-en- l-yl]methyl]piperazin- l-yl)-2-[(l2S or R)- 12- methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]- l3-oxa-2,4, 10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,2,5,7- tetraen-lO-yl] benzoate as a yellow
solid(Assumed).
Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl] methyl]piperazin- 1 -yl)-2- [( 12S or R)- 12-methyl- 13 -oxa-2,4, 10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzoate (Assumed): into a 100- mL round-bottom flask, was placed methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex- l-en-l-yl]methyl]piperazin-l-yl)-2-[(l2S or R)-l2-methyl-4-[[2-
(trimethylsilyl)ethoxy]methyl]-l3-oxa-2,4,l0-triazatricyc lo[7.4.0.0 A [3,7]]trideca-l(9),2 (250 mg, 0.32 mmol, 1 equiv), TBAF (3 g, 11.47 mmol, 35.36 equiv), THF (30 mL), ethane-l,2- diamine (2 g, 33.28 mmol, 102.56 equiv). The resulting solution was stirred for 12 h at 70 °C in an oil bath. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 2x50 mL of ethyl acetate. The resulting mixture was washed with 3 x50 mL of brine. The mixture was dried over anhydrous sodium sulfate and filtrate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0: 1- 1:3). This resulted in 90 mg (43%) of methyl 4-(4- [[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl]p iperazin-l-yl)-2-[(l2S or R)- l2-methyl-l3-oxa-2,4,l0-triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0- yl]benzoate as a yellow solid(Assumed).
LC-MS-PH-PHNW-4-38-50: (ES, m/z) M+l=640, R,T= 1.424 min. The
measurements of the retention were done with a reversed phase column (Cl 8). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18 , 2.6 microm; Eluent A: water (0.05 % TFA); Eluent B: Acetonitrile; linear gradient from 5 % acetonitrile to 100 % acetonitrile in 3.5 minutes; Oven temperature 40 °C; flow: l.5mL/min. H-NMR-PH-PHNW-4-38-50: (CDC13,
300 ppm): 8.24(s, 1H), 7.89-7.86(d, J= 9 Hz, 1H), 7.32-7.24 (m, 6H), 7.14-7.01 (m, 1H), 6.97-6.94(m, 2H), 6.73-6.65(m, 2H), 6. l8(s, 1H), 3.67-3.53(m, 3H), 3.32-3. l8(m, 3H), 2.98- 2.80(m, 1H), 2.30-2.04(m, 6H), l.99(s, 2H), l.56-l.50(m, 5H), 0.9l-0.88(m, 6H).
Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl] methyl]piperazin- 1 -yl)-2- [( 12S or R)- 12-methyl- 13 -oxa-2,4, 10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzoic acid (Assumed): Into a 8- mL vial, was placed methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl] methyl]piperazin- 1 -yl)-2- [( 12S or R)- 12-methyl- 13 -oxa-2,4, 10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzoate (90 mg, 0.14 mmol, 1 equiv), MeOH (1 mL), ¾0 (1 mL), THF (1 mL), NaOH (22.5 mg, 0.56 mmol, 4.00 equiv). The resulting solution was stirred for overnight at 60 °C in an oil bath. The pH value of the solution was adjusted to 5 with HC1 (1 mol/L). The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with chloroform/methanol (1:0- 10:1). This resulted in 80 mg (90%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l- en- l-yl]methyl]piperazin- l-yl)-2-[(l2S or R)-l2-methyl-l3-oxa-2,4,l0- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzoic acid as a solid( Assumed): LC-MS-PH-PHNW-4-38-60: (ES, m/z) M+l=626, R,T= 1.039 min. The measurements of the retention were done with a reversed phase column (C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18 , 2.6 microm; Eluent A: water (0.05 % TFA); Eluent B: Acetonitrile; linear gradient from 5 % acetonitrile to 100 % acetonitrile in 3.5 minutes; Oven temperature 40 °C; flow:l.5mL/min.
Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-N-(4-[[(4-fluorooxan-4-yl)methyl]a mino]-3-nitrobenzenesulfonyl)- 2-[(l2S or R)-l2-methyl-l3-oxa-2,4,l0-triazatricyclo[7.4.0.0 A [3,7]]trideca- 1(9), 2,5,7- tetraen-lO-yl]benzamide(Assumed): Into a 8-mL vial, was placed 4-(4-[[2-(4-chlorophenyl)- 4,4-dimethylcyclohex- l-en- l-yl]methyl]piperazin- l-yl)-2-[(l2S or R)-l2-methyl-l3-oxa- 2,4,l0-triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzoic acid (90 mg, 0.14 mmol, 1 equiv), 4-[[(4-fluorooxan-4-yl)methyl]amino]-3-nitrobenzene-l-sulfon amide (57.5 mg, 0.17 mmol, 1.2 equiv), DCM (5 mL), DMAP (70.2 mg, 0.57 mmol, 4 equiv), EDCI (55.1 mg, 0.29 mmol, 2 equiv). The resulting solution was stirred for overnight at room
temperature. The resulting mixture was concentrated. The crude product was purified by Flash- Prep-HPLC with the following conditions (IntelFlash-l): Column, C18 silica gel;
mobile phase, Water (0.l%FA) and ACN (48.0% ACN up to 53.0% in 7 min, hold 95.0% in 1 min, down to 48.0% in 1 min, hold 48.0% in 1 min) within 5 min; Detector, UV 254 nm. This resulted in 26 mg (19%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-N-(4-[[(4-fluorooxan-4-yl)methyl]a mino]-3-nitrobenzenesulfonyl)- 2-[(l2S or R)-l2-methyl-l3-oxa-2,4,l0-triazatricyclo[7.4.0.0 A [3,7]]trideca- 1(9), 2,5,7- tetraen-lO-yl]benzamide as a yellow solid. 19.6 mg product was submitted(Assumed). LC- MS-PH-PHNW-4-38-0: (ES, m/z) M+l=94l, R,T= 3.036 min. The measurements of the retention were done with a reversed phase column (C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18 , 2.6 microm; Eluent A: water (0.05 % TFA); Eluent B: Acetonitrile; linear gradient from 5 % acetonitrile to 100 % acetonitrile in 3.5 minutes; Oven temperature 40 °C; flow:l.5mL/min. H-NMR-PH-PHNW-4-38-0: (d-DMSO, 300 ppm): 8.56(s, 1H), 8.36(s, 1H), 7.62-7.54(m, 1H), 7.37-7.30 (m, 3H), 7.l4-7.04(m, 3H), 6.98-6.92(m, 3H), 5.94(m, 1H), 4.53(m, 1H), 3.79-3.7l(m, 4H), 3.65-3.54(m, 3H), 3.44(m, 4H), 2.78-2.73(m, 2H), 2.23-2. l8(m, 6H), l.97-l.9l(m, 2H), l.87-l.8l(m, 4H), l.50-l.20(m, 5H), 0.9l-0.88(m, 6H).
Example 20: Preparation of 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l’- biphenyl]-2-yl)methyl)piperazin-l-yl)-2-(3,3-dimethyl-2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((4-(((4-fluorotetraliydro-2H- pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide
Synthesis of l2,l2-dimethyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-l3-oxa-2 ,4,l0- triazatricyclo[7.4.0.0 A [3,7]]trideca-l,3(7),5,8-tetraen-l l-one: Into a 100- mL round-bottom flask, was placed 5-amino- l-[[2-(trimethylsilyl)ethoxy]methyl]-lH-pyrrolo[2,3-b]pyridi n-6- ol (1 g, 3.58 mmol, 1 equiv), CFLCN (20 mL), methyl 2-bromo-2-methylpropanoate (647.9 mg, 3.58 mmol, 1.0 equiv), CS 2 CO 3 (1.7 g, 5.37 mmol, 1.5 equiv). The resulting solution was stirred for 2 h at 80 °C in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3). This resulted in 270 mg (21%) of l2,l2-dimethyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-l3- oxa-2,4,l0-triazatricyclo[7.4.0.0 A [3,7]]trideca-l,3(7),5,8-tetraen-l l-one as a light yellow solid. LC-MS-PH-PHNW-4-40-2: (ES, m/z ): M+l=348, R,T= 1.164 min. The measurements of the retention were done with a reversed phase column (Cl 8). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18 , 2.6 microm; Eluent A: water (0.05 % TFA); Eluent B:
Acetonitrile; linear gradient from 5 % acetonitrile to 100 % acetonitrile in 3.5 minutes; Oven temperature 40 °C; flow:l.5mL/min.
Synthesis of l2,l2-dimethyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-l3-oxa-2 ,4,l0- triazatricyclo[7.4.0.0 A [3,7]]trideca-l,3(7),5,8-tetraene: Into a 8-mL vial, was placed 12,12- dimethyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-l3-oxa-2,4,l0- triazatricyclo[7.4.0.0 A [3,7]]trideca-l,3(7),5,8-tetraen-l l-one (250 mg, 0.72 mmol, 1 equiv), THF (3 mL). This was followed by the addition of L1AIH4 (54.6 mg, 1.44 mmol, 2 equiv), in portions at 0 °C. The resulting solution was stirred for overnight at room temperature. The reaction was then quenched by the addition of 5 mL of water. The solids were filtered out. The resulting solution was extracted with 2x10 mL of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0:1- 1:5). This resulted in 140 mg (58%) of l2,l2-dimethyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-l3-oxa-2 ,4,l0- triazatricyclo[7.4.0.0 A [3,7]]trideca-l,3(7),5,8-tetraene as a yellow solid. Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl] methyl]piperazin- 1 -yl)-2-( 12, l2-dimethyl-4- [[2-(trimethylsilyl)ethoxy] methyl] - 13-oxa- 2,4,l0-triazatricyclo[7.4.0.0 A [3,7]]trideca-l,3(7), 5,8-tetraen-l0-yl)benzoate: Into a 8-mL vial, was placed 12, l2-dimethyl-4-[[2-(trimethylsilyl)ethoxy]methyl]- l3-oxa-2,4, 10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l,3(7),5,8-tetraene (140 mg, 0.42 mmol, 1 equiv), methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex- l-en- l-yl]methyl]piperazin- 1- yl)benzoate (267.9 mg, 0.50 mmol, 1.2 equiv), CS 2 CO 3 (410.3 mg, 1.26 mmol, 3 equiv), Dioxane (2 mL), Chloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene][2-am ino-l,l- biphenyl-2-yl]palladium(II) (80 mg). The resulting solution was stirred for 2 h at 110 °C in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0:1- 1:3). This resulted in 130 mg (39%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl] methyl]piperazin- 1 -yl)-2-( 12, l2-dimethyl-4- [[2-(trimethylsilyl)ethoxy] methyl] - 13-oxa- 2,4,l0-triazatricyclo[7.4.0.0 A [3,7]]trideca-l,3(7), 5,8-tetraen-l0-yl)benzoate as a yellow solid. LC-MS-PH-PHNW-4-40-4: (ES, m/z) M+l=784, R,T= 1.331 min.The measurements of the retention were done with a reversed phase column (C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18 , 2.6 microm; Eluent A: water (0.05 % TFA); Eluent B: Acetonitrile; linear gradient from 5 % acetonitrile to 100 % acetonitrile in 3.5 minutes; Oven temperature 40 °C; flow:l.5mL/min.
Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin- l-yl)-2-[l2, l2-dimethyl- l3-oxa-2,4, 10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l,3(7),5,8-tetraen-l0-yl]benzoate: Into a 40-mL vial, was placed methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex- l-en- l-yl]methyl]piperazin- l-yl)-2-(l2,l2-dimethyl-4-[[2-(trimethylsilyl)ethoxy]methyl] -l3-oxa-2,4,l0- triazatricyclo[7.4.0.0 A [3,7]]trideca-l,3(7), (130 mg, 0.17 mmol, 1 equiv), TBAF (3 g), THF (10 mL), ethane- 1, 2-diamine (2 g). The resulting solution was stirred for overnight at 60 °C in an oil bath. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 2x10 mL of ethyl acetate. The resulting mixture was washed with 3 xlO mL of brine. The mixture was dried over anhydrous sodium sulfate and filtrate and concentrated under vacuum . The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0:1- 1:3). This resulted in 110 mg (crude) of methyl 4-(4- [[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl]p iperazin-l-yl)-2-[l2,l2- dimethyl-l3-oxa-2,4,l0-triazatricyclo[7.4.0.0 A [3,7]]trideca-l,3(7),5,8-tetraen-l0-yl]benzoate as a yellow solid. LC-MS-PH-PHNW-4-40-5: (ES, m/z) M+l=654, R,T= 1.107 min. The measurements of the retention were done with a reversed phase column (Cl 8). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18 , 2.6 microm; Eluent A: water (0.05 % TFA); Eluent B: Acetonitrile; linear gradient from 5 % acetonitrile to 100 % acetonitrile in 3.5 minutes; Oven temperature 40 °C; flow:l.5mL/min.
Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin- l-yl)-2-[l2, l2-dimethyl- l3-oxa-2,4, 10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l,3(7),5,8-tetraen-l0-yl]benzoic acid: Into a 8-mL vial, was placed methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin- l-yl)-2-[l2, l2-dimethyl- l3-oxa-2,4, 10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l,3(7),5,8-tetraen-l0-yl]benzoate (80 mg, 0.12 mmol, 1 equiv), MeOH (1 mL), THF (1 mL), ¾0 (1 mL), NaOH (19.6 mg, 0.49 mmol, 4 equiv). The resulting solution was stirred for overnight at 60 °C in an oil bath. The pH value of the solution was adjusted to 5 with HC1 (1 mol/L). The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (1:0-10:1). This resulted in 60 mg (76.64%) of 4-(4-[[2-(4-chlorophenyl)-4,4- dimethylcyclohex- l-en- l-yl]methyl]piperazin- l-yl)-2-[l2, l2-dimethyl- l3-oxa-2,4, 10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l,3(7),5,8-tetraen-l0-yl]benzoic acid as a yellow solid. LC-MS-PH-PHNW-4-40-6: (ES, m/z) M+l=640, R,T= 1.359 min.The measurements of the retention were done with a reversed phase column (C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18 , 2.6 microm; Eluent A: water (0.05 % TFA); Eluent B: Acetonitrile; linear gradient from 5 % acetonitrile to 100 % acetonitrile in 3.5 minutes; Oven temperature 40 °C; flow:l.5mL/min.
Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-2-[l2,l2-dimethyl-l3-oxa-2,4,l0- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]-N-(4-[[(4-fluo rooxan-4- yl)methyl]amino]-3-nitrobenzenesulfonyl)benzamide: Into a 8-mL vial, was placed 4-[[(4- fluorooxan-4-yl)methyl]amino]-3-nitrobenzene-l-sulfonamide (37.5 mg, 0.11 mmol, 1.2 equiv), DCM (5 mL), 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin- l-yl)-2-[l2, l2-dimethyl- l3-oxa-2,4, 10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l,3(7),5,8-tetraen-l0-yl]benzoic acid (60 mg, 0.09 mmol, 1 equiv), EDCI (35.9 mg, 0.19 mmol, 2 equiv), DMAP (45.8 mg, 0.37 mmol, 4 equiv). The resulting solution was stirred for overnight at room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-l): Column, C18 silica gel; mobile phase, Water(0.l%FA) and ACN (48.0% ACN up to 53.0% in 7 min, hold 95.0% in 1 min, down to 48.0% in 1 min within 5 ; Detector, UV 254 nm. This resulted in 25 mg (27 %) of 4-(4-[[2-(4-chlorophenyl)- 4,4-dimethylcyclohex- l-en- l-yl]methyl]piperazin- l-yl)-2-[l2, l2-dimethyl- l3-oxa-2,4, 10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]-N-(4-[[(4-fluo rooxan-4- yl)methyl]amino]-3-nitrobenzenesulfonyl)benzamide as a yellow solid. 20.6 mg product was submited. LC-MS-PH-PHNW-4-40-0: (ES, m/z) M+l=955, R,T= 2.655 min. The measurements of the retention were done with a reversed phase column (Cl 8). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18 , 2.6 microm; Eluent A: water (0.05 % TFA); Eluent B: Acetonitrile; linear gradient from 5 % acetonitrile to 100 % acetonitrile in 3.5 minutes; Oven temperature 40 °C; flow: l.5mL/min. H-NMR-PH-PHNW-4-40-0: (d-DMSO, 300 ppm): 8.56(s, 1H), 8.36(s, 1H), 7.56-7.49(m, 2H), 7.36-7.33 (m, 2H), 7.06-7.00(m, 3H), 6.93-6.90(m, 1H), 6.88-6.74(M, 2H), 5.99(m, 1H), 3.78-3.74(m, 4H), 3.67-3.50(m, 2H), 3.23(m, 4H), 2.76-2.72(m, 2H), 2.22-2. l6(m, 6H), l.96-l.75(m, 6H), l.4l-l.39(m, 8H), 0.91- 0.88(m, 6H).
Example 21: Preparation of 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l’- biphenyl]-2-yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[ 3’,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran -3- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide
Synthesis of 3-nitro-4-(((tetrahydro-2H-pyran-3- yl)methyl)amino)benzenesulfonamide : Into a 50-mL round-bottom flask, was placed (tetrahydro-2H-pyran-3-yl)methanamine (200mg, 1.74 mmol, 1.00 equiv), THF (5 mL), 4- fluoro-3-nitrobenzene-l-sulfonamide (383 mg, 1.74 mmol, 1.00 equiv), CS 2 CO 3 (1.134 g,
3.48 mmol, 2.00 equiv). The resulting solution was stirred for 3h at 50 degrees C in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/1). This resulted in 270mg (49.3%) of 3-nitro-4-(((tetrahydro-2H-pyran-3-yl)methyl)amino) benzenesulfonamide as a yellow solid. LC-MS-PH-PHNW-4-41-1: (ES, m/z) M+l=3 l6, R,T= 1.25 min. The measurements of the retention were done with a reversed phase column (C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-ODS , 2.6 microm; Eluent A: water (0.5 % FA); Eluent B:
Acetonitrile(0.05 % TFA); linear gradient from 5 % acetonitrile to 100 % acetonitrile in 2.6 minutes; Oven temperature 40 °C; flow: l.0mL/min.
Synthesis of 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l’-b iphenyl]-2- yl)methyl)piperazin-l-yl)-2-(2,3-dihydropyrrolo[3’,2’:5, 6]pyrido[2,3-b][l,4]oxazin-l(6H)- yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-3-yl)methyl)amino)p henyl)sulfonyl)benzamide:
Into a lOO-mL round-bottom flask, was placed 4-(4-[[2-(4-chlorophenyl)-4,4- dimethylcyclohex-l-en-l-yl]methyl]piperazin-l-yl)-2-[l3-oxa- 2,4,l0- triazatricyclo[7.4.0.0 A [3,7]]trideca-l,3(7),5,8-tetraen-l0-yl]benzoic acid (50 mg, 0.082 mmol, 1.00 equiv) in dichloromethane (5 mL), EDCI (63 mg, 0.328 mmol, 4.00 equiv), 4- dimethylaminopyridine (20 mg, 0.164 mmol, 2.00 equiv), 3-nitro-4-(((tetrahydro-2H-pyran- 4-yl)methyl)amino)benzenesulfonamide (26 mg, 0.082mmol, 1.00 equiv). The resulting solution was stirred for overnight at 40°C. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Waters-2767): Column, X-bridge RP18, 5um, l9* l00mm; mobile phase, 0.03% ammonia in water (0.03% NH4HCO3 & NH 4 OH ) and CH 3 CN (32% CH 3 CN up to 52% in 6 min);
Detector, UV 254 nm. This resulted in 12.8 mg (17%) of 4-(4-((4’-chloro-5,5-dimethyl- 3,4,5,6-tetrahydro-[l,l’-biphenyl]-2-yl)methyl)piperazin-l -yl)-2-(2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H- pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide as a yellow solid. LC-MS-PH-PHNW- 4-41-0: (ES, m/z ): M+l=909, R,T= 1.60 min. The measurements of the retention were done with a reversed phase column (C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18 , 2.6 microm; Eluent A: water (0.05 % TFA); Eluent B: Acetonitrile; linear gradient from 5 % acetonitrile to 100 % acetonitrile in 3.0 minutes; Oven temperature 40 °C; flow: l.5mL/min. 1H NMR (300 MHz, Chloroform-d) d 12.40 (s, 1H), 8.72 (s, 1H), 8.63 (s, 1H), 8.44 (t, J =
5.5 Hz, 1H), 8.10 (d, J = 9.0 Hz, 1H), 7.93 - 7.82 (m, 1H), 7.25 (s, 4H), 7.13 (t, J = 2.9 Hz, 1H), 7.00 - 6.68 (m, 6H), 6.52 (s, 1H), 6.17 (d, J = 3.3 Hz, 1H), 4.71 (dd, J = 23.6, 10.7 Hz, 2H), 3.99 - 3.79 (m, 3H), 3.70 (s, 1H), 3.57 (dd, J = 18.5, 10.9 Hz, 3H), 3.46 - 3.17 (m, 7H), 2.80 (s, 2H), 2.29 (s, 3H), 2.21 (s, 2H), 2.03 (d, J = 12.3 Hz, 5H), 1.75 - 1.60 (m, 4H), 1.44 (d, J = 8.7 Hz, 3H), 1.28 (s, 1H), 0.97 (s, 6H), 0.87 (s, 1H). The measurements of the NMR spectra were done with BrukerAvancelll HD 300MHzwith a probe head of BBOF.
