Amide compounds for HIV treatment

Abstract

To provide amide compounds for the treatment of HIV. [Solution] A compound of formula (I) or a salt thereof is disclosed. Also disclosed are a pharmaceutical composition comprising a compound of formula I, a process for preparing a compound of formula I, intermediates useful for preparing a compound of formula I, and a therapeutic method for treating Retroviridae virus infections, including infections caused by the HIV virus. Here, compounds and methods for treating HIV (i.e., human immunodeficiency virus) infections are provided. TIFF2026143805000636.tif5056

Description

[Technical Field]

[0001] therapeutic compounds Cross-reference of related applications This application claims the benefits and priority of U.S. Provisional Patent Application No. 61 / 771,655, filed on March 1, 2013, and U.S. Provisional Patent Application No. 61 / 857,636, filed on July 23, 2013. Accordingly, the disclosures of each of these U.S. Provisional Patent Applications are incorporated herein by reference in their entirety. [Background technology]

[0002] background Positive single-stranded RNA viruses, including the Retroviridae family, encompass subfamilies such as Orthoretrovirinae, as well as the genera Alpharetrovirus, Betaretrovirus, Gamaretrovirus, Deltaretrovirus, Epsilonretrovirus, Lentivirus, and Spumavirus, which cause numerous diseases in humans and animals. Among Lentiviruses, human HIV-1 infection leads to helper T cell depletion and immune dysfunction, resulting in immunodeficiency and vulnerability to opportunistic infections. Treatment of HIV-1 infection with highly active antiretroviral therapy (HAART) has proven effective in reducing the viral load and significantly slowing disease progression (Hammer, SM et al.; JAMA 2008, Vol. 300: pp. 555-570). However, these treatments can actually lead to the emergence of HIV strains that are resistant to current treatments (Taiwo, B., International Journal of Infectious Diseases 2009, Vol. 13: pp. 552-559; Smith, RJ et al., Science 2010, Vol. 327: pp. 697-701). Therefore, there is an urgent need to discover new antiretroviral agents that are active against emerging drug-resistant HIV variants. [Prior art documents] [Non-Patent Literature]

[0003] [Non-Patent Literature 1] Hammer, S.M. et al.; JAMA 2008, Volume 300: pages 555-570 [Non-Patent Literature 2] Taiwo, B., International Journal of Infectious Diseases 2009, Volume 13: pages 552-559 [Non-Patent Literature 3] Smith, R. J. et al., Science 2010, Volume 327: pages 697-701 [Summary of the Invention] [Means for Solving the Problems]

[0004] Summary Provided herein are compounds and methods for treating HIV (i.e., human immunodeficiency virus) infection. One embodiment is a compound of formula IIId [Chemical Formula] wherein: A 1 is CH, C-Z 3 or nitrogen, and A 2 is CH or nitrogen, and R 1 is 6- to 12-membered aryl, 5- to 12-membered heteroaryl, or 3- to 12-membered heterocyclic ring, and any 6- to 12-membered aryl, 5- to 12-membered heteroaryl, or 3- to 12-membered heterocyclic ring of R 1 is optionally substituted with 1, 2, 3, 4 or 5 Z 4 groups, and the Z 4 groups are the same or different from each other, and R 3a and R 3b are each independently H or (C1-C3)alkyl, and Z 1 Z is a 6-12 member aryl, a 5-14 member heteroaryl, or a 3-14 member heteroring. 1 Any 6-12 member aryl, 5-14 member heteroaryl, or 3-14 member heteroring can be any 1, 2, 3, 4, or 5 Z 1a or Z 1b It is optionally replaced by Z 1a and Z 1b The bases are the same or different. each Z 1a These are independently (C3-C7) carbon rings, 5-12 membered heteroaryls, 3-12 membered heterocycles, halogens, -CN, -OR n1 ,-OC(O)R p1 -OC(O)NR q1 R r1 , -SR n1 ,-S(O)R p1 -S(O)2OH, -S(O)2R p1 -S(O)2NR q1 R r1 , -NR q1 R r1 , -NR n1 COR p1 , -NR n1 CO2R p1 , -NR n1 CONR q1 R r1 , -NR n1 S(O)2R p1 , -NR n1 S(O)2OR p1 , -NR n1 S(O)2NR q1 R r1 , -C(O)R n1 , -C(O)OR n1 -C(O)NR q1 R r1 and -S(O)2NR n1 COR p1 Z 1a Any (C3-C7) carbon ring, 5-12 membered heteroaryl, and 3-12 membered heteroring can have 1, 2, 3, 4, or 5 Z 1c or Z 1d It is optionally substituted in the base, Z1c and Z 1d The bases are the same or different. each Z 1b These are (C1-C8) alkyl groups that are independently and optionally substituted with the same or different 1, 2, 3, 4, or 5 halogens. each Z 1c These are, independently, halogen, -CN, -OH, -NH2, and -C(O)NR q2 R r2 , or (C1~C8) heteroalkyl, each Z 1d These are independently (C1-C8) alkyl or (C1-C8) haloalkyl, Each R n1 R is independently H, (C1-C8) alkyl, (C3-C7) carbon ring, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl, n1 Any (C3-C7) carbon ring, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl can have 1, 2, 3, 4, or 5 Z 1c or Z 1d It is optionally substituted in the base, Z 1c and Z 1d The bases are the same or different, R n1 Any (C1-C8) alkyl group has 1, 2, 3, 4, or 5 Z 1c It is optionally substituted in the base, Z 1c The bases are the same or different. Each R p1 These are independently (C1-C8) alkyl, (C3-C7) carbon ring, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl, and R p1 Any (C3-C7) carbon A ring, a 3- to 7-membered heterocyclic ring, or a 5- to 6-membered monocyclic heteroaryl has 1, 2, 3, 4, or 5 Z 1c or Z 1d It is optionally substituted in the base, Z 1c and Z 1d The bases are the same or different, R p1 Any (C1-C8) alkyl group has 1, 2, 3, 4, or 5 Z 1cis optionally substituted with a group, Z 1c groups are the same or different, R q1 and R r1 each independently represent H, (C1~C8)alkyl, (C3~C7)carbocycle, 3- to 7-membered heterocycle, or 5- to 6-membered monocyclic heteroaryl, and R q1 or R r1 of any (C3~C7)carbocycle, 3- to 7-membered heterocycle, or 5- to 6-membered monocyclic heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 Z 1c or Z 1d is optionally substituted with a group, Z 1c and Z 1d groups are the same or different, and any (C1~C8)alkyl of R q1 or R r1 is optionally substituted with 1, 2, 3, 4 or 5 Z 1c is optionally substituted with a group, Z 1c groups are the same or different, or R q1 and R r1 together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered heterocycle, and the 5-, 6- or 7-membered heterocycle is optionally substituted with 1, 2, 3, 4 or 5 Z 1c or Z 1d is optionally substituted with a group, Z 1c and Z 1d groups are the same or different, R q2 and R r2 each independently represent H, (C1~C8)alkyl, (C3~C7)carbocycle, or R q2 and R r2 together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered heterocycle, Z 2 is (C2~C8)alkenyl, (C2~C8)alkynyl, 6- to 12-membered aryl, 5- to 12-membered C-linked heteroaryl, 3- to 12-membered C-linked heterocycle, -C(O)R n3 , or -C(O)NR q3 R r3 , Z 2Any 6-12 member aryl, 5-12 member C-linked heteroaryl, or 3-12 member C-linked heteroring can have 1, 2, 3, 4, or 5 Z 2b or Z 2c It is optionally substituted in the base, Z 2b and Z 2c The bases are the same or different, Z 2 Any (C2-C8) alkenyl or (C2-C8) alkinyl has 1, 2, 3, 4 or 5 Z 2c It is optionally substituted in the base, Z 2c The bases are the same or different. Each R n3 These are independently H or (C1-C4) alkyl, R q3 and R r3 Each of these is independently H or (C1-C4) alkyl, each Z 2b These are independently oxo, (C1-C4) alkyl, (C1-C4) heteroalkyl, or (C1-C4) haloalkyl. each Z 2c These are independently oxo, halogen, -CN, and -OR. n4 ,-OC(O)R p4 -OC(O)NR q4 R r4 , -SR n4 ,-S(O)R p4 -S(O)2OH, -S(O)2R p4 -S(O)2NR q4 R r4 , -NR q4 R r4 , -NR n4 COR p4 , -NR n4 CO2R p4 , -NR n4 CONR q4 R r4 , -NR n4 S(O)2R p4 , -NR n4 S(O)2OR p4 , -NR n4 S(O)2NR q4 R r4 -NO2, -C(O)R n4, -C(O)OR n4 , or -C(O)NR q4 R r4 And, Each R n4 These are independently H, (C1-C4) alkyl, (C1-C4) haloalkyl, or (C1-C4) heteroalkyl. Each R p4 These are independently (C1-C8) alkyl, (C1-C4) haloalkyl, or (C1-C4) heteroalkyl. R q4 and R r4 Each of these is independently H, (C1-C4) alkyl, (C1-C4) haloalkyl, or (C1-C4) heteroalkyl. each Z 3 These are independently (C1-C4) heteroalkyl groups. each Z 4 These are independently oxo, (C1-C8) alkyl, (C3-C7) carbon ring, halogen, -CN, and -OR. n5 , -NR q5 R r5 , -NR n5 COR p5 , -NR n5 CO2R p5 , -C(O)R n5 , -C(O)OR n5 , or -C(O)NR q5 R r5 Z 4 Any (C3-C7) carbon ring or (C1-C8) alkyl group has 1, 2, 3, 4, or 5 Z 4a It is optionally substituted in the base, Z 4a The bases are the same or different. each Z 4a These are, independently, halogen, -CN, or -OR n6 And, R n5 , R p5 , R q5 , R r5 , and R n6 Each of these is independently H or (C1-C4) alkyl, each Z 5These are halogens that can be the same or different, independently. n is 0, 1, 2, or 3. Alternatively, provide a pharmaceutically acceptable salt thereof.

[0005] One embodiment is a compound of formula III. [ka] [In the formula, A is a six-membered monocyclic heteroaryl having one or two nitrogen atoms, and the six-membered monocyclic heteroaryl has one Z at the indicated position. 1 Substituted with a base, and one Z 2 Substituted with a base, and one or two Z 3 It is optionally substituted in the base, Z 3 The bases are the same or different. R 1 R is a 6-12 member aryl, a 5-12 member heteroaryl, or a 3-12 member heteroring. 1 Any 6-12 member aryl, 5-12 member heteroaryl, or 3-12 member heteroring can be any 1, 2, 3, 4, or 5 Z 4 It is optionally substituted in the base, Z 4 The bases are the same or different. R 2 This is a phenyl compound that is optionally substituted with one, two, three, four, or five halogens, which are the same or different. R 3a and R 3b Each of these is independently H or (C1-C3) alkyl, Z 1 Z is a 6-12 member aryl, a 5-14 member heteroaryl, or a 3-14 member heteroring. 1 Any 6-12 member aryl, 5-14 member heteroaryl, or 3-14 member heteroring can be any 1, 2, 3, 4, or 5 Z 1a or Z 1b It is optionally replaced by Z1a and Z 1b The bases are the same or different. each Z 1a These are independently (C3-C7) carbon rings, 5-12 membered heteroaryls, 3-12 membered heterocycles, halogens, -CN, -OR n1 ,-OC(O)R p1 -OC(O)NR q1 R r1 , -SR n1 ,-S(O)R p1 -S(O)2OH, -S(O)2R p1 -S(O)2NR q1 R r1 , -NR q1 R r1 , -NR n1 COR p1 , -NR n1 CO2R p1 , -NR n1 CONR q1 R r1 , -NR n1 S(O)2R p1 , -NR n1 S(O)2OR p1 , -NR n1 S(O)2NR q1 R r1 , -C(O)R n1 , -C(O)OR n1 -C(O)NR q1 R r1 and -S(O)2NR n1 COR p1 Z 1a Any (C3-C7) carbon ring, 5-12 membered heteroaryl, and 3-12 membered heteroring can have 1, 2, 3, 4, or 5 Z 1c or Z 1d It is optionally substituted in the base, Z 1c and Z 1d The bases are the same or different. each Z 1b These are (C1-C8) alkyl groups that are independently and optionally substituted with the same or different 1, 2, 3, 4, or 5 halogens. each Z 1cThese are, independently, halogen, -CN, -OH, -NH2, and -C(O)NR q2 R r2 , or (C1~C8) heteroalkyl, each Z 1d These are independently (C1-C8) alkyl or (C1-C8) haloalkyl, Each R n1 R is independently H, (C1-C8) alkyl, (C3-C7) carbon ring, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl, n1 Any (C3-C7) carbon ring, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl can have 1, 2, 3, 4, or 5 Z 1c or Z 1d It is optionally substituted in the base, Z 1c and Z 1d The bases are the same or different, R n1 Any (C1-C8) alkyl group has 1, 2, 3, 4, or 5 Z 1c It is optionally substituted in the base, Z 1c The bases are the same or different. Each R p1 These are independently (C1-C8) alkyl, (C3-C7) carbon ring, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl, and R p1 Any (C3-C7) carbon ring, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl can have 1, 2, 3, 4, or 5 Z 1c or Z 1d It is optionally substituted in the base, Z 1c and Z 1d The bases are the same or different, R p1 Any (C1-C8) alkyl group has 1, 2, 3, 4, or 5 Z 1c It is optionally substituted in the base, Z 1c The bases are the same or different. R q1 and R r1 Each of these is independently H, (C1-C8) alkyl, (C3-C7) carbon ring, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl, and R q1 Or R r1Any (C3-C7) carbon ring, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl may have 1, 2, 3, 4, or 5 Z 1c Or Z 1d It is optionally substituted in the base, Z 1c and Z 1d The bases are the same or different, R q1 Or R r1 Any (C1-C8) alkyl group has 1, 2, 3, 4, or 5 Z 1c It is optionally substituted in the base, Z 1c The bases are the same or different, or R q1 and R r1 These, together with the nitrogen atoms they are bonded to, form a 5-membered, 6-membered, or 7-membered heterocycle, and these 5-membered, 6-membered, or 7-membered heterocycles contain 1, 2, 3, 4, or 5 Z atoms. 1c Or Z 1d It is optionally substituted in the base, Z 1c and Z 1d The base is either the same or different. R q2 and R r2 Each of them is independently either H, (C1-C8) alkyl, (C3-C7) carbon ring, or R q2 and R r2 These, together with the nitrogen atoms to which they are bonded, form a 5-membered, 6-membered, or 7-membered heterocycle. Z 2 These include (C2-C8) alkenyls, (C2-C8) alkynyls, 6-12 membered aryls, 5-12 membered C-linked heteroaryls, 3-12 membered C-linked heterocycles, and -C(O)R n3 , or -C(O)NR q3 R r3 Z 2 Any 6-12 member aryl, 5-12 member C-linked heteroaryl, or 3-12 member C-linked heteroring can have 1, 2, 3, 4, or 5 Z 2b or Z 2c It is optionally substituted in the base, Z 2b and Z 2c The bases are the same or different, Z 2Any (C2-C8) alkenyl or (C2-C8) alkinyl has 1, 2, 3, 4 or 5 Z 2c It is optionally substituted in the base, Z 2c The bases are the same or different. Each R n3 These are independently H or (C1-C4) alkyl, R q3 and R r3 Each of these is independently H or (C1-C4) alkyl, each Z 2b These are independently oxo, (C1-C4)alkyl, (C1-C4)heteroalkyl, or (C1-C4)haloalkyl. each Z 2c These are independently oxo, halogen, -CN, and -OR. n4 ,-OC(O)R p4 -OC(O)NR q4 R r4 , -SR n4 ,-S(O)R p4 -S(O)2OH, -S(O)2R p4 -S(O)2NR q4 R r4 , -NR q4 R r4 , -NR n4 COR p4 , -NR n4 CO2R p4 , -NR n4 CONR q4 R r4 , -NR n4 S(O)2R p4 , -NR n4 S(O)2OR p4 , -NR n4 S(O)2NR q4 R r4 -NO2, -C(O)R n4 , -C(O)OR n4 , or -C(O)NR q4 R r4 And, Each R n4 These are independently H, (C1-C4) alkyl, (C1-C4) haloalkyl, or (C1-C4) heteroalkyl. Each Rp4 These are independently (C1-C8) alkyl, (C1-C4) haloalkyl, or (C1-C4) heteroalkyl. R q4 and R r4 Each of these is independently H, (C1-C4) alkyl, (C1-C4) haloalkyl, or (C1-C4) heteroalkyl. each Z 3 These are independently (C1-C4) heteroalkyl or halogen, each Z 4 These are independently oxo, (C1-C8) alkyl, (C3-C7) carbon ring, halogen, -CN, and -OR. n5 , -NR q5 R r5 , -NR n5 COR p5 , -NR n5 CO2R p5 , -C(O)R n5 , -C(O)OR n5 , or -C(O)NR q5 R r5 Z 4 Any (C3-C7) carbon ring or (C1-C8) alkyl group has 1, 2, 3, 4, or 5 Z 4a It is optionally substituted in the base, Z 4a The bases are the same or different. each Z 4a These are, independently, halogen, -CN, or -OR n6 And, R n5 , R p5 , R q5 , R r5 , and R n6 Each of these is independently either H or (C1-C4) alkyl. Alternatively, provide a pharmaceutically acceptable salt thereof.