Example 22: Preparation of (S)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l - biphenyl]-2-yl)methyl)piperazin-l-yl)-2-(3-methyl-2,3-dihydr opyrrolo[3’,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran -4- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide
Synthesis of 6-(tert-butoxy)-N-(diphenylmethylidene)-l-[[2- (trimethylsilyl)ethoxy]methyl]-lH-pyrrolo[2,3-b]pyridin-5-am ine: Into a 250-mL round- bottom flask, was placed a solution of 5-bromo-6-fluoro-l-[[2- (trimethylsilyl)ethoxy]methyl]-lH-pyrrolo[2,3-b]pyridine (20.7 g, 60 mmol, 1.00 equiv) in dioxane (300 mL), t-BuOK (20.5 g, 180 mmol, 3.00 equiv), xantphos (6.9 g, 12 mmol, 0.20 equiv), Pd 2 (dba)3.CHCl3 (5.7 g, 0.10 equiv), diphenylmethanimine (14.04 g, 78 mmol, 1.20 equiv). The resulting solution was stirred for overnight at l00°C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0:1-1:20). This resulted in 15 g (crude) of 6-(tert-butoxy)-N- (diphenylmethylidene)- 1 - [[2-(trimethylsilyl)ethoxy] methyl] - lH-pyrrolo [2,3-b]pyridin-5- amine as white oil. LC-MS-PH-PHNW-4-7-9: (ES, m/z): M+l= 500.
Synthesis of 5-amino- l-[[2-(trimethylsilyl)ethoxy]methyl]- lH-pyrrolo[2,3-b]pyridin- 6-ol hydrogen chloride salt: Into a 500-mL round-bottom flask, was placed 6-(tert-butoxy)- N-(diphenylmethylidene)-l-[[2-(trimethylsilyl)ethoxy]methyl] -lH-pyrrolo[2,3-b]pyridin-5- amine (15 g, 30.02 mmol, 1.00 equiv) in dioxane (120 mL), HCl/dioxane(4M, 30 mL). The resulting solution was stirred for 5 h at room temperature. The resulting solution was diluted with 500 mL of ether. The solids were collected by filtration. This resulted in 5 g (crude) of 5-amino- l-[[2-(trimethylsilyl)ethoxy] methyl]- lH-pyrrolo[2,3-b]pyridin-6-ol hydrogen chloride salt as a red solid, Q-NMR show it might converted into 3 hydrogen chloride salt. LC-MS-PH-PHNW-4- 10- 1 : (ES, m/z) M+l=280, R,T= 0.811 min. The measurements of the retention were done with a reversed phase column (C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18 , 2.6 microm; Eluent A: water (0.05 % TLA); Eluent B: Acetonitrile; linear gradient.
Synthesis of l2-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-l3-oxa-2,4,l0 - triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l l-one: Into a lOO-mL round-bottom flask, was placed 5-amino- l-[[2-(trimethylsilyl)ethoxy]methyl]-lH-pyrrolo[2,3-b]pyridi n-6- ol (1.5 g, 5.37 mmol, 1 equiv), DML (50 mL), K 2 CO 3 (2.2 g, 16.11 mmol, 3 equiv). This was followed by the addition of 2-chloropropanoyl chloride (1.4 g, 10.74 mmol, 2 equiv) dropwise with stirring at 0 °C. The resulting solution was stirred for overnight at room temperature. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 2x50 mL of ethyl acetate. The resulting mixture was washed with 2 x50 mL of brine. The mixture was dried over anhydrous sodium sulfate and filtrate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0:1- 1:3). This resulted in 500 mg (27.93%) of l2-methyl- 4-[[2-(trimethylsilyl)ethoxy]methyl]-l3-oxa-2,4,l0-triazatri cyclo[7.4.0.0 A [3,7]]trideca- l(9),2,5,7-tetraen-l l-one as a yellow solid. LC-MS-PH-PHNW-4-37-1: (ES, m/z) M+l=334, R,T= 1.123 min. The measurements of the retention were done with a reversed phase column (C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18 , 2.6 microm; Eluent A: water (0.05 % TFA); Eluent B: Acetonitrile; linear gradient from 5 % acetonitrile to 100 % acetonitrile in 3.5 minutes; Oven temperature 40 °C; flow:l.5mL/min. H-NMR-PH-PHNW- 4-37-1: (CDC13, 300 ppm): 8.34 (s, 1H), 7.63 (d, J= 3 Hz, 1H), 7.42-7.28 (m, 1H), 6.46(d, J=
3 Hz, 1H), 5.68(s, 2H), 4.92-4.85(m, 1H), 3.63-3.53(m, 2H), l.85-l.8l(d, J= 12 Hz, 3H), 0.94-0.89(m, 2H), -0.l54(s, 9H).
Synthesis of l2-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-l3-oxa-2,4,l0 - triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraene & (12 S)-l2-methyl-4-[[2- (trimethylsilyl)ethoxy]methyl]-l3-oxa-2,4,l0-triazatricyclo[ 7.4.0.0 A [3,7]]trideca-l(9),2,5,7- tetraene & (12 R)-l2-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-l3-oxa-2,4 ,l0- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraene: Into a lOO-mL 3 -necked round-bottom flask, was placed l2-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-l3-oxa-2,4,l0 - triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l l-one (500 mg, 1.50 mmol, 1 equiv), THF (20 mL). This was followed by the addition of LiAlH 4 (113.8 mg, 3.00 mmol, 2 equiv), in portions at 0 °C. The resulting solution was stirred for 1 overnight at room temperature.
The reaction was then quenched by the addition of 20 mL of water. The solids were filtered out. The resulting solution was extracted with 2x20 mL of ethyl acetate. The resulting mixture was washed with 2 x20 mL of brine. The mixture was dried over anhydrous sodium sulfate and filtrate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0:1- 1:3). This resulted in 450 mg (93%) of 12- methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-l3-oxa-2,4,l0- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraene as a yellow solid.
The crude l2-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-l3-oxa-2,4,l0 - triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraene (450 mg) was purified by Chiral-Prep- HPLC with the following conditions: (SHIMADZU LC-20AT): Column, CHIRALPAK IC; mobile phase A:n-hexane, Phase B:ethanol; Detector, 220 nm. This resulted in 200 mg (44%) of (l2S)-l2-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-l3-oxa- 2,4,l0- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraene as a yellow solid.
This resulted in 200 mg (44%) of (l2R)-l2-methyl-4-[[2- (trimethylsilyl)ethoxy]methyl]-l3-oxa-2,4,l0-triazatricyclo[ 7.4.0.0 A [3,7]]trideca-l(9),2,5,7- tetraene as a yellow solid. LC-MS-PH-PHNW-4-37-2: (ES, m/z): M+l=320, R,T= 1.107 min.
The measurements of the retention were done with a reversed phase column (Cl 8). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18 , 2.6 microm; Eluent A: water (0.05 % TFA); Eluent B: Acetonitrile; linear gradient from 5 % acetonitrile to 100 % acetonitrile in 3.5 minutes; Oven temperature 40 °C; flow:l.5mL/min. H-NMR-PH-PHNW-4-37-2:
(CDC13, 300 ppm): 7.63 (s, 1H), 7.17 (s, 1H), 6.36-6.35(d, J= 3 Hz, 1H), 5.57-5.52(m, 2H), 4.59-4.55(m, 1H), 3.62-3.46(m, 3H), 3.l8-3.l4(m, 1H), l.62-l.44(m, 3H), 0.93-0.88(m, 2H), -0.l7(s, 9H).
Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-2-[(l2 S)-l2-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-l3-oxa-
2.4.10-triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,4,l0- triazatricyclo[7.4.0.0 A 3,7]trideca- 1(9), 2, 5, 7- tetraen-lO-yl]benzoate: Into a 8-mL vial, was placed (l2S)-l2-methyl-4-[[2- (trimethylsilyl)ethoxy]methyl]-l3-oxa-2,4,l0-triazatricyclo[ 7.4.0.0 A [3,7]]trideca-l(9),2,5,7- tetraene (200 mg, 0.63 mmol, 1 equiv), methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4- dimethylcyclohex-l-en-l-yl]methyl]piperazin-l-yl)benzoate (399.6 mg, 0.75 mmol, 1.2 equiv), CS 2 CO 3 (611.9 mg, 1.88 mmol, 3 equiv), Dioxane (5 mL), Chloro[9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene][2-amino-l,l-biphenyl-2-yl]pa lladium(II) (120 mg). The resulting solution was stirred for 2 hr at 110 °C in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0:1-1:10). This resulted in 250 mg (51.83%) of methyl 4-(4-[[2-(4- chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl]piperazi n-l-yl)-2-[(l2S)-l2-methyl-4- [[2-(trimethylsilyl)ethoxy]methyl]-l3-oxa-2,4,l0-triazatricy clo[7.4.0.0 A [3,7]]trideca-
1(9), 2, 4, 10- triazatricyclo[7.4.0.0 A 3,7]trideca-l(9),2,5,7- tetraen-lO-yl]benzoate as a yellow solid.
Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-2-[(l2S)-l2-methyl-l3-oxa-2,4,l0- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzoate. Into a lOO-mL round- bottom flask, was placed methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-2-[(l2S)-l2-methyl-4-[[2-(trimethy lsilyl)ethoxy]methyl]-l3-oxa-
2.4.10-triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2 (250 mg, 0.32 mmol, 1 equiv), TBAF (3 g, 11.47 mmol, 35.36 equiv), THF (30 mL), ethane- 1 ,2-diamine (2 g, 33.28 mmol, 102.56 equiv). The resulting solution was stirred for 12 h at 70 °C in an oil bath. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 2x50 mL of ethyl acetate. The resulting mixture was washed with 3 x50 mL of brine. The mixture was dried over anhydrous sodium sulfate and filtrate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0:1- 1:3). This resulted in 90 mg (43%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l- en-l-yl]methyl]piperazin-l-yl)-2-[(l2S)-l2-methyl-l3-oxa-2,4 ,l0- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzoate as a yellow solid. H- NMR-PH-PHNW-4-37-50: (CDC13, 300 ppm): 8.24(s, 1H), 7.89-7.86(d, J= 9 Hz, 1H), 7.32-7.24 (m, 6H), 7.14-7.01 (m, 1H), 6.97-6.94(m, 2H), 6.73-6.65(m, 2H), 6. l8(s, 1H), 3.67- 3.53(m, 3H), 3.32-3. l8(m, 3H), 2.98-2.80(m, 1H), 2.30-2.04(m, 6H), l.99(s, 2H), 1.56- l.50(m, 5H), 0.9l-0.88(m, 6H).
Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-2-[(l2 S)-l2-methyl-l3-oxa-2,4,l0- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzoic acid. Into a 8-mL vial, was placed methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-2-[(l2S)-l2-methyl-l3-oxa-2,4,l0- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzoate (90 mg, 0.14 mmol, 1 equiv), MeOH (1 mL), H 2 0 (1 mL), THF (1 mL), NaOH (22.5 mg, 0.56 mmol, 4 equiv). The resulting solution was stirred for overnight at 60 °C in an oil bath. The pH value of the solution was adjusted to 5 with HC1 (1 mol/L). The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (1:0-10: 1). This resulted in 80 mg (90%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex- l-en-l-yl]methyl]piperazin-l-yl)-2-[(l2S)-l2-methyl-l3-oxa-2 ,4,l0- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzoic acid as a yellow solid. LC-MS: (ES, m/z ): M+l=626, R,T= 1.035 min. The measurements of the retention were done with a reversed phase column (C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB- C18 , 2.6 microm; Eluent A: water (0.05 % TFA); Eluent B: Acetonitrile; linear gradient from 5 % acetonitrile to 100 % acetonitrile in 3.5 minutes; Oven temperature 40 °C;
flow: l.5mL/min.
Synthesis of (S)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l -biphenyl]-2- yl)methyl)piperazin-l-yl)-2-(3-methyl-2,3-dihydropyrrolo[3 ,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran -4- yl)methyl)amino)phenyl)sulfonyl)benzamide. Into a 8-mL vial, was placed 4-(4-[[2-(4- chlorophenyl)-4,4-dimethylcyclohex- l-en- l-yl]methyl]piperazin- l-yl)-2-[(l2R or S)- 12- methyl-l3-oxa-2,4,l0-triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzoic acid (90 mg, 0.14 mmol, 1 equiv), 4-[[(4-fluorooxan-4-yl)methyl]amino]-3-nitrobenzene-l- sulfonamide (57.5 mg, 0.17 mmol, 1.2 equiv), DCM (5 mL), DMAP (70.2 mg, 0.57 mmol, 4 equiv), EDCI (55.1 mg, 0.29 mmol, 2.00 equiv). The resulting solution was stirred for overnight at room temperature. The resulting mixture was concentrated. The crude product was purified by Flash- Prep-HPLC with the following conditions (IntelFlash-l): Column, C18 silica gel; mobile phase, Water(0. l%FA) and ACN (48.0% ACN up to 53.0% in 7 min, hold 95.0% in 1 min, down to 48.0% in 1 min, hold 48.0% in 1 min) within 5 min; Detector, UV 254 nm. This resulted in 22 mg (20%) of (S)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6- tetrahydro-[l,l’-biphenyl]-2-yl)methyl)piperazin-l-yl)-2-( 3-methyl-2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H- pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide. LC-MS: (ES, m/z): M+l=923, R,T= 2.653 min. The measurements of the retention were done with a reversed phase column (C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18 , 2.6 microm; Eluent A: water (0.05 % TFA); Eluent B: Acetonitrile; linear gradient from 5 % acetonitrile to 100 % acetonitrile in 3.5 minutes; Oven temperature 40 °C; flow: l.5mL/min. H-NMR: (d-CDCl 3 , 300 ppm): 8.62(s, 1H), 8.44-8.42(m, 2H),8.09-8.06(m, 1H), 7.85-7.70(m, 1H), 7.28-7.22(m, 2H), 6.94-6.80(m, 3H), 6.72-6.62(m, 2H), 6. l0(s, 1H), 4.05-4.00(m, 2H), 3.50-3. l7(m, 10H), 2.95-2.35(m, 2H), 2.27-2. l9(m, 4H), l.98-l.70(m, 5H), l.60-l.26(m, 11H), 0.95(s, 6H).
Example 23: Preparation of (R)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l - biphenyl]-2-yl)methyl)piperazin-l-yl)-2-(3-methyl-2,3-dihydr opyrrolo[3’,2’:5,6]pyrido[2,3- b][l,4]oxazin-l(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran -4- y 1) methyl) amino )pheny 1) sulfo ny l)benzamide
Synthesis of N-[(2R)-2-hydroxypropyl]-4-methylbenzene-l-sulfonamide: Into a 250- mL round-bottom flask, was placed (2R)-l -amino propan-2-ol (5 g, 1 equiv), DCM (70 mL), TsCl (12.67 g, 1 equiv). This was followed by the addition of TEA (7.41 g, 1.1 equiv) at 0 °C. The resulting solution was stirred for 3 hr at 0 °C. The resulting mixture was concentrated.
The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/1).
This resulted in 8 g of N-(2R)-2-hydroxypropyl]-4-methylbenzene-l-sulfonamide as a white solid.1H NMR ( (300 MHz, DMSO-d6, ppm): d 7.74-7.63 (m, 2H), 7.52-7.34 (m, 3H), 4.66 (d, J = 4.7 Hz, 1H), 3.58 (qd, J = 6.3, 4.8 Hz, 1H), 2.73-2.50 (m, 2H), 2.39 (s, 3H), 0.99 (d, J = 6.2 Hz, 3H).
Synthesis of methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en- l- yl]methyl]piperazin-l-yl) benzoate: Into a 250-mL round-bottom flask, was placed a solution of l-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl ]piperazine (15.09 g, 47.32 mmol, 1.00 equiv) in DMA (150 mL), DIEA (12.9 g, 99.81 mmol, 2.00 equiv), methyl 2- bromo-4-fluorobenzoate (11.6 g, 49.78 mmol, 1.00 equiv). The resulting solution was stirred for 12 h at 100 degree. The reaction mixture was cooled to room temperature. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x100 mL of brine. The mixture was dried over anhydrous sodium sulfate, then filtered and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0:1- 1:5). This resulted in 7 g (crude) of methyl 2-bromo- 4-(4- [[2-(4-chlorophenyl)-4,4-dimethylcyclo hex- l-en- l-yl]methyl]piperazin- l-yl) benzoate as yellow oil. LC-MS: (ES, m/z): M+l=533, 531.
Synthesis of N-[(2R)-2-[(5-bromo-l-[[2-(trimethylsilyl)ethoxy]methyl]-lH- pyrrolo[2,3-b]pyridin-6-yl)oxy]propyl]-4-methylbenzene-l-sul fonamide: Into a lOO-mL round-bottom flask, was placed N-[(2R)-2-hydroxypropyl]-4-methylbenzene-l-sulfonamide (1 g, 1.5 equiv), DMF (3 mL). This was followed by the addition of NaH (0.35 g, 3 equiv) at 0 °C inlO min. To this was added 5-bromo-6-fluoro-l-[[2-(trimethylsilyl)ethoxy]methyl]-lH- pyrrolo[2,3-b]pyridine (1 g, 1 equiv) at 0 °C. The resulting solution was stirred for 4 hr at room temperature. The reaction was then quenched by the addition of 20mL of water. The resulting solution was extracted with 3x50 mL of ethyl acetate and the organic layers combined and concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/3). This resulted in 400 mg of N-[(2R)-2-[(5-bromo-l-[[2- (trimethylsilyl)ethoxy]methyl]-lH-pyrrolo[2,3-b]pyridin-6-yl )oxy]propyl]-4-methylbenzene- l-sulfonamide as a yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): d 8.18 (s, 1H), 7.72- 7.62 (m, 2H), 7.41 (d, / = 3.5 Hz, 1H), 7.28 (d, / = 8.0 Hz, 2H), 6.42 (d, / = 3.6 Hz, 1H), 5.50 (q, / = 10.8 Hz, 2H), 5.16 (q, / = 6.1 Hz, 1H), 3.53-3.38 (m, 2H), 3.13 (dd, / = 13.4, 6.0 Hz, 1H), 2.98 (dd, / = 13.4, 5.8 Hz, 1H), 2.29 (s, 3H), 1.28 (d, / = 6.2 Hz, 3H), 0.80 (ddt, / =
16.1, 14.1, 7.1 Hz, 2H), 0.13 (s, 9H).
Synthesis of (l2R)-l2-methyl-lO-(4-methylbenzenesulfonyl)-4-[[2- (trimethylsilyl)ethoxy]methyl]-l3-oxa-2,4,l0-triazatricyclo[ 7.4.0.0 A [3,7]]trideca-l(9),2,5,7- tetraene: Into a lOO-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed N-[(2R)-2-[(5-bromo-l-[[2-(trimethylsilyl)ethoxy]methyl]-lH- pyrrolo[2,3-b]pyridin-6-yl)oxy]propyl]-4-methylbenzene-l-sul fonamide (3.9 g, 1 equiv), dioxane (50 mL), t-BuXPhos 3G (560 mg, 0.1 equiv), CS 2 O 3 (6.9 g, 3 equiv). The resulting solution was stirred for 4 hr at 90 °C. The resulting mixture was concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/3). This resulted in 3.3 g of (l2R)-l2-methyl-lO-(4-methylbenzenesulfonyl)-4-[[2-
(trimethylsilyl)ethoxy]methyl]-l3-oxa-2,4,l0-triazatricyc lo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7- tetraene as colorless oil. 1H-NMR (300 MHz, DMSO-d6, ppm): d 8.28 (s, 1H), 7.56-7.39 (m, 3H), 7.39-7.30 (m, 2H), 6.52 (d, / = 3.6 Hz, 1H), 5.43 (s, 2H), 4.28 (dd, / = 14.6, 2.6 Hz, 1H), 3.61-3.41 (m, 3H), 3.26-3.11 (m, 1H), 2.35 (s, 3H), 1.32-1.11 (m, 3H), 0.89-0.74 (m, 2H), 0.11 (s, 9H).
Synthesis of (12R)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa- 2,4,10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraene: Into a lOO-mL 3-necked round-bottom flask, was placed Na (1.3 lg, 9.4 equiv), naphthalene (0.76 g, 6 equiv). This was followed by the addition of DME (15 mL) for 30 min at room temperature. To this was added the solution (12R)-12-methyl-10-(4-methylbenzenesulfonyl)-4-[[2-
(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyc lo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7- tetraene (2.8 g, 1 equiv) in THF (15 mL) at -78 °C. The resulting solution was stirred for 3 hr at room temperature. The reaction was then quenched by the addition of 30 mL of NH 4 CI.
The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined and concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/3). This resulted in 1.4 g of (12R)-12-methyl-4-[[2- (trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10-triazatricyclo[ 7.4.0.0 A [3,7]]trideca-l(9),2,5,7- tetraene as a colorless oil. LC-MS (ES, m/z ): 320 [M+l] + ; RT = 1.61 min.
Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-2-[(12S)-12-methyl-4-[[2-(trimethy lsilyl)ethoxy]methyl]-13-oxa- 2,4,l0-triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzoate: Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed (12R)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa- 2,4,10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraene (1.178 g, 1 equiv), methyl 2-bromo-4- (4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1-en- l-yl]methyl]piperazin- l-yl)benzoate (2.35 g, 1.2 equiv), dioxane (15 mg, 15 equiv), CS 2 CO 3 (3.62 g, 3 equiv), XantPhos (328 mg, 0.1 equiv). The resulting solution was stirred for 2 hr at 110 °C. The resulting mixture was concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/3). This resulted in 3.2 g of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1 -en- 1 -yl] methyl]piperazin- 1 -yl)-2- [( 12S)- 12- methyl-4- [[2-(trimethylsilyl)ethoxy] methyl] - 13-oxa-2,4,10-triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-10-yl]benzoate as a yellow solid. LC-MS (ES, m/z) 770 [M+l] + ; RT = 1.33 min.
Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin- l-yl)-2-[(12R)- 12-methyl- 13-oxa-2, 4, 10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-10-yl]benzoate: Into a 250-mL round- bottom flask, was placed methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl] methyl]piperazin- 1 -yl)-2- [( 12R)- 12-methyl-4- [[2-(trimethylsilyl)ethoxy] methyl] - 13-oxa- 2,4,l0-triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzoate (3.2 g, 1 equiv), THF (50 mL), TBAF (20 g), ethane- 1, 2-diamine (33 g). The resulting solution was stirred for 5 hr at 70 °C. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined and concentrated. The residue was applied onto a silica gel column with dichloromethane/methanol (10/1). This resulted in 2.2 g of methyl 4-(4-[[2-(4-chlorophenyl)- 4,4-dimethylcyclohex- l-en- l-yl]methyl]piperazin- l-yl)-2-[(l2R)- l2-methyl- l3-oxa-2,4, 10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzoate as a yellow solid. LC- MS- (ES, m/z): 640 [M+l] + ; RT = 2.51 min.
Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin- l-yl)-2-[(l2R)- l2-methyl- l3-oxa-2,4, 10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzoic acid: Into a 250-mL round-bottom flask, was placed methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l- en- l-yl]methyl]piperazin- l-yl)-2-[(l2R)- l2-methyl- l3-oxa-2,4, 10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzoate (2.2 g, 1 equiv), MEOH/FLO/THF (lOmL/lOml/lO mL). The resulting solution was stirred for 5 hr at 60 °C. The resulting mixture was concentrated. The resulting solution was extracted with 3x100 mL of dichloro methane and the organic layers combined and concentrated. The residue was applied onto a silica gel column with dichloromethane/methanol (10/1). This resulted in 1.6 g of 4-(4- [[2-(4-chlorophenyl)-4,4-dimethylcyclo hex- l-en- l-yl]methyl]piperazin- l-yl)-2- [(l2R)-l2-methyl-l3-oxa-2,4,l0-triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0- yl]benzoic acid as yellow oil. LC-MS (ES, m/z): 626 [M+l] + ; RT = 2.47 min.
Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-2-[(l2R)-l2-methyl-l3-oxa-2,4,l0- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]-N-(3-nitro-4-[ [(oxan-4- yl)methyl]amino]benzenesulfonyl)benzamide: Into a 250-mL round-bottom flask, was placed 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]met hyl]piperazin-l-yl)-2-[(l2R)- l2-methyl-l3-oxa-2,4,l0-triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzoic acid (1.6 g, 1 equiv), DCM (20 mL), 3-nitro-4-[[(oxan-4-yl)methyl]amino]benzene-l- sulfonamide (890 mg, 1.2 equiv), DMAP (1.25 g, 4 equiv), EDCI (980 mg, 2 equiv). The resulting solution was stirred for 14 hr at room temperature. The resulting mixture was concentrated. The residue was applied onto a silica gel column with EA/DCM (1/10). This resulted in 0.82 g of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin- l-yl)-2-[(l2R)- l2-methyl- l3-oxa-2,4, 10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]-N-(3-nitro-4-[ [(oxan-4- yl)methyl]amino]benzenesulfonyl)benzamide as a yellow solid. LC-MS (ES, m/z): 923
[M+l] + ; RT = 3.50 min. Ή NMR (300 MHz, CDCl 3 , ppm): d 12.48 (s, 1H), 8.62 (d, / = 2.4 Hz, 2H), 8.54-8.38 (m, 1H), 8.16-7.95 (m, 1H), 7.81-7.71 (m, 1H), 7.32-7.12 (m, 6H), 7.07 (t, J = 2.9 Hz, 1H), 6.97-6.77 (m, 3H), 6.76-6.60 (m, 2H), 6.52 (s, 1H), 6.09 (d, J = 3.0 Hz, 1H), 4.88 (d, J = 7.7 Hz, 1H), 4.02 (dd, J = 11.8, 4.2 Hz, 2H), 3.55-3.34 (m, 4H), 3.32-3.14 (m,
5H), 3.08 (s, 1H), 2.77 (d, / = 9.6 Hz, 2H), 2.28 (s, 3H), 2.19 (s, 2H), 1.99 (d, / = 7.6 Hz, 4H), 1.72 (d, / = 12.7 Hz, 2H), 1.45 (ddd, / = 24.5, 12.3, 5.8 Hz, 6H), 0.94 (d, / = 2.1 Hz, 6H).
Example 32: Preparation of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-N-(4-[[(2S)-l,4-dioxan-2-ylmethyl] amino]-3- nitrobenzenesulfonyl)-2-[l3-thia-2,4,l0-triazatricyclo[7.4.0 .0 A [3,7]]trideca-l(9),2,5,7- tetraen- l0-yl]benzamide
Into a 250- mL round-bottom flask, was placed cysteamine hydrochloride (5.00 g, 44.0l4mmol, l.OOequiv), DCM (100.00 mL), TEA (13.36 g, O. l32mmol, 3equiv), acetic anhydride (4.94 g, 0.048mmol, l. lequiv). The resulting solution was stirred for overnight at room temperature. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3x50 mL of ethyl acetate dried over anhydrous sodium sulfate. The resulting solution was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (7: 1). This resulted in 7.2 g (crude) of 2-acetamidoethanethiol as light yellow oil. 1H 1H NMR (300 MHz, DMSO-i/ 6 ) d 7.99 (s, 1H), 3.20-3.214 (m, 2H), 2.54 - 2.47 (m, 2H), 1.90 (s, 1H), 1.81 (s, 3H).
Into a lOO-mL round-bottom flask, was placed 2-acetamidoethanethiol (1.19 g, 9.985mmol, l.OOequiv), DML (30.00 mL), 5-bromo-6-fluoro-l-[[2- (trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-b]pyridine (3.45 g, O.OlOmmol, lequiv), CS 2 CO 3 (9.76 g, 0.030mmol, 3equiv). The resulting solution was stirred for 5 h at 80 degrees C in an oil bath. The reaction mixture was cooled to room temperature with a water/ice bath. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3x50 mL of ethyl acetate dried over anhydrous sodium sulfate and
concentrated. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1: 1). The collected fractions were combined and concentrated. This resulted in 2 g (45.07%) of N-[2-[(5-bromo-l-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2 ,3- b]pyridin-6-yl)sulfanyl]ethyl]acetamide as yellow oil. LCMS-PH-PHNW-4- 121-2 (ES, m/z) M+l: 444/446. Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed N-[2-[(5-bromo-l-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2 ,3- b]pyridin-6-yl)sulfanyl]ethyl]acetamide (2.00 g, 0.004mmol, l.OOequiv), DMF(30ml) , CS 2 CO 3 (4.40 g, 0.0l3mmol, 3equiv), BrettPhos Pd G3 Precatalyst (0.61 mg, O.OOlmmol, 0.l5equiv). The resulting solution was stirred for overnight at 100 degrees C in an oil bath. The reaction was cooled down to r.t then quenched by the addition of 30 mL of water. The resulting solution was extracted with 3x50 mL of ethyl acetate dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (5:2). The collected fractions were combined and concentrated. This resulted in 670 mg (40.96%) of l-(4-[[2-(trimethylsilyl)ethoxy]methyl]-l3-thia-2,4,l0- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl)ethanone as yellow oil. LCMS- PH-PHNW-4- 121-3 (ES, m/z) M+l: 364.
Into a 40-mL vial, was placed l-(4-[[2-(trimethylsilyl)ethoxy]methyl]-l3-thia-2,4,l0- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl)ethanone (600.00 mg, l.650mmol, l.OOequiv), MeOH (10.00 mL), NaOH(4M) (10.00 mL). The resulting solution was stirred for overnight at 80 degrees C in an oil bath. The resulting mixture was concentrated. The resulting solution was extracted with 3x30 L of ethyl acetate dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (3:1). The collected fractions were combined and concentrated. This resulted in 410 mg (77.27%) of 4-[[2-(trimethylsilyl)ethoxy]methyl]- l3-thia-2,4,l0-triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraene as yellow oil. LC-MS- PH-PHNW-4- 121-4: (ES, m/z) M+L322.
Into a lOO-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-[[2-(trimethylsilyl)ethoxy]methyl]-l3-thia-2,4,l0- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraene (200.00 mg, 0.622mmol, l.OOequiv), 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex- l-en- l-yl]methyl]piperazin- l-yl)- N-(4-[[(2S)-l,4-dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfo nyl)benzamide (1016.69 mg, l.244mmol, 2equiv), DMF (20.00 mL), CS 2 CO 3 (608.04 mg, l.866mmol, 3equiv), Cul (47.39 mg, 0.249mmol, 0.4equiv), l,lO-phenanthroline (22.42 mg, O.l24mmol, 0.2equiv). The resulting solution was stirred for 4 h at 95 degrees C in an oil bath. The reaction was then quenched by the addition of 30 mL of water. The solids were filtered out. The resulting solution was extracted with 3x20 mL of ethyl acetate concentrated. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (2:1). The collected fractions were combined and concentrated. This resulted in 300 mg (45.59%) of 4-(4-[[2-(4- chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl]piperazi n-l-yl)-N-(4-[[(2S)-l,4- dioxan-2-ylmethyl] amino] -3-nitrobenzenesulfonyl)-2-(4- [[2-(trimethylsilyl)ethoxy] methyl] - l3-thia-2,4,l0-triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl)benzamide as yellow oil. LC-MS-PH-PHNW-4-121-5: (ES, m/z) M+E 1057.
Into a lOO-mL round-bottom flask, was placed 4-(4-[[2-(4-chlorophenyl)-4,4- dimethylcyclohex- l-en- l-yl]methyl]piperazin- l-yl)-N-(4-[[(2S)- l,4-dioxan-2- ylmethyl] amino] -3-nitrobenzenesulfonyl)-2-(4- [[2-(trimethylsilyl)ethoxy] methyl] - 13-thia- 2,4,l0-triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl)benzamide (300.00 mg, 0.284mmol, l.OOequiv), THF (20.00 mL, 0.277mmol, 0.98equiv), TBAF (741.53 mg, 2.836mmol, lO.OOequiv), ethane- 1, 2-diamine (170.44 mg, 2.836mmol, lOequiv). The resulting solution was stirred for overnight at 70 degrees C in an oil bath. The resulting mixture was concentrated. The crude product was purified by Chiral-Prep-HPFC with the following conditions :Column, XBridge Prep C18 OBD l9* l50mm 5um; mobile phase, A: 0. l%HCl in water; B: ACN; Gradient: 24-95%B in 7.9min; Flow rate: 20ml/min; Detector, 220nm.This resulted in 50 mg (18.29%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex- l-en-l-yl]methyl]piperazin-l-yl)-N-(4-[[(2S)-l,4-dioxan-2-yl methyl]amino]-3- nitrobenzenesulfonyl)-2-[l3-thia-2,4,l0-triazatricyclo[7.4.0 .0 A [3,7]]trideca-l(9),2,5,7- tetraen-lO-yl]benzamide hydrochloride as a yellow solid. FC-MS-PH-PHNW-4- 121-0: (ES, m/z) M+1-HC1: 963. H-NMR-PH-PHNW-4-121-0: 1H 1H NMR (300 MHz, DMSO-d 6 ) d 8.35 (d, J = 2.4 Hz, 1H), 7.53 (d, J = 8.7 Hz, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.32 (dd, J = 9.3, 2.4 Hz, 1H), 7.15 - 7.06 (m, 3H), 6.86 (d, / = 8.7 Hz, 1H), 6.74 (s, 1H), 6.62 (d, / = 9.3 Hz, 1H), 6.45 (s, 1H), 5.94 (d, J = 3.3 Hz, 1H), 3.88 - 3.74 (m, 6H), 3.61 (d, J = 9.9 Hz, 4H), 3.49 (dd, / = 12.0, 9.6 Hz, 2H), 3.43 - 3.26 (m, 7H), 3.15 (s, 2H), 2.74 (s, 2H), 2.21 (s, 2H), 2.03 (s, 2H), 1.45 (d, J = 6.9 Hz, 2H), 0.94 (s, 6H).
Example 33: Preparation of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-2-(3,4-dihydro-2H-l,4-benzoxazin-4 -yl)-N-(3-nitro-4-[[(oxan-4- y 1) methyl] amino ] benzene sulfo ny l)benzamide
Into a 50-mF round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en- l- yl]methyl]piperazin-l-yl)-N-(3-nitro-4-[[(oxan-4- yl)methyl]amino]benzenesulfonyl)benzamide (1568.13 mg, l.924mmol, l.30equiv), 3,4- dihydro-2H-l,4-benzoxazine (200 mg, l.480mmol, l.OOequiv), DMF (20.00 mF), CS 2 CO 3 (1.45 g, 4.450mmol, 3.0lequiv), Cul (112.00 mg, 0.588mmol, 0.40equiv), 1,10- phenanthroline (53.30 mg, 0.296mmol, 0.20equiv). The resulting solution was stirred for 5 h at 90 degrees C in an oil bath. The solids were filtered out. The resulting solution was extracted with 3x40 mL of ethyl acetate concentrated. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (5: 1). The collected fractions were combined and concentrated. This resulted in 100 mg (7.77%) of 4-(4-[[2-(4-chlorophenyl)- 4,4-dimethylcyclohex-l-en-l-yl]methyl]piperazin- l-yl)-2-(3,4-dihydro-2H-l,4-benzoxazin- 4-yl)-N-(3-nitro-4-[[(oxan-4-yl)methyl]amino]benzenesulfonyl )benzamide as a yellow solid. LC-MS-PH-PHNW-4- 101-0: (ES, m/z) M+l: 869. H-NMR-PH-PHNW-4- 101-0: 1H NMR (300 MHz, DMSO -d 6 ) d 11.87 (s, 1H), 8.64 (t, J = 6.0 Hz, 1H), 8.36 (d, / = 2.4 Hz, 1H), 7.69 - 7.56 (m, 1H), 7.48 (d, / = 8.7 Hz, 1H), 7.41 - 7.32 (m, 2H), 7.13 - 7.01 (m, 3H), 6.81 (dd, / = 9.0, 2.4 Hz, 1H), 6.73 (d, / = 2.4 Hz, 1H), 6.58 (dd, / = 7.8, 1.8 Hz, 1H), 6.37 (dtd, / = 20.1, 7.5, 1.8 Hz, 2H), 6.09 (dd, 7 = 7.8, 1.8 Hz, 1H), 4.22 (s, 2H), 3.88 (dd, / = 11.4, 4.2 Hz, 2H), 3.54 (s, 2H), 3.35 (d, J = 7.2 Hz, 2H), 3.30 (s, 2H), 3.21 (s, 4H), 2.81 (s, 2H), 2.23 (d, J = 24.3 Hz, 6H), 1.99 (d, / = 2.1 Hz, 3H), 1.66 (d, / = 12.6 Hz, 2H), 1.42 (t, / = 6.3 Hz, 2H), 1.30 (tt, / = 12.5, 6.3 Hz, 2H), 0.95 (s, 6H).
Example 34. Preparation of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-N-[3-nitro-4-[(oxan-4-ylmethyl)ami no]benzenesulfonyl]-2-
[2H,3H-pyrido[4,3-b][l,4]oxazin-4-yl]benzamide
Into a 8-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex- l-en- l-yl]methyl]piperazin- l-yl)-N-[3-nitro-4-[(oxan-4-ylmethyl)amino]benzenesulfonyl]b enzamide (233.51 mg, 0.286mmol, l.30equiv), DMF (4.00 mL), 2H,3H,4H-pyrido[4,3-b][l,4]oxazine (30.00 mg, 0.220mmol, l.OOequiv), l,lO-phenanthroline (7.94 mg, 0.044mmol, 0.2equiv), Cul (16.79 mg, 0.088mmol, 0.4equiv), CS 2 CO 3 (215.37 mg, 0.66lmmol, 3equiv). The resulting solution was stirred for 3 h at 95 degrees C in an oil bath. The solids were filtered out. The resulting solution was quenched with 10 mL water and extracted with 3x10 mL of ethyl acetate concentrated. The crude product was purified by Prep-HPLC with the following conditions (2#S HIM ADZU (HPLC-01)): Column, SunFire Prep C18 OBD Column, 19* 150mm 5um lOnm; mobile phase, Water(0. l%HCl) and ACN (20% PhaseB up to 40% in 8 min);
Detector, UV=254nm.This resulted in 8 mg (4.17%) of 4-(4-[[2-(4-chlorophenyl)-4,4- dimethylcyclohex- l-en- l-yl]methyl]piperazin- l-yl)-N-[3-nitro-4-[(oxan-4- ylmethyl)amino]benzenesulfonyl]-2-[2H,3H-pyrido[4,3-b][l,4]o xazin-4-yl]benzamide as a yellow solid as HC1 salt. LC-MS-PH-PHNW-4- 104-0: (ES, m/z) M+1-HC1: 870. H-NMR- PH-PHNW-4- 104-0: 1H NMR (300 MHz, DMSO-d 6 ) d 12.30 (s, 1H), d 10.37 (s, 1H), 8.64 (d, / = 6.3 Hz, 1H), 8.43 (d, / = 2.4 Hz, 1H), 7.88 (d, / = 6.3 Hz, 1H), 7.80 - 7.65 (m, 1H), 7.54 (d, J = 9.3 Hz, 1H), 7.42 (d, J = 8.1 Hz, 2H), 7.30 (s, 1H), 7.19 - 7.09 (m, 4H), 6.96 (s, 2H), 4.58 (s, 1H), 4.31 (s, 1H), 3.89 (dd, J = 11.7, 4.2 Hz, 4H), 3.66 - 3.56 (m, 4H), 3.29 (d, J = 12.0 Hz, 6H), 2.76 (d, / = 16.8 Hz, 2H), 2.42 - 2.24 (m, 4H), 2.06 (s, 2H), 1.95 (s, 1H),
1.66 (d, J = 13.2 Hz, 2H), 1.49 (d, 7 = 6.6 Hz, 2H), 1.40 - 1.21 (m, 2H), 0.97 (s, 6H).