[0006] One embodiment is a compound of formula I. [ka] [In the formula, A is a six-membered monocyclic heteroaryl having one or two nitrogen atoms, and the six-membered monocyclic heteroaryl has one Z at the indicated position. 1 Substituted with a base, and one Z 2 Substituted with a base, and one or more (e.g., one or two) Z 3 It is optionally substituted in the base, R 1 R is a 6-12 member aryl, a 5-12 member heteroaryl, or a 3-12 member heteroring. 1 Any 6-12 member aryl, 5-12 member heteroaryl, or 3-12 member heteroring of Z is one or more (e.g., 1, 2, 3, 4, or 5) Z 4 It is optionally substituted in the base, R 2 R is a phenyl, a 5-membered monocyclic heteroaryl, a 6-membered monocyclic heteroaryl, or a (C3-C7) carbon ring. 2 Any phenyl, 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl, or (C3-C7) carbon ring may contain one or more (e.g., 1, 2, 3, 4, or 5) Z 5 It is optionally substituted in the base, R 3a and R 3b Each of these is independently selected from H, halogen, (C1-C3) alkyl and (C1-C3) haloalkyl, or R 3a R is selected from H, (C1-C3) alkyl and (C1-C3) haloalkyl, 3b It is selected from -OH and -CN, Z 1 Z is selected from 6-12 membered aryl rings, 5-14 membered heteroaryl rings, and 3-14 membered heterorings. 1 Any 6-12 member aryl, 5-14 member heteroaryl, and 3-14 member heteroring of Z can be one or more (e.g., 1, 2, 3, 4, or 5) Z 1a or Z 1b It is optionally replaced by each Z 1aThese are independently (C3-C7) carbon rings, 6-12 membered aryl groups, 5-12 membered heteroaryl groups, 3-12 membered heterocycles, halogens, -CN, -OR n1 ,-OC(O)R p1 -OC(O)NR q1 R r1 , -SR n1 ,-S(O)R p1 -S(O)2OH, -S(O)2R p1 -S(O)2NR q1 R r1 , -NR q1 R r1 , -NR n1 COR p1 , -NR n1 CO2R p1 , -NR n1 CONR q1 R r1 , -NR n1 S(O)2R p1 , -NR n1 S(O)2OR p1 , -NR n1 S(O)2NR q1 R r1 NO2, -C(O)R n1 , -C(O)OR n1 -C(O)NR q1 R r1 and -S(O)2NR n1 COR p1 Selected from, Z 1a Any (C3-C7) carbon ring, 6-12 membered aryl, 5-12 membered heteroaryl, and 3-12 membered heteroring can have one or more (e.g., 1, 2, 3, 4, or 5) Z 1c or Z 1d It is optionally substituted in the base, each Z 1b Z is independently selected from (C1-C8) alkyl, (C2-C8) alkenyl, and (C2-C8) alkynyl. 1b Any (C1-C8) alkyl, (C2-C8) alkenyl, and (C2-C8) alkynyl may have one or more (e.g., 1, 2, 3, 4, or 5) Z 1c It is optionally substituted in the base, each Z 1cThese are independently (C3-C7) carbon rings, phenyl, 5-6 member monocyclic heteroaryls, 3-7 member heterocycles, halogens, -CN, -OR n2 ,-OC(O)R p2 -OC(O)NR q2 R r2 , -SR n2 ,-S(O)R p2 -S(O)2OH, -S(O)2R p2 -S(O)2NR q2 R r2 , -NR q2 R r2 , -NR n2 COR p2 , -NR n2 CO2R p2 , -NR n2 CONR q2 R r2 , -NR n2 S(O)2R p2 , -NR n2 S(O)2OR p2 , -NR n2 S(O2NR q2 R r2 NO2, -C(O)R n2 , -C(O)OR n2 -C(O)NR q2 R r2 Selected from halophenyl, 5-6 membered haloheteroaryl, 3-7 membered haloheterocycle, and (C1-C8) heteroalkyl, each Z 1d These are independently selected from (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, and (C1-C8) haloalkyl. Each R n1 R is independently selected from H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C7) carbocyclic, 3-7 membered heterocyclic, 5-6 membered monocyclic heteroaryl, and phenyl. n1 Any (C3-C7) carbon ring, 3-7 membered heterocycle, 5-6 membered monocyclic heteroaryl, and phenyl are one or more (e.g., 1, 2, 3, 4, or 5) Z 1c or Z 1dIt is arbitrarily substituted in the base, R n1 Any (C1-C8) alkyl, (C2-C8) alkenyl, and (C2-C8) alkynyl may have one or more (e.g., 1, 2, 3, 4, or 5) Z 1c It is optionally substituted in the base, Each R p1 R is independently selected from (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C7) carbocyclic, 3-7 membered heterocyclic, 5-6 membered monocyclic heteroaryl, and phenyl. p1 Any (C3-C7) carbon ring, 3-7 membered heterocycle, 5-6 membered monocyclic heteroaryl, and phenyl are one or more (e.g., 1, 2, 3, 4, or 5) Z 1c or Z 1d It is arbitrarily substituted in the base, R p1 Any (C1-C8) alkyl, (C2-C8) alkenyl, and (C2-C8) alkynyl may have one or more (e.g., 1, 2, 3, 4, or 5) Z 1c It is optionally substituted in the base, R q1 and R r1 Each of these is independently selected from H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C7) carbon ring, 3-7 membered heterocycle, 5-6 membered monocyclic heteroaryl, and phenyl, R q1 Or R r1 Any (C3-C7) carbon ring, 3-7 membered heterocycle, 5-6 membered monocyclic heteroaryl, and phenyl can have one or more (e.g., 1, 2, 3, 4, or 5) Z 1c Or Z 1d It is arbitrarily substituted in the base, R q1 Or R r1 Any (C1-C8) alkyl, (C2-C8) alkenyl, and (C2-C8) alkynyl are present in one or more groups. This is a multiple (for example, 1, 2, 3, 4, or 5) Z 1c It is either arbitrarily substituted in the base, or R q1 and R r1These, together with the nitrogen atoms they are bonded to, form a 5-membered, 6-membered, or 7-membered heterocycle, and this 5-membered, 6-membered, or 7-membered heterocycle contains one or more (e.g., 1, 2, 3, 4, or 5) Z atoms. 1c Or Z 1d It is optionally substituted in the base, Each R n2 These are independently selected from H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C7) carbocyclic, 3-7 membered heterocyclic, 5-6 membered monocyclic heteroaryl, phenyl, halophenyl, 5-6 membered monocyclic haloheteroaryl, 3-7 membered haloheterocyclic, (C1-C8) haloalkyl, and (C1-C8) heteroalkyl. Each R p2 These are independently selected from (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C7) carbocyclic, 3-7 membered heterocyclic, 5-6 membered monocyclic heteroaryl, phenyl, halophenyl, 5-6 membered monocyclic haloheteroaryl, 3-7 membered haloheterocyclic, (C1-C8) haloalkyl, and (C1-C8) heteroalkyl. R q2 and R r2 Each of these is independently selected from H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C7) carbocyclic, 3-7 membered heterocyclic, 5-6 membered monocyclic heteroaryl, phenyl, halophenyl, 5-6 membered monocyclic haloheteroaryl, 3-7 membered haloheterocyclic, (C1-C8) haloalkyl and (C1-C8) heteroalkyl, or R q2 and R r2 These, together with the nitrogen atoms to which they are bonded, form a 5-membered, 6-membered, or 7-membered heterocycle. Z 2 These include (C2-C8) alkenyls, (C2-C8) alkynyls, 6-12 membered aryls, 5-12 membered C-linked heteroaryls, 3-12 membered C-linked heterocycles, and -C(O)R n3 and -C(O)NR q3 R r3 Selected from, Z 2Any 6-12 member aryl, 5-12 member C-linked heteroaryl, and 3-12 member C-linked heteroring can be one or more (e.g., 1, 2, 3, 4, or 5) Z 2b or Z 2c It is optionally substituted in the base, Z 2 Any (C2-C8) alkenyl and (C2-C8) alkinyl can be one or more (e.g., 1, 2, 3, 4, or 5) Z 2c It is optionally substituted in the base, each Z 2a These are independently (C3-C7) carbon rings, 6-12 membered aryl groups, 5-12 membered heteroaryl groups, 3-12 membered heterocycles, halogens, -CN, -OR n4 ,-OC(O)R p4 -OC(O)NR q4 R r4 , -SR n4 ,-S(O)R p4 -S(O)2OH, -S(O)2R p4 -S(O)2NR q4 R r4 , -NR q4 R r4 , -NR n4 COR p4 , -NR n4 CO2R p4 , -NR n4 CONR q4 R r4 , -NR n4 S(O)2R p4 , -NR n4 S(O)2OR p4 , -NR n4 S(O)2NR q4 R r4 NO2, -C(O)R n4 , -C(O)OR n4 and -C(O)NR q4 R r4 Selected from, Z 2a Any (C3-C7) carbon ring, 6-12 membered aryl, 5-12 membered heteroaryl, and 3-12 membered heteroring can have one or more (e.g., 1, 2, 3, 4, or 5) Z 2b or Z 2c It is optionally substituted in the base, each Z 2b These are independently selected from (C1-C4) alkyl, (C1-C4) heteroalkyl, and (C1-C4) haloalkyl. each Z 2c These are, independently, halogen, -CN, and -OR. n4 ,-OC(O)R p4 -OC(O)NR q4 R r4 , -SR n4 ,-S(O)R p4 -S(O)2OH, -S(O)2R p4 -S(O)2NR q4 R r4 , -NR q4 R r4 , -NR n4 COR p4 , -NR n4 CO2R p4 , -NR n4 CONR q4 R r4 , -NR n4 S(O)2R p4 , -NR n4 S(O)2OR p4 , -NR n4 S(O)2NR q4 R r4 NO2, -C(O)R n4 , -C(O)OR n4 and -C(O)NR q4 R r4 Selected from, Each R n3 R is independently selected from H, (C1-C4) alkyl, (C2-C4) alkenyl, (C3-C7) carbon ring, 3-12 membered heterocycle, 5-12 membered heteroaryl, and 6-12 membered aryl. n3 Any (C3-C7) carbon ring, 3-12 membered heterocycle, 5 ~12-membered heteroaryls and 6~12-membered aryls are one or more (e.g., 1, 2, 3, 4, or 5) Z 2b or Z 2c It is arbitrarily substituted in the base, R n3Any (C1-C4) alkyl, (C2-C4) alkenyl, and (C2-C4) alkynyl may have one or more (e.g., 1, 2, 3, 4, or 5) Z 2a It is optionally substituted in the base, R q3 and R r3 Each of these is independently selected from H, (C1-C4) alkyl, (C2-C4) alkenyl, (C3-C7) carbon ring, 3-12 membered heterocycle, 5-12 membered heteroaryl, and 6-12 membered aryl, R q3 Or R r3 Any (C3-C7) carbon ring, 3-12 membered heteroring, 5-12 membered heteroaryl, and 6-12 membered aryl may have one or more (e.g., 1, 2, 3, 4, or 5) Z 2b Or Z 2c It is arbitrarily substituted in the base, R q3 Or R r3 Any (C1-C4) alkyl and (C2-C4) alkenyl in the group may have one or more (e.g., 1, 2, 3, 4, or 5) Z 2a It is either arbitrarily substituted in the base, or R q3 and R r3 These, together with the nitrogen atoms to which they are bonded, form a heterocycle or heteroaryl, and the heterocycle or heteroaryl contains one or more (e.g., 1, 2, 3, 4, or 5) Z atoms. 2b Or Z 2c It is optionally substituted in the base, Each R n4 These are independently selected from H, (C1-C4) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C1-C4) haloalkyl and (C1-C4) heteroalkyl. Each R p4 These are independently selected from (C1-C8) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C1-C4) haloalkyl and (C1-C4) heteroalkyl. R q4 and R r4Each of these is independently selected from H, (C1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C1-C4) haloalkyl, and (C1-C4) heteroalkyl. each Z 3 These are independently selected from halogens, (C1-C4) alkyls, -OH, -CN, (C1-C4) heteroalkyls, and (C1-C4) haloalkyls. each Z 4 These are independently (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C7) carbon ring, halogen, -CN, -OR n5 ,-OC(O)R p5 -OC(O)NR q5 R r5 , -SR n5 ,-S(O)R p5 -S(O)2OH, -S(O)2R p5 -S(O)2NR q5 R r5 , -NR q5 R r5 , -NR n5 COR p5 , -NR n5 CO2R p5 , -NR n5 CONR q5 R r5 , -NR n5 S(O)2R p5 , -NR n5 S(O)2OR p5 , -NR n5 S(O)2NR q5 R r5 NO2, -C(O)R n5 , -C(O)OR n5 and -C(O)NR q5 R r5 Selected from, Z 4 Any (C3-C7) carbon ring can have one or more (e.g., 1, 2, 3, 4, or 5) Z 4a or Z 4b It is optionally substituted in the base, Z 4 Any (C1-C8) alkyl, (C2-C8) alkenyl, and (C2-C8) alkynyl may have one or more (e.g., 1, 2, 3, 4, or 5) Z4a It is optionally substituted in the base, each Z 4a These are, independently, halogen, -CN, and -OR. n6 ,-OC(O)R p6 -OC(O)NR q6 R r6 , -SR n6 ,-S(O)R p6 -S(O)2OH, -S(O)2R p6 -S(O)2NR q6 R r6 , -NR q6 R r6 , -NR n6 COR p6 , -NR n6 CO2R p6 , -NR n6 CONR q6 R r6 , -NR n6 S(O)2R p6 , -NR n6 S(O)2OR p6 , -NR n6 S(O)2NR q6 R r6 NO2, -C(O)R n6 , -C(O)OR n6 and -C(O)NR q6 R r6 Selected from, each Z 4b These are independently selected from (C1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, and (C1-C4) haloalkyl. Each R n5 These are independently selected from H, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) heteroalkyl, (C2-C4) alkenyl, and (C2-C4) alkynyl. Each R p5 These are independently selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) heteroalkyl, (C2-C4) alkenyl, and (C2-C4) alkynyl. R q5 and R r5Each of these is independently selected from H, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) heteroalkyl, (C2-C4) alkenyl, and (C2-C4) alkynyl. Each R n6 These are independently selected from H, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) heteroalkyl, (C2-C4) alkenyl, and (C2-C4) alkynyl. Each R p6 These are independently selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) heteroalkyl, (C2-C4) alkenyl, and (C2-C4) alkynyl. R q6 and R r6 Each of these is independently selected from H, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) heteroalkyl, (C2-C4) alkenyl, and (C2-C4) alkynyl. each Z 5 These are independently (C1-C6) alkyl, halogen, -CN and -OR n7 Selected from, Z 5 Any (C1-C6) alkyl group is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) halogens. Each R n7 [These are independently selected from H, (C1-C3) alkyl, (C1-C3) haloalkyl, and (C3-C7) carbocyclic.] Alternatively, provide a pharmaceutically acceptable salt thereof.

[0007] One embodiment provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Another embodiment provides a pharmaceutical composition comprising a compound detailed herein, comprising any one of the compounds of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, III, IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIi, IIIj, and IIIk, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0008] One embodiment provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, as well as additional therapeutic agents which are HIV protease inhibitors, non-nucleoside inhibitors of HIV reverse transcriptase, nucleoside inhibitors of HIV reverse transcriptase, nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, or non-catalytic site HIV integrase inhibitors, and combinations thereof. Another embodiment provides a pharmaceutical composition comprising any one compound of formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, III, IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIi, IIIj, and IIIk or a pharmaceutically acceptable salt thereof, as well as additional therapeutic agents which are HIV protease inhibitors, non-nucleoside inhibitors of HIV reverse transcriptase, nucleoside inhibitors of HIV reverse transcriptase, nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, or non-catalytic site HIV integrase inhibitors, and combinations thereof.

[0009] One embodiment provides a method for treating a Retroviridae virus infection (e.g., HIV virus infection) in a mammal (e.g., human), comprising the step of administering a compound of formula I or a pharmaceutically acceptable salt thereof to a mammal. Another embodiment provides a compound detailed herein, comprising any one of the compounds of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, III, IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIi, IIIj, and IIIk, or a pharmaceutically acceptable salt thereof. A method is provided for treating a Retroviridae virus infection (e.g., HIV virus infection) in a mammal (e.g., a human), comprising the step of administering a salt of the compound to the mammal. Another embodiment provides a method for treating an HIV infection in a patient in need, comprising the step of administering a therapeutically effective amount of the compound detailed herein or a pharmaceutically acceptable salt thereof to the patient.

[0010] One embodiment provides a method for inhibiting the replication of the HIV virus in a mammal (e.g., a human), treating AIDS, or delaying the onset of AIDS or ARC symptoms, comprising the step of administering a mammal a compound of formula I or a pharmaceutically acceptable salt thereof. Another embodiment provides a method for inhibiting the replication of the HIV virus in a mammal (e.g., a human), treating AIDS, or delaying the onset of AIDS or ARC symptoms, comprising the step of administering a mammal a mammal a compound detailed herein, comprising one of the compounds of formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, III, IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIi, IIIj, and IIIk, or a pharmaceutically acceptable salt thereof.

[0011] One embodiment provides a method for treating HIV infection in a mammal (e.g., a human), comprising the step of administering a compound of formula I or a pharmaceutically acceptable salt thereof to a mammal. Another embodiment provides a method for treating HIV infection in a mammal (e.g., a human), comprising the step of administering a compound detailed herein, comprising one of the compounds of formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, III, IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIi, IIIj, and IIIk, or a pharmaceutically acceptable salt thereof to a mammal.

[0012] One embodiment provides a method for treating HIV infection in a mammal (e.g., a human), comprising the step of administering to a mammal in need of the treatment a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof in combination with one or more additional therapeutic agents selected from the group consisting of HIV protease inhibitors, non-nucleoside inhibitors of HIV reverse transcriptase, nucleoside inhibitors of HIV reverse transcriptase, nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors and other drugs for treating HIV, and combinations thereof. Another embodiment provides a method for treating HIV infection in a mammal (e.g., a human), comprising the step of administering to a mammal in need of the treatment, in combination with a therapeutically effective amount of one compound or a pharmaceutically acceptable salt thereof of any of the formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, III, IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIi, IIIj, and IIIk, in combination with one or more additional therapeutic agents selected from the group consisting of HIV protease inhibitors, non-nucleoside inhibitors of HIV reverse transcriptase, nucleoside inhibitors of HIV reverse transcriptase, nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, and other drugs for treating HIV, and combinations thereof, in a therapeutically effective amount. Another embodiment provides a method for treating HIV infection in a patient in need, comprising the step of administering to the patient a therapeutically effective amount of an additional therapeutic agent which is an HIV protease inhibitor, a non-nucleoside inhibitor of HIV reverse transcriptase, a nucleoside inhibitor of HIV reverse transcriptase, a nucleotide inhibitor of HIV reverse transcriptase, an integrase inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gp120 inhibitor, a CCR5 inhibitor, a capsid polymerization inhibitor, or a non-catalytic site HIV integrase site inhibitor, or a combination thereof.

[0013] One embodiment provides a method for treating HIV infection in a mammal (e.g., a human), comprising the step of administering to a mammal in need of the treatment a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof in combination with one or more additional therapeutic agents selected from the group consisting of HIV protease inhibitors, non-nucleoside inhibitors of HIV reverse transcriptase, nucleoside inhibitors of HIV reverse transcriptase, nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, and non-catalytic site HIV integrase inhibitors, and combinations thereof. Another embodiment provides a method for treating HIV infection in a mammal (e.g., a human), comprising the step of administering to a mammal in need of the treatment, in combination with one or more additional therapeutic agents selected from the group consisting of HIV protease inhibitors, non-nucleoside inhibitors of HIV reverse transcriptase, nucleoside inhibitors of HIV reverse transcriptase, nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, and non-catalytic site HIV integrase inhibitors, and combinations thereof, in a therapeutic amount.

[0014] One embodiment provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in medical therapy (for example, for use in the treatment of Retroviridae virus infection (e.g., HIV virus infection) or HIV virus replication or AIDS, or for use in delaying the onset of AIDS or ARC symptoms in mammals (e.g., humans). Another embodiment provides a compound detailed herein or a pharmaceutically acceptable salt thereof, comprising any one of the compounds of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, III, IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIi, IIIj, and IIIk, for use in medical therapy (for example, for use in the treatment of Retroviridae virus infection (e.g., HIV virus infection) or HIV virus replication or AIDS, or for use in delaying the onset of AIDS or ARC symptoms in mammals (e.g., humans).

[0015] One embodiment provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for treating Retroviridae virus infection (e.g., HIV virus infection) or HIV virus replication or AIDS, or for delaying the onset of AIDS or ARC symptoms in mammals (e.g., humans). Another embodiment provides a compound detailed herein or a pharmaceutically acceptable salt thereof, comprising any one of the compounds of formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, III, IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIi, IIIj, and IIIk, for use in the manufacture of a medicament for treating Retroviridae virus infection (e.g., HIV virus infection) or HIV virus replication or AIDS, or for delaying the onset of AIDS or ARC symptoms in mammals (e.g., humans).

[0016] One embodiment provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in the proliferation of Retroviridae viruses, HIV viruses, or in the prophylactic or therapeutic treatment of AIDS, or for use in therapeutic treatment to delay the onset of AIDS or ARC symptoms. Another embodiment provides a compound of formula I, for use in the proliferation of Retroviridae viruses, HIV viruses, or in the prophylactic or therapeutic treatment of AIDS, or for use in therapeutic treatment to delay the onset of AIDS or ARC symptoms. This specification provides compounds described in detail or pharmaceutically acceptable salts thereof, comprising one of the compounds Ia, Ib, Ic, Id, Ie, If, Ig, III, IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIi, IIIj, and IIIk.

[0017] One embodiment provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in the prophylactic or therapeutic treatment of Retroviridae virus infections (e.g., HIV infection). Another embodiment provides a compound detailed herein or a pharmaceutically acceptable salt thereof comprising any one of the compounds of formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, III, IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIi, IIIj, and IIIk for use in the prophylactic or therapeutic treatment of Retroviridae virus infections (e.g., HIV infection).

[0018] One embodiment provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for Retroviridae virus infections (e.g., HIV virus infection) in mammals (e.g., humans). Another embodiment provides a compound detailed herein or a pharmaceutically acceptable salt thereof, comprising any one of the compounds of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, III, IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIi, IIIj, and IIIk, for the manufacture of a medicament for Retroviridae virus infections (e.g., HIV virus infection) in mammals (e.g., humans).

[0019] One embodiment provides a process and intermediates disclosed herein that are useful for preparing compounds of formula I or salts thereof. Another embodiment provides a process and intermediates disclosed herein that are useful for preparing any one of the compounds of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, III, IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIi, IIIj, and IIIk or salts thereof.

[0020] Other embodiments, purposes, features, and advantages are described in the detailed descriptions of the embodiments below, will be partially apparent from the descriptions below, or can be learned by practicing the claimed invention. These purposes and advantages are realized and achieved by the processes and compositions specifically indicated in the descriptions and claims herein. The preceding summary is written with the understanding that it should be considered a compilation of some of the embodiments disclosed herein and a general summary thereof, and is provided solely for the benefit and convenience of the reader and does not in any way limit the scope of the area or equivalent of which the appended claims are lawfully entitled. [Modes for carrying out the invention]

[0021] Detailed explanation The following description is provided with the understanding that this disclosure should be considered an example of the subject matter claimed, and the attached claims are not intended to limit the specific embodiments described herein. The headings used throughout this disclosure are provided solely for convenience and should not be construed as limiting the claims in any way. Embodiments described under any heading may be combined with embodiments described under any other heading.

[0022] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art. A dash preceding or trailing a chemical group means: This is for convenience only. Chemical groups can be illustrated with or without one or more dashes without losing their usual meaning. In a structure, wavy lines drawn through a line indicate the bonding point of a group. Dashed lines indicate an optional bond. u~v " or (C u ~C v Prefixes such as ) indicate that the subsequent group has u to v carbon atoms. For example, "C 1~6 The term "alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0023] Unless otherwise stated, the following terms and phrases, when used herein, shall have the following meanings:

[0024] Where a trade name is used herein, the applicants intend to independently include the trademarked product and its active pharmaceutical component(s).

[0025] "Alkyl" refers to a straight-chain or branched saturated hydrocarbon. For example, an alkyl group can have 1 to 8 carbon atoms (i.e., (C1-C8) alkyl), 1 to 6 carbon atoms (i.e., (C1-C6 alkyl), or 1 to 4 carbon atoms (i.e., (C1-C4) alkyl). Suitable examples of alkyl groups include methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), and 1-butyl (n-Bu, n- Butyl (-CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2 CH3), 3-methyl-2-butyl(-CH(CH3)CH(CH3)2), 3-methyl-1-butyl(-CH2CH2CH(CH3)2), 2-methyl-1-butyl(-CH2CH(CH3)CH2CH3), 1-hexyl(-CH2CH2CH2CH2CH2CH3), 2-hexyl(-CH(CH3)CH2CH2CH2CH3), 3-hexyl(-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl(-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl Examples include, but are not limited to, hydroxyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), and octyl (-(CH2)7CH3).

[0026] "Alkenyl" is a group of at least one carbon-carbon atoms, sp2 Alkenyl groups are straight-chain or branched hydrocarbons having double bonds. For example, an alkenyl group can have 2 to 8 carbon atoms (i.e., C2-C8 alkenyls) or 2 to 6 carbon atoms (i.e., C2-C6 alkenyls). Suitable examples of alkenyl groups include, but are not limited to, ethylene or vinyl (-CH=CH2), allyl (-CH2CH=CH2), and 5-hexenyl (-CH2CH2CH2CH2CH=CH2).