Example 37: Preparation of 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,l’- biphenyl]-2-yl)methyl)piperazin-l-yl)-2-((R)-3-methyl-2,3- dihydropyrrolo[3’,2’:5,6]pyrido[2,3-b][l,4]oxazin- l(6H)-yl)-N-(((S)-5-nitro-3-(tetrahydro- 2H-pyran-4-yl)-3,4-dihydro-2H-benzo[b][l,4]oxazin-7-yl)sulfo nyl)benzamide, and 4-(4-((4’- chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2-yl)m ethyl)piperazin-l-yl)-2-((R)-3- methyl-2, 3-dihydropyrrolo[3’, 2’ :5,6]pyrido[2,3-b][l,4]oxazin-l(6H)-yl)-N-(((R)-5-nitro-3- (tetrahydro-2H-pyran-4-yl)-3,4-dihydro-2H-benzo[b][l,4]oxazi n-7-yl)sulfonyl)benzamide Synthesis of 3-bromo-4-chloro-5-nitrobenzenesulfonamide, Into a 50-mL round- bottom flask, was placed 4-chloro-3-nitrobenzenesulfonamide (20.00 g, 84.520 mmol, 1.00 equiv), H 2 SO 4 (20.00 mL). This was followed by the addition of NBS (22.56 g, 126.753 mmol, 1.50 equiv), in portions at 50 degrees C. The resulting solution was stirred for 2 hr at 60 degrees C. The resulting solution was diluted with 200 mL of cold H 2 0. The resulting solution was extracted with 3x30 mL of ethyl acetate. The resulting mixture was washed with 1x20 ml of H 2 0. The resulting mixture was washed with 1x20 mL of NaCl (aq.). The residue was applied onto a silica gel column with ethyl and eluted with ethyl acetate/petroleum ether (1:3). This resulted in 5 g (18.75%) of 3-bromo-4-chloro-5- nitrobenzenesulfonamide as a white solid. LC-MS-l: (ES, m/z): 312.9 [M-H]
Synthesis of 2-amino-2-(oxan-4-yl)ethanol: Into a lOO-mL round-bottom flask, was placed amino(oxan-4-yl)acetic acid (4.00 g, 25.128 mmol, 1.00 equiv), THF (50.00 mL), L1AIH4 (1.91 g, 50.324 mmol, 2.00 equiv). The resulting solution was stirred for 3 hr at 60 degrees C in an oil bath. The reaction was then quenched by the addition of 10 mL of water. The resulting mixture was concentrated. This resulted in 6 g (crude) of 2-amino-2-(oxan-4- yl)ethanol as a white solid. LC-MS-21: (ES, m/z): 146.2 [M+H] +
Synthesis of 3-bromo-4-[[2-hydroxy-l-(oxan-4-yl)ethyl]amino]-5- nitrobenzenesulfonamide: Into a lOO-mL round-bottom flask, was placed 3-bromo-4- chloro-5-nitrobenzenesulfonamide (5.00 g, 15.847 mmol, 1.00 equiv), 2-amino-2-(oxan-4- yl)ethanol (5.00 g), CH 3 CN (30.00 mL, 0.731 mmol), DIEA (6.10 g, 47.198 mmol, 2.98 equiv). The resulting solution was stirred for 48 hr at 80 degrees C in an oil bath. The resulting mixture was concentrated. The residue was applied onto a silica gel column and eluted with dichloro methane/methanol (10:1). This resulted in 1.2 g (17.85%) of 3-bromo-4- [[2-hydroxy-l-(oxan-4-yl) ethyl]amino]-5-nitrobenzenesulfonamide as a yellow solid. LC- MS-2: (ES, m/z): 424.1 [M+H] +
Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl) -2-[(12R)-12-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-13- oxa-2,4,10-triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-10-yl]benzoate. Into a 50-mL round-bottom flask, was placed (l2R)-l2-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl] -l3-oxa-2,4,l0-triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraene (500.00 mg, 1.565 mmol, 1.00 equiv), methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en- l- yl]methyl]piperazin-l-yl) benzoate (832.48 mg, 1.565 mmol, 1.00 equiv), xantphos Pd 2G (138.82 mg, 0.157 mmol, 0.10 equiv), CS 2 CO 3 (1529.77 mg, 4.695 mmol, 3.00 equiv), dioxane (10.00 mL). The resulting solution was stirred for 14 hr at 80 degrees C. The resulting mixture was concentrated. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:3). This resulted in 611 mg (50.67%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]met hyl]piperazin-l-yl)-2-[(l2R)- l2-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-l3-oxa-2,4,l0 - triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzoate as a yellow solid. LC- MS-l l: (ES, m/z):770.4 [M+H] +
Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl) -2-[(12R)-12-methyl-13-oxa-2,4,10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-10-yl]benzoate. Into a 8-mL vial, was placed methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]
methyl]piperazin- 1 -yl)-2- [( 12R)- l2-methyl-4- [[2-(trimethylsilyl)ethoxy] methyl] - 13-oxa- 2,4,l0-triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzoate (300.00 mg, 0.389 mmol,), ethane- 1, 2-diamine (0.20 mL), TBAF in THF(l ml, 2M). The resulting solution was stirred for 24 hr at 70 degrees C in an oil bath. The resulting mixture was concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 100 mg (40.12%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4- dimethylcyclohex- l-en- l-yl]methyl]piperazin- l-yl)-2-[(l2R)- l2-methyl- l3-oxa-2,4, 10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzoate as a white solid. LC- MS-l l: (ES, m/z): 640.3 [M+H] + Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-2-[(12R) -12-methyl-13-oxa-2,4,10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-10-yl]benzoic acid. Into a 8-mL vial, was placed methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl] methyl]piperazin- l-yl)-2-[( 12R)- l2-methyl- l3-oxa-2,4, 10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzoate (100.00 mg, 0.156 mmol, 1.00 equiv), NaOH (37.49 mg, 0.937 mmol, 6.00 equiv), MeOH (0.50 mL), dioxane (0.50 mL), H 2 0 (0.20 mL). The resulting solution was stirred for 14 hr at 70 degrees C in an oil bath. The resulting mixture was concentrated. The resulting solution was diluted with 1 mL of H 2 0. The pH value of the solution was adjusted to 6 with CH 3 COOH. The resulting mixture was concentrated. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (10:1). This resulted in 60 mg of 4-(4-[[2-(4-chlorophenyl)-4,4- dimethy lcyclo hex- l-en- l-yl] methyl] piperazin- l-yl)-2-[(l2R)- l2-methyl- l3-oxa-2,4, 10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzoic acid as a brown solid. LC-MS-13: (ES, m/z):626.3 [M+H] +
Synthesis of 5-nitro-3-(oxan-4-yl)-3,4-dihydro-2H-l,4-benzoxazine-7- sulfonamide. Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-bromo-4-[[2-hydroxy-l-(oxan-4-yl)ethyl]amino]-5- nitrobenzenesulfonamide (1.40 g, 3.300 mmol, 1.00 equiv), dioxane (20.00 mL), Pd 2 (dba) 3 (604.34 mg, 0.660 mmol, 0.20 equiv), XantPhos (763.73 mg, 1.320 mmol, 0.40 equiv), Cs 2 C0 3 (3.23 g, 9.913 mmol, 3.00 equiv). The resulting solution was stirred for 2 hr at 100 degrees C in an oil bath. The resulting mixture was concentrated. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:1). This resulted in 230 mg (20.30%) of 5-nitro-3-(oxan-4-yl)-3,4-dihydro-2H-l,4-benzoxazine-7-sulfo namide as a yellow solid. LC-MS-3: (ES, m/z):342.l [M-H]
Synthesis of (3S)-5-nitro-3-(oxan-4-yl)-3,4-dihydro-2H-l,4-benzoxazine-7- sulfonamide and (3R)-5-nitro-3-(oxan-4-yl)-3,4-dihydro-2H-l,4-benzoxazine-7- sulfonamide. Into a 50-mL round-bottom flask, was placed 5-nitro-3-(oxan-4-yl)-3,4- dihydro-2H-l,4-benzoxazine-7- sulfonamide (150.00 mg) and DMF(l0 ml). The sample was purified by Chiral-Prep-HPLC with the following conditions (WATERS 2767): Column, CHIRALPAK IA, 250*20mm, 5um; Mobile phase : A:n-Hexane:DMC=3:l, 0.1% DEA), B:EtOH; Gradient: 10% B in 20 min; Detector, 220 nm. This resulted in 30 mg of (3S)-5- nitro-3-(oxan-4-yl)-3,4-dihydro-2H-l,4-benzoxazine-7-sulfona mide as a yellow solid. This resulted in 32 mg of (3R)-5-nitro-3-(oxan-4-yl)-3,4-dihydro-2H-l,4-benzoxazine-7- sulfonamide as a yellow solid.
Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-2-[(12R) -12-methyl-13-oxa-2,4,10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-10-yl]-N-[(3S)-5-nitr o-3-(oxan-4- yl)-3,4-dihydro-2H-l,4-benzoxazin-7-ylsulfonyl]benzamide hydrochloride: Into a 8-mL vial, was placed (3S)-5-nitro-3-(oxan-4-yl)-3,4-dihydro-2H-l,4-benzoxazine-7- sulfonamide (20 mg, 0.058 mmol, 1.00 equiv), 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl] methyl]piperazin- l-yl)-2-[( 12R)- l2-methyl- l3-oxa-2,4, 10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzoic acid (36.48 mg, 0.058 mmol, 1.00 equiv), DCM (0.5 mL), EDC.HC1 (22.33 mg, 0.116 mmol, 2.00 equiv), DMAP (17.79 mg, 0.146 mmol, 2.50 equiv). The resulting solution was stirred for 14 hr at room temperature. The resulting mixture was concentrated. The residue was purified with Prep- TLC with dichloro methane/methanol (10: 1). The crude product (30 mg) was purified by Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD 19* 150 mm 5 um; Mobile phase, A: 0.1% HC1 in water; B: ACN; Gradient: 38-58%B in 7 min; Flow rate: 20 ml/min; Detector, 220 nm. This resulted in 10 mg (17.38%) of 4-(4-[[2-(4-chlorophenyl)-
4.4-dimethylcyclohex- l-en- l-yl]methyl]piperazin- l-yl)-2-[(l2R) -l2-methyl-l3-oxa-2,4,l0- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]-N-[(3S)-5-nitr o-3-(oxan-4-yl)-
3.4-dihydro-2H-l,4-benzoxazin-7-ylsulfonyl]benzamide hydrochloride as a yellow solid. LC- MS-0A: (ES, m/z): 951.4 [M-HCl+H] + VH NMR- 0A (300 MHz, DMSO , rrhi): d 12.15 (s, 1H), 10.86 (s, 1H), 9.68 (s, 1H), 8.78 (s, 1H), 8.05-7.81 (m,lH), 7.58-7.31 (m, 1H), 7.21-6.72 (m, 6H), 6.70-6.40 (m, 1H), 6.02-5.81 (m, 1H), 4.61-4.11 (m, 3H), 3.92-3.78 (m, 4H), 3.65- 3.61 (m, 2H), 3.38-3.13 (m, 8H), 2.90-2.72 (m, 2H), 2.30-2.21 (m, 2H), 2.13-1.94 (m,
2H), 1.92-1.51 (m, 3H), 1.51-1.23 (m, 8H), 0.96 (s, 6H).
Synthesis of 4-(4-[[2-(4-chlorophenyl)-4-methylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-2-[(12R)- 12-methyl-13-oxa-2,4,10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-10-yl]-N-[(3R)-5-nitr o-3-(oxan-4- yl)-3,4-dihydro-2H-l,4-benzoxazin-7-ylsulfonyl]benzamide hydrochloride. Into a 8-mL vial, was placed (3R)-5-nitro-3-(oxan-4-yl)-3,4-dihydro-2H-l,4-benzoxazine-7- sulfonami de (20.00 mg, 0.058 mmol, 1.00 equiv), 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex- l-en- 1- yl]methyl] piperazin-l-yl)-2-[(l2R)-l2-methyl-l3-oxa-2,4,l0- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzoic acid (36.48 mg, 0.058 mmol, 1.00 equiv), DCM , EDCI (22.33 mg, 0.116 mmol, 2.00 equiv), DMAP (17.79 mg, 0.146 mmol, 2.50 equiv). The resulting solution was stirred for 14 hr at room temperature. The resulting mixture was concentrated. The residue was purified with Prep-TLC with DCM/methanol (10: 1). The crude product (30 mg ) was purified by Prep-HPLC with the following conditions : Column, XBridge Prep C18 OBD 19* 150 mm 5 um; Mobile phase, A: 0.1% HC1 in water; B: ACN; Gradient: 38-58%B in 7 min; Flow rate: 20 ml/min; Detector, 220 nm. This resulted in 10.3 mg (18.16%) of 4-(4-[[2-(4-chlorophenyl)-4-methylcyclohex-l- en-l-yl]methyl]piperazin-l-yl)-2-[(l2R)-l2-methyl-l3-oxa-2,4 ,l0- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]-N-[(3R)-5-nitr o-3-(oxan-4-yl)- 3,4-dihydro-2H-l,4-benzoxazin-7-ylsulfonyl]benzamide hydrochloride as a yellow solid. LC-MS-0B: (ES, m/z): 951.4 [M-HCl+H] + Ή NMR- 0B (300 MHz, DMSO, ppm): d 12.16 (s, 1H), 10.89 (s, 1H), 10.02 (s, 1H), 8.78 (s, 1H), 8.05-7.41 (m,5H), 7.21-6.52 (m, 6H), 6.02- 5.91 (m, 1H), 4.61-4.21 (m, 2H), 4.15-3.78 (m, 5H), 3.71-3.65 (m, 2H), 3.38-3.13 (m, 8H), 2.88-2.72 (m, 2H), 2.35-2.30 (m, 2H), 2.13-1.94 (m, 2H), 1.92-1.59 (m, 3H), 1.51-1.23 (m, 8H), 0.96 (s, 6H).
Example 43: Preparation of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-N-[(3S)-3-[(2S)-l,4-dioxan-2-yl]-5 -nitro-3,4-dihydro-2H-l,4- benzoxazin-7-ylsulfonyl] -2- [( 12R)- 12-methyl- 13 -oxa-2,4, 10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzamide hydrochloride, and 4- (4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methy l]piperazin-l-yl)-N-[(3R)-3- [(2S)-l,4-dioxan-2-yl]-5-nitro-3,4-dihydro-2H-l,4-benzoxazin -7-ylsulfonyl]-2-[(l2R)-l2- methyl-l3-oxa-2,4,l0-triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0- yl]benzamide hydrochloride
Synthesis of (2R)-l,4-dioxane-2-carbaldehyde: Into a lOO-mL round-bottom flask, was placed (2S)-l,4-dioxan-2-ylmethanol (2.36 g, l9.978mmol , l.OOequiv), CH 3 CN (50.00 mL, l.2l8mmol, O.Oequiv), IBX (9.51 g, 33.962mmol, l.70equiv). The resulting solution was stirred for 4 h at 70 degrees C in an oil bath. The solids were filtered out. The resulting mixture was concentrated. This resulted in 2.0 g (86.22%) of (2R)-l,4-dioxane-2- carbaldehyde as colorless oil. H-NMR-l: 1H NMR (300 MHz, CDCl 3 , ppm) d 9.66 (s,
1H), 4.12-3.77 (m, 7H).
Synthesis of 2-amino-2-[(2S)-l,4-dioxan-2-yl]acetonitrile: Into a lOO-mL pressure tank reactor, was placed (2R)-l,4-dioxane-2-carbaldehyde (2.00 g, l7.224mmol, l.OOequiv). NH 3 /MeOH(7M) (40.00 mL) . This was followed by the addition of TMSCN (2.97 g, 29.970mmol, l.74equiv). The resulting solution was stirred for overnight at 70 degrees C in an oil bath. The resulting mixture was concentrated. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (3:1). The collected fractions were combined and concentrated. This resulted in 2.0 g (81.68%) of 2-amino-2-[(2S)-l,4-dioxan- 2-yl] acetonitrile as brown oil. LCMS-2 (ES, m/z): M+l: 143
Synthesis of amino((2S)-l,4-dioxan-2-yl)acetic acid: Into a 20-mL round-bottom flask, was placed 2-amino-2-[(2S)-l,4-dioxan-2-yl]acetonitrile (2.00 g, l4.069mmol, l.OOequiv), NaOH(4M) (5.00 mL). The resulting solution was stirred for overnight at 70 degrees C in an oil bath. The pH value of the solution was adjusted to 6 with HOAc. The solids were collected by filtration. The solid was dried in an oven under reduced pressure. This resulted in 1.2 g (52.93%) of amino((2S)-l,4-dioxan-2-yl)acetic acid as a white solid. LCMS-3 (ES, m/z) M+l: 162
Synthesis of 2-amino-2-[(2S)-l,4-dioxan-2-yl]ethanol: Into a lOO-mL round-bottom flask, was placed amino((2S)-l,4-dioxan-2-yl)acetic acid (1.20 g, 7.446mmol, l.OOequiv), THF (40.00 mL, 0.555mmol, 0.07equiv), LiAlH 4 (0.85 g, 22.396mmol, 3.01equiv). The resulting solution was stirred for 4 h at 60 degrees C in an oil bath. The reaction was then quenched by the addition of 2.4 g of Na 2 SO 4 .10H 2 O. The solids were filtered out. The resulting mixture was concentrated. This resulted in 1.8 g (crude) of 2-amino-2-[(2S)-l,4- dioxan-2-yl]ethanol as colorless oil. LCMS-4 (ES, m/z) M+l: 148
Synthesis of 3-bromo-4-([l-[(2S)-l,4-dioxan-2-yl]-2-hydroxyethyl]amino)-5 - nitrobenzenesulfonamide: Into a 50-mL round-bottom flask, was placed 3-bromo-4- chloro-5-nitrobenzenesulfonamide (1.19 g, 3.772mmol, l.OOequiv), 2-amino-2-[(2S)-l,4- dioxan-2-yl]ethanol (0.72 g, 0.005mmol, 1.3equiv), CH 3 CN (30.00 mL), DIEA (1.46 g,
0.01 lmmol, 3equiv). The resulting solution was stirred for 48 h at 80 degrees C in an oil bath. The resulting mixture was concentrated. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (9:1). The collected fractions were combined and concentrated. This resulted in 120 mg (7.46%) of 3-bromo-4-([l-[(2S)-l,4- dioxan-2-yl]-2-hydroxyethyl]amino)-5-nitrobenzenesulfonamide as a yellow solid. LCMS-5 (ES, m/z): M-l: 424
Synthesis of (3S)-3-[(2S)-l,4-dioxan-2-yl]-5-nitro-3,4-dihydro-2H-l,4- benzoxazine-7-sulfonamide &(3R)-3-[(2S)-l,4-dioxan-2-yl]-5-nitro-3,4-dihydro-2H-l, 4- benzoxazine-7-sulfonamide(assumed): Into a 8-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-bromo-4-([l-[(2S)-l,4- dioxan-2-yl]-2-hydroxyethyl]amino)-5-nitrobenzenesulfonamide (120.00 mg, 0.282mmol, l.OOequiv), dioxane (8.00 mL), CS 2 CO 3 (229.32 mg, 0.704mmol, 2.50equiv), t-BuXPhos Pd G3 (22.33 mg, 0.028mmol, O.lequiv). The resulting solution was stirred for 8 h at 100 degrees C in an oil bath. The reaction was then quenched by the addition of water (8mL).
The resulting solution was extracted with 3x8 mL of ethyl acetate concentrated. The crude product was purified by Prep-HPLC with the following conditions: Column, X-bridge RP18; mobile phase, 0.05% ammonia in water and CH 3 CN (45% CH 3 CN up to 60% in 5 min); Detector, UV 254 nm. This resulted in 7 mg (7.20%) of (3S or 3R)-3-[(2S)-l,4-dioxan-2- yl]-5-nitro-3,4-dihydro-2H-l,4-benzoxazine-7-sulfonamide as a yellow solid. This resulted in 10 mg (10.29%) of (3R or 3S)-3-[(2S)-l,4-dioxan-2-yl]-5-nitro-3,4-dihydro-2H-l,4- benzoxazine-7-sulfonamide as a yellow solid. LC-MS-6: (ES, m/z): M- 1:344
Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-N-[(3S)-3-[(2S)-l,4-dioxan-2-yl]-5 -nitro-3,4-dihydro-2H-l,4- benzoxazin-7-ylsulfonyl]-2-[(12R)-12-methyl-13-oxa-2,4,10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-10-yl]benzamide
hydrochloride(assumed): Into a 8-mL round-bottom flask, was placed 4-(4-[[2-(4- chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl]piperazi n-l-yl)-2-[(l2R)-l2-methyl- l3-oxa-2,4,l0-triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzoic acid (12.69 mg, 0.020mmol, l.OOequiv), (3S)-3-[(2S)-l,4-dioxan-2-yl]-5-nitro-3,4-dihydro-2H-
1.4-benzoxazine-7-sulfonamide (7.00 mg, 0.020mmol, l.OOequiv), DCM (5.00 mL), EDCI (7.77 mg, 0.04lmmol, 2.00equiv), DMAP (7.43 mg, 0.06lmmol, 3.00equiv). The resulting solution was stirred for overnight at room temperature. The resulting mixture was
concentrated. The crude product was purified by Prep-HPLC with the following conditions (2#S HIM ADZU (HPLC-01)): Column, Sun Fire Prep C18 OBD Column, 19*150mm 5um lOnm; mobile phase, Water (0.05% TFA) and ACN (38% Phase B up to 58% in 7 min); Detector, UV 254 nm. The collected solution was concentrated under vacuum to remove CH3CN and the resulting solution was dried by lyophilization (added with con.HCl (1 drop)). This resulted in 5 mg (24.92%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex- l-en-l-yl]methyl]piperazin-l-yl)-N-[(3S)-3-[(2S)-l,4-dioxan- 2-yl]-5-nitro-3,4-dihydro-2H-
1.4-benzoxazin-7-ylsulfonyl] -2- [( 12R)- 12-methyl- 13 -oxa-2,4, 10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzamide hydrochloride as a yellow solid. LC-MS-0A: (ES, m/z) M+1-HC1: 953 Synthesis of4- (4- [ [2- (4-chlorophenyl) -4,4-dimethylcyclohex- 1-en-l- yl]methyl]piperazin-l-yl)-N-[(3R)-3-[(2S)-l,4-dioxan-2-yl]-5 -nitro-3,4-dihydro-2H-l,4- benzoxazin-7-ylsulfonyl]-2-[(12R)-12-methyl-13-oxa-2,4,10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-10-yl]benzamide
hydrochloride(assumed): Into a 8-mL round-bottom flask, was placed (3R)-3-[(2S)-l,4- dioxan-2-yl]-5-nitro-3,4-dihydro-2H-l,4-benzoxazine-7-sulfon amide (10.00 mg,
0.029mmol, l.OOequiv), 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-2-[(l2R)-l2-methyl-l3-oxa-2,4,l0- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzoic acid (18.13 mg, 0.029mmol, l.OOequiv), DCM (5.00 mL), EDCI (11.10 mg, 0.058mmol, 2equiv), DMAP (14.15 mg, O. H6mmol, 4equiv). The resulting solution was stirred for overnight at room temperature. The resulting mixture was concentrated. The crude product was purified by Prep-HPLC with the following conditions (2#SHIMADZU (HPLC-01)): Column, Sun Fire Prep C18 OBD Column, l9??l50mm 5um lOnm; mobile phase, Water (0.05% TFA) and ACN (38% Phase B up to 58% in 7 min); Detector, UV=254nm. . The collected solution was concentrated under vacuum to remove CFPCN and the resulting solution was dried by lyophilization (added with con.HCl(l drop)). This resulted in 10 mg of 4-(4-[[2-(4- chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl]piperazi n-l-yl)-N-[(3R)-3-[(2S)-l,4- dioxan-2-yl]-5-nitro-3,4-dihydro-2H-l,4-benzoxazin-7-ylsulfo nyl]-2-[(l2R)-l2-methyl-l3- oxa-2,4,l0-triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzamide hydrochloride as a yellow solid. FC-MS-0B: (ES, m/z ): M+1-HC1: 953; H-NMR-0B: 1H NMR (300 MHz, Methanol-^ , ppm) d 8.01 (s, 1H), 7.65 (d, / = 8.4 Hz, 1H), 7.41 (d, / = 8.4 Hz, 1H), 7.25 (s, 1H), 7.13 (d, / = 8.4 Hz, 2H), 6.94 (s, 2H), 6.82 (s, 1H), 6.66(s, 1H), 5.94 (s, 1H), 4.70 (s, 1H), 4.31 (s, 1H), 4.04 (s, 1H), 3.98 - 3.58 (m, 12H), 3.48 (s, 3H), 3.22 (s, 2H), 2.90 (s, 2H), 2.33 (s, 2H), 2.16 (s, 2H), 1.62 (t, / = 6.3 Hz, 2H), 1.51 (d, / = 6.3 Hz, 3H), 1.32 (s, 1H), 1.05 (s, 6H).
Example 44: Preparation of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-N-(4-[[(2S)-l,4-dioxan-2-ylmethyl] amino]-3- nitrobenzenesulfonyl)-2-[(l lS,l5S)-l6-oxa-2,4,lO- triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca-l(9),2,5,7-tetraen-l0- yl]benzamide( Assumed) and 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-N-(4-[[(2S)-l,4-dioxan-2-ylmethyl] amino]-3- nitrobenzenesulfonyl)-2-[(HR,l5R)-l6-oxa-2,4,lO- triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca-l(9),2,5,7-tetraen-l0- yl] benzamide( As sumed) :
Synthesis of N-[(trans)-2-hydroxycyclopentyl]-4-methylbenzenesulfonamide: Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed (trans)-2-aminocyclopentan-l-ol (2.10 g, 20.761 mmol, 1.00 equiv), DCM (30.00 mL), TEA (3.18 g, 31.426 mmol, 1.51 equiv). This was followed by the addition of P-toluenesulfonyl chloride (4.35 g, 22.818 mmol, 1.10 equiv), in portions at 0 degrees C. The resulting solution was stirred for 3 hr at 25 degrees C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1.5: 1). This resulted in 5 g (94.32%) of N-[(trans)-2- hydroxycyclopentyl]-4-methylbenzenesulfonamide as light yellow oil. 1H NMR (300 MHz, Chloroform-7, ppm) d 7.84 - 7.77 (m, 2H), 7.38 - 7.30 (m, 2H), 5.27 (s, 1H), 4.06 (dt, / = 7.2, 6.3 Hz, 1H), 3.25 (q, / = 7.7 Hz, 1H), 2.91 (s, 1H), 2.45 (s, 3H), 2.06 - 1.81 (m, 2H), 1.72 - 1.46 (m, 3H), 1.45 - 1.23 (m, 1H).
Synthesis of N-[(trans)-2-[(5-bromo-l-[[2- (trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-b]pyridin-6-yl)oxy ]cyclopentyl]-4- methylbenzenesulfonamide: Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed N-[(trans)-2-hydroxycyclopentyl]-4- methylbenzenesulfonamide (5.00 g, 19.583 mmol, 1.30 equiv), THF (50.00 mL). This was followed by the addition of NaH (1.81 g, 45.254 mmol, 3.01 equiv, 60%), in portions at 0 degrees C. The resulting solution was stirred for 0.5 h at 0 degrees C. To this was added 5- bromo-6-fluoro-l-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2 ,3-b]pyridine (5.19 g, 15.031 mmol, 1.00 equiv) at 0 degrees C. The resulting solution was stirred for 2 hr at 70 degrees C in an oil bath. The reaction mixture was cooled to room temperature. The reaction was then quenched by the addition of aqueous NH4CI. The resulting solution was extracted with 3x200 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1 xlOOO ml of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3). This resulted in 4.8 g (55.00%) of N-[(trans)-2-[(5-bromo-l- [[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-b]pyridin-6-yl )oxy]cyclopentyl]-4- methylbenzenesulfonamide as yellow oil. 1H NMR (300 MHz, Ch loro form-7, ppm) d 8.00 (s, 1H), 7.56 - 7.47 (m, 2H), 7.19 (d, / = 3.6 Hz, 1H), 7.11 - 7.02 (m, 2H), 6.42 (d, 7 = 3.6 Hz, 1H), 5.70 (d, J = 10.9 Hz, 1H), 5.49 (d, J = 10.9 Hz, 1H), 5.33 - 5.20 (m, 1H), 3.69 - 3.43 (m, 3H), 2.31 (s, 3H), 1.93 - 1.63 (m, 4H), 1.01 - 0.93 (m, 2H), 0.89 (dd, 7 = 7.0, 1.5 Hz, 2H), 0.01 (s, 9H).
Synthesis of (trans)-10-(4-methylbenzenesulfonyl)-4-[[2- (trimethylsilyl)ethoxy]methyl]-16-oxa-2,4,10- triazatetracyclo[7.7.0.0 A [3,7].0 A [ll,15]]hexadeca-l(9),2,5,7-tetraene: Into a lOO-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed N-[(trans)-2-[(5-bromo-l-[[2-(trimethylsilyl)ethoxy]methyl]p yrrolo[2,3-b]pyridin-6- yl)oxy]cyclopentyl]-4-methylbenzenesulfonamide (2.90 g, 4.995 mmol, 1.00 equiv), DMF (30.00 mL), phen (902.00 mg, 5.005 mmol, 1.00 equiv), Cul (952.00 mg, 4.999 mmol, 1.00 equiv), K 2 C0 3 (2.07 g, 14.978 mmol, 3.00 equiv). The resulting solution was stirred overnight at 120 degrees C in an oil bath. The reaction mixture was cooled to room temperature. The resulting solution was diluted with 500 mL of water. The resulting solution was extracted with 3x200 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1 xlOOO ml of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3). This resulted in 2.1 g (84.14%) of (trans)- l0-(4-methylbenzenesulfonyl)-4-[[2-(trimethylsilyl)ethoxy]me thyl]- l6-oxa-2,4, 10- triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca-l(9),2,5,7-tetraene as colorless o i 1. 1 H NMR (300 MHz, Chloroform-7, ppm) d 8.68 (s, 1H), 7.43 - 7.34 (m, 2H), 7.24 (d, / = 3.6 Hz, 1H), 7.15 (d, J = 8.0 Hz, 2H), 6.53 (d, 7 = 3.6 Hz, 1H), 5.54 (d, J = 1.4 Hz, 2H), 4.00 (td, / = 10.0, 7.6 Hz, 1H), 3.52 (t, / = 8.2 Hz, 2H), 3.43 - 3.28 (m, 1H), 2.68 - 2.49 (m, 1H), 2.35 (s, 3H), 2.21 - 1.88 (m, 4H), 1.77 (td, J = 10.8, 7.6 Hz, 1H), 0.97 - 0.86 (m, 2H), -0.05 (s, 9H)
Synthesis of (llS,15S)-4-[[2-(trimethylsilyl)ethoxy]methyl]-16-oxa-2,4,10 - triazatetracyclo[7.7.0.0 A [3,7].0 A [ll,15]]hexadeca-l(9),2,5,7-tetraene(Assumed) and (llR,15R)-4-[[2-(trimethylsilyl)ethoxy]methyl]-16-oxa-2,4,10 - triazatetracyclo[7.7.0.0 A [3,7].0 A [ll,15]]hexadeca-l(9),2,5,7-tetraene(Assumed): Into a lOO-mL round-bottom flask, was placed Mg (1.92 g, 78.996 mmol, 19.74 equiv), MeOH (20.00 mL), (trans)- l0-(4-methylbenzenesulfonyl)-4-[[2-(trimethylsilyl)ethoxy]me thyl]- 16- oxa-2,4,l0-triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca-l(9),2,5,7-tetraene (2.00 g, 4.002 mmol, 1.00 equiv). The resulting solution was stirred for 2 hr at 60 degrees C in an oil bath. The reaction mixture was cooled to room temperature. The resulting solution was diluted with 300/300 mL of NaHC0 3 and CH 2 CI 2 . The solids were filtered out and the organic was separated. The mixture was dried over anhydrous sodium sulfate and
concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3). The crude product was purified by Chiral- Prep-HPLC with the following conditions: Mobile phase: A: n- Hexane B: ETOH; Flow rate: 20 mL/min; Column: DAICEL CHIRALPAK OD, 250*20mm, 5um; Gradient: 20%B in l5min; 220 nm. This resulted in 360 mg (26.03%) of (HS,l5S)-4-[[2-(trimethylsilyl)ethoxy]methyl]-l6- oxa-2,4,l0-triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca-l(9),2,5,7-tetraene(Assumed) as yellow oil. This resulted in 400 mg (28.92%) of (HR,l5R)-4-[[2- (trimethylsilyl)ethoxy]methyl]-l6-oxa-2,4,l0- triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca-l(9),2,5,7-tetraene(Assumed) as yellow oil. Peak 1: LC-MS (ES, m/z ): M+l=346, 1H NMR (300 MHz, Chloroform-d, ppm) d 7.28 (s, 1H), 7.15 (d, / = 3.5 Hz, 1H), 6.33 (d, 7 = 3.5 Hz, 1H), 5.56 (s, 2H), 4.30 - 4.07 (m, 1H), 3.55 (dd, / = 8.8, 7.5 Hz, 2H), 3.29 (dt, / = 11.4, 7.5 Hz, 1H), 2.37 - 2.19 (m, 1H), 2.18 - 2.04 (m, 1H), 2.04 - 1.79 (m, 3H), 1.68 - 1.40 (m, 1H), 0.90 (dd, J = 8.7, 7.5 Hz, 2H), -0.06 (s, 9H). Peak 2: LC-MS (ES, m/z) M+l=346, 1H NMR (300 MHz, Chloroform-J, ppm) d 7.28 (s, 1H), 7.15 (d, / = 3.5 Hz, 1H), 6.33 (d, / = 3.5 Hz, 1H), 5.56 (s, 2H), 4.30 - 4.07 (m, 1H), 3.55 (dd, / = 8.8, 7.5 Hz, 2H), 3.29 (dt, / = 11.4, 7.5 Hz, 1H), 2.37 - 2.19 (m, 1H), 2.18 - 2.04 (m, 1H), 2.04 - 1.79 (m, 3H), 1.68 - 1.40 (m, 1H), 0.90 (dd, / = 8.7, 7.5 Hz,
2H), -0.06 (s, 9H).
Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-2-[(llS,15S)-4-[[2-(trimethylsilyl )ethoxy]methyl]-16-oxa- 2,4,10-triazatetracyclo[7.7.0.0 A [3,7].0 A [ll,15]]hexadeca-l(9),2,5,7-tetraen-10- yl]benzoate( Assumed): Into a 40-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed (HS,l5S)-4-[[2-(trimethylsilyl)ethoxy]methyl]-l6-oxa-2,4,l0- triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca-l(9),2,5,7-tetraene(Assumed) (340.00 mg, 0.984 mmol, 1.00 equiv), toluene (15.00 mL), methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)- 4, 4-dimethylcyclo hex- l-en-l-yl]methyl]piperazin- l-yl) benzoate (1.04 g, 1.955 mmol, 1.99 equiv), Pd 2 (dba) 3 .CHCl 3 (204.00 mg, 0.197 mmol, 0.20 equiv), Xantphos (228.00 mg, 0.394 mmol, 0.40 equiv), CS 2 CO 3 (961.00 mg, 2.949 mmol, 3.00 equiv). The resulting solution was stirred for 4 hr at 100 degrees C in an oil bath. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2). This resulted in 630 mg (80.38%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-2-[(l lS,l5S)-4-[[2-(trimethylsilyl)ethoxy]methyl]-l6-oxa-2,4,l0- triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca-l(9),2,5,7-tetraen-l0- yl]benzoate( Assumed) as a yellow solid. LC-MS (ES, m/z ): M+l=796.
Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-2-[(llS,15S)-16-oxa-2,4,10- triazatetracyclo[7.7.0.0 A [3,7].0 A [ll,15]]hexadeca-l(9),2,5,7-tetraen-10- yl]benzoate( Assumed): Into a 40-mL vial, was placed methyl 4-(4-[[2-(4-chlorophenyl)- 4,4-dimethylcyclohex-l-en-l-yl]methyl]piperazin-l-yl)-2-[(l lS,l5S)-4-[[2- (trimethylsilyl)ethoxy]methyl]-l6-oxa-2,4,l0- triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca-l(9),2,5,7-tetraen-l0- yl]benzoate( Assumed) (630.00 mg, 0.791 mmol, 1.00 equiv), TBAF in THF (10.00 mF, 1.0 M), ethylenediamine (1.30 g, 21.631 mmol, 27.35 equiv). The resulting solution was stirred for 8 hr at 70 degrees C in an oil bath. The reaction mixture was cooled to room
temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:1). This resulted in 300 mg (56.93%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-2-[(HS,l5S)-l6-oxa-2,4,lO- triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca-l(9),2,5,7-tetraen-l0- yl]benzoate( Assumed) as a yellow solid. FC-MS: (ES, m/z) M+l=666.
Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-2-[(llS,15S)-16-oxa-2,4,10- triazatetracyclo[7.7.0.0 A [3,7].0 A [ll,15]]hexadeca-l(9),2,5,7-tetraen-10-yl]benzoic acid(Assumed): Into a 40-mF vial, was placed methyl 4-(4-[[2-(4-chlorophenyl)-4,4- dimethylcyclohex-l-en-l-yl]methyl]piperazin-l-yl)-2-[(l lS,l5S)-l6-oxa-2,4,lO- triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca-l(9),2,5,7-tetraen-l0- yl]benzoate( Assumed) (300.00 mg, 0.450 mmol, 1.00 equiv), dioxane (5.00 mF), MeOH (5.00 mF), NaOH (1.00 mF, 4.000 mmol, 8.88 equiv). The resulting solution was stirred for 4 hr at 70 degrees C in an oil bath. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 6-7 with HC1 (2 mol/H). The resulting solution was extracted with 3x50 mF of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1 x300 ml of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Prep-TLC with ethyl acetate. This resulted in 130 mg (44.26%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-2-[(HS,l5S)-l6-oxa-2,4,lO- triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca-l(9),2,5,7-tetraen-l0-yl]benzoic acid( Assumed) as a white solid. LC-MS: (ES, m/z ): M+l=652.
Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-N-(4-[[(2S)-l,4-dioxan-2-ylmethyl] amino]-3- nitrobenzenesulfonyl)-2-[(llS,15S or HR, 15R)-16-oxa-2,4,10- triazatetracyclo[7.7.0.0 A [3,7].0 A [ll,15]]hexadeca-l(9),2,5,7-tetraen-10- yl]benzamide( Assumed): Into a 40-mL vial, was placed 4-(4-[[2-(4-chlorophenyl)-4,4- dimethylcyclohex-l-en-l-yl]methyl]piperazin-l-yl)-2-[(l lS,l5S)-l6-oxa-2,4,lO- triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca-l(9),2,5,7-tetraen-l0-yl]benzoic acid( Assumed) (50.00 mg, 0.077 mmol, 1.00 equiv), DCM (5.00 mL), 4-[[(2S)-l,4-dioxan- 2-ylmethyl]amino]-3-nitrobenzenesulfonamide (24.00 mg, 0.076 mmol, 0.99 equiv), EDCI (30.00 mg, 0.156 mmol, 2.04 equiv), DMAP (38.00 mg, 0.311 mmol, 4.06 equiv). The resulting solution was stirred overnight at 30 degrees C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-006): Column, X Bridge Shield RP18 OBD Column, 5um, l9* l50mm; mobile phase, Water (0.05% NH 3 .H 2 O) and ACN (40% Phase B up to 70% in 7 min); Detector, UV 254/220 nm. This resulted in 25 mg (34.27%) of 4-(4-[[2-(4- chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl]piperazi n-l-yl)-N-(4-[[(2S)-l,4- dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfonyl)-2-[(l lS,l5S or 11R, l5R)-l6-oxa- 2,4,l0-triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca-l(9),2,5,7-tetraen-l0- yl]benzamide( Assumed) as a yellow solid. LC-MS (ES, m/z): M+l=95l, 1H NMR (300 MHz, DMSO-de, ppm ) d 12.90 (s, 1H), 11.21 (s, 1H), 8.54 (s, 1H), 8.35 (d, J = 2.3 Hz, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.46 - 7.30 (m, 3H), 7.18 - 6.99 (m, 3H), 6.93 (d, J = 9.2 Hz, 1H), 6.80 (s, 2H), 6.49 (s, 1H), 6.07 - 5.99 (m, 1H), 4.33 (d, J = 7.2 Hz, 1H), 3.79 (dd, J = 9.9, 5.9 Hz, 4H), 3.73 - 3.33 (m, 7H), 3.27 (d, J = 13.6 Hz, 4H), 3.12 (d, J = 6.5 Hz, 1H), 2.75 (s, 2H), 2.20 (s, 6H), 1.97 (s, 2H), 1.83 (s, 2H), 1.68 (s, 1H), 1.40 (s, 3H), 0.94 (d, J = 2.2 Hz, 6H). Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-2-[(llR,15R)-4-[[2-(trimethylsilyl )ethoxy]methyl]-16-oxa-
2.4.10-triazatetracyclo[7.7.0.0 A [3,7].0 A [ll,15]]hexadeca-l(9),2,5,7-tetraen-10- yl]benzoate( Assumed): Into a 40-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed (HR,l5R)-4-[[2-(trimethylsilyl)ethoxy]methyl]-l6-oxa-2,4,l0- triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca-l(9),2,5,7-tetraene(Assumed) (400.00 mg, 1.158 mmol, 1.00 equiv), toluene (15 mL), methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4- dimethylcyclohex-l-en-l-yl]methyl]piperazin-l-yl)benzoate (1.23 g, 2.312 mmol, 2.00 equiv), Pd 2 (dba) 3 .CHCl 3 (239.00 mg, 0.231 mmol, 0.20 equiv), Xantphos (268.00 mg, 0.463 mmol, 0.40 equiv), CS 2 CO 3 (1.13 g, 3.468 mmol, 3.00 equiv). The resulting solution was stirred for 4 hr at 100 degrees C in an oil bath. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2). This resulted in 680 mg (73.74%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-2-[(HR,l5R)-4-[[2-(trimethylsilyl) ethoxy]methyl]-l6-oxa-
2.4.10-triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca-l(9),2,5,7-tetraen-l0- yl]benzoate( Assumed) as a yellow solid. LC-MS (ES, m/z ): M+l=796.
Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-2-[(llR,15R)-16-oxa-2,4,10- triazatetracyclo[7.7.0.0 A [3,7].0 A [ll,15]]hexadeca-l(9),2,5,7-tetraen-10- yl]benzoate( Assumed): Into a 40-mL vial, was placed methyl 4-(4-[[2-(4-chlorophenyl)- 4,4-dimethylcyclohex-l-en-l-yl]methyl]piperazin-l-yl)-2-[(l lR,l5R)-4-[[2- (trimethylsilyl)ethoxy]methyl]-l6-oxa-2,4,l0- triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca-l(9),2,5,7-tetraen-l0- yl]benzoate(Assumed) (670.00 mg, 0.841 mmol, 1.00 equiv), TBAF in THF (10.00 mL, 1.0 M), ethylenediamine (1.30 g, 21.631 mmol, 25.72 equiv). The resulting solution was stirred for 8 hr at 70 degrees C in an oil bath. The reaction mixture was cooled to room
temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:1). This resulted in 320 mg (57.10%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl] methyl]piperazin- 1 -yl)-2- [( 11R, 15R)- 16-oxa-2,4, 10- triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca-l(9),2,5,7-tetraen-l0- yl]benzoate( Assumed) as a yellow solid. LC-MS (ES, m/z) M+l=666. Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-2-[(llR,15R)-16-oxa-2,4,10- triazatetracyclo[7.7.0.0 A [3,7].0 A [ll,15]]hexadeca-l(9),2,5,7-tetraen-10-yl]benzoic acid(Assumed): Into a 40-mL vial, was placed methyl 4-(4-[[2-(4-chlorophenyl)-4,4- dimethylcyclohex-l-en-l-yl]methyl]piperazin-l-yl)-2-[(HR,l5R )-l6-oxa-2,4,lO- triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca-l(9),2,5,7-tetraen-l0- yl]benzoate( Assumed) (140.00 mg, 0.210 mmol, 1.00 equiv), dioxane (3.00 mL), MeOH (3.00 mL), NaOH (0.60 mL, 2.400 mmol, 11.42 equiv). The resulting solution was stirred for 4 hr at 70 degrees C in an oil bath. The reaction mixture was cooled to room
temperature. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 6-7 with HC1 (2 mol/L). The resulting solution was extracted with 3x50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1 x300 ml of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Prep-TLC with ethyl acetate. This resulted in 80 mg (58.37%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl] methyljpiperazin- 1 -yl)-2- [( 11R, 15R)- 16-oxa-2,4, 10- triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca-l(9),2,5,7-tetraen-l0-yl]benzoic acid( Assumed) as a white solid. LC-MS (ES, m/z ): M+l=652.
Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-N-(4-[[(2S)-l,4-dioxan-2-ylmethyl] amino]-3- nitrobenzenesulfonyl)-2-[(llR,15R or 11S, 15S)-16-oxa-2,4,10- triazatetracyclo[7.7.0.0 A [3,7].0 A [ll,15]]hexadeca-l(9),2,5,7-tetraen-10-yl]benzamide:
Into a 40-mL vial, was placed 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl] methyljpiperazin- 1 -yl)-2- [( 11R, 15R)- 16-oxa-2,4, 10- triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca-l(9),2,5,7-tetraen-l0-yl]benzoic acid (20.00 mg, 0.031 mmol, 1.00 equiv), DCM (5.00 mL), 4-[[(2S)-l,4-dioxan-2- ylmethyl]amino]-3-nitrobenzenesulfonamide(Assumed) (9.70 mg, 0.031 mmol, 1.00 equiv), EDCI (12.00 mg, 0.063 mmol, 2.04 equiv), DMAP (15.00 mg, 0.123 mmol, 4.00 equiv). The resulting solution was stirred overnight at 30 degrees C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-006): Column, X Bridge Shield RP18 OBD Column, 5um, l9*l50mm; mobile phase, Water (0.05% NH3.H2O) and ACN (40% Phase B up to 70% in 7 min); Detector, UV 254/220 nm. This resulted in 4.7 mg (16.11%) of 4-(4- [[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl]p iperazin-l-yl)-N-(4-[[(2S)- l,4-dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfonyl)-2-[(HR, l5R or 11S, l5S)-l6-oxa- 2,4,l0-triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca-l(9),2,5,7-tetraen-l0- yl]benzamide( Assumed) as a yellow solid. LC-MS (ES, m/z): M+l=95l, 1H NMR (300 MHz, DMSO-de, ppm ) d 12.90 (s, 1H), 11.21 (s, 1H), 8.54 (s, 1H), 8.35 (d, J = 2.3 Hz, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.46 - 7.30 (m, 3H), 7.18 - 6.99 (m, 3H), 6.93 (d, J = 9.2 Hz, 1H), 6.80 (s, 2H), 6.49 (s, 1H), 6.07 - 5.99 (m, 1H), 4.33 (d, J = 7.2 Hz, 1H), 3.79 (dd, J = 9.9, 5.9 Hz, 4H), 3.73 - 3.33 (m, 7H), 3.27 (d, / = 13.6 Hz, 4H), 3.12 (d, / = 6.5 Hz, 1H), 2.75 (s, 2H), 2.20 (s, 6H), 1.97 (s, 2H), 1.83 (s, 2H), 1.68 (s, 1H), 1.40 (s, 3H), 0.94 (d, / = 2.2 Hz, 6H).