[0027] An "alkynyl" is a linear or branched hydrocarbon having at least one carbon-carbon sp triple bond. For example, an alkynyl group can have 2 to 8 carbon atoms (i.e., C2-C8 alkynes) or 2 to 6 carbon atoms (i.e., C2-C6 alkynyls). Suitable examples of alkynyl groups include, but are not limited to, acetylenic (-C≡CH) and propargyl (-CH2C≡CH). It will not be done.

[0028] The term "halo" or "halogen" as used herein refers to fluoro, chloro, bromo, and iodine.

[0029] The term "haloalkyl," as used herein, refers to an alkyl group in which one or more hydrogen atoms of the alkyl group as defined herein are independently replaced by halo substituents. For example, a (C1-C6) haloalkyl is a (C1-C6) alkyl group in which one or more hydrogen atoms of the (C1-C6) alkyl group are replaced by halo substituents. Examples of haloalkyls include, but are not limited to, fluoromethyl, fluorochloromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, 1,1,1,trifluoroethyl, and pentafluoroethyl.

[0030] When used herein, the term "heteroalkyl" means that one or more of the carbon atoms of the alkyl as defined herein are O, S, or NR. q (Each R qThe carbon atoms are independently H or (C1-C6) alkyl) and (if the carbon atom being replaced is a terminal carbon, OH, SH or N(R) q This refers to alkyl groups that are replaced by (2). For example, (C1~C8) heteroalkyl groups consist of 1 to 8 carbon atoms and 1 or more heteroatoms (e.g., O, S, NR). q , OH, SH or N(R q )2) includes heteroalkyls. Therefore, for example, C1 heteroalkyls include, for example, -CH2-NH2. Examples of heteroalkyls include, but are not limited to, methoxymethyl, ethoxymethyl, methoxy, 2-hydroxyethyl, and N,N'-dimethylpropylamine.

[0031] The term "aryl," as used herein, refers to an all-carbon single aromatic ring or an all-carbon multiple condensed ring system in which at least one of the rings is aromatic. For example, in certain embodiments, an aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryls include phenyl radicals. Also, aryls are multiple condensed ring systems having about 9 to 20 carbon atoms in which at least one ring is aromatic and the other rings may or may not be aromatic (i.e., carbon rings). This includes condensed ring systems (e.g., ring systems containing two, three, or four rings). Such multiple condensed ring systems are optionally substituted with one or more (e.g., one, two, or three) oxo groups on any carbocyclic portion of the multiple condensed ring system. The rings of a multiple condensed ring system can be connected to each other by condensation, spiro, and bridging bonds, where the valency requirements allow. It should be understood that the bonding points of the multiple condensed ring systems defined above can be at any position in the ring system, including the aromatic or carbocyclic portions of the rings. Also, when referring to aryls of a particular atomic range (e.g., 6- to 12-membered aryls), it should be understood that the atomic range refers to the entire ring atom of the aryl. For example, 6-membered aryls include phenyl, and 10-membered aryls include naphthyl and 1,2,3,4-tetrahydronaphthyl. Non-exclusive examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, and anthracenyl.

[0032] The term “heteroaryl,” as used herein, refers to a single aromatic ring having at least one non-carbon atom in the ring, selected from the group consisting of oxygen, nitrogen, and sulfur. “Heteroaryl” also includes a polyfused ring system having at least one such aromatic ring, which is further described below. Thus, “heteroaryl” includes a single aromatic ring having about 1 to 6 carbon atoms and about 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Sulfur and nitrogen atoms may also exist in oxidized forms if the ring is aromatic. Exemplary heteroaryl ring systems include pyridyl, pyrimidinyl, oxazolyl, or furyl, but these include Not limited to these definitions. Furthermore, "heteroaryl" includes multiple fused ring systems (e.g., ring systems containing two, three, or four rings) in which the previously defined heteroaryl group condenses with one or more rings selected from heteroaryl (e.g., forming 1,8-naphthilidinyl), heterocyclic (e.g., forming 1,2,3,4-tetrahydro-1,8-naphthilidinyl), carbocyclic (e.g., forming 5,6,7,8-tetrahydroquinolyl), and aryl (e.g., forming indazolyl) to form a multiple fused ring system. Thus, a heteroaryl (single aromatic ring or multiple fused ring system) has about 1 to 20 carbon atoms and about 1 to 6 heteroatoms within the heteroaryl ring. Such multiple fused ring systems may be optionally substituted with one or more (e.g., one, two, three, or four) oxo groups on the carbocyclic or heterocyclic portion of the fused ring. The rings in a polyfused ring system can be connected to each other by condensation, spiro, and bridging bonds, provided the valency requirements allow. It should be understood that the individual rings in a polyfused ring system can be connected to each other in any order. It should be understood that the bonding sites in a polyfused ring system (as previously defined for heteroaryls) can be at any position in the polyfused ring system, including the heteroaryl, heterocyclic, aryl, or carbocyclic portions of the polyfused ring system. Furthermore, it should be understood that the bonding sites in a heteroaryl or polyfused heteroaryl system may be at any suitable atom in the heteroaryl or polyfused heteroaryl system, including carbon atoms and heteroatoms (e.g., nitrogen). Also, when referring to heteroaryls of a specific atomic range (e.g., 5- to 14-membered heteroaryls), the atomic range should be understood to refer to the entire ring of heteroaryl atoms, including carbon atoms and heteroatoms. For example, a 5-membered heteroaryl contains thiazolyl, and a 10-membered heteroaryl contains quinolinyl.Examples of heteroaryls include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridadinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl, benzofuranil, benzimidazolyl, thianaftenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-1H-indazole, and 3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole.

[0033] The term "C-linked heteroaryl" (carbon-linked heteroaryl) as used herein refers to a heteroaryl compound where the carbon atom of the heteroaryl is linked to the rest of the compound of formula I (for example, a Z-linked heteroaryl compound where the carbon atom of the C-linked heteroaryl is linked to the A ring of formula I). 2 This refers to a C-linked heteroaryl

[0034] The term “heterocyclyl” or “heterocycle,” as used herein, refers to a single saturated or partially unsaturated ring having at least one non-carbon atom in the ring, selected from the group consisting of oxygen, nitrogen, and sulfur. The term also includes a polycondensed ring system having at least one such saturated or partially unsaturated ring, which is further described below. Therefore, the term includes a single saturated or partially unsaturated ring (e.g., a 3-membered, 4-membered, 5-membered, 6-membered, or 7-membered ring) having about 1 to 6 carbon atoms and about 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. The ring may be substituted with one or more (e.g., 1, 2, or 3) oxo groups, and the sulfur and nitrogen atoms may exist in their oxidized forms. Exemplary heterocyclyls include, but are not limited to, azetidinyl, tetrahydrofuranil, and piperidinyl. Furthermore, the term "heterocycle" includes multiple fused ring systems (e.g., ring systems containing two, three, or four rings) in which a single heterocycle (as defined above) can condense with one or more groups selected from heterocycles (e.g., 1,8-decahydronaphthylidinyl), carbocyclic rings (e.g., decahydroquinolyl), and aryl groups to form a multiple fused ring system. Therefore, a heterocycle (a single saturated or single partially unsaturated ring, or a polyfused ring system) has approximately 2 to 20 carbon atoms and 1 to 6 heteroatoms within the heterocycle. Such polyfused ring systems may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups on the carbocyclic or heterocyclic portion of the polyfused ring. The rings of a polyfused ring system may be connected to one another by condensation, spiro, and bridging bonds, wherever the valence requirements permit. It should be understood that the individual rings of a polyfused ring system may be connected to one another in any order. It should also be understood that the bond points of a polyfused ring system (as previously defined for heterocycles) may be at any position within the polyfused ring system, including the heterocyclic, aryl, and carbocyclic portions of the ring. It should be understood that the bonding sites of a heterocycle or a polyfused heterocycle may be on any suitable atom of the heterocycle or polyfused heterocycle, including carbon atoms and heteroatoms (e.g., nitrogen). Furthermore, when referring to a heterocycle of a specific atomic range (e.g., a 3- to 14-membered heterocycle), the atomic range should be understood to refer to the entire ring of the heterocycle, including carbon atoms and heteroatoms. For example, a 3-membered heterocycle contains aziridinyl, and a 10-membered heterocycle contains 1,2,3,4-tetrahydroquinolyl. Exemplary heterocycles include, but are not limited to, azilidinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydroxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4-tetrahydroquinolyl, benzoxadinyl, dihydroxazolyl, chromanil, 1,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, spiro[cyclopropan-1,1'-isoindlinyl]-3'-one, isoindlinyl-1-one, 2-oxa-6-azaspiro[3.3]heptanyl, imidazolidine-2-one, and pyrrolidine-2-one.

[0035] The term "C-linked heterocycle" (carbon-linked heterocycle), as used herein, refers to a heterocycle linked at a carbon atom of the heterocycle to the rest of the compound of formula I (for example, a Z-linked heterocycle bonded to ring A of formula I via a carbon atom of the C-linked heterocycle). 2 This refers to the C-linked complex algebra.

[0036] The term "carbocyclyl" refers to an all-carbon ring having 3 to 7 carbon atoms (i.e., (C3-C7) carbocyclyls), a single saturated (i.e., cycloalkyl) or a single partially unsaturated (e.g., cycloalkenyl, cycloalkadienyl, etc.) ring. The term "carbocyclyl" also includes multiple condensed, saturated, and partially unsaturated all-carbon ring systems (e.g., ring systems containing 2, 3, or 4 carbocyclic rings). Therefore, carbocyclyls include polycyclic carbocyclyls, such as bicyclic carbocyclyls (e.g., bicyclic carbocyclyls having approximately 6 to 12 carbon atoms, e.g., bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane), and polycyclic carbocyclyls (e.g., tricyclic and tetracyclic carbocyclyls having up to approximately 20 carbon atoms). Rings in multiple condensed ring systems may be linked to each other by condensation, spiro, and bridging bonds, where valency requirements permit. For example, polycyclic carbocyclic rings can be connected to each other via a single carbon atom to form spirolinks (e.g., spiropentane, spiro[4,5]decane), connected to each other via two adjacent carbon atoms to form condensed links (e.g., carbocyclic rings, e.g., decahydronaphthalene, norsabinane, norcalane), or connected to each other via two non-adjacent carbon atoms to form bridging links (e.g., norbornane, bicyclo[2.2.2]octane). Furthermore, "carbocyclic rings" or "carbocyclyls" may be optionally substituted with one or more (e.g., 1, 2, or 3) oxo groups. Non-limiting examples of monocyclic carbocyclic compounds include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopenta-1-enyl, 1-cyclopenta-2-enyl, 1-cyclopenta-3-enyl, cyclohexyl, 1-cyclohexa-1-enyl, 1-cyclohexa-2-enyl, and 1-cyclohexa-3-enyl.

[0037] As used herein, the term "halophenyl" refers to a phenyl molecule in which one or more (e.g., 1, 2, 3, 4, or 5) hydrogen atoms are independently replaced by halo substituents. Examples of halophenyls include, but are not limited to, fluorophenyl, 2,3-dichlorophenyl, 3-bromo-4-fluorophenyl, and pentafluorophenyl.

[0038] As used herein, the term "haloheteroaryl" refers to a heteroaryl molecule in which one or more (e.g., 1, 2, 3, 4, or 5) hydrogen atoms are independently replaced by halo substituents. Examples of haloheteroaryls include, but are not limited to, 2-fluorofuryl, 2,3-dichloropyridinyl, and 8-chloro-3-fluoroquinolinyl.

[0039] As used herein, the term "haloheterocyclic" refers to a heterocyclic ring in which one or more (e.g., 1, 2, 3, 4, or 5) hydrogen atoms are independently replaced by halo substituents. Examples of haloheteroaryls include, but are not limited to, 2-fluoropiperizinyl, 2-chloro-3-fluoropiperazinyl, and 3-bromopyrrolidinyl.

[0040] Those skilled in the art will recognize that substituents and other parts of compounds of formula I should be selected to provide compounds that are sufficiently stable to provide pharmaceutically useful compounds that can be formulated into acceptable and stable pharmaceutical compositions. Compounds of formula I having such stability are intended to be included within the scope of the present invention. Similarly, those skilled in the art will recognize that substituents and other parts of compounds detailed herein, including any one of the compounds of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, III, IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIi, IIIj, and IIIk, or pharmaceutically acceptable salts thereof, should be selected to provide compounds that are sufficiently stable to provide pharmaceutically useful compounds that can be formulated into acceptable and stable pharmaceutical compositions. Compounds detailed herein having such stability are intended to be included within the scope of the present invention.

[0041] The modifier "approximately," used in relation to quantity, includes the stated value and has a meaning determined by the context (e.g., including the degree of error associated with the measurement of a particular quantity). In the context of chemical measurements, the term "approximately" can also be represented by the symbol "~" (e.g., ~50 mg or pH ~7).

[0042] The term “treatment” or “to treat” includes, in the context of a disease or condition, the prevention of the onset of a disease or condition, the inhibition of a disease or condition, the elimination of a disease or condition, and / or the reduction of one or more symptoms of a disease or condition.

[0043] In one embodiment, “treatment” or “to treat” includes one or more of the following: a) inhibiting the disease or condition (e.g., reducing one or more symptoms resulting from the disease or condition, and / or reducing the severity of the disease or condition); b) slowing or stopping the onset of one or more symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, delaying the worsening or progression of the disease or condition); and c) alleviating the disease or condition, e.g., causing regression of clinical symptoms, easing the condition, delaying the progression of the disease, improving quality of life, and / or extending survival.

[0044] stereoisomer The definitions and conventions of stereochemistry used herein generally refer to the McGraw-Hill Dictionary of Chemical Technology, edited by SP. Parker. rms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., New York.

[0045] The term "chiral" refers to a molecule that cannot be superimposed on its mirror image partner, while the term "achiral" refers to a molecule that can be superimposed on its mirror image partner.

[0046] The term "stereoisomer" refers to a compound that has the same chemical structure but differs in the arrangement of atoms or groups in space.

[0047] A "diastereomer" refers to a stereoisomer of molecules that are not mirror images of each other and have two or more centers or axes of chirality. Diastereomers typically have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. Mixtures of diastereomers can be separated by high-resolution analytical procedures, such as electrophoresis and chromatography.

[0048] "Enantiomers" refer to two stereoisomers of a compound that are mirror images of each other and cannot be superimposed.

[0049] The compounds disclosed herein may have a chiral center, for example, a chiral carbon atom. Therefore, such compounds include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers. Furthermore, the compounds disclosed herein include optical isomers enriched or divided at any or all asymmetric chiral atoms. Similarly, the compositions disclosed herein also include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers of the compounds disclosed herein. Furthermore, the compounds and compositions disclosed herein include optical isomers enriched or divided at any or all asymmetric chiral atoms. In other words, chiral centers evident from the description are provided as chiral isomers or racemic mixtures. Both racemic mixtures and diastereomer mixtures, as well as isolated or synthesized individual optical isomers substantially free of enantiomer or diastereomer partners, are all within the scope of the present invention. Racemic mixtures can be separated into their substantially optically pure individual isomers by known techniques, such as separating diastereomer salts formed with optically active auxiliaries (e.g., acids or bases) and then converting them back to optically active substances. Furthermore, desired optical isomers can be synthesized starting with appropriate stereoisomers of the desired starting materials using stereospecific reactions.

[0050] The present invention encompasses any or all of the stereochemical forms of the described compounds, including any enantiomers or diastereomers and geometric isomers, or mixtures thereof. Unless stereochemistry is explicitly indicated in the chemical structure or name, such structure or name is intended to encompass all possible stereoisomers, including geometric isomers, of the illustrated compound. Furthermore, compositions containing the compounds of the present invention are intended, such as compositions of substantially pure compounds (including specific stereochemical forms, including their particular geometric isomers). Compositions containing mixtures of the compounds of the present invention in any ratio, including mixtures of two or more types of stereochemical forms of the compounds of the present invention in any ratio, are also encompassed in the present invention, and therefore include racemic, non-racemic, enantiomerically enriched scalemic mixtures, or mixtures thereof, of the compounds.

[0051] The compounds disclosed herein are shown with bonds in a non-stereochemical manner (e.g., flat). If a bond is shown, it should be understood that the atom to which the bond is attached includes all possible stereochemistrys. Also, if a bond is shown in a stereochemical manner (e.g., bold, bold wedge, dotted line, or dotted wedge), it should be understood that the atom to which the stereochemical bond is attached has the shown stereochemistry unless otherwise indicated. Therefore, in one embodiment, more than 50% of the compounds disclosed herein are single enantiomers. In another embodiment, at least 80% of the compounds disclosed herein are single enantiomers. In another embodiment, at least 90% of the compounds disclosed herein are single enantiomers. In another embodiment, at least 98% of the compounds disclosed herein are single enantiomers. In another embodiment, at least 99% of the compounds disclosed herein are single enantiomers. In another embodiment, more than 50% of the compounds disclosed herein are single diastereomers. In another embodiment, at least 80% of the compounds disclosed herein are single diastereomers. In another embodiment, the compounds disclosed herein are at least 90% single diastereomers. In yet another embodiment, the compounds disclosed herein are at least 98% single diastereomers. In yet another embodiment, the compounds disclosed herein are at least 99% single diastereomers.

[0052] Therefore, in one embodiment, the composition disclosed herein is more than 50% a single enantiomer. In another embodiment, the composition disclosed herein is at least 80% a single enantiomer. In another embodiment, the composition disclosed herein is at least 90% a single enantiomer. In another embodiment, the composition disclosed herein is at least 98% a single enantiomer. In another embodiment, the composition disclosed herein is at least 99% a single enantiomer. In another embodiment, the composition disclosed herein is more than 50% a single diastereomer. In another embodiment, the composition disclosed herein is at least 80% a single diastereomer. In another embodiment, the composition disclosed herein is at least 90% a single diastereomer. In another embodiment, the composition disclosed herein is at least 98% a single diastereomer. In another embodiment, the composition disclosed herein is at least 99% a single diastereomer.

[0053] In certain embodiments, the compounds disclosed herein exhibit atropisomerism arising from steric hindrance affecting the axial rotational velocity around single bonds. Under certain conditions, the resulting conformational isomers are observed as distinct entities by characterization techniques such as NMR and HPLC. In certain embodiments, the compounds disclosed herein exist as a mixture of atropisomers. The synthesis examples presented herein describe cases where such a mixture of atropisomers is observed. However, the detection of atropisomers depends on factors such as temperature, solvent, purification conditions, and the timescale of the spectroscopic technique. The characterization data presented herein may not represent equilibrium states depending on the purification conditions, isolation conditions, handling conditions, solvents used, and temperature.

[0054] Tautomers The compounds disclosed herein may also exist as tautomers in certain cases. While only one delocalized resonance structure may be illustrated, all such forms are intended to be included within the scope of the invention. For example, en-amine tautomers may exist in purines, pyrimidines, imidazoles, guanidines, amidines, and tetrazoles, and all possible tautomer forms of these are included within the scope of the invention. Another non-limiting example is the keto-enol tautomers of heteroaryls. Such tautomers are exemplified by T1 / T1', T2 / T2', and T3 / T3'. All such tautomer forms are also included within the scope of the invention. [ka]

[0055] protecting group A "protecting group" refers to a part of a compound that shields or alters the properties of a functional group or the compound as a whole. Chemical protecting groups and strategies for protection / deprotection are well known in the art. See, for example, Protective Groups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991. Protecting groups are often used to shield the reactivity of a particular functional group and to assist the efficiency of a desired chemical reaction, for example, to create and break chemical bonds in an ordered and planned manner. Protection of a functional group in a compound alters other physical properties, such as polarity, lipophilicity (hydrophobicity), and other properties that can be measured by common analytical tools, in addition to the reactivity of the protected functional group. Chemically protected intermediates may be biologically active or inactive themselves.

[0056] Salts and hydrates A “pharmaceutically acceptable salt” refers to a salt of a compound that is pharmaceutically acceptable and possesses (or can be converted to) the desired pharmacological activity of the parent compound. Pharmaceutically acceptable salts are generally considered safe, suitable for use without excessive toxicity, irritation, allergic reactions, etc., and are considered to have a reasonable benefit / risk ratio. Examples of “pharmaceutically acceptable salts” of the compounds disclosed herein include suitable bases, e.g., alkali metals (e.g., sodium), alkaline earth metals (e.g., magnesium), ammonium, and NX4. + Examples of pharmaceutically acceptable salts of nitrogen atoms or amino groups include, for example, organic carboxylic acids, such as acetic acid, benzoic acid, camphor sulfonic acid, citric acid, glucoheptonic acid, gluconic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, malonic acid, malic acid, mandelic acid, isethionic acid, lactobionic acid, succinic acid, 2-naphthalenesulfonic acid, oleic acid, palmitic acid, propionic acid, stearic acid and trimethylacetic acid; organic sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid; and inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and sulfamic acid salts. Examples of pharmaceutically acceptable salts of the hydroxyl group of a compound include appropriate cations, such as Na + and NX4 + Examples of anions of the compound that are combined with (X is independently selected from H or C1-C4 alkyl groups) include salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion, or when it is coordinated with an organic base, such as diethanolamine, triethanolamine, or N-methylglucamine. This definition also includes ammonium and substituted or quaternized ammonium salts. A representative, non-limiting list of pharmaceutically acceptable salts can be found in S.M. Berge et al., J. These can be found in Pharma Sci., Vol. 66 (No. 1), pp. 1-19 (1977), and Remington: The Science and Practice of Pharmacy, edited by R. Hendrickson, 21st edition, Lippincott, Williams & Wilkins, Philadelphia, PA, (2005), p. 732, Table 38-5, and both of these references are incorporated herein by reference.

[0057] For therapeutic use, salts of the active ingredients of the compounds disclosed herein are typically salts derived from pharmaceutically acceptable, i.e., physiologically acceptable acids or bases. However, salts of pharmaceutically unacceptable acids or bases may also be useful, for example, in the preparation or purification of the compounds of formula I or other compounds disclosed herein. Any salt, whether or not it is derived from a physiologically acceptable acid or base, is included within the scope of the present invention.

[0058] Metal salts are typically prepared by the reaction of a metal hydroxide with a compound disclosed herein. An example of a metal salt prepared in this way is Li + na + and K + It is a salt containing [a specific substance]. Less soluble metal salts can be precipitated from solutions of more soluble salts by adding a suitable metal compound.

[0059] Furthermore, salts can be formed by acid addition of certain organic and inorganic acids, such as HCl, HBr, H2SO4, H3PO4, or organic sulfonic acids, to a base center, such as an amine. Finally, it should be understood that the compositions herein contain the compounds disclosed herein in their non-ionized forms, as well as their zwitterionic forms and in combination with stoichiometric amounts of water, such as hydrates.

[0060] Often, crystallization produces solvates of the compounds of the present invention. As used herein, the term “solvate” refers to an aggregate comprising one or more molecules of the compound of the present invention and one or more molecules of a solvent. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present invention may exist as hydrates, including monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, etc., and as corresponding solvated forms. The compounds of the present invention may be true solvates, while in other cases, the compounds of the present invention may simply retain incidental water, or be a mixture of water and some incidental solvent.

[0061] Isotopes The present invention also relates to any or all atoms, and to one or more isotopes in proportion to naturally occurring isotopic ratios, for example, deuterium (but is not limited to) 2 Those skilled in the art will understand that the claimed compounds may be enriched with H or D. In a non-limiting example, in certain embodiments, the -CH3 group is replaced with -CD3.

[0062] The specific values ​​listed below with respect to the radicals, substituents, and ranges of embodiments of the present invention are for illustrative purposes only and do not exclude other values ​​defined for radicals and substituents, or other values ​​that fall within the ranges defined for them.

[0063] Compound of formula I The specific group of compounds of formula I is the compound of formula Ia. [ka] Or a pharmaceutically acceptable salt thereof.

[0064] Another specific group of compounds of formula I is the compounds of formula Ib. [ka] Or a pharmaceutically acceptable salt thereof.

[0065] Another specific group of compounds of formula I is the compounds of formula Ic. [ka] Or a pharmaceutically acceptable salt thereof.

[0066] Another specific group of compounds of formula I is the compounds of formula Id. [ka] Or a pharmaceutically acceptable salt thereof.

[0067] Another specific group of compounds of formula I is the compounds of formula Ie. [ka] Or a pharmaceutically acceptable salt thereof.

[0068] Another specific group of compounds of formula I is the compounds of formula If. [ka] Or a pharmaceutically acceptable salt thereof.

[0069] Another specific group of compounds of formula I is the compounds of formula Ig. [ka] Or a pharmaceutically acceptable salt thereof.

[0070] The specific values ​​listed below pertain to compounds of formula I and all related formulas (e.g., formulas Ia, Ib, Ic, Id, Ie, If, Ig). It should be understood that two or more values ​​can be combined. Therefore, any variable in a compound of formula I can be combined with any other variable in a compound of formula I, just as if each combination of variables were specifically listed individually. For example, R, which is detailed herein for compounds of formula I... 1 Any specific value of can be any combination of variables A and Z, just as if each combination were specifically listed individually. 1 , R 2 , R 3a or R 3b It is understood that it can be combined with one or more other specific values.

[0071] The specific values ​​listed for compounds of formula I can be applied equally to compounds of formula III and all related formulas (e.g., formulas IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIi, IIIj, and IIIk), where applicable. For example, the specific value of ring A in formula I can be applied equally to ring A in formula III, provided that ring A in formula III encompasses the specific value within its range. Furthermore, any combination of variables in a compound of formula I can be understood to be applied equally to compounds of formula III and all related formulas (e.g., formulas IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIi, IIIj, and IIIk), where applicable, as if each combination were specifically listed individually. For example, rings A and Z 1 The specific value of is AZ in Equation III. 1 Under the condition that the range of the part includes specific values, the AZ of Equation III 1 It can be applied equally to the parts.

[0072] The specific group of compounds of formula I is R 3a and R 3b Each of these compounds is independently selected from H, halogen, (C1-C3) alkyl, and (C1-C3) haloalkyl.

[0073] The specific group of compounds of formula I is R 3a and R 3b Each of these compounds is independently selected from H, (C1-C3) alkyl, and (C1-C3) haloalkyl.

[0074] The specific group of compounds of formula I is R 3a and R 3b Each of them independently, H and (C1~C 3) A compound selected from alkyl groups.

[0075] The specific group of compounds of formula I is R 3a and R 3b Each of these is an independent compound selected from H, methyl, and ethyl.

[0076] The specific group of compounds of formula I is R 3a and R 3b Each of these compounds is independently selected from H and methyl.

[0077] The specific group of compounds of formula I is R 3a H is R 3b It is a compound in which (C1-C3) alkyl.

[0078] The specific group of compounds of formula I is R 3a H is R 3b It is a compound in which the parent molecule is methyl or ethyl.

[0079] The specific group of compounds of formula I is R 3a H is R 3b It is a compound in which methyl is present.

[0080] R 3a and R 3b The specific value of is H.

[0081] R 2 The specific value is phenyl or a 5-membered monocyclic heteroaryl, R 2 Any phenyl or 5-membered monocyclic heteroaryl can be one or more (e.g., 1, 2, 3, 4, or 5) Z 5 It is optionally substituted in the base.

[0082] R 2 The specific value is phenyl or a 5-membered monocyclic heteroaryl, R 2 Any phenyl or 5-membered monocyclic heteroaryl can be one or more (e.g., 1, 2, 3, 4, or 5) Z 5 It is substituted with the base.

[0083] R 2 The specific value of is one or more (e.g., 1, 2, 3, 4, or 5) Z 5 This is a phenyl compound that is optionally substituted with a group.

[0084] R 2 The specific value of is one or more (e.g., 1, 2, 3, 4, or 5) Z 5 It is a phenyl compound substituted with a group.

[0085] Z 5 The specific value is halogen.

[0086] Z 5 The specific value is fluoro.

[0087] R 2 The specific value is 3,5-difluorophenyl.

[0088] The specific values ​​of A are pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and any pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl of A has one Z at the indicated position. 1 Substituted with a base, and one Z 2Substituted with a base, and one or more (e.g., one or two) Z 3 It is optionally substituted in the base.

[0089] The specific values ​​of A are pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and any pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl of A has one Z at the indicated position. 1 Substituted with a base, and one Z 2 It is substituted with the base.

[0090] The specific value of A is pyridinyl, and any pyridinyl in A has one Z at the indicated position. 1 Substituted with a base, and one Z 2 Substituted by the base, and one or Multiple (e.g., one or two) Z 3 It is optionally substituted in the base.

[0091] The specific value of A is pyridinyl, and any pyridinyl in A has one Z at the indicated position. 1 Substituted with a base, and one Z 2 It is substituted with the base.

[0092] The specific value of A is, [ka] Selected from, each Z 3a These are H and Z independently. 3 Selected from.

[0093] The specific value of A is, [ka] Selected from, each Z 3a These are H and Z independently. 3 Selected from.

[0094] The specific value of A is, [ka] Selected from, each Z 3a These are H and Z independently. 3 Selected from.

[0095] The specific value of A is, [ka] And each Z 3a These are H and Z independently. 3 Selected from.

[0096] The specific value of A is, [ka] And each Z 3a These are H and Z independently. 3 Selected from.

[0097] The specific value of A is, [ka] And each Z 3a These are H and Z independently. 3 Selected from.

[0098] Z 3a The specific value of is H.

[0099] Z 1 The specific values ​​are selected from phenyl, 5-14 membered heteroaryls, and 3-14 membered heterocycles, Z 1Any phenyl, 5-14 membered heteroaryl, and 3-14 membered heterocycle can have one or more (e.g., 1, 2, 3, 4, or 5) Z 1a or Z 1b It is optionally substituted in the base.

[0100] Z 1 The specific value of Z is selected from phenyl, 5-12 membered heteroaryls, and 3-12 membered heterocycles. 1 Any phenyl, 5-12 membered heteroaryl, and 3-12 membered heterocycle can have one or more (e.g., 1, 2, 3, 4, or 5) Z 1a or Z 1b It is optionally substituted in the base.

[0101] Z 1 The specific values ​​are selected from phenyl, 5-14 membered heteroaryls, and 3-14 membered heterocycles, Z 1 Any phenyl, 5-14 membered heteroaryl, and 3-14 membered heterocycle can have one or more (e.g., 1, 2, 3, 4, or 5) Z 1a It is optionally substituted in the base.

[0102] Z 1 The specific values ​​are selected from phenyl, 5-12 membered heteroaryls, and 3-12 membered heterocycles, Z 1 Any phenyl, 5-12 membered heteroaryl, and 3-12 membered heterocycle can have one or more (e.g., 1, 2, 3, 4, or 5) Z 1a It is optionally substituted in the base.

[0103] Z 1 The specific values ​​are selected from phenyl, 5-6 member monocyclic heteroaryls, 8-10 member bicyclic heteroaryls, 8-10 member bicyclic heterocycles, and 9-12 member tricyclic heterocycles, Z 1 Any phenyl, 5-6 member monocyclic heteroaryl, 8-10 member bicyclic heteroaryl, 8-10 member bicyclic heterocycle, and 9-12 member tricyclic heterocycle may have one or more (e.g., 1, 2, 3, 4, or 5) Z 1a or Z1b It is optionally substituted in the base.

[0104] Z 1 The specific values ​​are selected from phenyl, 5-6 member monocyclic heteroaryls, 8-10 member bicyclic heteroaryls, 8-10 member bicyclic heterocycles, and 9-12 member tricyclic heterocycles, Z 1 Any phenyl, 5-6 member monocyclic heteroaryl, 8-10 member bicyclic heteroaryl, 8-10 member bicyclic heterocycle, and 9-12 member tricyclic heterocycle may have one or more (e.g., 1, 2, 3, 4, or 5) Z 1a It is optionally substituted in the base.

[0105] Z 1 The specific values ​​are selected from phenyl, 5-6 membered monocyclic heteroaryls, 8-10 membered bicyclic heteroaryls, 8-10 membered bicyclic heterocycles, and 9-12 membered tricyclic heterocycles, and the 5-6 membered monocyclic heteroaryls, 8-10 membered bicyclic heteroaryls, 8-10 membered bicyclic heterocycles, and 9-12 membered tricyclic heterocycles have 1-11 carbon atoms and 1-5 heteroatoms in the ring system, Z 1 Any phenyl, 5-6 member monocyclic heteroaryl, 8-10 member bicyclic heteroaryl, 8-10 member bicyclic heterocycle, and 9-12 member tricyclic heterocycle may have one or more (e.g., 1, 2, 3, 4, or 5) Z 1a or Z 1b It is optionally substituted in the base.

[0106] Z 1 The specific values ​​are selected from phenyl, 5-6 membered monocyclic heteroaryls, 8-10 membered bicyclic heteroaryls, 8-10 membered bicyclic heterocycles, and 9-12 membered tricyclic heterocycles, and the 5-6 membered monocyclic heteroaryls, 8-10 membered bicyclic heteroaryls, 8-10 membered bicyclic heterocycles, and 9-12 membered tricyclic heterocycles have 1-11 carbon atoms and 1-5 heteroatoms in the ring system, Z 1Any phenyl, 5-6 member monocyclic heteroaryl, 8-10 member bicyclic heteroaryl, 8-10 member bicyclic heterocycle, and 9-12 member tricyclic heterocycle may have one or more (e.g., 1, 2, 3, 4, or 5) Z 1a It is optionally substituted in the base.

[0107] Z 1 The specific value is selected from phenyl, 5-6 member monocyclic heteroaryls, 8-10 member bicyclic heteroaryls, 8-10 member bicyclic heterocycles, and 9-12 member tricyclic heterocycles. Furthermore, monocyclic heteroaryls with 5-6 members, bicyclic heteroaryls with 8-10 members, bicyclic heterocycles with 8-10 members, and tricyclic heterocycles with 9-12 members have 4-11 carbon atoms and 1-3 heteroatoms in the ring system, Z 1 Any phenyl, 5-6 member monocyclic heteroaryl, 8-10 member bicyclic heteroaryl, 8-10 member bicyclic heterocycle, and 9-12 member tricyclic heterocycle may have one or more (e.g., 1, 2, 3, 4, or 5) Z 1a or Z 1b It is optionally substituted in the base.

[0108] Z 1 The specific values ​​are selected from phenyl, 5-6 membered monocyclic heteroaryls, 8-10 membered bicyclic heteroaryls, 8-10 membered bicyclic heterocycles, and 9-12 membered tricyclic heterocycles, and the 5-6 membered monocyclic heteroaryls, 8-10 membered bicyclic heteroaryls, 8-10 membered bicyclic heterocycles, and 9-12 membered tricyclic heterocycles have 4-11 carbon atoms and 1-3 heteroatoms in the ring system, Z 1 Any phenyl, 5-6 member monocyclic heteroaryl, 8-10 member bicyclic heteroaryl, 8-10 member bicyclic heterocycle, and 9-12 member tricyclic heterocycle may have one or more (e.g., 1, 2, 3, 4, or 5) Z 1a It is optionally substituted in the base.

[0109] Z 1 The specific value of Z is selected from 8-10 membered bicyclic heteroaryls and 8-10 membered bicyclic heterocycles.1 Any 8-10 member bicyclic heteroaryl and 8-10 member bicyclic heterocyclic rings may have one or more Z 1a or Z 1b It is optionally substituted in the base.

[0110] Z 1 The specific value of Z is selected from 8-10 membered bicyclic heteroaryls and 8-10 membered bicyclic heterocycles. 1 Any 8-10 member bicyclic heteroaryl and 8-10 member bicyclic heterocyclic rings may have one or more Z 1a It is optionally substituted in the base.

[0111] Z 1 The specific value is selected from 8-10 membered bicyclic heteroaryls and 8-10 membered bicyclic heterocycles, which have 3-9 carbon atoms and 1-5 heteroatoms in the ring system, Z 1 Any 8-10 member bicyclic heteroaryl and 8-10 member bicyclic heterocyclic rings may have one or more Z 1a or Z 1b It is optionally substituted in the base.

[0112] Z 1 The specific value is selected from 8-10 membered bicyclic heteroaryls and 8-10 membered bicyclic heterocycles, which have 3-9 carbon atoms and 1-5 heteroatoms in the ring system, Z 1 Any 8-10 member bicyclic heteroaryl and 8-10 member bicyclic heterocyclic rings may have one or more Z 1a It is optionally substituted in the base.

[0113] Z 1The specific values ​​are selected from phenyl, 1H-pyrrolo[2,3-b]pyridinyl, 1-oxoisoindolinyl, 4-oxo-3,4-dihydroquinazolinyl, 3-oxospiro[cyclopropane-1,1'-isoindolin]-yl, 1H-2-oxopyridinyl, and 2,4-dioxo-1,2,3,4-tetrahydroquinazolinyl, Z 1 Any phenyl, 1H-pyrrolo[2,3-b]pyridinyl, 1-oxoisoindolinyl, 4-oxo-3,4-dihydroquinazolinyl, 3-oxospiro[cyclopropane-1,1'-isoindolin]-yl, 1H-2-oxopyridinyl, and 2,4-dioxo-1,2,3,4-tetrahydroquinazolinyl can be one or more (e.g., 1, 2, 3, 4, or 5) Z 1a or Z 1b It is arbitrarily substituted at the base. Z 1 The specific value is 1H-indazole-7-yl, Z 1 is one or more Z 1a or Z 1b It is optionally substituted in the base.

[0114] Z 1 The specific value is selected from phenyl, 1H-pyrrolo[2,3-b]pyridinyl, 1-oxoisoindolinyl, 4-oxo-3,4-dihydroquinazolinyl, 3-oxospiro[cyclopropane-1,1'-isoindolin]-yl, 1H-2-oxopyridinyl, and 2,4-dioxo-1,2,3,4-tetrahydroquinazolinyl, as shown by the following formula. [ka] Z 1Any phenyl, 1H-pyrrolo[2,3-b]pyridinyl, 1-oxoisoindolinyl, 4-oxo-3,4-dihydroquinazolinyl, 3-oxospiro[cyclopropane-1,1'-isoindolin]-yl, 1H-2-oxopyridinyl, and 2,4-dioxo-1,2,3,4-tetrahydroquinazolinyl can be one or more (e.g., 1, 2, 3, 4, or 5) Z 1a or Z 1b It is arbitrarily substituted at the base. Z 1 The specific value is, [ka] Z 1 The specific value is, [ka] That is the case.

[0115] Z 1 The specific values ​​are selected from phenyl, 1H-pyrrolo[2,3-b]pyridinyl, 1-oxoisoindolinyl, 3-oxospiro[cyclopropane-1,1'-isoindolin]-yl, pyridinyl, and quinazolinyl, Z 1 Any phenyl, 1H-pyrrolo[2,3-b]pyridinyl, 1-oxoisoindolinyl, 3-oxospiro[cyclopropane-1,1'-isoindolin]-yl, pyridinyl, and quinazolinyl may be one or more (e.g., 1, 2, 3, 4, or 5) Z 1a or Z 1b It is optionally substituted in the base.

[0116] Z 1The specific values ​​are selected from phenyl, 1H-pyrrolo[2,3-b]pyridinyl, 1-oxoisoindolinyl, 4-oxo-3,4-dihydroquinazolinyl, 3-oxospiro[cyclopropane-1,1'-isoindolin]-yl, 1H-2-oxopyridinyl and 2,4-dioxo-1,2,3,4-tetrahydroquinazolinyl, Z 1 Any phenyl, 1H-pyrrolo[2,3-b]pyridinyl, 1-oxoisoindolinyl, 4-oxo-3,4-dihydroquinazolinyl, 3-oxospiro[cyclopropane-1,1'-isoindolin]-yl, 1H-2-oxopyridinyl, and 2,4-dioxo-1,2,3,4-tetrahydroquinazolinyl can be one or more (e.g., 1, 2, 3, 4, or 5) Z 1a It is optionally substituted in the base.

[0117] Z 1 The specific values ​​are selected from phenyl, 1H-pyrrolo[2,3-b]pyridinyl, 1-oxoisoindolinyl, 3-oxospiro[cyclopropane-1,1'-isoindolin]-yl, pyridinyl, and quinazolinyl, Z 1 Any phenyl, 1H-pyrrolo[2,3-b]pyridinyl, 1-oxoisoindolinyl, 3-oxospiro[cyclopropane-1,1'-isoindolin]-yl, pyridinyl, and quinazolinyl may be one or more (e.g., 1, 2, 3, 4, or 5) Z 1a It is optionally substituted in the base.

[0118] Z 1 The specific values ​​are selected from phenyl, 1H-pyrrolo[2,3-b]pyridine-5-yl, 1-oxoisoindoline-5-yl, 1-oxoisoindoline-4-yl, 4-oxo-3,4-dihydroquinazoline-8-yl, 3'-oxospiro[cyclopropane-1,1'-isoindoline]-5'-yl, 1H-2-oxopyridine-4-yl and 2,4-dioxo-1,2,3,4-tetrahydroquinazoline-8-yl, Z 1Any phenyl, 1H-pyrrolo[2,3-b]pyridine-5-yl, 1-oxoisoindorin-5-yl, 1-oxoisoindorin-4-yl, 4-oxo-3,4-dihydroquinazolin-8-yl, 3'-oxospiro[cyclopropane-1,1'-isoindorin]-5'-yl, 1H-2-oxopyridine-4-yl and 2,4-dioxo-1,2,3,4-tetrahydroquinazolin-8-yl may be one or more (e.g., 1, 2, 3, 4 or 5) Z 1a or Z 1b It is optionally substituted in the base.

[0119] Z 1 The specific values ​​are selected from phenyl, 1H-pyrrolo[2,3-b]pyridine-5-yl, 1-oxoisoindoline-5-yl, 1-oxoisoindoline-4-yl, 3'-oxospiro[cyclopropane-1,1'-isoindoline]-5'-yl, pyridine-4-yl, and quinazoline-8-yl, Z 1 Any phenyl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1-oxoisoindorin-5-yl, 1-oxoisoindorin-4-yl, 3'-oxospiro[cyclopropane-1,1'-isoindorin]-5'-yl, pyridine-4-yl, and quinazolin-8-yl may be one or more (e.g., 1, 2, 3, 4, or 5) Z 1a or Z 1b It is optionally substituted in the base.

[0120] Z 1 The specific value is given by the following formula: phenyl, 1H-pyrrolo[2,3-b] Selected from lysine-5-yl, 1-oxoisoindoline-5-yl, 1-oxoisoindoline-4-yl, 4-oxo-3,4-dihydroquinazoline-8-yl, 3'-oxospiro[cyclopropane-1,1'-isoindoline]-5'-yl, 1H-2-oxopyridine-4-yl and 2,4-dioxo-1,2,3,4-tetrahydroquinazoline-8-yl, [ka] Z 1 Any phenyl, 1H-pyrrolo[2,3-b]pyridine-5-yl, 1-oxoisoindorin-5-yl, 1-oxoisoindorin-4-yl, 4-oxo-3,4-dihydroquinazolin-8-yl, 3'-oxospiro[cyclopropane-1,1'-isoindorin]-5'-yl, 1H-2-oxopyridine-4-yl and 2,4-dioxo-1,2,3,4-tetrahydroquinazolin-8-yl may be one or more (e.g., 1, 2, 3, 4 or 5) Z 1a or Z 1b It is arbitrarily substituted at the base. Z 1 The specific value is, [ka] Z 1 The specific value is, [ka] That is the case.