Example 45: Preparation of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl] methyl]piperazin- l-yl)-2-[(HR,l5S)-l3,l 6-dioxa-2,4, 10- triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca-l(9),2,5,7-tetraen-l0-yl]-N-(4-[[(2S)-l,4- dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfonyl)benzamide (assumed) and 4-(4-[[2-(4- chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl]piperazi n-l-yl)-2-[(HS,l5R)-l3,l6- dioxa-2,4,l0-triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca-l(9),2,5,7-tetraen-l0-yl]-N- (4-[[(2S)-l,4-dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfony l)benzamide (assumed):
Synthesis of N-[(trans)-4-hydroxyoxolan-3-yl]-4-methylbenzenesulfonamide: Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3,6-dioxabicyclo[3. l.0]hexane (5.00 g, 58.079 mmol, 1.00 equiv), dioxane (100.00 mL), p-toluenesulfonamide (11.93 g, 69.681 mmol, 1.20 equiv), TEBAC (1.33 g, 5.833 mmol, 0.10 equiv), K 2 C0 3 (0.80 g, 5.788 mmol, 0.10 equiv). The resulting solution was stirred for 3 days at 90 degrees C in an oil bath. The reaction mixture was cooled to room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl
acetate/petroleum ether (2: 1). This resulted in 10.69 g (25.75%) of N-[(trans) -4- hydroxyoxolan-3-yl]-4-methylbenzenesulfonamide as a white solid. LC-MS: (ES, m/z): M+l=258.
Synthesis of N-[(trans) -4-[(5-bromo-l-[[2- (trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-b]pyridin-6-yl)oxy ]oxolan-3-yl]-4- methylbenzenesulfonamide: Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed N-[(trans)-4-hydroxyoxolan-3-yl]-4- methylbenzenesulfonamide (10.50 g, 14.691 mmol, 1.30 equiv, 36%), THF (100 mL). This was followed by the addition of NaH (2.71 g, 67.756 mmol, 6.01 equiv, 60%), in portions at 0 degrees C. The resulting solution was stirred for 30 min at 0 degrees C. To this was added 5-bromo-6-fluoro-l-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo [2,3-b]pyridine (3.89 g,
11.266 mmol, 1.00 equiv) at 0 degrees C. The resulting solution was stirred for 4 hr at 70 degrees C in an oil bath. The reaction mixture was cooled to room temperature. The reaction was then quenched by the addition of 500 mL of aqueous NH4CI. The resulting solution was extracted with 3x300 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1 xl500 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2). This resulted in 3 g (45.71%) of N-[(trans) -4-[(5-bromo-l-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3 -b]pyridin-6- yl)oxy]oxolan-3-yl]-4-methylbenzenesulfonamide as light yellow oil. 1H NMR (300 MHz, Chloroform-d, ppm) d 8.04 (s, 1H), 7.78 - 7.61 (m, 2H), 7.25 - 7.10 (m, 3H), 6.43 (d, / =
3.6 Hz, 1H), 5.67 (d, / = 10.8 Hz, 1H), 5.60 (d, / = 5.7 Hz, 1H), 5.49 (d, / = 10.8 Hz, 1H), 5.40 (dt, / = 6.1, 3.1 Hz, 1H), 4.27 (dd, / = 10.5, 5.9 Hz, 1H), 4.21 - 4.03 (m, 1H), 4.03 - 3.86 (m, 2H), 3.70 - 3.52 (m, 3H), 2.32 (s, 3H), 0.93 (ddt, J = 10.6, 5.5, 2.6 Hz, 2H), -0.02 (s, 9H).
Synthesis of (trans) -10-(4-methylbenzenesulfonyl)-4-[[2- (trimethylsilyl)ethoxy]methyl]-13,16-dioxa-2,4,10- triazatetracyclo[7.7.0.0 A [3,7].0 A [ll,15]]hexadeca-l(9),2,5,7-tetraene: Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed N-[(trans)(3S,4R)-4-[(5-bromo-l-[[2-(trimethylsilyl)ethoxy]m ethyl]pyrrolo[2,3-b]pyridin-6- yl)oxy]oxolan-3-yl]-4-methylbenzenesulfonamide (3.00 g, 5.149 mmol, 1.00 equiv), DMF (50.00 mL), phen (743.00 mg, 4.123 mmol, 0.80 equiv), Cul (785.00 mg, 4.122 mmol, 0.80 equiv), K 2 C0 3 (2.14 g, 15.484 mmol, 3.01 equiv). The resulting solution was stirred for 2 days at 120 degrees C in an oil bath. The reaction mixture was cooled to room temperature. The resulting solution was diluted with 500 mL of water. The resulting solution was extracted with 3x200 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1 xlOOO mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2). This resulted in 2.5 g (82.26%) of (trans) - l0-(4-methylbenzenesulfonyl)-4-[[2-(trimethylsilyl)ethoxy]me thyl]- 13, l6-dioxa-2,4, 10- triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca-l(9),2,5,7-tetraene as yellow oil. LC-MS: (ES, m/z) M+l=502.
Synthesis of (llS,15R)-4-[[2-(trimethylsilyl)ethoxy]methyl]-13,16-dioxa-2 ,4,10- triazatetracyclo[7.7.0.0 A [3,7].0 A [ll,15]]hexadeca-l(9),2,5,7-tetraene (assumed) and (llR,15S)-4-[[2-(trimethylsilyl)ethoxy]methyl]-13,16-dioxa-2 ,4,10- triazatetracyclo[7.7.0.0 A [3,7].0 A [ll,15]]hexadeca-l(9),2,5,7-tetraene (assumed): Into a lOO-mL round-bottom flask, was placed Mg (2.04 g, 83.933 mmol, 19.81 equiv), MeOH (30.00 mL), (trans) -l0-(4-methylbenzenesulfonyl)-4-[[2-(trimethylsilyl)ethoxy]m ethyl]- l3,l6-dioxa-2,4,l0-triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca-l(9),2,5,7-tetraene (2.50 g, 4.236 mmol, 1.00 equiv, 85%). The resulting solution was stirred for 2 hr at 60 degrees C in an oil bath. The reaction mixture was cooled to room temperature. The resulting solution was diluted with 300/300 mL of NaHC0 3 and CH2CI2. The solids were filtered out and the organic was separated. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3). The crude product was purified by Chiral- Prep- HPLC with the following conditions: Mobile phase: A:n- Hexane (0.1% DEA) B:ETOH; Flow rate: 20mL/min; Column: DAICEL CHIRALPAK IA, 250*20mm, 5um;
Gradient:l2%B in 20min; 220nm This resulted in 350 mg (23.78%) of (HR,l5S)-4-[[2- (trimethylsilyl)ethoxy]methyl]- 13, l6-dioxa-2,4, 10- triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca-l(9),2,5,7-tetraene (assumed) as yellow oil. and 400 mg (27.18%) of (HS,l5R)-4-[[2-(trimethylsilyl)ethoxy]methyl]-l3,l6-dioxa- 2,4,l0-triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca-l(9),2,5,7-tetraene (assumed) as yellow oil. Peak 1: LC-MS: (ES, m/z) M+l=348. 'H NMR (300 MHz, Chloroform·;/, ppm) d 7.39 (s, 1H), 7.21 (d, 7 = 3.6 Hz, 1H), 6.37 (d, 7= 3.6 Hz, 1H), 5.57 (s, 2H), 4.60 (dt, 7 = 10.1, 7.6 Hz, 1H), 4.39 - 4.22 (m, 2H), 3.94 (dd, 7 = 9.9, 7.9 Hz, 1H), 3.86 - 3.69 (m, 2H), 3.64 - 3.45 (m, 2H), 0.91 (dd, 7 = 8.8, 7.5 Hz, 2H), -0.04 (s, 9H). Peak 2: LC-MS: (ES, m/z) M+l=348. 1H NMR (300 MHz, Chloroform-7, ppm) d 7.39 (s, 1H), 7.21 (d, 7 = 3.6 Hz,
1H), 6.37 (d, 7 = 3.6 Hz, 1H), 5.57 (s, 2H), 4.60 (dt, 7 = 10.1, 7.6 Hz, 1H), 4.39 - 4.22 (m, 2H), 3.94 (dd, 7 = 9.9, 7.9 Hz, 1H), 3.86 - 3.69 (m, 2H), 3.64 - 3.45 (m, 2H), 0.91 (dd, 7 = 8.8, 7.5 Hz, 2H), -0.04 (s, 9H). Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-2-[(llR,15S)-4-[[2-(trimethylsilyl )ethoxy]methyl]-13,16- dioxa-2,4,10-triazatetracyclo[7.7.0.0 A [3,7].0 A [ll,15]]hexadeca-l(9),2,5,7-tetraen-10- yl]benzoate (assumed): Into a 40-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed (HR,l5S)-4-[[2-(trimethylsilyl)ethoxy]methyl]-l3,l6-dioxa-2, 4,l0- triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca-l(9),2,5,7-tetraene (assumed) (350.00 mg, 1.007 mmol, 1.00 equiv), toluene (15.00 mL), methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)- 4, 4-dimethylcyclo hex- l-en-l-yl]methyl]piperazin-l-yl) benzoate (1.07 g, 2.012 mmol, 2.00 equiv), Pd 2 (dba) 3 .CHCl 3 (208.00 mg, 0.201 mmol, 0.20 equiv), Xantphos (234.00 mg, 0.404 mmol, 0.40 equiv), CS 2 CO 3 (985.00 mg, 3.023 mmol, 3.00 equiv). The resulting solution was stirred for 3 hr at 100 degrees C in an oil bath. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2). This resulted in 720 mg (89.52%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-2-[(HR,l5S)-4-[[2-(trimethylsilyl) ethoxy]methyl]-l3,l6-dioxa- 2,4,l0-triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca-l(9),2,5,7-tetraen-l0-yl]benzoate (assumed) as a yellow solid. LC-MS: (ES, m/z) M+l=798.
Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-2-[(llR,15S)-13,16-dioxa-2,4,10- triazatetracyclo[7.7.0.0 A [3,7].0 A [ll,15]]hexadeca-l(9),2,5,7-tetraen-10-yl]benzoate (assumed): Into a 40-mL vial, was placed methyl 4-(4-[[2-(4-chlorophenyl)-4,4- dimethylcyclohex- 1 -en- 1 -yl] methyl]piperazin- l-yl)-2-[(HR,l5S)-4-[[2- (trimethylsilyl)ethoxy]methyl]- 13, l6-dioxa-2,4, 10- triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca-l(9),2,5,7-tetraen-l0-yl]benzoate
(assumed) (720.00 mg, 0.902 mmol, 1.00 equiv), 1.0 M TBAF/THF (15.00 mL), ethylenediamine (1.30 g, 21.631 mmol, 23.99 equiv). The resulting solution was stirred for 8 hr at 70 degrees C in an oil bath. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:1). This resulted in 350 mg (58.09%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex- l-en- l-yl]methyl]piperazin- l-yl)-2- [(HR,l5S)-l3,l6-dioxa-2,4,l0-triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca- l(9),2,5,7-tetraen-l0-yl]benzoate (assumed) as a light yellow solid. LC-MS: (ES, m/z ) M+l=668. Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-2-[(llR,15S)-13,16-dioxa-2,4,10- triazatetracyclo[7.7.0.0 A [3,7].0 A [ll,15]]hexadeca-l(9),2,5,7-tetraen-10-yl]benzoic acid (assumed): Into a 40-mL vial, was placed methyl 4-(4-[[2-(4-chlorophenyl)-4,4- dimethylcyclohex-l-en-l-yl]methyl]piperazin-l-yl)-2-[(HR,l5S )-l3,l6-dioxa-2,4,l0- triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca-l(9),2,5,7-tetraen-l0-yl]benzoate
(assumed) (150.00 mg, 0.224 mmol, 1.00 equiv), dioxane (3.00 mL), MeOH (3.00 mL), NaOH (0.60 mL, 2.400 mmol, 10.69 equiv). The resulting solution was stirred for 4 hr at 70 degrees C in an oil bath. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 5-6 with HC1 (2 mol/L). The resulting solution was extracted with 3x50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1 x300 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Prep-TLC with dichloromethane/methanol (10:1). This resulted in 80 mg (54.48%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex- l-en-l-yl]methyl]piperazin-l-yl)-2-[(HR,l5S)-l3,l6-dioxa-2,4 ,l0- triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca-l(9),2,5,7-tetraen-l0-yl]benzoic acid (assumed) as a white solid. LC-MS: (ES, m/z) M+l=654.
Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-2-[(llR,15S)-13,16-dioxa-2,4,10- triazatetracyclo[7.7.0.0 A [3,7].0 A [ll,15]]hexadeca-l(9),2,5,7-tetraen-10-yl]-N-(4-[[(2S) - l,4-dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfonyl)benzamid e (assumed): Into a 40- mL vial, was placed 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl] methyljpiperazin- l-yl)-2-[(HR,l5S)-l3,l 6-dioxa-2,4, 10- triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca-l(9),2,5,7-tetraen-l0-yl]benzoic acid (assumed) (50.00 mg, 0.076 mmol, 1.00 equiv), DCM (5.00 mL), 4-[[(2S)-l,4-dioxan-2- ylmethyl]amino]-3-nitrobenzenesulfonamide (24.00 mg, 0.076 mmol, 0.99 equiv), EDCI (29.00 mg, 0.151 mmol, 1.98 equiv), DMAP (37.00 mg, 0.303 mmol, 3.96 equiv). The resulting solution was stirred overnight at 30 degrees C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-006): Column, XBridge Shield RP18 OBD Column, 5um, l9*l50mm; mobile phase, Water (0.05%NH 3 .H 2 0) and ACN (40% Phase B up to 70% in 7 min); Detector, UV 254/220 nm. This resulted in 25 mg (34.31%) of 4-(4-[[2-(4- chlorophenyl)-4,4-dimethylcyclohex- l-en- l-yl]methyl]piperazin- l-yl)-2-[(l 1R, 15S)- 13, 16- dioxa-2,4,l0-triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca-l(9),2,5,7-tetraen-l0-yl]-N- (4-[[(2S)-l,4-dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfony l)benzamide (assumed) as a yellow solid. LC-MS: (ES, m/z) M+l=953. 1H NMR (300 MHz, DMSO-7 6 , ppm) d 12.27 (s, 1H), 11.05 (d, 7 = 66.1 Hz, 1H), 8.42 (d, 7 = 30.6 Hz, 1H), 8.32 (d, 7 = 2.3 Hz, 1H), 7.57 (s, 1H), 7.36 (dd, 7 = 8.4, 4.1 Hz, 3H), 7.08 (ddd, 7 = 14.1, 5.9, 2.6 Hz, 3H), 6.78 (t, 7 = 29.3 Hz, 3H), 6.57 (s, 1H), 6.06 - 5.94 (m, 1H), 4.45 (dd, 7 = 98.7, 9.1 Hz, 3H), 3.96 - 3.34 (m, 12H), 3.19 (d, 7 = 16.7 Hz, 4H), 2.81 - 2.71 (m, 2H), 2.24 (d, 7 = 19.4 Hz, 6H), 1.98 (s,
2H), 1.41 (s, 2H), 0.94 (s, 6H)
Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-2-[(llS,15R)-4-[[2-(trimethylsilyl )ethoxy]methyl]-13,16- dioxa-2,4,10-triazatetracyclo[7.7.0.0 A [3,7].0 A [ll,15]]hexadeca-l(9),2,5,7-tetraen-10- yl]benzoate (assumed): Into a 40-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed (HS,l5R)-4-[[2-(trimethylsilyl)ethoxy]methyl]-l3,l6-dioxa-2, 4,l0- triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca-l(9),2,5,7-tetraene (assumed) (400.00 mg, 1.151 mmol, 1.00 equiv), toluene (15.00 mL), methyl 2-bromo-4-(4-[[2-(4-chlorophenyl)- 4, 4-dimethylcyclo hex- l-en-l-yl]methyl]piperazin- l-yl) benzoate (1.22 g, 2.294 mmol, 1.99 equiv), Pd 2 (dba) 3 .CHCl 3 (237.00 mg, 0.229 mmol, 0.20 equiv), Xantphos (266.00 mg, 0.460 mmol, 0.40 equiv), CS 2 CO 3 (1.12 g, 3.437 mmol, 2.99 equiv). The resulting solution was stirred for 3 hr at 100 degrees C in an oil bath. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2). This resulted in 820 mg (89.21%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-2-[(HS,l5R)-4-[[2-(trimethylsilyl) ethoxy]methyl]-l3,l6-dioxa- 2,4,l0-triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca-l(9),2,5,7-tetraen-l0-yl]benzoate (assumed) as a yellow solid. LC-MS: (ES, m/z) M+l=798.
Synthesis of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-2-[(llS,15R)-13,16-dioxa-2,4,10- triazatetracyclo[7.7.0.0 A [3,7].0 A [ll,15]]hexadeca-l(9),2,5,7-tetraen-10-yl]benzoate (assumed): Into a 40-mL vial, was placed methyl 4-(4-[[2-(4-chlorophenyl)-4,4- dimethylcyclohex- 1 -en- 1 -yl] methyl]piperazin- l-yl)-2-[(HS,l5R)-4-[[2- (trimethylsilyl)ethoxy]methyl]- 13, l6-dioxa-2,4, 10- triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca-l(9),2,5,7-tetraen-l0-yl]benzoate (assumed) (820.00 mg, 1.027 mmol, 1.00 equiv), TBAF in THF (15.00 mL), ethylenediamine (1.30 g, 21.631 mmol, 21.06 equiv). The resulting solution was stirred for 8 hr at 70 degrees C in an oil bath. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:1). This resulted in 380 mg (55.37%) of methyl 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex- l-en- l-yl]methyl]piperazin- l-yl)-2- [(HS,l5R)-l3,l6-dioxa-2,4,l0-triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca- l(9),2,5,7-tetraen-l0-yl]benzoate (assumed) as a light yellow solid. LC-MS: (ES, m/z) M+l=668.
Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-2-[(llS,15R)-13,16-dioxa-2,4,10- triazatetracyclo[7.7.0.0 A [3,7].0 A [ll,15]]hexadeca-l(9),2,5,7-tetraen-10-yl]benzoic acid (assumed): Into a 40-mL vial, was placed methyl 4-(4-[[2-(4-chlorophenyl)-4,4- dimethylcyclohex-l-en-l-yl]methyl]piperazin-l-yl)-2-[(l lS,l5R)-l3,l6-dioxa-2,4,l0- triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca-l(9),2,5,7-tetraen-l0-yl]benzoate
(assumed) (150.00 mg, 0.224 mmol, 1.00 equiv), dioxane (3.00 mL), MeOH (3.00 mL), NaOH (0.60 mL, 2.400 mmol, 10.69 equiv). The resulting solution was stirred for 4 hr at 70 degrees C in an oil bath. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 5-6 with HC1 (2 mol/L). The resulting solution was extracted with 3x50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1 x300 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Prep-TLC with dichloromethane/methanol (10:1). This resulted in 80 mg (54.48%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex- l-en-l-yl]methyl]piperazin-l-yl)-2-[(HS,l5R)-l3,l6-dioxa-2,4 ,l0- triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca-l(9),2,5,7-tetraen-l0-yl]benzoic acid (assumed) as a white solid. LC-MS: (ES, m/z ) M+l=654.
Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-2-[(llS,15R)-13,16-dioxa-2,4,10- triazatetracyclo[7.7.0.0 A [3,7].0 A [ll,15]]hexadeca-l(9),2,5,7-tetraen-10-yl]-N-(4-[[(2S) - l,4-dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfonyl)benzamid e (assumed): Into a 40- mL vial, was placed 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclo hex- l-en- 1- yl] methyljpiperazin- l-yl)-2-[( 11S, 15R)- 13,16-dioxa-2,4, 10- triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca-l(9),2,5,7-tetraen-l0-yl]benzoic acid (assumed) (50.00 mg, 0.076 mmol, 1.00 equiv), DCM (5.00 mL), 4-[[(2S)-l,4-dioxan-2- ylmethyl]amino]-3-nitrobenzenesulfonamide (24.00 mg, 0.076 mmol, 0.99 equiv), EDCI (29.00 mg, 0.151 mmol, 1.98 equiv), DMAP (37.00 mg, 0.303 mmol, 3.96 equiv). The resulting solution was stirred overnight at 30 degrees C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-006): Column, XBridge Shield RP18 OBD Column, 5um, l9* l50mm; mobile phase, Water (0.05%NH 3 .H 2 0) and ACN (40% Phase B up to 70% in 7 min); Detector, UV 254/220 nm. This resulted in 25 mg (34.31%) of 4-(4-[[2-(4- chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl]piperazi n-l-yl)-2-[(l lS,l5R)-l3,l6- dioxa-2,4,l0-triazatetracyclo[7.7.0.0 A [3,7].0 A [l l,l5]]hexadeca-l(9),2,5,7-tetraen-l0-yl]-N- (4-[[(2S)-l,4-dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfony l)benzamide (assumed) as a yellow solid. LC-MS: (ES, m/z) M+l=953. 1H NMR (300 MHz, DMSO -d 6 , ppm) d 12.27 (s, 1H), 11.05 (d, 7 = 66.1 Hz, 1H), 8.42 (d, 7 = 30.6 Hz, 1H), 8.32 (d, 7 = 2.3 Hz, 1H), 7.57 (s, 1H), 7.36 (dd, 7 = 8.4, 4.1 Hz, 3H), 7.08 (ddd, 7 = 14.1, 5.9, 2.6 Hz, 3H), 6.78 (t, 7 = 29.3 Hz, 3H), 6.57 (s, 1H), 6.06 - 5.94 (m, 1H), 4.45 (dd, 7 = 98.7, 9.1 Hz, 3H), 3.96 - 3.34 (m, 12H), 3.19 (d, 7 = 16.7 Hz, 4H), 2.81 - 2.71 (m, 2H), 2.24 (d, 7 = 19.4 Hz, 6H), 1.98 (s,
2H), 1.41 (s, 2H), 0.94 (s, 6H).