[0121] Z 1 The specific values ​​are selected from phenyl, 1H-pyrrolo[2,3-b]pyridine-5-yl, 1-oxoisoindoline-5-yl, 1-oxoisoindoline-4-yl, 4-oxo-3,4-dihydroquinazoline-8-yl, 3'-oxospiro[cyclopropane-1,1'-isoindoline]-5'-yl, 1H-2-oxopyridine-4-yl and 2,4-dioxo-1,2,3,4-tetrahydroquinazoline-8-yl, Z 1Any phenyl, 1H-pyrrolo[2,3-b]pyridine-5-yl, 1-oxoisoindorin-5-yl, 1-oxoisoindorin-4-yl, 4-oxo-3,4-dihydroquinazolin-8-yl, 3'-oxospiro[cyclopropane-1,1'-isoindorin]-5'-yl, 1H-2-oxopyridine-4-yl and 2,4-dioxo-1,2,3,4-tetrahydroquinazolin-8-yl may be one or more (e.g., 1, 2, 3, 4 or 5) Z 1a It is optionally substituted in the base.

[0122] Z 1 The specific values ​​are selected from phenyl, 1H-pyrrolo[2,3-b]pyridine-5-yl, 1-oxoisoindoline-5-yl, 1-oxoisoindoline-4-yl, 3'-oxospiro[cyclopropane-1,1'-isoindoline]-5'-yl, pyridine-4-yl, and quinazoline-8-yl, Z 1 Any phenyl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1-oxoisoindorin-5-yl, 1-oxoisoindorin-4-yl, 3'-oxospiro[cyclopropane-1,1'-isoindorin]-5'-yl, pyridine-4-yl, and quinazolin-8-yl may be one or more (e.g., 1, 2, 3, 4, or 5) Z 1a It is optionally substituted in the base.

[0123] The specific group of compounds of formula I is Z 1 However, Z 1b It is a compound that is not substituted with [a specific compound].

[0124] each Z 1a The specific values ​​are, independently, halogen, -OR n1 and -C(O)NR q1 R r1 Selected from.

[0125] each Z 1a The specific values ​​are, independently, halogen and -C(O)NR q1 R r1 Selected from.

[0126] Each R n1 , each R q1 and each R r1 The specific values ​​for each are H.

[0127] each Z 1a The specific values ​​are independently selected from halogens, -OH, and -C(O)NH2.

[0128] each Z 1a The specific values ​​are independently selected from fluoro, -OH, and -C(O)NH2.

[0129] R q1 and R r1 The specific value of is H.

[0130] each Z 1a The specific values ​​are, independently, halogen and -NR n1 S(O)2R p1 Selected from.

[0131] each Z 1b The specific values ​​of are alkyl groups (C1-C8) which may be the same or different.

[0132] In a particular embodiment, each Z 1a These are, independently, halogen and -NR n1 S(O)2R p1 Selected from, each Z 1b These are alkyl groups (C1-C8) that may be the same or different.

[0133] Z 1 The specific value is, [ka] Selected from.

[0134] Z 1 The specific value is, [ka] Z 1 The specific value is, [ka] That is the case.

[0135] Z 2 The specific values ​​are (C2~C8) alkynyls, 6~12 membered aryls, 5~12 membered C-linked heteroaryls, 3~12 membered C-linked heterocycles, and -C(O)NR q3 R r3 Selected from, Z 2 Any 6-12 member aryl, 5-12 member C-linked heteroaryl, and 3-12 member C-linked heteroring can be one or more (e.g., 1, 2, 3, 4, or 5) Z 2b or Z 2c It is optionally substituted in the base, Z 2 Any (C2-C8) alkynnyl can be one or more (e.g., 1, 2, 3, 4, or 5) Z 2c It is optionally substituted in the base.

[0136] Z 2 The specific values ​​are (C2~C8) alkynyl, 6~12 member aryl, 5~12 member C-linked heteroaryls, 3-12 membered C-linked heterocycles, and -C(O)NR q3 R r3 Selected from, Z 2 Any 6-12 member aryl, 5-12 member C-linked heteroaryl, and 3-12 member C-linked heteroring can be one or more (e.g., 1, 2, 3, 4, or 5) Z 2c It is optionally substituted in the base, Z 2 Any (C2-C8) alkynnyl can be one or more (e.g., 1, 2, 3, 4, or 5) Z 2c It is optionally substituted in the base.

[0137] Z 2 The specific values ​​are (C2~C8) alkynyl, phenyl, 5~6 member C-linked monocyclic heteroaryl, 8~10 member C-linked bicyclic heteroaryl, 8~10 member C-linked bicyclic heterocycle and -C(O)NR q3 R r3 Selected from, Z 2 Any phenyl, 5-6 member C-linked monocyclic heteroaryl, 8-10 member C-linked bicyclic heteroaryl, and 8-10 member C-linked bicyclic heterocycle may have one or more (e.g., 1, 2, 3, 4, or 5) Z 2b or Z 2c It is optionally substituted in the base, Z 2 Any (C2-C8) alkynnyl can be one or more (e.g., 1, 2, 3, 4, or 5) Z 2c It is optionally substituted in the base.

[0138] Z 2 The specific values ​​are (C2~C8) alkynyl, phenyl, 5~6 member C-linked monocyclic heteroaryl, 8~10 member C-linked bicyclic heteroaryl, 8~10 member C-linked bicyclic heterocycle and -C(O)NR q3 R r3 Selected from, Z 2 Any phenyl, 5-6 member C-linked monocyclic heteroaryl, 8-10 member C-linked bicyclic heteroaryl, and 8-10 member C-linked bicyclic heterocycle may have one or more (e.g., 1, 2, 3, 4, or 5) Z 2c It is optionally substituted in the base, Z 2 Any (C2-C8) alkynnyl can be one or more (e.g., 1, 2, 3, 4, or 5) Z 2c It is optionally substituted in the base.

[0139] Z 2 The specific values ​​are (C2~C8) alkynyl, phenyl, 5~6 member C-linked monocyclic heteroaryl, 8~10 member C-linked bicyclic heteroaryl, 8~10 member C-linked bicyclic heterocycle and -C(O)NR q3 R r3Selected from, 5-6 member C-linked monocyclic heteroaryls, 8-10 member C-linked bicyclic heteroaryls, and 8-10 member C-linked bicyclic heterocycles have 1-9 carbon atoms and 1-4 heteroatoms in the ring system, Z 2 Any phenyl, 5-6 member C-linked monocyclic heteroaryl, 8-10 member C-linked bicyclic heteroaryl, and 8-10 member C-linked bicyclic heterocycle may have one or more (e.g., 1, 2, 3, 4, or 5) Z 2b or Z 2c It is optionally substituted in the base, Z 2 Any (C2-C8) alkynnyl can be one or more (e.g., 1, 2, 3, 4, or 5) Z 2c It is optionally substituted in the base.

[0140] Z 2 The specific values ​​are (C2~C8) alkynyl, phenyl, 5~6 member C-linked monocyclic heteroaryl, 8~10 member C-linked bicyclic heteroaryl, 8~10 member C-linked bicyclic heterocycle and -C(O)NR q3 R r3 Selected from, 5-6 member C-linked monocyclic heteroaryls, 8-10 member C-linked bicyclic heteroaryls, and 8-10 member C-linked bicyclic heterocycles have 1-9 carbon atoms and 1-4 heteroatoms in the ring system, Z 2 Any phenyl, 5-6 member C-linked monocyclic heteroaryl, 8-10 member C-linked bicyclic heteroaryl, and 8-10 member C-linked bicyclic heterocycle may have one or more (e.g., 1, 2, 3, 4, or 5) Z 2c It is optionally substituted in the base, Z 2 Any (C2-C8) alkynnyl can be one or more (e.g., 1, 2, 3, 4, or 5) Z 2c It is optionally substituted in the base.

[0141] Z 2 The specific values ​​are 4-methylpentynyl, phenyl, pyridinyl, 1H-2-oxopyridinyl, triazolyl, 1-oxoisoindlinyl, 1H-pyrrolo[2,3-b]pyridinyl, and -C(O)NR q3 Rr3 is selected from, and Z 2 any phenyl, pyridinyl, 1H-2-oxo-pyridinyl, triazolyl, 1-oxoisoindolinyl and 1H-pyrrolo[2,3-b]pyridinyl are each optionally substituted with one or more (for example, 1, 2, 3, 4 or 5) Z 2b or Z 2c groups, and any 4-methylpentynyl of Z 2 is optionally substituted with one or more (for example, 1, 2, 3, 4 or 5) Z 2c groups.

[0142] Z 2 specific values are selected from 4-methylpentynyl, phenyl, pyridinyl, 1H-2-oxo-pyridinyl, triazolyl, 1-oxoisoindolinyl, 1H-pyrrolo[2,3-b]pyridinyl and -C(O)NR q3 R r3 is selected from, and Z 2 any phenyl, pyridinyl, 2-oxopyridinyl, triazolyl, 1-oxoisoindolinyl and 1H-pyrrolo[2,3-b]pyridinyl are each optionally substituted with one or more (for example, 1, 2, 3, 4 or 5) Z 2c groups, and any 4-methylpentynyl of Z 2 is optionally substituted with one or more (for example, 1, 2, 3, 4 or 5) Z 2c groups.

[0143] Z 2 specific values are selected from 4-methylpentyn-1-yl, phenyl, pyridin-4-yl, 1H-2-oxo-pyridin-2-yl, triazol-4-yl, 1-oxoisoindolin-6-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl and -C(O)NR q3 R r3 is selected from, and Z 2Any phenyl, pyridin-4-yl, 1H-2-oxo-pyridin-2-yl, triazol-4-yl, 1-oxoisoindoline-6-yl and 1H-pyrrolo[2,3-b]pyridin-5-yl is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z 2b or Z 2c groups, and any 4-methylpentyn-1-yl of Z 2 is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z 2c groups.

[0144] Z 2 specific values are selected from 4-methylpentyn-1-yl, phenyl, pyridin-4-yl, 1H-2-oxo-pyridin-2-yl, triazol-4-yl, 1-oxoisoindoline-6-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl and -C(O)NR q3 R r3 , and any phenyl, pyridin-4-yl, 1H-2-oxo-pyridin-2-yl, triazol-4-yl, 1-oxoisoindoline-6-yl and 1H-pyrrolo[2,3-b]pyridin-5-yl of Z 2 is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z 2c groups, and any 4-methylpentyn-1-yl of Z 2 is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z 2c groups.

[0145] A specific group of compounds of formula I is compounds wherein each Z 2 is unsubstituted with Z 2b .

[0146] A specific group of compounds of formula I is compounds wherein each Z 2 is optionally substituted with one or more Z 2c groups.

[0147] each Z 2cThe specific values ​​are, independently, halogen, -OR n4 and -C(O)NR q4 R r4 Selected from.

[0148] The specific group of compounds of formula I is R n4 However, it is H or methyl, and R q4 and R r4 However, each of these compounds is H.

[0149] R n4 The specific value is either H or methyl.

[0150] Each R q4 and each R r4 The specific value of is H.

[0151] Z 2 The specific value is, [ka] Selected from.

[0152] AZ 1 The specific value is, [ka] [ka] Selected from.

[0153] AZ 1 The specific value is, [ka] Selected from.

[0154] R 1 The specific values ​​are 5-12 member heteroaryls, and R 1 Any 5 to 12 members A heteroaryl is one or more (e.g., 1, 2, 3, 4, or 5) Z 4 It is optionally substituted in the base.

[0155] R 1 The specific values ​​are 8-12 member bicyclic heteroaryls or 8-12 member tricyclic heteroaryls, and R 1 Any 8-12 member bicyclic heteroaryl or 8-12 member tricyclic heteroaryl can be one or more (e.g., 1, 2, 3, 4, or 5) Z 4 It is optionally substituted in the base.

[0156] R 1 The specific values ​​are 8-12 membered bicyclic heteroaryls or 8-12 membered tricyclic heteroaryls, and 8-12 membered bicyclic heteroaryls or 8-12 membered tricyclic heteroaryls have 4-10 carbon atoms and 1-5 heteroatoms in the ring system, R 1 Any 8-12 member bicyclic heteroaryl or 8-12 member tricyclic heteroaryl can be one or more (e.g., 1, 2, 3, 4, or 5) Z 4 It is optionally substituted in the base.

[0157] R 1 The specific value is an 8-12 member bicyclic heteroaryl or an 8-12 member tricyclic heteroaryl, and the 8-12 member bicyclic heteroaryl or the 8-12 member tricyclic heteroaryl contains at least one partially unsaturated ring, R 1 Any 8-12 member bicyclic heteroaryl or 8-12 member tricyclic heteroaryl can be one or more (e.g., 1, 2, 3, 4, or 5) Z 4 It is optionally substituted in the base.

[0158] R 1The specific value of has the following equation IIa [ka] [In the formula, C, together with the two carbon atoms of the bonded ring B, forms a 3- to 7-membered monocyclic carbon ring, a 5- to 8-membered bicyclic carbon ring, a 3- to 7-membered monocyclic heterocycle, or a 5- to 8-membered bicyclic heterocycle, and any 3- to 7-membered monocyclic carbon ring, 5- to 8-membered bicyclic carbon ring, 3- to 7-membered monocyclic heterocycle, or 5- to 8-membered bicyclic heterocycle of C, one or more (e.g., 1, 2, 3, 4, or 5) Z 4 It is optionally substituted in the base, B is a 5- or 6-membered monocyclic heteroaryl having 1, 2, or 3 nitrogen atoms, and B has one or more (e.g., 1, 2, 3, 4, or 5) Z atoms. 4 [It is optionally substituted in the base.]

[0159] R 1 The specific values ​​of have the following IIb [ka] [In the formula, C, together with the two carbon atoms of the bonded ring B, forms a 3- to 7-membered monocyclic carbon ring, a 5- to 8-membered bicyclic carbon ring, a 3- to 7-membered monocyclic heterocycle, or a 5- to 8-membered bicyclic heterocycle, and any 3- to 7-membered monocyclic carbon ring, 5- to 8-membered bicyclic carbon ring, 3- to 7-membered monocyclic heterocycle, or 5- to 8-membered bicyclic heterocycle of C, one or more (e.g., 1, 2, 3, 4, or 5) Z 4 It is optionally substituted in the base, B is a 5-membered or 6-membered monocyclic heteroaryl having 1, 2, or 3 nitrogen atoms. V is either C or N, W is CZ 4c , NZ 4c or N, X is CZ 4c, NZ 4c or N, Y is CZ 4c Or it is N, or it does not exist. The dashed bonds are selected from single and double bonds, and the dashed bonds V, W, X, and Y are selected so that a 5-membered or 6-membered monocyclic heteroaryl B becomes aromatic. each Z 4c These are, independently, H or Z 4 [Selected from].

[0160] R 1 The specific value of has the following equation IIc [ka] [In the formula, C, together with the two carbon atoms of the bonded ring B, forms a 3- to 7-membered monocyclic carbon ring, a 5- to 8-membered bicyclic carbon ring, a 3- to 7-membered monocyclic heterocycle, or a 5- to 8-membered bicyclic heterocycle, and any 3- to 7-membered monocyclic carbon ring, 5- to 8-membered bicyclic carbon ring, 3- to 7-membered monocyclic heterocycle, or 5- to 8-membered bicyclic heterocycle of C, one or more (e.g., 1, 2, 3, 4, or 5) Z 4 It is optionally substituted in the base, B is a 5-membered or 6-membered monocyclic heteroaryl having 1, 2, or 3 nitrogen atoms. V is either C or N, W is CZ 4c or N, X is CZ 4c , NZ 4c or N, Y is CZ 4c Or it is N, or it does not exist. The dashed bonds are selected from single and double bonds, and the dashed bonds V, W, X, and Y are selected so that a 5-membered or 6-membered monocyclic heteroaryl B becomes aromatic. each Z 4c These are, independently, H or Z 4 [Selected from].

[0161] R 1 The specific value of has the following equation IId [ka] [In the formula, C, together with two bonded carbon atoms, forms a 3-7 member monocyclic carbon ring, a 5-9 member bicyclic carbon ring, a 3-7 member monocyclic heterocycle, or a 5-9 member bicyclic heterocycle, and any 3-7 member monocyclic carbon ring, 5-9 member bicyclic carbon ring, 3-7 member monocyclic heterocycle, or 5-9 member bicyclic heterocycle of C can have one or more (e.g., 1, 2, 3, 4, or 5) Z atoms. 4 It is optionally substituted in the base, each Z 4c These are, independently, H or Z 4 [Selected from].

[0162] each Z 4 The specific values ​​of are independently selected from (C1~C6) alkyl and halogen, and Z 4 Any (C1-C6) alkyl group is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) halogens.

[0163] each Z 4 The specific values ​​are independently selected from fluoromethyl, trifluoromethyl, and difluoromethyl.

[0164] R 1 The specific value is, [ka] Selected from.

[0165] R 1 The specific value is, [ka] is selected from.

[0166] R 1 , specific values of are

Chemical

Chemical

[0167] R 1 , specific values of are 8- to 12-membered bicyclic heteroaryl or 8- to 12-membered tricyclic heteroaryl, wherein the 8- to 12-membered bicyclic heteroaryl or 8- to 12-membered tricyclic heteroaryl has 4 to 9 carbon atoms and 1 to 5 heteroatoms in the ring system, and R 1 any 8- to 12-membered bicyclic heteroaryl or 8- to 12-membered tricyclic heteroaryl of is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z 4 groups.

[0168] R 1 , specific values of are 8- to 12-membered bicyclic heteroaryl, wherein the 8- to 12-membered bicyclic heteroaryl has 6 to 9 carbon atoms and 1 to 3 heteroatoms in the ring system, and R 1 any 8- to 12-membered bicyclic heteroaryl of is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z 4 groups.

[0169] R 1The specific values ​​are 8-12 membered bicyclic heteroaryls or 8-12 membered tricyclic heteroaryls, and 8-12 membered bicyclic heteroaryls or 8-12 membered tricyclic heteroaryls have 6-9 carbon atoms and 1-3 heteroatoms in the ring system, R 1 Any 8-12 member bicyclic heteroaryl or 8-12 member tricyclic heteroaryl The letter is one or more (for example, 1, 2, 3, 4, or 5) Z 4 It is optionally substituted in the base.

[0170] R 1 The specific value of is selected from indolyl and 4,5,6,7-tetrahydro-indazolyl, R 1 Any indolyl and 4,5,6,7-tetrahydro-indazolyl may be present in one or more (e.g., 1, 2, 3, 4, or 5) Z 4 It is optionally substituted in the base.

[0171] R 1 The specific values ​​of R are selected from indolyl, 4,5,6,7-tetrahydro-indazolyl, 3b,4,4a,5-tetrahydro-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole and 1,4,5,5a,6,6a-hexahydrocyclopropa[g]indazole, 1 Any indolyl, 4,5,6,7-tetrahydro-indazolyl, 3b,4,4a,5-tetrahydro-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole, and 1,4,5,5a,6,6a-hexahydrocyclopropa[g]indazole may be used in one or more (e.g., 1, 2, 3, 4, or 5) Z 4 It is optionally substituted in the base.

[0172] R 1 The specific value of is selected from indole-3-yl and 4,5,6,7-tetrahydro-1H-indazole-1-yl, R 1Any indole-3-yl and 4,5,6,7-tetrahydro-1H-indazole-1-yl may be one or more (e.g., 1, 2, 3, 4, or 5) Z 4 It is optionally substituted in the base.

[0173] R 1 The specific values ​​are selected from indole-3-yl, 4,5,6,7-tetrahydro-1H-indazole-1-yl, 3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl and 1,4,5,5a,6,6a-hexahydrocyclopropa[g]indazole-1-yl, R 1 Any indole-3-yl, 4,5,6,7-tetrahydro-1H-indazole-1-yl, 3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl and 1,4,5,5a,6,6a-hexahydrocyclopropa[g]indazole-1-yl may be one or more (e.g., 1, 2, 3, 4 or 5) Z 4 It is optionally substituted in the base.

[0174] each Z 4 The specific values ​​of are independently selected from (C1~C6) alkyl and halogen, and Z 4 Any (C1-C6) alkyl group is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) halogens.

[0175] each Z 4 The specific values ​​of are independently selected from (C1~C6) alkyl, -CN, and halogen, and Z 4 Any (C1-C6) alkyl group is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) halogens.

[0176] each Z 4 The specific values ​​are independently selected from fluoromethyl, trifluoromethyl, and difluoromethyl.

[0177] each Z 4 The specific values ​​are independently selected from fluoromethyl, trifluoromethyl, -CN, and difluoromethyl.

[0178] R 1 The specific value is, [ka] Selected from.

[0179] R 1 The specific value is, [ka] Selected from.

[0180] R 1 The specific value is, [ka] Selected from.

[0181] R 1 The specific value is, [ka] That is. R 1 The specific value is, [ka] That is the case.

[0182] In one variation of formula I, A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and R 1These are 1, 2, 3, 4, or 5 Z which may be the same or different. 4 It is a 5- to 12-membered heteroaryl that is optionally substituted with a group. In another variant, A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and R 1 R is an 8-12 member bicyclic heteroaryl or an 8-12 member tricyclic heteroaryl, 1 Any 8-12 member bicyclic heteroaryl or 8-12 member tricyclic heteroaryl can have 1, 2, 3, 4, or 5 Z 4 The base is optionally substituted. In another variant, A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and R 1 R is an 8-12 member bicyclic heteroaryl or an 8-12 member tricyclic heteroaryl, 1 Any 8-12 member bicyclic heteroaryl or 8-12 member tricyclic heteroaryl can have 1, 2, 3, 4, or 5 Z 4 It is arbitrarily substituted at the base, and each Z 4 These are independently fluoromethyl, trifluoromethyl, or difluoromethyl.