Example 60: Preparation of 4-(4-[[2-(4-chlorophenyl) -4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-N-(4-[[(2S)-l,4-dioxan-2-ylmethyl] amino]-3- nitrobenzenesulfonyl)-2-[(l2R)-l2-methyl-l3-oxa-2,4,l0- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzamide
Synthesis of (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolan e: Into a 3L 4-necked round-bottom flask, was placed ethyl vinyl ether (2000.00 g, 27777.778 mmol, 3.00 equiv), 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (508.00 g, 9259.259 mmol, 1.00 equiv). This solution was cooled to 5 degrees C in an ice/salt bath. This followed by the addition of Pd(OAc) 2 (10.39 g, 46.296 mmol, 0.005 equiv) in portions at 0-5 degrees C. The resulting solution was stirred for l8h at room temperature. The resulting mixture was concentrated. This resulted in l500g (crude) and purify by rectification, collect 65-70 degree at 25 mm Hg, got 890 g(Y=50%, LCMS OK, Q-NMR=87%) of 2-[(Z,E mixtures)-2- ethoxyethenyl]-4,4,5,5-tetramethyl-l,3-dioxolane as light yellow oil. LC-MS: (ES, m/z): M+l=l99, R.T=l.979 min, 2.440 min. H-NMR: (300 MHz, DMSO-7 6 , ppm ): d 6.71 - 6.95 (m, 1H), 4.29 - 4.34 (m, 1H), 3.80 - 3.93 (m, 2H), 1.15 - 1.21 (m, 16H).
Synthesis of N-[(2R)-2-hydroxypropyl]acetamide: Into a 250-mL 3-necked round- bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed (2R)- l-aminopropan-2-ol (10 g, 133.136 mmol, 1 equiv), DCM (100 mL), TEA (16 g, 159.764 mmol, 1.2 equiv). This was followed by the addition of a solution of acetyl acetate (13.6 g, 133.136 mmol, 1.0 equiv) in DCM (10 mL) dropwise with stirring at 0 °C. The resulting solution was stirred for 14 hr at room temperature. The resulting mixture was concentrated. The residue was applied onto a silica gel column with dichloro methane/methanol (100:5). This resulted in 13.5 g (69.25%) of N-[(2R)-2-hydroxypropyl]acetamide as a yellow oil. LC-MS: (ES, m/z ): M+l=l l8
Synthesis of 4-([[(2S)-l,4-dioxan-2-yl]methyl]amino)-3-nitrobenzene-l- sulfonamide: Into a lOO-mL round-bottom flask, was placed 4-fluoro-3-nitrobenzene-l- sulfonamide (1.43 g, 0.007 mmol, 1 equiv), l-[(2S)-l,4-dioxan-2-yl]methanamine hydrochloride (1 g, 6.510 mmol, 1 equiv), THF (30 mL), CS 2 CO 3 (8.48 g, 0.026 mmol, 4 equiv). The resulting solution was stirred overnight at 50°C in an oil bath. The solids were collected by filtration. The solid was dried in an oven under reduced pressure. This resulted in 1.82 g (88.10%) of 4-([[(2S)-l,4-dioxan-2-yl]methyl]amino)-3-nitrobenzene-l- sulfonamide as a yellow solid. LC-MS: (ES, m/z): M+l=3l8, R,T= 0.741 min.
Synthesis of methyl 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-l- enyl)methyl)piperazin-l-yl)benzoate: Into a 20000-mL round-bottom flask, was placed 1- ((2-(4-chlorophenyl)-4,4-dimethylcyclohex- l-enyl)methyl)piperazine dihydrochloride (600 g, 1.53 mol, 1 equiv), methyl 2-bromo-4-fluorobenzoate (357 g, 1.53 mol, 1 equiv), DBU (319 g, 6.12 mol, 4 equiv) and DMSO (8000 mL). The resulting solution was stirred for 20 h at 70 degrees C. LCMS showed material was completely consumed. The resulting mixture was cooled to R,T and poured into water (32 L). The mixture was filtrated, collection of filter cake and the filter cake was washed by water (3000 mL x 3) and dried by oven to give product 740 g (Y=9l%) methyl 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4- dimethylcyclohex-l-enyl)methyl)piperazin-l-yl)benzoate as a white solid. H-NMR: (300 MHz, DMSO -d 6, ppm) d: 7.73 (d, 7=9.0 Hz, 1H), 7.42-7.39 (m, 2H), 7.18-7.12 (m, 3H), 6.97-6.94 (m, 1H), 4.00-3.84 (m, 2H), 3.76 (s, 2H), 3.57 (s, 3H), 3.51-3.33 (m, 4H), 2.79- 2.60 (m, 2H), 2.32-2.30 (m, 2H), 2.03-1.97 (m, 2H), 1.47-1.45 (m, 2H), 0.96 (s, 6H) Synthesis of 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-l- enyl)methyl)piperazin-l-yl)benzoic acid: Into a 20000-mL round-bottom flask, was placed methyl 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex- 1- enyl)methyl)piperazin-l-yl) benzoate (730 g, 1.37 mol, 1 equiv), LiOH (131.5 g, 5.48 mol,
4 equiv) and MeOH/THF/water (4500mL/3000mL/l000 mL). The resulting solution was stirred for 16 h at 70 degrees C. LCMS showed material was completely consumed. The resulting mixture was cooled to R,T and concentrated. The residue was diluted with water (5000 mL) and the mixture was adjust PH to 3-5 with HC1 (6 M), followed by filtrated, collection of filter cake and dried by oven to give product 650 g 2-bromo-4-(4-((2-(4- chlorophenyl)-4,4-dimethylcyclohex-l-enyl)methyl)piperazin-l -yl)benzoic acid as a white solid. H-NMR-PH-PHNW-4-55-400: (300 MHz, DMSO -άb , rrhi) d: 10.60 (bs, 1H), 7.73 (d, 7=8.4 Hz, 1H), 7.42-7.39 (m, 2H), 7.14-7.11 (m, 3H), 6.95-6.92 (m, 1H), 4.00-3.84 (m,
2H), 3.76 (s, 2H), 3.51-3.33 (m, 4H), 2.79-2.60 (m, 2H), 2.32-2.30 (m, 2H), 2.03-1.97 (m, 2H), 1.47-1.45 (m, 2H), 0.97 (s, 6H).
Synthesis of 5-bromo-6-fluoropyridin-2-amine: Into a 100L 4-necked round- bottom flask, was placed 6-fluoropyridin-2-amine (4500.00 g, 40178.571 mmol, 1.00 equiv), ACN (25000.00 mL). This was followed by the addition of NBS (7100.00 g, 41764.706 mmol, 1.03 equiv) in portions (2 h) at 5-15 degrees C. The resulting solution was stirred for 3h at room temperature. The resulting solution was diluted with 50 L of water. The resulting solution was extracted with 2x32 L of ethyl acetate. The resulting mixture was washed with 10L of brine. The mixture was dried over anhydrous sodium sulfate and concentrated. The resulting mixture was washed with 3xl3L of PE. This mixture was dried by oven to give product 6900 g(Y=90%) of 5-bromo-6-fluoropyridin-2-amine as a light brown solid. LC-MS: (ES, m/z) M+l=l9l, 193, R.T=0.85l min. H-NMR: (300 MHz, DMSO -d 6 , ppm): d 7.63 - 7.71 (m, 1H), 6.57 (s, 2H), 6.27 - 631 (m, 1H).
Synthesis of 5-bromo-6-fluoro-3-iodopyridin-2-amine: Into a 100L 4-necked round-bottom flask, was placed 5-bromo-6-fluoropyridin-2-amine (6500.00 g, 34219.531 mmol, 1.00 equiv), AcOH (39000.00 mL). The solution was cooled to 15 degree C in a water/ice bath. This was followed by the addition of NIS (8470.00 g, 37641.484 mmol, 1.10 equiv) in portions (3h) at 10-20 degrees C. The resulting solution was stirred for 3h at room temperature. The resulting solution was added into 100 L of water. The mixture was filtrated, collection of filter cake and the filter cake was washed by water (25L x 3) and dried by oven to give product 9840 g(Y=85%) of 5-bromo-6-fluoro-3-iodopyridin-2-amine as a brown solid. LC-MS: (ES, m/z) M+l=3l7, 319, R.T=l.072 min. H-NMR: (300 MHz, DMSO -d 6 , ppm): d 8.17 - 8.20 (m, 1H), 6.69 (s, 2H).
Synthesis of 5-bromo-3-(2-ethoxyvinyl)-6-fluoropyridin-2-amine: Into a 20L 4- necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 5-bromo-6-fluoro-3-iodopyridin-2-amine (855.00 g, 2705.696 mmol, 1.00 equiv), i- PrOH (10000.00 mL), 2-[(E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-l,3-dioxolane (1000.00 g, 5050.505 mmol, 1.87 equiv), K 3 PO 4 (1720.00 g, 8113.207 mmol, 3.00 equiv), Ruphos (12.00 g, 27.060 mmol, 0.02 equiv), Pd(OAc)2 (10.00 g, 44.643 mmol, 0.02 equiv). The resulting solution was stirred for l2h at room temperature in a liquid nitrogen bath. The solids were filtered out. The filter cake was washed by 3x2L DCM. The organic layer was collected and concentrated. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:5). This concentrated and resulted in 680g (80%) of 5- bromo-3-[(Z,E mixtures)-2-ethoxyethenyl]-6-fluoropyridin-2-amine as dark brown oil. LC- MS: (ES, m/z): M+l= 261, 263, R.T=l.090 min.
Synthesis of 5-bromo-6-fluoro-lH-pyrrolo [2, 3-b] pyridine: Into a 10L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 5-bromo-3-[(E)-2-ethoxyethenyl]-6-fluoropyridin-2-amine (680.00 g, 2605.364 mmol, 1.00 equiv), EtOH (5000.00 mL), HC1 (1000.00 mL). The resulting solution was stirred for 5h at room temperature. The resulting mixture was concentrated. The pH value of the solution was adjusted to 6 with NaOH (4mol/L). The solids were collected by filtration and washed with 3x500mL water. This resulted in 4l0g(Y=75%) of 5-bromo-6-fluoro-lH-pyrrolo [2, 3- b] pyridine as a light brown solid. LC-MS: (ES, m/z) M+l=2l5, 217, R.T=0.993 min. H- NMR: (300 MHz, DMSO-d 6 , ppm): d 9.53 (brs, 1H), 8.19 - 8.22 (d, J = 9.0 Hz, 1H), 7.32 - 7.34 (m, 1H), 6.50 - 6.52 (m, 1H).
Synthesis of 5-bromo-6-fluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- pyrrolo[2,3-b]pyridine: Into a 5L 4-necked round-bottom flask was placed 5-bromo-6- fluoro-lH-pyrrolo [2, 3-b] pyridine (200.00 g, 930.232 mmol, 1.00 equiv), DMF (2500.00 mL). This solution was cooled to 0 degrees C in a water/ice bath. This was followed by the addition of NaH (75.00 g, 1860.464 mmol, 2.00 equiv) in portions at 0 degrees C. To this was added SEM-C1 (233.00 g, 1395.210 mmol, 1.50 equiv) dropwise with stirring at 0 degrees C. The resulting solution was stirred for lh at room temperature. The reaction was then quenched by the addition of 1000 mL of water/ice. The resulting solution was diluted with 5 L of water. The resulting solution was extracted with 2x10 L of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x5L of water. The resulting mixture was washed with 3L of brine. The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:20). This resulted in 298 g (87%) of 5-bromo-6- fluoro-l-[[2-(trimethylsilyl) ethoxy] methyl] pyrrolo [2, 3-b] pyridine as light yellow oil. LC-MS: (ES, m/z) M+l=345, 347, R.T=l.435 min. H-NMR (300 MHz, DMSO -d 6 , ppm): d 8.46 - 8.49 (d, J = 9.0 Hz, 1H), 7.68 - 7.69 (m, 1H), 6.57 - 6.58 (m, 1H), 5.52 - 5.55 (m, 2H), 3.47 - 3.60 (m, 2H), 0.79 - 0.90 (m, 2H), 0.01 (s, 9H).
Synthesis of (R)-N-(2-(5-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- pyrrolo[2,3-b]pyidin-6-yloxy)propyl)acetamide: Into a 50-mL round-bottom flask, was placed N-[(2R)-2-hydroxypropyl] acetamide (680 mg, 5.8 mmol, 2.00 equiv), dioxane (10 mL). This was followed by the addition of NaH (348 mg, 8.7 mmol, 3 equiv), in portions at 15 °C. The resulting solution was stirred for 10 min at RT. To this was added a solution of 5-bromo-6-fluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyr rolo[2,3-b]pyridine (1 g, 2.9 mmol, 1 equiv) in dioxane (5 mL) . The resulting solution was stirred for 4 hr at 80 °C in an oil bath. The reaction was cooled to r.t then quenched by the addition of 5 mL of water. The resulting solution was extracted with 3x10 mL of ethyl acetate. The resulting mixture was washed with 3 x5 ml of H 2 0. The resulting mixture was washed with 1x10 mL of NaCl (aq). The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with PE/EA (100:20). This resulted in 880 mg (73%) of (R)-N-(2-(5-bromo- 1-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridin-6- yloxy)propyl) acetamide as a white solid.
Synthesis of l-[(12R)-4-(trimethylsilyl)ethoxy)methyl)-12-methyl-13-oxa-2 ,4,10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-10-yl]ethan-l-one: Into a 25-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed (R)-N-(2-(5-bromo- 1-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridin-6- yloxy)propyl) acetamide (500 mg, 1.13 mmol, 1 equiv), dioxane (8 mL), Cs2C03 (1.1 g, 3.4 mmol, 3 equiv), BrettPhos Pd G3 (102 mg, 0.11 mmol, 0.10 equiv). The resulting solution was stirred for 14 hr at 80 °C in an oil bath. The resulting mixture was concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (50:50). This resulted in 300 mg (73.3%) of l-[(l2R)-4-(trimethylsilyl)ethoxy) methyl)- l2-methyl- 13- oxa-2,4,l0-triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]ethan-l-one as light yellow oil. Synthesis of (12R)-4-(trimethylsilyl)ethoxy)methyl)-12-methyl-13-oxa-2,4, 10 - triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraene: Into a 8-mL vial, was placedl- [( l2R)-4-(trimethylsilyl)ethoxy) methyl)- 12 -methyl- l3-oxa-2,4, 10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]ethan-l-one (50 mg), methanol (0.5 mL), NaOH/H 2 0 (1M, 0.5 ml). The resulting solution was stirred for 14 hr at 80°C in an oil bath. The resulting mixture was concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 15 mg (34%) of (12R)- 4-(trimethylsilyl)ethoxy) methyl)- l2-methyl- l3-oxa-2,4, 10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraene as brown oil.
Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-N- (4-[[(2S)-l,4-dioxan-2-ylmethyl]amino]-3- nitrobenzenesulfonyl)-2-[(12R)-12-methyl-4-[[2-(trimethylsil yl)ethoxy]methyl]-13-oxa- 2,4,10-triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-10-yl]benzamide: Into a 8- mL vial purged and maintained with an inert atmosphere of nitrogen, was placed (l2R)-l2- methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-l3-oxa-2,4,l0- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraene (100.00 mg, 0.313 mmol, 1.00 equiv), 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex- l-en- l-yl]methyl]piperazin- l-yl)- N-(4-[[(2S)-l,4-dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfo nyl)benzamide (255.79 mg, 0.313 mmol, 1.00 equiv), DMF (2.00 mL), Cul (23.84 mg, 0.125 mmol, 0.40 equiv), N I ,N 2 - bis(4-hydroxy-2,6-dimethylphenyl)oxalamide (20.53 mg, 0.063 mmol, 0.20 equiv), K 2 C0 3 (129.78 mg, 0.939 mmol, 3.00 equiv). The resulting solution was stirred for 4 hr at 100 degrees C in an oil bath. The resulting solution was diluted with 10 mL of H 2 0. The resulting solution was extracted with 3x5 mL of ethyl acetate. The resulting mixture was washed with 3 x5 ml of H 2 0. The mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (10:1). This resulted in 220 mg (66.57%) of 4-(4-[[2-(4-chlorophenyl)-4,4- dimethylcyc lo hex- l-en- l-yl]methyl]piperazin- l-yl)-N-(4-[[(2S)- l,4-dioxan-2- ylmethyl]amino]-3-nitrobenzenesulfonyl)-2-[(l2R)-l2-methyl-4 -[[2- (trimethylsilyl)ethoxy]methyl]-l3-oxa-2,4,l0-triazatricyclo[ 7.4.0.0 A [3,7]]trideca-l(9),2,5,7- tetraen-lO-yl]benzamide as a yellow solid. LC-MS: (ES, m/z): 1055.5 [M +H] Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl) -N-(4-[[(2S)-l,4-dioxan-2-ylmethyl]amino]-3- nitrobenzenesulfonyl)-2-[(12R)-12-methyl-13-oxa-2,4,10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-10-yl]benzamide: Into a 25-mL round-bottom flask, was placed 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-N- (4-[[(2S)-l,4-dioxan-2-ylmethyl]amino]-3- nitrobenzenesulfonyl)-2-[(l2R)-l2-methyl-4-[[2-(trimethylsil yl)ethoxy]methyl]-l3-oxa- 2,4,l0-triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0-yl]benzamide (210.00 mg), ethane- 1, 2-diamine (1.00 mL), TBAF in THF (3M, 5.00 mL). The resulting solution was stirred for 14 hr at 70 degrees C in an oil bath. The resulting mixture was concentrated. The resulting solution was diluted with 20 mL of DCM. The resulting mixture was washed with 3x5 ml of H 2 0. The mixture was dried over anhydrous sodium sulfate. The residue was purified with Prep-TLC with dichloromethane/methanol (100:5). This resulted in 70 mg (38.02%) of 4-(4-[[2-(4-chlorophenyl) -4,4-dimethylcyclohex-l-en-l-yl]methyl]piperazin-l- yl)-N-(4-[[(2S)-l,4-dioxan-2-ylmethyl]amino]-3-nitrobenzenes ulfonyl)-2-[(l2R)-l2- methyl-l3-oxa-2,4,10-triazatricyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-l0- yl]benzamide as a yellow solid. LC-MS: (ES, m/z): 925.4 [M +H]. Ή NMR (300 MHz, CDCh, ppm): d 12.38 (s, 1H), 8.68-8.46 (m, 3H), 8.16-7.97 (m, 1H), 7.90-7.81 (m, 1H), 7.28-7.05 (m, 3H), 7.02-6.78 (m, 3H), 6.77-6.63 (m, 2H), 6.54 (s, 1H), 6.11-6.03 (m, 1H), 4.98-4.83 (m, 1H), 4.10-2.99 (m, 17H), 2.91-2.79 (m, 2H), 2.40-2.17 (m, 6H), 2.10-2.02 (m, 2H), 1.70-1.61 (m, 3H), 0.97 (s, 6H).
Example 76: Preparation of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperaz in-l-yl)-N-(4-[[(2S)-l,4-dioxan-2-ylmethyl] amino]-3- nitrobenzenesulfonyl)-2-[l l-oxo-l3-oxa-2,4,l0-tr iazatricyclo[7.4.0. 0 A [3,7]]trideca- 1 (9) ,2,5 ,7-tetraen- 10-yl] benzamide
Synthesis of 5-bromo-6-fluoropyridin-2-amine. Into a 5000-mL 3-necked round- bottom flask, was placed 6-fluoropyridin-2-amine (220 g, 2 mol, 1.00 equiv), CH ,CN (2.0 L), NBS (420 g, 2.2 mol, 1.20 equiv). The resulting solution was stirred for overnight at room temperature. The reaction was then quenched by the addition of 2 L of water. The resulting solution was extracted with 3x1 L of ethyl acetate and the organic layers combined. The resulting organic phase was washed with 3x1 L of brine. The mixture was dried over anhydrous sodium sulfate, then filtered and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0:1- 1:5). This resulted in 200 g (60%) of 5-bromo-6-fluoropyridin-2-amine as a white solid. LCMS: (ES, m/z): M+l: 191, 193
Synthesis of 5-bromo-6-fluoro-3-iodopyridin-2-amine. Into a 2000-mL 4-necked round-bottom flask, was placed 5-bromo-6-fluoropyridin-2-amine (200 g, 1.05 mol, 1.00 equiv) in AcOH (1500 mL), iodo(sulfanyl)amine(NIS) (200 g, 1.15 mol, 1.10 equiv). The resulting solution was stirred for overnight at room temperature. The reaction was then quenched by the addition of 3000 mL of water. The solids were collected by filtration and wash by Et 2 0. This resulted in 170 g (50%) of 5-bromo-6-fluoro-3-iodopyridin-2-amine as a white solid. The organic phase was concentrated under vacuum, result in 150 g crude product oil. 1H-NMR: (CDCl 3 , 300 MHz) d: 7.98 (d, 7=14.4 Hz, 1H), 4.94-5.00 (bs, 2H).