[0183] In one variant of formula I, A is pyridinyl, and R 1 R is an 8-12 member bicyclic heteroaryl or an 8-12 member tricyclic heteroaryl, 1 Any 8-12 member bicyclic heteroaryl or 8-12 member tricyclic heteroaryl can have 1, 2, 3, 4, or 5 Z 4 It is optionally substituted in the base.

[0184] In one variation of formula I, A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and R 2 is 3,5-difluorophenyl. In another variant, A is pyridinyl and R 2 is 3,5-difluorophenyl. In another variant, A is pyrimidinyl and R 2 is 3,5-difluorophenyl. In another variant, A is pyrazinyl and R 2is 3,5-difluorophenyl. In another variant, A is pyridazinyl and R 2 It is 3,5-difluorophenyl.

[0185] In one variation of formula I, A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and Z 1 These are phenyl, a 5-6 member monocyclic heteroaryl, an 8-10 member bicyclic heteroaryl, an 8-10 member bicyclic heterocycle, or a 9-12 member tricyclic heterocycle. Ri, Z 1 Any phenyl, 5-6 member monocyclic heteroaryl, 8-10 member bicyclic heteroaryl, 8-10 member bicyclic heterocycle, or 9-12 member tricyclic heterocycle may have 1, 2, 3, 4, or 5 Z 1a The base is optionally substituted. In another variant, A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and Z 1 This is 1, 2, 3, 4 or 5 Z 1a It is a phenyl compound that is optionally substituted with a group. In another variant, A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridadinyl, and Z 1 These are monocyclic heteroaryl compounds with 5-6 members or bicyclic heteroaryl compounds with 8-10 members, and Z 1 Any 5-6 member monocyclic heteroaryl or 8-10 member bicyclic heteroaryl can have 1, 2, 3, 4, or 5 Z 1a The base is optionally substituted. In another variant, A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and Z 1 Z is a biring heteroalgebra with 8 to 10 members or a triring heteroalgebra with 9 to 12 members. 1 Any 8-10 member biring complex or 9-12 member triring complex can be any 1, 2, 3, 4, or 5 Z 1a It is optionally substituted in the base.

[0186] In one variation of formula I, A is pyridinyl, and Z 1Z is a phenyl molecule, a 5-6 member monocyclic heteroaryl molecule, an 8-10 member bicyclic heteroaryl molecule, an 8-10 member bicyclic heterocycle, or a 9-12 member tricyclic heterocycle. 1 Any phenyl, 5-6 member monocyclic heteroaryl, 8-10 member bicyclic heteroaryl, 8-10 member bicyclic heterocycle, or 9-12 member tricyclic heterocycle may have 1, 2, 3, 4, or 5 Z 1a It is optionally substituted at the base. In another variant, A is pyridinyl and Z 1 This is 1, 2, 3, 4 or 5 Z 1a It is a phenyl compound that is optionally substituted with a group. In another variant, A is pyridinyl and Z 1 These are monocyclic heteroaryl compounds with 5-6 members or bicyclic heteroaryl compounds with 8-10 members, and Z 1 Any 5-6 member monocyclic heteroaryl or 8-10 member bicyclic heteroaryl can have 1, 2, 3, 4, or 5 Z 1a It is optionally substituted at the base. In another variant, A is pyridinyl and Z 1 Z is a biring heteroalgebra with 8 to 10 members or a triring heteroalgebra with 9 to 12 members. 1 Any 8-10 member biring complex or 9-12 member triring complex can be any 1, 2, 3, 4, or 5 Z 1a It is optionally substituted in the base.

[0187] In one variation of formula I, A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and Z 2 These are (C2-C8) alkynyls, 6-12 membered aryls, 5-12 membered C-linked heteroaryls, 3-12 membered C-linked heterocycles, or -C(O)NR q3 R r3 Z 2 Any 6-12 member aryl, 5-12 member C-linked heteroaryl, or 3-12 member C-linked heteroring can have 1, 2, 3, 4, or 5 Z 2b or Z 2c It is optionally substituted in the base, Z 2 Any (C2-C8) alkynnyl has 1, 2, 3, 4, or 5 Z 2cIt is optionally substituted at the base. In another variant, A is pyridinyl and Z 2 These are (C2-C8) alkynyls, 6-12 membered aryls, 5-12 membered C-linked heteroaryls, 3-12 membered C-linked heterocycles, or -C(O)NR q3 R r3 Z 2 Any 6-12 member aryl, 5-12 member C-linked heteroaryl, or 3-12 member C-linked heteroring can have 1, 2, 3, 4, or 5 Z 2b or Z 2c It is optionally substituted in the base, Z 2 Any (C2-C8) alkynnyl has 1, 2, 3, 4, or 5 Z 2c It is optionally substituted at the base. In another variant, A is pyrimidinyl and Z 2 These are (C2-C8) alkynyls, 6-12 membered aryls, 5-12 membered C-linked heteroaryls, 3-12 membered C-linked heterocycles, or -C(O)NR q3 R r3 Z 2 Any 6-12 member aryl, 5-12 member C-linked heteroaryl, or 3-12 member C-linked heteroring can have 1, 2, 3, 4, or 5 Z 2b or Z 2c It is optionally substituted in the base, Z 2 Any (C2-C8) alkynnyl has 1, 2, 3, 4, or 5 Z 2c It is optionally substituted at the base. In another variant, A is pyrazinyl and Z 2 These are (C2-C8) alkynyls, 6-12 membered aryls, 5-12 membered C-linked heteroaryls, 3-12 membered C-linked heterocycles, or -C(O)NR q3 R r3 and , Z 2 Any 6-12 member aryl, 5-12 member C-linked heteroaryl, or 3-12 member C-linked heteroring can have 1, 2, 3, 4, or 5 Z 2b or Z 2c It is optionally substituted in the base, Z 2 Any (C2-C8) alkynnyl has 1, 2, 3, 4, or 5 Z 2cIt is optionally substituted at the base. In another variant, A is pyridazinyl and Z 2 These are (C2-C8) alkynyls, 6-12 membered aryls, 5-12 membered C-linked heteroaryls, 3-12 membered C-linked heterocycles, or -C(O)NR q3 R r3 Z 2 Any 6-12 member aryl, 5-12 member C-linked heteroaryl, or 3-12 member C-linked heteroring can have 1, 2, 3, 4, or 5 Z 2b or Z 2c It is optionally substituted in the base, Z 2 Any (C2-C8) alkynnyl has 1, 2, 3, 4, or 5 Z 2c It is optionally substituted in the base.

[0188] In one variation of equation I, A is one Z 1 Part and one Z 2 It is partially replaced and Z 3 It is a pyridinyl that is not partially substituted (0 copies), Z 2 is (C2~C8) alkynyl or aryl, Z 2 This may be substituted at will, as shown by equation I. In another variant, A is one Z 1 Part and one Z 2 It is partially replaced and Z 3 It is a pyridinyl that is not partially substituted (0 copies), Z 2 is (C2~C8)alkynyl, and Z 2 This may be optionally substituted, as shown by Equation I. In certain variants, A is one Z 1 It is partially substituted, and there is one Z at the alpha position relative to the nitrogen atom of the pyridinyl ring. 2 It is partially replaced, and Z 3 It is a pyridinyl that is not partially substituted (0 copies), Z 2 is (C2~C8)alkynyl, and Z 2 This can be optionally substituted, as shown by Equation I.

[0189] In one variation of equation I, R 1 These are 1, 2, 3, 4, or 5 Z which may be the same or different. 4 A 5-12 member heteroaryl that is optionally substituted at the base, Z 1 Z is a phenyl molecule, a 5-6 member monocyclic heteroaryl molecule, an 8-10 member bicyclic heteroaryl molecule, an 8-10 member bicyclic heterocycle, or a 9-12 member tricyclic heterocycle. 1 Any phenyl, 5-6 member monocyclic heteroaryl, 8-10 member bicyclic heteroaryl, 8-10 member bicyclic heterocycle, or 9-12 member tricyclic heterocycle may have 1, 2, 3, 4, or 5 Z 1a It is optionally substituted in the base. In another variant, R 1 R is an 8-12 member bicyclic heteroaryl or an 8-12 member tricyclic heteroaryl, 1 Any 8-12 member bicyclic heteroaryl or 8-12 member tricyclic heteroaryl can have 1, 2, 3, 4, or 5 Z 4 It is optionally substituted in the base, Z 1 Z is a phenyl molecule, a 5-6 member monocyclic heteroaryl molecule, an 8-10 member bicyclic heteroaryl molecule, an 8-10 member bicyclic heterocycle, or a 9-12 member tricyclic heterocycle. 1 Any phenyl, 5-6 member monocyclic heteroaryl, 8-10 member bicyclic heteroaryl, 8-10 member bicyclic heterocycle, or 9-12 member tricyclic heterocycle may have 1, 2, 3, 4, or 5 Z 1a It is optionally substituted in the base.

[0190] In one variation of equation I, R 1 R is an 8-12 member bicyclic heteroaryl or an 8-12 member tricyclic heteroaryl, 1 Any 8-12 member bicyclic heteroaryl or 8-12 member tricyclic heteroaryl can have 1, 2, 3, 4, or 5 Z 4 It is optionally substituted in the base, Z 1 Z is an 8-10 membered bicyclic heteroaryl or 8-10 membered bicyclic heterocycle. 1Any 8-10 member bicyclic heteroaryl or 8-10 member bicyclic heterocycle can have 1, 2, 3, 4, or 5 Z 1a It is optionally substituted in the base.

[0191] In one variation of equation I, R 1 These are 1, 2, 3, 4, or 5 Z which may be the same or different. 4 A 5-12 member heteroaryl that is optionally substituted at the base, Z 2 (C2-C8) alkynyl, 6-12 member aryl, 5-12 member C-linked hete Loaryl, a 3- to 12-membered carbon-linked heterocycle, or -C(O)NR q3 R r3 Z 2 Any 6-12 member aryl, 5-12 member C-linked heteroaryl, or 3-12 member C-linked heteroring can have 1, 2, 3, 4, or 5 Z 2b or Z 2c It is optionally substituted in the base, Z 2 Any (C2-C8) alkynnyl has 1, 2, 3, 4, or 5 Z 2c It is optionally substituted in the base. In another variant, R 1 R is an 8-12 member bicyclic heteroaryl or an 8-12 member tricyclic heteroaryl, 1 Any 8-12 member bicyclic heteroaryl or 8-12 member tricyclic heteroaryl can have 1, 2, 3, 4, or 5 Z 4 It is optionally substituted in the base, Z 2 These are (C2-C8) alkynyls, 6-12 membered aryls, 5-12 membered C-linked heteroaryls, 3-12 membered C-linked heterocycles, or -C(O)NR q3 R r3 Z 2 Any 6-12 member aryl, 5-12 member C-linked heteroaryl, or 3-12 member C-linked heteroring can have 1, 2, 3, 4, or 5 Z 2b or Z 2c It is optionally substituted in the base, Z 2 Any (C2-C8) alkynnyl has 1, 2, 3, 4, or 5 Z 2cIt is optionally substituted in the base.

[0192] In one variation of equation I, Z 1 Z is a phenyl molecule, a 5-6 member monocyclic heteroaryl molecule, an 8-10 member bicyclic heteroaryl molecule, an 8-10 member bicyclic heterocycle, or a 9-12 member tricyclic heterocycle. 1 Any phenyl, 5-6 member monocyclic heteroaryl, 8-10 member bicyclic heteroaryl, 8-10 member bicyclic heterocycle, or 9-12 member tricyclic heterocycle may have 1, 2, 3, 4, or 5 Z 1a It is optionally substituted in the base, Z 2 These are (C2-C8) alkynyls, 6-12 membered aryls, 5-12 membered C-linked heteroaryls, 3-12 membered C-linked heterocycles, or -C(O)NR q3 R r3 Z 2 Any 6-12 member aryl, 5-12 member C-linked heteroaryl, or 3-12 member C-linked heteroring can have 1, 2, 3, 4, or 5 Z 2b or Z 2c It is optionally substituted in the base, Z 2 Any (C2-C8) alkynnyl has 1, 2, 3, 4, or 5 Z 2c It is optionally substituted in the base.

[0193] In one variation of equation I, Z 1 This is 1, 2, 3, 4 or 5 Z 1a It is a bicyclic heteroaryl that is optionally substituted with Z 2 This is 1, 2, 3, 4 or 5 Z 2c These are (C2-C8) alkynyl groups that are optionally substituted at the base.

[0194] In one variation of equation I, R 1 It is a 5-12 member heteroaryl, Z 1 Z is a phenyl molecule, a 5-6 member monocyclic heteroaryl molecule, an 8-10 member bicyclic heteroaryl molecule, an 8-10 member bicyclic heterocycle, or a 9-12 member tricyclic heterocycle. 1Any phenyl, 5-6 member monocyclic heteroaryl, 8-10 member bicyclic heteroaryl, 8-10 member bicyclic heterocycle, or 9-12 member tricyclic heterocycle may have 1, 2, 3, 4, or 5 Z 1a It is optionally substituted in the base, Z 2 These are (C2-C8) alkynyls, 6-12 membered aryls, 5-12 membered C-linked heteroaryls, 3-12 membered C-linked heterocycles, or -C(O)NR q3 R r3 Z 2 Any 6-12 member aryl, 5-12 member C-linked heteroaryl, or 3-12 member C-linked heteroring can have 1, 2, 3, 4, or 5 Z 2b or Z 2c It is optionally substituted in the base, Z 2 Any (C2-C8) alkynnyl has 1, 2, 3, 4, or 5 Z 2c It is optionally substituted in the base.

[0195] Compounds of formula III This disclosure relates to the compound of formula III. [ka] [In the formula, A is a six-membered monocyclic heteroaryl having one or two nitrogen atoms, and the six-membered monocyclic heteroaryl has one Z at the indicated position. 1 Substituted with a base, and one Z 2 Substituted with a base, and one or two Z 3 It is optionally substituted in the base, Z 3 The bases are the same or different. R 1 R is a 6-12 member aryl, a 5-12 member heteroaryl, or a 3-12 member heteroring. 1 Any 6-12 member aryl, 5-12 member heteroaryl, or 3-12 member heteroring can be any 1, 2, 3, 4, or 5 Z 4 It is optionally substituted in the base, Z 4The bases are the same or different. R 2 This is a phenyl compound that is optionally substituted with one, two, three, four, or five halogens, which are the same or different. R 3a and R 3b Each of these is independently H or (C1-C3) alkyl, Z 1 Z is a 6-12 member aryl, a 5-14 member heteroaryl, or a 3-14 member heteroring. 1 Any 6-12 member aryl, 5-14 member heteroaryl, or 3-14 member heteroring can be any 1, 2, 3, 4, or 5 Z 1a or Z 1b It is optionally replaced by Z 1a and Z 1b The bases are the same or different. each Z 1a These are independently (C3-C7) carbon rings, 5-12 membered heteroaryls, 3-12 membered heterocycles, halogens, -CN, -OR n1 ,-OC(O)R p1 -OC(O)NR q1 R r1 , -SR n1 ,-S(O)R p1 -S(O)2OH, -S(O)2R p1 -S(O)2NR q1 R r1 , -NR q1 R r1 , -NR n1 COR p1 , -NR n1 CO2R p1 , -NR n1 CONR q1 R r1 , -NR n1 S(O)2R p1 , -NR n1 S(O)2OR p1 , -NR n1 S(O)2NR q1 R r1 , -C(O)R n1 , -C(O)OR n1 -C(O)NR q1 R r1and -S(O)2NR n1 COR p1 Z 1a Any (C3-C7) carbon ring, 5-12 membered heteroaryl, and 3-12 membered heteroring can have 1, 2, 3, 4, or 5 Z 1c or Z 1d It is optionally substituted in the base, Z 1c and Z 1d The bases are the same or different. each Z 1b These are (C1-C8) alkyl groups that are independently and optionally substituted with the same or different 1, 2, 3, 4, or 5 halogens. each Z 1c These are, independently, halogen, -CN, -OH, -NH2, and -C(O)NR q2 R r2 , or (C1~C8) heteroalkyl, each Z 1d These are independently (C1-C8) alkyl or (C1-C8) haloalkyl, Each R n1 R is independently H, (C1-C8) alkyl, (C3-C7) carbon ring, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl, n1 Any (C3-C7) carbon ring, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl can have 1, 2, 3, 4, or 5 Z 1c or Z 1d It is optionally substituted in the base, Z 1c and Z 1d The bases are the same or different, R n1 Any (C1-C8) alkyl group has 1, 2, 3, 4, or 5 Z 1c It is optionally substituted in the base, Z 1c The base is the same or They are different, Each R p1 These are independently (C1-C8) alkyl, (C3-C7) carbon ring, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl, and R p1Any (C3-C7) carbon ring, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl can have 1, 2, 3, 4, or 5 Z 1c or Z 1d It is optionally substituted in the base, Z 1c and Z 1d The bases are the same or different, R p1 Any (C1-C8) alkyl group has 1, 2, 3, 4, or 5 Z 1c It is optionally substituted in the base, Z 1c The bases are the same or different. R q1 and R r1 Each of these is independently H, (C1-C8) alkyl, (C3-C7) carbon ring, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl, and R q1 Or R r1 Any (C3-C7) carbon ring, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl may have 1, 2, 3, 4, or 5 Z 1c Or Z 1d It is optionally substituted in the base, Z 1c and Z 1d The bases are the same or different, R q1 Or R r1 Any (C1-C8) alkyl group has 1, 2, 3, 4, or 5 Z 1c It is optionally substituted in the base, Z 1c The bases are the same or different, or R q1 and R r1 These, together with the nitrogen atoms they are bonded to, form a 5-membered, 6-membered, or 7-membered heterocycle, and these 5-membered, 6-membered, or 7-membered heterocycles contain 1, 2, 3, 4, or 5 Z atoms. 1c Or Z 1d It is optionally substituted in the base, Z 1c and Z 1d The base is either the same or different. R q2 and R r2 Each of them is independently either H, (C1-C8) alkyl, (C3-C7) carbon ring, or R q2 and R r2These, together with the nitrogen atoms to which they are bonded, form a 5-membered, 6-membered, or 7-membered heterocycle. Z 2 These include (C2-C8) alkenyls, (C2-C8) alkynyls, 6-12 membered aryls, 5-12 membered C-linked heteroaryls, 3-12 membered C-linked heterocycles, and -C(O)R n3 , or -C(O)NR q3 R r3 Z 2 Any 6-12 member aryl, 5-12 member C-linked heteroaryl, or 3-12 member C-linked heteroring can have 1, 2, 3, 4, or 5 Z 2b or Z 2c It is optionally substituted in the base, Z 2b and Z 2c The bases are the same or different, Z 2 Any (C2-C8) alkenyl or (C2-C8) alkinyl has 1, 2, 3, 4 or 5 Z 2c It is optionally substituted in the base, Z 2c The bases are the same or different. Each R n3 These are independently H or (C1-C4) alkyl, R q3 and R r3 Each of these is independently H or (C1-C4) alkyl, each Z 2b These are independently oxo, (C1-C4)alkyl, (C1-C4)heteroalkyl, or (C1-C4)haloalkyl. each Z 2c These are independently oxo, halogen, -CN, and -OR. n4 ,-OC(O)R p4 -OC(O)NR q4 R r4 , -SR n4 ,-S(O)R p4 -S(O)2OH, -S(O)2R p4 -S(O)2NR q4 R r4 , -NR q4 R r4 , -NR n4 COR p4 , -NR n4CO2R p4 , -NR n4 CONR q4 R r4 , -NR n4 S(O)2R p4 , -NR n4 S(O)2OR p4 , -NR n4 S(O)2NR q4 R r4 -NO2, -C(O)R n4 , -C(O)OR n4 , or -C(O)NR q4 R r4 And, Each R n4 These are independently H, (C1-C4) alkyl, (C1-C4) haloalkyl, or (C1-C4) heteroalkyl. Each R p4 These are independently (C1-C8) alkyl, (C1-C4) haloalkyl, or (C1-C4) heteroalkyl. R q4 and R r4 Each of these is independently H, (C1-C4) alkyl, (C1-C4) haloalkyl, or (C1-C4) heteroalkyl. each Z 3 These are independently (C1-C4) heteroalkyl or halogen, each Z 4 These are independently oxo, (C1-C8) alkyl, (C3-C7) carbon ring, halogen, -CN, and -OR. n5 , -NR q5 R r5 , -NR n5 COR p5 , -NR n5 CO2R p5 , -C(O)R n5 , -C(O)OR n5 , or -C(O)NR q5 R r5 and , Z 4 Any (C3-C7) carbon ring or (C1-C8) alkyl group has 1, 2, 3, 4, or 5 Z 4a It is optionally substituted in the base, Z 4a The bases are the same or different. each Z 4a These are, independently, halogen, -CN, or -OR n6 And, R n5 , R p5 , R q5 , R r5 , and R n6 Each of these is independently either H or (C1-C4) alkyl. Alternatively, provide a pharmaceutically acceptable salt thereof.

[0196] In a particular embodiment, the compound of formula III is the compound of formula IIIa. [ka] Or a pharmaceutically acceptable salt thereof.

[0197] In a particular embodiment, the compound of formula III is the compound of formula IIIb. [ka] Or a pharmaceutically acceptable salt thereof.

[0198] In a particular embodiment, the compound of formula III is the compound of formula IIIc. [ka] Or a pharmaceutically acceptable salt thereof.

[0199] This disclosure relates to compounds of formula IIId. [ka] [In the formula, A 1 CH, CZ3 or nitrogen, A 2 is CH or nitrogen, R 1 R is a 6-12 member aryl, a 5-12 member heteroaryl, or a 3-12 member heteroring. 1 Any 6-12 member aryl, 5-12 member heteroaryl, or 3-12 member heteroring can be any 1, 2, 3, 4, or 5 Z 4 It is optionally substituted in the base, Z 4 The bases are the same or different. R 3a and R 3b Each of these is independently H or (C1-C3) alkyl, Z 1 Z is a 6-12 member aryl, a 5-14 member heteroaryl, or a 3-14 member heteroring. 1 Any 6-12 member aryl, 5-14 member heteroaryl, or 3-14 member heteroring can be any 1, 2, 3, 4, or 5 Z 1a or Z 1b It is optionally replaced by Z 1a and Z 1b The bases are the same or different. each Z 1a These are independently (C3-C7) carbon rings, 5-12 membered heteroaryls, 3-12 membered heterocycles, halogens, -CN, -OR n1 ,-OC(O)R p1 -OC(O)NR q1 R r1 , -SR n1 ,-S(O)R p1 -S(O)2OH, -S(O)2R p1 -S(O)2NR q1 R r1 , -NR q1 R r1 , -NR n1 COR p1 , -NR n1 CO2R p1 , -NR n1 CONR q1 R r1 , -NR n1 S(O)2R p1, -NR n1 S(O)2OR p1 , -NR n1 S(O)2NR q1 R r1 , -C(O)R n1 , -C(O)OR n1 -C(O)NR q1 R r1 and -S(O)2NR n1 COR p1 Z 1a Any (C3-C7) carbon ring, 5-12 membered heteroaryl, and 3-12 membered heteroring can have 1, 2, 3, 4, or 5 Z 1c or Z 1d It is optionally substituted in the base, Z 1c and Z 1d The bases are the same or different. each Z 1b These are (C1-C8) alkyl groups that are independently and optionally substituted with the same or different 1, 2, 3, 4, or 5 halogens. each Z 1c These are, independently, halogen, -CN, -OH, -NH2, and -C(O)NR q2 R r2 , or (C1~C8) heteroalkyl, each Z 1d These are independently (C1-C8) alkyl or (C1-C8) haloalkyl, Each R n1 R is independently H, (C1-C8) alkyl, (C3-C7) carbon ring, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl, n1 Any (C3-C7) carbon ring, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl can have 1, 2, 3, 4, or 5 Z 1c or Z 1d It is optionally substituted in the base, Z 1c and Z 1d The bases are the same or different, R n1 Any (C1-C8) alkyl group has 1, 2, 3, 4, or 5 Z 1c It is optionally substituted in the base, Z 1cThe bases are the same or different. Each R p1 These are independently (C1-C8) alkyl, (C3-C7) carbon ring, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl, and R p1 Any (C3-C7) carbon ring, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl can have 1, 2, 3, 4, or 5 Z 1c or Z 1d It is optionally substituted in the base, Z 1c and Z 1d The bases are the same or different, R p1 Any (C1-C8) alkyl group has 1, 2, 3, 4, or 5 Z 1c It is optionally substituted in the base, Z 1c The bases are the same or different. R q1 and R r1 Each of these is independently H, (C1-C8) alkyl, (C3-C7) carbon ring, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl, and R q1 Or R r1 Any (C3-C7) carbon ring, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl may have 1, 2, 3, 4, or 5 Z 1c Or Z 1d It is optionally substituted in the base, Z 1c and Z 1d The bases are the same or different, R q1 Or R r1 Any (C1-C8) alkyl group has 1, 2, 3, 4, or 5 Z 1c It is optionally substituted in the base, Z 1c The bases are the same or different, or R q1 and R r1 These, together with the nitrogen atoms they are bonded to, form a 5-membered, 6-membered, or 7-membered heterocycle, and these 5-membered, 6-membered, or 7-membered heterocycles contain 1, 2, 3, 4, or 5 Z atoms. 1c Or Z 1d It is optionally substituted in the base, Z 1c and Z 1d The base is either the same or different. R q2 and R r2 Each of them is independently either H, (C1-C8) alkyl, (C3-C7) carbon ring, or R q2 and R r2 These, together with the nitrogen atoms to which they are bonded, form a 5-membered, 6-membered, or 7-membered heterocycle. Z 2 These include (C2-C8) alkenyls, (C2-C8) alkynyls, 6-12 membered aryls, 5-12 membered C-linked heteroaryls, 3-12 membered C-linked heterocycles, and -C(O)R n3 , or -C(O)NR q3 R r3 Z 2 Any 6-12 member aryl, 5-12 member C-linked heteroaryl, or 3-12 member C-linked heteroring can have 1, 2, 3, 4, or 5 Z 2b or Z 2c It is optionally substituted in the base, Z 2b and Z 2c The bases are the same or different, Z 2 Any (C2-C8) alkenyl or (C2-C8) alkinyl has 1, 2, 3, 4 or 5 Z 2c It is optionally substituted in the base, Z 2c The bases are the same or different. Each R n3 These are independently H or (C1-C4) alkyl, R q3 and R r3 Each of these is independently H or (C1-C4) alkyl, each Z 2b These are independently oxo, (C1-C4) alkyl, (C1-C4) heteroalkyl, or (C1-C4) haloalkyl. each Z 2c These are independently oxo, halogen, -CN, and -OR. n4 ,-OC(O)R p4 ,- OC(O)NR q4 R r4 , -SR n4 ,-S(O)R p4 -S(O)2OH, -S(O)2Rp4 -S(O)2NR q4 R r4 , -NR q4 R r4 , -NR n4 COR p4 , -NR n4 CO2R p4 , -NR n4 CONR q4 R r4 , -NR n4 S(O)2R p4 , -NR n4 S(O)2OR p4 , -NR n4 S(O)2NR q4 R r4 -NO2, -C(O)R n4 , -C(O)OR n4 , or -C(O)NR q4 R r4 And, Each R n4 These are independently H, (C1-C4) alkyl, (C1-C4) haloalkyl, or (C1-C4) heteroalkyl. Each R p4 These are independently (C1-C8) alkyl, (C1-C4) haloalkyl, or (C1-C4) heteroalkyl. R q4 and R r4 Each of these is independently H, (C1-C4) alkyl, (C1-C4) haloalkyl, or (C1-C4) heteroalkyl. each Z 3 These are independently (C1-C4) heteroalkyl groups. each Z 4 These are independently oxo, (C1-C8) alkyl, (C3-C7) carbon ring, halogen, -CN, and -OR. n5 , -NR q5 R r5 , -NR n5 COR p5 , -NR n5 CO2R p5 , -C(O)R n5 , -C(O)OR n5 , or -C(O)NR q5 R r5 Z 4Any (C3-C7) carbon ring or (C1-C8) alkyl group has 1, 2, 3, 4, or 5 Z 4a It is optionally substituted in the base, Z 4a The bases are the same or different. each Z 4a These are, independently, halogen, -CN, or -OR n6 And, R n5 , R p5 , R q5 , R r5 , and R n6 Each of these is independently H or (C1-C4) alkyl, each Z 5 These are halogens that can be the same or different, independently. n is 0, 1, 2, or 3. Alternatively, provide a pharmaceutically acceptable salt thereof.

[0200] In a particular embodiment, the compound of formula IIId is the compound of formula IIIe. [ka] Or a pharmaceutically acceptable salt thereof.

[0201] This disclosure relates to compounds of formula IIIf. [ka] [In the formula, A 1 CH, CZ 3 or nitrogen, A 2 is CH or nitrogen, R 1 R is a 6-12 member aryl, a 5-12 member heteroaryl, or a 3-12 member heteroring. 1Any 6-12 member aryl, 5-12 member heteroaryl, or 3-12 member heteroring can be any 1, 2, 3, 4, or 5 Z 4 It is optionally substituted in the base, Z 4 The bases are the same or different. R 3a and R 3b Each of these is independently H or (C1-C3) alkyl, Z 1 Z is a 6-12 member aryl, a 5-14 member heteroaryl, or a 3-14 member heteroring. 1 Any 6-12 member aryl, 5-14 member heteroaryl, or 3-14 member heteroring can be any 1, 2, 3, 4, or 5 Z 1a or Z 1b It is optionally replaced by Z 1a and Z 1b The bases are the same or different. each Z 1a These are independently (C3-C7) carbon rings, 5-12 membered heteroaryls, 3-12 membered heterocycles, halogens, -CN, -OR n1 ,-OC(O)R p1 -OC(O)NR q1 R r1 , -SR n1 ,-S(O)R p1 -S(O)2OH, -S(O)2R p1 -S(O)2NR q1 R r1 , -NR q1 R r1 , -NR n1 COR p1 , -NR n1 CO2R p1 , -NR n1 CONR q1 R r1 , -NR n1 S(O)2R p1 , -NR n1 S(O)2OR p1 , -NR n1 S(O)2NR q1 R r1 , -C(O)R n1 , -C(O)OR n1 -C(O)NRq1 R r1 and -S(O)2NR n1 COR p1 Z 1a Any (C3-C7) carbon ring, 5-12 membered heteroaryl, and 3-12 membered heteroring can have 1, 2, 3, 4, or 5 Z 1c or Z 1d It is optionally substituted in the base, Z 1c and Z 1d The bases are the same or different. each Z 1b These are (C1-C8) alkyl groups that are independently and optionally substituted with the same or different 1, 2, 3, 4, or 5 halogens. each Z 1c These are, independently, halogen, -CN, -OH, -NH2, and -C(O)NR q2 R r2 , or (C1~C8) heteroalkyl, each Z 1d These are independently (C1-C8) alkyl or (C1-C8) haloalkyl, Each R n1 R is independently H, (C1-C8) alkyl, (C3-C7) carbon ring, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl, n1 Any (C3-C7) carbon ring, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl can have 1, 2, 3, 4, or 5 Z 1c or Z 1d It is optionally substituted in the base, Z 1c and Z 1d The bases are the same or different, R n1 Any (C1-C8) alkyl group has 1, 2, 3, 4, or 5 Z 1c It is optionally substituted in the base, Z 1c The bases are the same or different. Each R p1 These are independently (C1-C8) alkyl, (C3-C7) carbon ring, and 3-7 member complex. A ring, or a monocyclic heteroaryl with 5-6 members, R p1Any (C3-C7) carbon ring, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl can have 1, 2, 3, 4, or 5 Z 1c or Z 1d It is optionally substituted in the base, Z 1c and Z 1d The bases are the same or different, R p1 Any (C1-C8) alkyl group has 1, 2, 3, 4, or 5 Z 1c It is optionally substituted in the base, Z 1c The bases are the same or different. R q1 and R r1 Each of these is independently H, (C1-C8) alkyl, (C3-C7) carbon ring, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl, and R q1 Or R r1 Any (C3-C7) carbon ring, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl may have 1, 2, 3, 4, or 5 Z 1c Or Z 1d It is optionally substituted in the base, Z 1c and Z 1d The bases are the same or different, R q1 Or R r1 Any (C1-C8) alkyl group has 1, 2, 3, 4, or 5 Z 1c It is optionally substituted in the base, Z 1c The bases are the same or different, or R q1 and R r1 These, together with the nitrogen atoms they are bonded to, form a 5-membered, 6-membered, or 7-membered heterocycle, and these 5-membered, 6-membered, or 7-membered heterocycles contain 1, 2, 3, 4, or 5 Z atoms. 1c Or Z 1d It is optionally substituted in the base, Z 1c and Z 1d The base is either the same or different. R q2 and R r2 Each of them is independently either H, (C1-C8) alkyl, (C3-C7) carbon ring, or R q2 and R r2These, together with the nitrogen atoms to which they are bonded, form a 5-membered, 6-membered, or 7-membered heterocycle. Z 2 These include (C2-C8) alkenyls, (C2-C8) alkynyls, 6-12 membered aryls, 5-12 membered C-linked heteroaryls, 3-12 membered C-linked heterocycles, and -C(O)R n3 , or -C(O)NR q3 R r3 Z 2 Any 6-12 member aryl, 5-12 member C-linked heteroaryl, or 3-12 member C-linked heteroring can have 1, 2, 3, 4, or 5 Z 2b or Z 2c It is optionally substituted in the base, Z 2b and Z 2c The bases are the same or different, Z 2 Any (C2-C8) alkenyl or (C2-C8) alkinyl has 1, 2, 3, 4 or 5 Z 2c It is optionally substituted in the base, Z 2c The bases are the same or different. Each R n3 These are independently H or (C1-C4) alkyl, R q3 and R r3 Each of these is independently H or (C1-C4) alkyl, each Z 2b These are independently oxo, (C1-C4) alkyl, (C1-C4) heteroalkyl, or (C1-C4) haloalkyl. each Z 2c These are independently oxo, halogen, -CN, and -OR. n4 ,-OC(O)R p4 -OC(O)NR q4 R r4 , -SR n4 ,-S(O)R p4 -S(O)2OH, -S(O)2R p4 -S(O)2NR q4 R r4 , -NR q4 R r4 , -NR n4 COR p4 , -NR n4CO2R p4 , -NR n4 CONR q4 R r4 , -NR n4 S(O)2R p4 , -NR n4 S(O)2OR p4 , -NR n4 S(O)2NR q4 R r4 -NO2, -C(O)R n4 , -C(O)OR n4 , or -C(O)NR q4 R r4 And, Each R n4 These are independently H, (C1-C4) alkyl, (C1-C4) haloalkyl, or (C1-C4) heteroalkyl. Each R p4 These are independently (C1-C8) alkyl, (C1-C4) haloalkyl, or (C1-C4) heteroalkyl. R q4 and R r4 Each of these is independently H, (C1-C4) alkyl, (C1-C4) haloalkyl, or (C1-C4) heteroalkyl. each Z 3 These are independently (C1-C4) heteroalkyl groups. each Z 4 These are independently oxo, (C1-C8) alkyl, (C3-C7) carbon ring, halogen, -CN, and -OR. n5 , -NR q5 R r5 , -NR n5 COR p5 , -NR n5 CO2R p5 , -C(O)R n5 , -C(O)OR n5 , or -C(O)NR q5 R r5 Z 4 Any (C3-C7) carbon ring or (C1-C8) alkyl group has 1, 2, 3, 4, or 5 Z 4a It is optionally substituted in the base, Z 4a The base is the same or different And, each Z 4a These are, independently, halogen, -CN, or -OR n6 And, R n5 , R p5 , R q5 , R r5 , and R n6 Each of these is independently H or (C1-C4) alkyl, each Z 5 These are halogens that can be the same or different, independently. n is 0, 1, 2, or 3. Alternatively, provide a pharmaceutically acceptable salt thereof.

[0202] In a particular embodiment, the compound of formula IIIf is the compound of formula IIIg. [ka] Or a pharmaceutically acceptable salt thereof.

[0203] This disclosure relates to compounds of formula IIIh. [ka] [In the formula, A 1 CH, CZ 3 or nitrogen, A 2 is CH or nitrogen, C, together with two bonded carbon atoms, forms a 3- to 7-membered monocyclic carbon ring or a 5- to 9-membered bicyclic heterocycle, and any 3- to 7-membered monocyclic carbon ring or 5- to 9-membered bicyclic heterocycle of C contains 1, 2, 3, 4, or 5 Z 4 It is optionally substituted in the base, Z 4 The bases are the same or different. each Z 1w Z 1a , Z 1b or H, each Z 1a These are independently (C3-C7) carbon rings, 5-12 membered heteroaryls, 3-12 membered heterocycles, halogens, -CN, -OR n1 ,-OC(O)R p1 -OC(O)NR q1 R r1 , -SR n1 ,-S(O)R p1 -S(O)2OH, -S(O)2R p1 -S(O)2NR q1 R r1 , -NR q1 R r1 , -NR n1 COR p1 , -NR n1 CO2R p1 , -NR n1 CONR q1 R r1 , -NR n1 S(O)2R p1 , -NR n1 S(O)2OR p1 , -NR n1 S(O)2NR q1 R r1 , -C(O)R n1 , -C(O)OR n1 -C(O)NR q1 R r1 and -S(O)2NR n1 COR p1 Z 1a Any (C3-C7) carbon ring, 5-12 membered heteroaryl, and 3-12 membered heteroring can have 1, 2, 3, 4, or 5 Z 1c or Z 1d It is optionally substituted in the base, Z 1c and Z 1d The bases are the same or different. each Z 1b These are (C1-C8) alkyl groups that are independently and optionally substituted with the same or different 1, 2, 3, 4, or 5 halogens. each Z 1c These are, independently, halogen, -CN, -OH, -NH2, and -C(O)NR q2 R r2, or (C1~C8) heteroalkyl, each Z 1d These are independently (C1-C8) alkyl or (C1-C8) haloalkyl, Each R n1 R is independently H, (C1-C8) alkyl, (C3-C7) carbon ring, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl, n1 Any (C3-C7) carbon ring, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl can have 1, 2, 3, 4, or 5 Z 1c or Z 1d It is optionally substituted in the base, Z 1c and Z 1d The bases are the same or different, R n1 Any (C1-C8) alkyl group has 1, 2, 3, 4, or 5 Z 1c It is optionally substituted in the base, Z 1c The bases are the same or different. Each R p1 These are independently (C1-C8) alkyl, (C3-C7) carbon ring, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl, and R p1 Any (C3-C7) carbon ring, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl can have 1, 2, 3, 4, or 5 Z 1c or Z 1d It is optionally substituted in the base, Z 1c and Z 1d The bases are the same or different, R p1 Any (C1-C8) alkyl group has 1, 2, 3, 4, or 5 Z 1c It is optionally substituted in the base, Z 1c The bases are the same or different. R q1 and R r1 Each of these is independently H, (C1-C8) alkyl, (C3-C7) carbon ring, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl, and R q1 Or R r1Any (C3-C7) carbon ring, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl may have 1, 2, 3, 4, or 5 Z 1c Or Z 1d It is optionally substituted in the base, Z 1c and Z 1d The bases are the same or different, R q1 Or R r1 Any (C1-C8) alkyl group has 1, 2, 3, 4, or 5 Z 1c It is optionally substituted in the base, Z 1c The bases are the same or different, or R q1 and R r1 These, together with the nitrogen atoms they are bonded to, form a 5-membered, 6-membered, or 7-membered heterocycle, and these 5-membered, 6-membered, or 7-membered heterocycles contain 1, 2, 3, 4, or 5 Z atoms. 1c Or Z 1d It is optionally substituted in the base, Z 1c and Z 1d The base is either the same or different. R q2 and R r2 Each of them is independently either H, (C1-C8) alkyl, (C3-C7) carbon ring, or R q2 and R r2 These, together with the nitrogen atoms to which they are bonded, form a 5-membered, 6-membered, or 7-membered heterocycle. Z 2 These include (C2-C8) alkenyls, (C2-C8) alkynyls, 6-12 membered aryls, 5-12 membered C-linked heteroaryls, 3-12 membered C-linked heterocycles, and -C(O)R n3 , or -C(O)NR q3 R r3 Z 2 Any 6-12 member aryl, 5-12 member C-linked heteroaryl, or 3-12 member C-linked heteroring can have 1, 2, 3, 4, or 5 Z 2b or Z 2c It is optionally substituted in the base, Z 2b and Z 2c The basis is, They are the same or different, Z 2Any (C2-C8) alkenyl or (C2-C8) alkinyl has 1, 2, 3, 4 or 5 Z 2c It is optionally substituted in the base, Z 2c The bases are the same or different. Each R n3 These are independently H or (C1-C4) alkyl, R q3 and R r3 Each of these is independently H or (C1-C4) alkyl, each Z 2b These are independently oxo, (C1-C4) alkyl, (C1-C4) heteroalkyl, or (C1-C4) haloalkyl. each Z 2c These are independently oxo, halogen, -CN, and -OR. n4 ,-OC(O)R p4 -OC(O)NR q4 R r4 , -SR n4 ,-S(O)R p4 -S(O)2OH, -S(O)2R p4 -S(O)2NR q4 R r4 , -NR q4 R r4 , -NR n4 COR p4 , -NR n4 CO2R p4 , -NR n4 CONR q4 R r4 , -NR n4 S(O)2R p4 , -NR n4 S(O)2OR p4 , -NR n4 S(O)2NR q4 R r4 -NO2, -C(O)R n4 , -C(O)OR n4 , or -C(O)NR q4 R r4 And, Each R n4 These are independently H, (C1-C4) alkyl, (C1-C4) haloalkyl, or (C1-C4) heteroalkyl. Each Rp4 These are independently (C1-C8) alkyl, (C1-C4) haloalkyl, or (C1-C4) heteroalkyl. R q4 and R r4 Each of these is independently H, (C1-C4) alkyl, (C1-C4) haloalkyl, or (C1-C4) heteroalkyl. Z 3 These are independently (C1-C4) heteroalkyl groups. each Z 4 These are independently oxo, (C1-C8) alkyl, (C3-C7) carbon ring, halogen, -CN, and -OR. n5 , -NR q5 R r5 , -NR n5 COR p5 , -NR n5 CO2R p5 , -C(O)R n5 , -C(O)OR n5 , or -C(O)NR q5 R r5 Z 4 Any (C3-C7) carbon ring or (C1-C8) alkyl group has 1, 2, 3, 4, or 5 Z 4a It is optionally substituted in the base, Z 4a The bases are the same or different. each Z 4a These are, independently, halogen, -CN, or -OR n6 And, R n5 , R p5 , R q5 , R r5 , and R n6 Each of these is independently H or (C1-C4) alkyl, Z 5a [is H or halogen] Alternatively, provide a pharmaceutically acceptable salt thereof.