Synthesis of 5-bromo-6-fluoro-3-[2-(trimethylsilyl)ethynyl]pyridin-2-amin e. Into a 3000- mL 3-necked round-bottom flask, was placed a solution of 5-bromo-6-fluoro-3-iodopyridin- 2-amine (170 g, 536.45 mmol, 1.00 equiv) in tetrahydrofuran (1500 mL), Cul (10.2 g, 53.56 mmol, 0.10 equiv), TEA (500 mL), dichloropalladium; bis(triphenylphosphane) (11.2 g,
15.96 mmol, 0.03 equiv), ethyl(ethynyl)dimethylsilane (63 g, 561.27 mmol, 1.20 equiv). The resulting solution was stirred for 16 hours at room temperature. The reaction was then quenched by the addition of 2000 mL of water. The resulting solution was extracted with 3x1000 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x1000 mL of brine. The mixture was dried over anhydrous sodium sulfate, then filtered and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0:1- 1:1). This resulted in 120 g (78%) of 5-bromo-6- fluoro-3-[2-(trimethylsilyl)ethynyl]pyridin-2-amine as yellow oil. LC-MS (ES, m/z): M+l: 289, 287
Synthesis of N-[5-bromo-6-fluoro-3-[2-(trimethylsilyl)ethynyl]pyridin-2- yl] acetamide. Into a 2000-mL 4-necked round-bottom flask, was placed a solution of 5- bromo-6-fluoro-3-[2-(trimethylsilyl)ethynyl]pyridin-2-amine (84 g, 292.48 mmol, 1.00 equiv) in dichloro methane (1000 mL), pyridine (57.8 g, 730.72 mmol, 2.50 equiv). This was followed by the addition of acetyl chloride (50.2 g, 639.51 mmol, 2.20 equiv) dropwise with stirring at 0 degree. The resulting solution was stirred for overnight at room temperature. The reaction was then quenched by the addition of 1000 mL of water. The resulting mixture was washed with 2x1000 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0:1-1:10). This resulted in 80 g (83%) of N-[5-bromo-6-fluoro-3-[2- (trimethyl silyl)ethynyl]pyridin-2-yl] acetamide as a white solid. LC-MS: (ES, m/z)
M+l=33l.
Synthesis of 5-bromo-6-fluoro-lH-pyrrolo[2,3-b]pyridine. Into a 2000-mL round- bottom flask, was placed a solution of N-[5-bromo-6-fluoro-3-[2- (trimethylsilyl)ethynyl]pyridin-2-yl]acetamide (80 g, 242.98 mmol, 1.00 equiv) in tetrahydrofuran (300 mL), TBAF(lM in tetrahydrofuran) (729 mL, 3.00 equiv). The resulting solution was stirred for 12 h at 70 degree. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The reaction was then quenched by the addition of 500 mL of water. The resulting solution was extracted with 3x300 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x300 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleu m ether (0: 1-4:1). This resulted in 15 g (29%) of 5-bromo-6-fluoro-lH- pyrrolo[2,3-b]pyridine as a white solid. LC-MS: (ES, m/z) M+l=2l3.
Synthesis of 5-bromo-6-fluoro-l-[[2-(trimethylsilyl)ethoxy]methyl]-lH- pyrrolo[2,3-b]pyridine. Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 5-bromo-6-fluoro-lH- pyrrolo[2,3-b]pyridine (15 g, 69.76 mmol, 1.00 equiv) in N,N-dimethylformamide (150 mL). This was followed by the addition of sodium hydride (4.2 g, 175.00 mmol, 1.50 equiv), in portions at 0 degree. After 0.5 h stirring, to this was added SEM-C1 (14 g, 84.34 mmol, 1.20 equiv) dropwise with stirring at 0 degree. The resulting solution was allowed to react, with stirring, for an additional 3 h at room temperature. The reaction was then quenched by the addition of 300 mL of water. The resulting solution was extracted with 3x200 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x200 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0:1-1:10). This resulted in 15 g (62%) of 5-bromo-6-fluoro-l-[[2- (trimethylsilyl)ethoxy]methyl]-lH-pyrrolo[2,3-b]pyridine as yellow oil.
Synthesis of 6-(tert-butoxy)-N-(diphenylmethylidene)-l-[[2- (trimethylsilyl)ethoxy] methyl] -lH-pyrro lo[2,3-b]pyridin-5-amine. Into a 250-mL round- bottom flask, was placed a solution of 5-bromo-6-fluoro-l-[[2-
(trimethylsilyl)ethoxy]methyl]-lH-pyrrolo[2,3-b]pyridine (20.7 g, 60 mmol, 1.00 equiv) in dioxane (300 mL), t-BuOK (20.5 g, 180 mmol, 3.00 equiv), xantphos (6.9 g, 12 mmol, 0.20 equiv), Pd 2 (dba)3.CHCl3 (5.7 g, 0.10 equiv), diphenylmethanimine (14.04 g, 78 mmol, 1.20 equiv). The resulting solution was stirred for overnight at l00°C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0:1-1:20). This resulted in 15 g (crude) of 6-(tert-butoxy)-N- (diphenylmethylidene)- 1 - [[2-(trimethylsilyl)ethoxy] methyl] - lH-pyrrolo [2,3-b]pyridin-5- amine as white oil. LC-MS: (ES, m/z): M+l= 500.
Synthesis of 5-amino- l-[[2-(trimethylsilyl)ethoxy]methyl]- lH-pyrrolo[2,3-b]pyridin- 6-ol hydrogen chloride salt. Into a 500-mL round-bottom flask, was placed 6-(tert-butoxy)-N- (diphenylmethylidene)- 1 - [[2-(trimethylsilyl)ethoxy] methyl] - lH-pyrrolo [2,3-b]pyridin-5- amine (15 g, 30.02 mmol, 1.00 equiv) in dioxane (120 mL), HCl/dioxane(4M, 30 mL). The resulting solution was stirred for 5 h at room temperature. The resulting solution was diluted with 500 mL of ether. The solids were collected by filtration. This resulted in 5 g (crude) of 5-amino- l-[[2-(trimethylsilyl)ethoxy] methyl]- lH-pyrrolo[2,3-b]pyridin-6-ol hydrogen chloride salt as a red solid, Q-NMR show it might converted into 3 hydrogen chloride salt. LC-MS: (ES, m/z): M+l=280.
Synthesis of 4-[[2-(trimethylsilyl)ethoxy]methyl]-13-oxa-2,4,10- triazatricyclo[7.4.0.0 A [3,7]]trideca-l,3(7),5,8-tetraen-ll-one. Into a 250-mL round-bottom flask, was placed 5-amino- l-[[2-(trimethylsilyl) ethoxy]methyl]-lH-pyrrolo[2,3-b]pyridin-6- ol hydrogen chloride salt (5 g, 17.89 mmol, 1.00 equiv) in N,N-dimethylformamide (100 mL), potassium carbonate (7.4 g, 53.54 mmol, 3.00 equiv), and add 2-chloroacetyl chloride (4 g, 35.42 mmol, 2.00 equiv) at 0 degree by dropwise. The resulting solution was stirred for overnight at 70°C. The reaction mixture was cooled to room temperature. The reaction was then quenched by the addition of 200 mL of water. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x100 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0:1- 1:1). This resulted in 2.5 g (44%) of 4-[[2- (trimethylsilyl)ethoxy] methyl]- l3-oxa-2, 4, l0-triazatricyclo[7.4.0.0 A [3,7]]trideca- 1,3(7), 5,8- tetraen-l l-one as a white solid. LC-MS: (ES, m/z): M+l=320.
Synthesis of methyl 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-l- enyl)meth yl)piperazin-l-yl)benzoate. Into a 2000-mL round-bottom flask, was placed 1- ((2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-enyl)methyl)pipe razine dihydrochloride (60 g, 0.153 mol, 1 equiv), methyl 2-bromo-4-fluorobenzoate (35.7 g, 0.153 mol, 1 equiv), DBU (31.9 g, 0.612 mol, 4 equiv) and DMSO (800 mL). The resulting solution was stirred for 20 h at 70 degrees C. LCMS showed material was completely consumed. The resulting mixture was cooled to R.T and poured into water (3 L). The mixture was filtrated, collection of filter cake and the filter cake was washed by water (300 mL x 3) and dried by oven to give product 74 g (Y: 91%) methyl 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-l- enyl)methyl)piperazin-l-yl) benzoate as a white solid.
Synthesis of 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-l- enyl)methyl)piperazin-l-yl)benzoic acid. Into a 2000-mL round-bottom flask, was placed methyl 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex- l-enyl)methyl)piperazin- 1- yl)benzoate (73 g, 0.137 mol, 1 equiv), LiOH (13.15 g, 0.548 mol, 4 equiv) and
MeOH/THF/water (450mL/300mL/l00 mL). The resulting solution was stirred for 16 h at 70 degrees C. LCMS showed material was completely consumed. The resulting mixture was cooled to R.T and concentrated. The residue was diluted with water (500 mL) and the mixture was adjust PH to 3-5 with HC1 (6 M), followed by filtrated, collection of filter cake and dried by oven to give product 65 g (Y: 93%)2-bromo-4-(4-((2-(4-chlorophenyl)-4,4- dimethylcyclohex-l-enyl)methyl)piperazin -l-yl)benzoic acid as a white solid.
Synthesis of 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en- l- yl]methyl]piperazin-l-yl)-N-(4-[[(2S)-l,4-dioxan-2-ylmethyl] amino]-3- nitrobenzenesulfonyl)benzamide. Into a 2000-mL round-bottom flask, was placed 2-bromo- 4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex- l-enyl)methyl) piperazin- l-yl) benzoic acid (55 g, 0.107 mol, 1 equiv), DCM (1 L), (S)-4-(((l,4-dioxan-2-yl)methyl)amino)-3- nitrobenzenesulfonamide (32 g, 0.102 mol, 0.95 equiv), EDCI (30.8 g, 0.161 mol, 1.5 equiv), DMAP (52.2 g, 0.428 mol, 4 equiv). The resulting solution was stirred for overnight at 25 degrees C. LCMS showed material was completely consumed. The resulting mixture is followed by dilute hydrochloric acid (1.0 M) (100 mL x 3), saturated sodium bicarbonate (100 mL x 3) and brine (100 mL x 1), and then the organic phase was dried by Na 2 S0 4 , filtrated. The filtrate was concentrated to give product 81 g (Y: 93%) as a light brown yellow solid 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex- l-en- l-yl]methyl]piperazin- l-yl)-N-(4-[[(2S)-l,4-dioxan-2-ylmethyl]amino]-3-nitrobenzen esulfonyl)benzamide as a brown yellow solid. LC-MS: (ES, m/z ): M+1=816/819, R.T=2.0l min.
Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-N-(4-[[(2S)-l,4-dioxan-2-ylmethyl] amino]-3- nitrobenzenesulfonyl)-2-(ll-oxo-4-[[2-(trimethylsilyl)ethoxy ] methyl]-13-oxa-2,4,10- triazatri cyclo[7.4.0.0 A [3,7]]trideca-l(9),2,5,7-tetraen-10-yl)benzamide. Into a 40-mL round-bottom flask, was placed 2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l- en-l-yl]methyl]piperazin-l-yl)-N-(4-[[(2S)-l,4-dioxan-2-ylme thyl]amino]-3- nitrobenzenesulfonyl)benzamide (214.89 mg, 0.263 mmol, 1.2 equiv), 4-[[2- (trimethylsilyl)ethoxy]methyl]-l3-oxa-2,4,l0-triazatricyclo[ 7.4.0.0 A [3,7]]trideca-l(9),2,5,7- tetraen-l l-one (70.00 mg, 0.219 mmol, 1.00 equiv), 4,7-dimethoxy-l,l0-phenanthroline (26.33 mg, 0.110 mmol, 0.5 equiv), CS 2 CO 3 (214.20 mg, 0.657 mmol, 3 equiv), Dioxane (10.00 mL), Cul (20.87 mg, 0.110 mmol, 0.5 equiv). The resulting solution was stirred for 3 h at 110 degrees C. The resulting mixture was concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0: 1- 1: 1). This resulted in 200 mg (86.45%) of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]met hyl]piperazin-l- yl)-N-(4-[[(2S)-l,4-dioxan-2-ylmethyl]amino]-3-nitrob enzenesulfonyl)-2-(l l-oxo-4-[[2- (trimethylsilyl)ethoxy]methyl]-l3-oxa-2,4,l0-triazatricyclo[ 7.4.0.0 A [3,7]] trideca- 1(9), 2,5,7- tetraen-lO-yl)benzamide as a yellow crude solid. LC-MS: (ES, m/z): M+l=l055.
Synthesis of 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l- yl]methyl]piperazin-l-yl)-N-(4-[[(2S)-l,4-dioxan-2-ylmethyl] amino]-3- nitrobenzenesulfonyl)-2-[ll-oxo-13-oxa-2,4,10-triazatricyclo [7.4.0.0 A [3,7]]trideca- l(9),2,5,7-tetraen-10-yl]benzamide. Into a 40-mL round-bottom flask, was placed 4-(4-[[2- (4-chlorophenyl)-4,4-dimethylcyclohex- l-en- l-yl]methyl]piperazin- l-yl)-N-(4-[[(2S)- 1,4- dioxan-2-ylmethyl]amino]-3-nitrobenzenesulfonyl)-2-(l l-oxo-4-[[2- (trimethylsilyl)ethoxy]methyl]-l3-oxa-2,4,l0-triazatricyclo[ 7.4.0.0 A [3,7]]trideca-l(9),2,5,7- tetraen-lO-yl)benzamide (200.00 mg, 0.189 mmol, 1.00 equiv), THF (10 mL),
ethylenediamine (227.71 mg, 3.789 mmol, 20.00 equiv), TBAF (990.65 mg, 3.789 mmol, 20 equiv). The resulting solution was stirred for 12 h at 70 degrees C. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 2x10 mL of ethyl acetate concentrated. The crude product was purified by Prep-HPLC with the following conditions (Waters-2767): Column, X-bridge RP18, 5um, l9* l00mm; mobile phase, 0.03% acerbity in water (0.03% HC1 ) and CH 3 CN (32% CH 3 CN up to 52% in 6 min); Detector, UV 254 nm. This resulted in 25 mg (14.26%) of 4-(4-[[2-(4-chlorophenyl)- 4,4-dimethylcyclohex-l-en-l-yl]methyl]piperazin- l-yl)-N-(4-[[(2S)-l,4-dioxan-2-ylmethyl] amino]-3-nitrobenzenesulfonyl)-2-[l l-oxo-l3-oxa-2,4,l0-triazatricyclo[7.4.0.0 A [3,7]]trideca- l(9),2,5,7-tetraen-l0-yl]benzamide as a yellow solid. LC-MS: (ES, m/z) M+l=925. 1H NMR (300 MHz, DMSO -d 6 ) d 11.32 (d, / = 7.2 Hz, 1H), 8.52 (s, 1H), 8.37 (dd, / = 4.6, 2.3 Hz,
1H), 7.72 (d, / = 8.5 Hz, 1H), 7.65 (s, 1H), 7.41 (d, / = 8.1 Hz, 2H), 7.19 (d, / = 5.8 Hz, 1H), 7.11 (d, / = 8.3 Hz, 2H), 6.92 (d, / = 9.7 Hz, 2H), 6.60 (d, / = 1.8 Hz, 1H), 6.15 - 6.07 (m, 1H), 4.67 (d, J = 15.0 Hz, 1H), 4.36 (s, 1H), 3.98 - 3.75 (m, 5H), 3.75 - 3.47 (m, 7H), 3.32 (s, 4H), 2.80 (s, 2H), 2.05 (s, 2H), 1.48 (s, 2H), 0.96 (s, 6H). Biological Example 1: BCL-2 Competition Binding (Fluorescence Polarization) Assay
The fluorescence-labeled 23 amino acid peptide BH3 was purchased from
CalBiochem (NLW A AQRY GRELRRMS D KFVD ) . An unbound Fluorescein labeled BH3 peptide emits random light with respect to the plane of polarization plane of excited light, resulting in a lower polarization degree (mP) value. When the peptide is bound to BCL-2, the complex tumble slower and the emitted light can have a higher level of polarization, resulting in a higher mP value. This binding assay was performed in 96-well plate and with each assay contained 15 and 30nM of labeled peptide and purified BCL-2 protein (purchased from R&D Systems, Inc). The assay buffer contained 20mM Hepes (pH 7.0), 50mM KC1, 5mM MgCl 2 , 20mM Na 2 Mo0 4 , O.lmg/ml Bovine Gamma Globulin and 0.01% NP40. Compounds were diluted in DMSO and added to the final assay with concentration range from 20mM to 2nM. The polarization degree (mP) value was determined by BioTek Synergy II with background subtraction after 3 hours of incubation at room temperature. IC50 was calculated using Prism software with sigmoidal dose-response curve fitting. ABT-737 was used as reference compound. Such assays, carried out with a range of doses of test compounds, allowed the determination of an approximate IC50 value. Although the inhibitory properties of the compounds of the present invention vary with structural change as expected, the activity generally exhibited by these agents was in the range of IC50 =0.1 - 1000 nM.
The following table lists the IC 50 values of certain compounds of the invention.
Biological Example 2: In vitro Anti-proliferation Assay in B CL- 2-dependent acute lymphoblastic leukemia (ALL) cell line RS4;l l
Cell antiproliferation was assayed by PerkinElmer ATPlite™ Luminescence Assay System. Briefly, the various test cancer cell lines were plated at a density of about 1 x 10 4 cells per well in Costar 96-well plates, and were incubated with different concentrations of compounds for about 72 hours in medium supplemented with 5% FBS or 10% normal human serum(NHS). One lyophilized substrate solution vial was then reconstituted by adding 5 mL of substrate buffer solution, and was agitated gently until the solution was homogeneous. About 50 pL of mammalian cell lysis solution was added to 100 pL of cell suspension per well of a microplate, and the plate was shaken for about five minutes in an orbital shaker at -700 rpm. This procedure was used to lyse the cells and to stabilize the ATP. Next, 50 pL substrate solution was added to the wells and microplate was shaken for five minutes in an orbital shaker at -700 rpm. Finally, the luminescence was measured by a PerkinElmer TopCount® Microplate Scintillation Counter. Such assays, carried out with a range of doses of test compounds, allowed the determination of the cellular anti-antiproliferative IC50 of the compounds of the present invention. The following table lists the IC50 values of certain compounds of the invention.
The following table lists the IC50 values of certain compounds of the invention.
Biological Example 3: mice PK study
The pharmacokinetics of compounds were evaluated in CD-l mouse via Intravenous and Oral Administration. The IV dose was administered as a slow bolus in the Jugular vein, and oral doses were administered by gavage. The fomulaltion for IV dosing was 5% DMSO in 20% HPBCD in water, and the PO formulation was 2.5% DMSO, 10% EtOH, 20%
Cremphor EL, 67.5% D5W. The PK time point for the IV arm was 5, 15, 30 min, 1, 2, 4, 6, 8, 12, 24 hours post dose, and for PO arm was 15, 30 min, 1, 2, 4, 6, 8, 12, 24 hours post dose. Approximately 0.03 mL blood was collected at each time point. Blood of each sample was transferred into plastic micro centrifuge tubes containing EDTA-K2 and collect plasma within 15 min by centrifugation at 4000 g for 5 minutes in a 4 ° C centrifuge. Plasma samples were stored in polypropylene tubes. The samples were stored in a freezer at -75±l5°C prior to analysis. Concentrations of compounds in the plasma samples were analyzed using a LC- MS/MS method. WinNonlin (Phoenix™, version 6.1) or other similar software was used for pharmacokinetic calculations. The following pharmacokinetic parameters were calculated, whenever possible from the plasma concentration versus time data: IV administration: Co, CL, V d , T i /2 , AUC mf , AUCi ast , MRT, Number of Points for Regression; PO administration: C max , T max , T i /2 , AUQ nf , AUCi ast , F%, Number of Points for Regression. The pharmacokinetic data was described using descriptive statistics such as mean, standard deviation. Additional pharmacokinetic or statistical analysis was performed at the discretion of the contributing scientist, and was documented in the data summary.
Biological Example 4: In vivo Xenograft Studies
Compound of Example 3 is selected for in vivo studies in the BCL- 2-dependent acute lymphoblastic leukemia (ALL) RS4;l l xenograft model. The CB.17 SCID mice are obtained at age 6-8 weeks from vendors and acclimated for a minimum 7-day period. The cancer cells are then implanted into the nude mice. Depending on the specific tumor type, tumors are typically detectable about two weeks following implantation. When tumor sizes reach -100- 200 mm , the animals with appreciable tumor size and shape are randomly assigned into groups of 8 mice each, including one vehicle control group and treatment groups. Dosing varies depending on the purpose and length of each study, which typically proceeds for about 3-4 weeks. Tumor sizes and body weight are typically measured three times per week. In addition to the determination of tumor size changes, the last tumor measurement is used to generate the tumor size change ratio (T/C value), a standard metric developed by the National Cancer Institute for xenograft tumor evaluation. In most cases, %T/C values are calculated using the following formula: % T/C = 100 x AT/AC if AT > 0. When tumor regression occurred (AT < 0), however, the following formula is used: % T/T0 = 100 x DT/T0. Values of <42% are considered significant.
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