[0204] In a particular embodiment, the compound of formula IIIh is the compound of formula IIIi. [ka] Or a pharmaceutically acceptable salt thereof.

[0205] This disclosure relates to compounds of formula IIIj. [ka] [In the formula, A 1 CH, CZ 3 , or nitrogen, A 2 is CH or nitrogen, Z 1x is H or (C1-C8) alkyl, Z 1y -NR n1 S(O)2R p1 , -NR n1 S(O)2NR q1 R r1 , -NR q1 R r1 , -NR n1 COR p1 , -NR n1 CONR q1 R r1 , or -NR n1 CO2R p1 And, Z 1z H, halogen, -CN, -OR n1 , (C1~C8)alkyl, and the (C1~C8)alkyl is optionally substituted with one, two, or three halogens that are the same or different. Each R n1 These are independently H or (C1-C8) alkyl, Each R p1 These are independently (C1-C8) alkyl groups, R q1 and R r1 Each of these is independently H or (C1-C8) alkyl, Z 3 It is a (C1-C4) heteroalkyl, Z2 This is 1, 2, 3, 4 or 5 Z 2c It is an (C2~C8) alkynyl that is optionally substituted at the base, and Z 2c The bases are the same or different, Z 2c These are, independently, halogen, -OR n4 , -NR n4 CO2R p4 , -C(O)OR n4 , or -NR q4 R r4 And, Each R n4 These are independently H or (C1-C4) alkyl, Each R p4 These are independently (C1-C4) alkyl groups. R q4 and R r4 Each of these is independently H, (C1-C4) alkyl, or (C1-C4) heteroalkyl. Z 4 These are hydrogen, (C1~C8) alkyl, halogen, -CN, C(O)R n5 , -C(O)OR n5 -C(O)NR q5 R r5 , -NR n5 COR p5 , -NR q5 R r5 , or (C3~C7) carbon ring, Z 4 Any (C3-C7) carbon ring or (C1-C8) alkyl group is optionally substituted with a halogen or hydroxyl group. Each R n5 These are independently H or (C1-C4) alkyl, Each R p5 These are independently H or (C1-C4) alkyl, R q5 and R r5 Each of these is independently H or (C1-C4) alkyl, Z 5a [is H or halogen] Alternatively, provide a pharmaceutically acceptable salt thereof.

[0206] In a particular embodiment, the compound of formula IIIj is a compound of formula IIIk. [ka] Or a pharmaceutically acceptable salt thereof.

[0207] The specific values ​​listed below are for compounds of formula III and all related formulas (e.g., formulas IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIi, IIIj, and IIIk), where applicable. For example, the values ​​below, when applied to formula III, are equally applicable to all related formulas of formula III that allow such variables to exist (e.g., formulas IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIi, IIIj, and IIIk). It should be understood that two or more types of values ​​can be combined. Therefore, it should be understood that any variable in a compound of formula III can be combined with any other variable in a compound of formula III, as if all of the combinations of variables were specifically listed individually. For example, R, which is detailed herein for compounds of formula III. 1 Any specific value of is as if every single combination were specifically listed individually, just as variables A and Z in Equation III are. 1 , R 2 , R 3a or R 3b It is understood that these can be combined with one or more of any other specific values.

[0208] In a particular embodiment of Equation III, A 1 is CH. In a particular embodiment, A 1 CZ 3 In a particular embodiment, A 1 It is nitrogen.

[0209] In a particular embodiment of Equation III, A2 is CH. In a particular embodiment, A 2 It is nitrogen.

[0210] In a particular embodiment of Equation III, A 1 CH is, A 2 is CH. In a particular embodiment, A 1 CZ 3 A 2 is CH. In a particular embodiment, A 1 It is nitrogen, and A 2 It is CH.

[0211] In a particular embodiment of Equation III, A 1 CH is, A 2 is nitrogen. In a particular embodiment, A 1 CZ 3 A 2 is nitrogen. In a particular embodiment, A 1 It is nitrogen, and A 2 It is nitrogen.

[0212] In a particular embodiment of Equation III, Z 5 is F. In a particular embodiment of Equation III, n is 1. In a particular embodiment, n is 2. In this embodiment, n is 1, Z 5 is F. In a particular embodiment, n is 2, and each Z 5 It is F.

[0213] In a particular embodiment of Equation III, Z 5a H is H. In a particular embodiment, Z 5a It is F.

[0214] In a particular embodiment of Equation III, each Z 1w Z 1a or Z 1b Z 1a and Z 1bThe bases may be the same or different. In a particular embodiment, each Z 1w These are independently (C1-C8) alkyl, halogen, or -NR elements, which may be the same or different. n1 S(O)2R p1 That is the case.

[0215] In a particular embodiment of Equation III, Z 1x H is H. In a particular embodiment, Z 1x is (C1-C8) alkyl. In certain embodiments, Z 1x is a (C1-C4) alkyl group. In certain embodiments, Z 1x is a (C1-C3) alkyl group. In a particular embodiment, Z 1x It is methyl.

[0216] In a particular embodiment of Equation III, Z 1y -NR n1 S(O)2R p1 , -NR n1 S(O)2NR q1 R r1 , or -NR q1 R r1 In a particular embodiment, Z 1y -NR n1 S(O)2R p1 or -NR n1 S(O)2NR q1 R r1 In a particular embodiment, Z 1y -NR n1 S(O)2R p1 In a particular embodiment, Z 1y -NR n1 S(O)2NR q1 R r1 In a particular embodiment, Z 1y -NR q1 R r1 That is the case.

[0217] In a particular embodiment of Equation III, Z 1z is H or a halogen. In certain embodiments, Z1z H is H. In a particular embodiment, Z 1z is a halogen. In a particular embodiment, Z 1z is Cl. In a particular embodiment, Z 1z In a particular embodiment, Z 1z It is Br.

[0218] In a particular embodiment of Equation III, Z 1y -NR n1 S(O)2R p1 or -NR n1 S(O)2NR q1 R r1 Z 1z is a halogen. In a particular embodiment, Z 1y -NR n1 S(O)2R p1 Z 1z is a halogen. In a particular embodiment, Z 1x is an (C1~C4) alkyl, and Z 1y -NR n1 S(O)2R p1 or -NR n1 S(O)2NR q1 R r1 Z 1z is a halogen. In a particular embodiment, Z 1x is an (C1~C4) alkyl, and Z 1y -NR n1 S(O)2R p1 Z 1z It is a halogen.

[0219] In a particular embodiment of formula III, A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and any pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl of A is one Z at the indicated position. 1 Substituted with a base, and one Z 2 Substituted with a base, and one or two Z 3The group is optionally substituted with a Z group. In a particular embodiment, A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and any pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl of A is a single Z group at the indicated position. 1 Substituted with a base, and one Z 2 Substituted with a base, and one Z 3 It is optionally substituted in the base.

[0220] In a particular embodiment, A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and any pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl of A is one Z at the indicated position. 1 Substituted with a base, and one Z 2 It is substituted with Z. In one embodiment, A is Z 3 It is not substituted by the base.

[0221] In a particular embodiment, A is a pyridinyl, and any pyridinyl of A has one Z at the indicated position. 1 Substituted with a base, and one Z 2 Substituted with a base, and one or two Z 3 It is optionally substituted with a Z group. In a particular embodiment, A is a pyridinyl, and any pyridinyl of A is a single Z group at the indicated position. 1 Substituted with a base, and one Z 2 Substituted with a base, and one Z 3 It is optionally substituted in the base.

[0222] In a particular embodiment, A is a pyridinyl, and any pyridinyl of A has one Z at the indicated position. 1 Substituted with a base, and one Z 2 It is substituted with Z. In one embodiment, Z 2 The group is bonded to the nitrogen of the pyridinyl group at the alpha position. In a further embodiment, A is Z 3 It is not substituted by the base.

[0223] In a particular embodiment, A is a pyrimidinyl, and any pyridinyl of A has one Z at the indicated position. 1 Substituted with a base, and one Z 2 Substituted with a base, and one or two Z 3 It is optionally substituted with a Z group. In a particular embodiment, A is a pyrimidinyl, and any pyridinyl of A is a single Z group at the indicated position. 1 Substituted with a base, and one Z 2 Substituted with a base, and one Z 3 It is optionally substituted in the base.

[0224] In a particular embodiment, A is a pyrimidinyl, and any pyridinyl of A has one Z at the indicated position. 1 Substituted with a base, and one Z 2 It is substituted with Z. In one embodiment, A is Z 3 It is not substituted by the base.

[0225] In a particular embodiment, A is pyrazinyl, and any pyrazinyl of A is one Z at the indicated position. 1 Substituted with a base, and one Z 2 Substituted with a base, and one or two Z 3 It is optionally substituted with a Z group. In a particular embodiment, A is a pyrazinyl, and any pyrazinyl of A is a single Z group at the indicated position. 1 Substituted with a base, and one Z 2 Substituted with a base, and one Z 3 It is optionally substituted in the base.

[0226] In a particular embodiment, A is pyrazinyl, and any pyrazinyl of A is one Z at the indicated position. 1 Substituted with a base, and one Z 2 It is substituted with Z. In one embodiment, A is Z 3 It is not substituted by the base.

[0227] In a particular embodiment, A is [ka] That is the case.

[0228] In a particular embodiment, A is [ka] That is the case.

[0229] In a particular embodiment, A is [ka] That is the case.

[0230] In a particular embodiment, A is [ka] That is the case.

[0231] In a particular embodiment, A is [ka] That is the case.

[0232] In a particular embodiment of Equation III, R 2 R is a phenyl compound that is optionally substituted with one, two, or three halogens, which may be the same or different. In certain embodiments, R 2 is a phenyl compound that is optionally substituted with one or two halogens, which may be the same or different. In certain embodiments, R2 R is a phenyl compound that is optionally substituted with two halogens, which may be the same or different. In a particular embodiment, R 2 This is a phenyl compound that is optionally substituted with a single halogen.

[0233] In a particular embodiment, R 2 is 3,5-difluorophenyl or 3-fluorophenyl. In certain embodiments, R 2 is 3,5-difluorophenyl. In certain embodiments, R 2 It is 3-fluorophenyl.

[0234] In a particular embodiment, part [ka] teeth, [ka] And in the formula, Z 5a This is H or a halogen.

[0235] In a particular embodiment of Equation III, each Z 3 If present, Z is independently methoxy, dimethylamino, or methylamino. In certain embodiments, Z 3 If present, it is methoxy. In a particular embodiment, Z 3 If present, it is dimethylamino. In certain embodiments, Z 3 If present, it is methylamino. In a particular embodiment, Z 3 If present, it is a halogen. In a particular embodiment, Z 3 If present, it is fluoro. In a particular embodiment, Z 3 If present, it is chloro. In a particular embodiment, Z 3If present, it is a bromo.

[0236] In a particular embodiment of Equation III, each R 3a and each R 3b These are H, respectively. In a particular embodiment, R 3a It is methyl, and R 3b H is H.

[0237] In a particular embodiment of Equation III, Z 2 These are (C2-C8) alkynyls, 6-12 membered aryls, 5-12 membered C-linked heteroaryls, 3-12 membered C-linked heterocycles, or -C(O)NR q3 R r3 Z 2 Any 6-12 member aryl, 5-12 member C-linked heteroaryl, or 3-12 member C-linked heteroring can have 1, 2, 3, 4, or 5 Z 2b or Z 2c It is optionally substituted in the base, Z 2 Any (C2-C8) alkynnyl has 1, 2, 3, 4, or 5 Z 2c It is optionally substituted in the base.

[0238] In a particular embodiment, Z 2 These are (C2-C8) alkynyls, 6-12 membered aryls, 5-12 membered C-linked heteroaryls, 3-12 membered C-linked heterocycles, or -C(O)NR q3 R r3 Z 2 Any 6-12 member aryl, 5-12 member C-linked heteroaryl, or 3-12 member C-linked heteroring can have 1, 2, 3, 4, or 5 Z 2c It is optionally substituted in the base, Z 2 Any (C2-C8) alkynnyl has 1, 2, 3, 4, or 5 Z 2c It is optionally substituted in the base.

[0239] In a particular embodiment, Z 2These include (C2-C8) alkynyls, phenyls, 5-6 member C-linked monocyclic heteroaryls, 8-10 member C-linked bicyclic heteroaryls, 8-10 member C-linked bicyclic heterocycles, or -C(O)NR q3 R r3 Z 2 Any phenyl, 5-6 member C-linked monocyclic heteroaryl, 8-10 member C-linked bicyclic heteroaryl, or 8-10 member C-linked bicyclic heterocycle may have 1, 2, 3, 4, or 5 Z 2b or Z 2c It is optionally substituted in the base, Z 2 Any (C2-C8) alkynnyl has 1, 2, 3, 4, or 5 Z 2c It is optionally substituted in the base.

[0240] In a particular embodiment, Z 2 These include (C2-C8) alkynyls, phenyls, 5-6 member C-linked monocyclic heteroaryls, 8-10 member C-linked bicyclic heteroaryls, 8-10 member C-linked bicyclic heterocycles, or -C(O)NR q3 R r3 Z 2 Any phenyl, 5-6 member C-linked monocyclic heteroaryl, 8-10 member C-linked bicyclic heteroaryl, or 8-10 member C-linked bicyclic heterocycle may have 1, 2, 3, 4, or 5 Z 2c It is optionally substituted in the base, Z 2 Any (C2-C8) alkynnyl has 1, 2, 3, 4, or 5 Z 2c It is optionally substituted in the base.

[0241] In a particular embodiment, Z 2 These include (C2-C8) alkynyls, phenyls, 5-6 member C-linked monocyclic heteroaryls, 8-10 member C-linked bicyclic heteroaryls, 8-10 member C-linked bicyclic heterocycles, or -C(O)NR q3 R r3 Therefore, a 5-6 member carbon-linked monocyclic heteroaryl, an 8-10 member carbon-linked bicyclic heteroaryl, or an 8-10 member carbon-linked bicyclic heterocycle has 1-9 carbon atoms and 1-4 heteroatoms in the ring system, Z 2Any phenyl, 5-6 member C-linked monocyclic heteroaryl, 8-10 member C-linked bicyclic heteroaryl, and 8-10 member C-linked bicyclic heterocycle may have 1, 2, 3, 4, or 5 Z 2b or Z 2c It is optionally substituted in the base, Z 2 Any (C2-C8) alkynnyl has 1, 2, 3, 4, or 5 Z 2c It is optionally substituted in the base.

[0242] In a particular embodiment, Z 2 These include (C2-C8) alkynyls, phenyls, 5-6 member C-linked monocyclic heteroaryls, 8-10 member C-linked bicyclic heteroaryls, 8-10 member C-linked bicyclic heterocycles, or -C(O)NR q3 R r3 Therefore, a 5-6 member carbon-linked monocyclic heteroaryl, an 8-10 member carbon-linked bicyclic heteroaryl, or an 8-10 member carbon-linked bicyclic heterocycle has 1-9 carbon atoms and 1-4 heteroatoms in the ring system, Z 2 Any phenyl, 5-6 member C-linked monocyclic heteroaryl, 8-10 member C-linked bicyclic heteroaryl, and 8-10 member or C-linked bicyclic heterocycle may have 1, 2, 3, 4, or 5 Z 2c It is optionally substituted in the base, Z 2 Any (C2-C8) alkynnyl has 1, 2, 3, 4, or 5 Z 2c It is optionally substituted in the base.

[0243] In a particular embodiment of Equation III, Z 2 This is 1, 2, 3, 4 or 5 Z 2c It is an (C2-C8) alkynyl that is optionally substituted with a group. In a particular embodiment, Z 2 is 1, 2, 3 or 4 Z 2c It is an (C2-C8) alkynyl that is optionally substituted with a group. In a particular embodiment, Z 2 is 1, 2, or 3 Z 2c Based These are (C2~C8) alkynyls that are optionally substituted. In a particular embodiment, Z2 is 1 or 2 Z 2c These are (C2-C8) alkynyl groups that are optionally substituted at the base.

[0244] In a particular embodiment, Z 2 is, formula [ka] It is Z 2 Each of the (C1-C4) alkyl moieties, if present, contains 1, 2, or 3 Z 2c It is optionally substituted in the base, Z 2b The base can be the same or different.

[0245] In a particular embodiment, Z 2 is, formula [ka] It is Z 2 Each of the (C1-C4) alkyl moieties contains 1, 2, or 3 Z 2c It is optionally substituted in the base, Z 2b The base can be the same or different.

[0246] In a particular embodiment, Z 2 is, formula [ka] It is Z 2 Each of the (C1-C4) alkyl moieties contains 1, 2, or 3 Z 2c It is optionally substituted in the base, Z 2b The base can be the same or different.

[0247] In a particular embodiment of Equation III, Z2 is 1, 2, 3 or 4 Z 2b or Z 2c It is substituted with Z 2b and Z 2c The bases may be the same or different. In a particular embodiment, Z 2 is 1, 2, or 3 Z 2b or Z 2c It is substituted with Z 2b and Z 2c The bases may be the same or different. In a particular embodiment, Z 2 is 1 or 2 Z 2b or Z 2c It is substituted with Z 2b and Z 2c The bases may be the same or different. In a particular embodiment, Z 2 is one Z 2b or Z 2c It is substituted with the base.

[0248] In a particular embodiment of Equation III, Z 2 is 1, 2, or 3 Z 2b or Z 2c It is optionally substituted in the base, Z 2b and Z 2c The bases may be the same or different. In a particular embodiment, Z 2 is one Z 2b or Z 2c It is replaced by the base. In a particular embodiment, Z 2 This is two Z 2b or Z 2c It is substituted with Z 2b and Z 2c The bases may be the same or different. In a particular embodiment, Z 2 This is three Z 2b or Z 2c It is substituted with Z 2b and Z 2c The base can be the same or different.

[0249] In a particular embodiment of Equation III, Z 2 is 1, 2, 3 or 4 Z 2c It is substituted with Z 2c The bases may be the same or different. In a particular embodiment, Z 2 is 1, 2, or 3 Z 2c It is substituted with Z 2c The bases may be the same or different. In a particular embodiment, Z 2 is 1 or 2 Z 2c It is substituted with Z 2c The bases may be the same or different. In a particular embodiment, Z 2 is one Z 2c It is substituted with the base.

[0250] In a particular embodiment of Equation III, Z 2 is 1, 2, or 3 Z 2c It is optionally substituted in the base, Z 2c The bases may be the same or different. In a particular embodiment, Z 2 is one Z 2c It is replaced by the base. In a particular embodiment, Z 2 This is two Z 2c It is substituted with Z 2c The bases may be the same or different. In a particular embodiment, Z 2 This is three Z 2c It is substituted with Z 2c The base can be the same or different.

[0251] In a particular embodiment, each Z 2c These are, independently, halogen, -OR n4 , NR q4 R r4 , -NR n4 CO2R p4 , -C(O)OR n4 , or -C(O)NR q4 R r4 In a particular embodiment, each Z 2c These are, independently, halogen or -OR n4That is the case.

[0252] In a particular embodiment, there are 1, 2, 3, 4, or 5 Z 2b or Z 2c Z is arbitrarily substituted in the base. 2 teeth, [ka] That is the case.

[0253] In a particular embodiment, there are 1, 2, 3, 4, or 5 Z 2b or Z 2c Z is arbitrarily substituted in the base. 2 teeth, [ka] That is the case.

[0254] In a particular embodiment, there are 1, 2, 3, 4, or 5 Z 2b or Z 2c Z is arbitrarily substituted in the base. 2 teeth, [ka] That is the case.

[0255] In a particular embodiment, there are 1, 2, 3, 4, or 5 Z 2b or Z 2c Z is arbitrarily substituted in the base. 2 teeth, [ka] That is the case.

[0256] In a particular embodiment, there are 1, 2, 3, 4, or 5 Z2b or Z 2c Z is arbitrarily substituted in the base. 2 teeth, [ka] That is the case.

[0257] In a particular embodiment, there are 1, 2, 3, 4, or 5 Z 2b or Z 2c Z is arbitrarily substituted in the base. 2 teeth, [ka] That is the case.

[0258] In a particular embodiment of Equation III, R 1 It is a 5-12 member heteroaryl, and R 1 Any 5-12 member heteroaryl can have 1, 2, 3, 4, or 5 Z 4 It is optionally substituted in the base.

[0259] In a particular embodiment of Equation III, R 1 R is an 8-12 member bicyclic heteroaryl or an 8-12 member tricyclic heteroaryl, 1 Any 8-12 member bicyclic heteroaryl or 8-12 member tricyclic heteroaryl can have 1, 2, 3, 4, or 5 Z 4 It is optionally substituted in the base.

[0260] In a particular embodiment, R 1 It is an 8-12 member tricyclic heteroaryl, and R 1 The 8-12 member tricyclic heteroaryls have 1, 2, 3, 4, or 5 Z 4 It is optionally substituted in the base.

[0261] In a particular embodiment, R1 These are 8-12 membered bicyclic heteroaryls or 8-12 membered tricyclic heteroaryls, and each of these has 4-10 carbon atoms and 1-5 heteroatoms in its ring system, R 1 Any 8-12 member bicyclic heteroaryl or 8-12 member tricyclic heteroaryl can have 1, 2, 3, 4, or 5 Z 4 It is optionally substituted in the base.

[0262] In a particular embodiment, R 1 is an 8-12 membered bicyclic heteroaryl or an 8-12 membered tricyclic heteroaryl, and the 8-12 membered bicyclic heteroaryl or the 8-12 membered tricyclic heteroaryl contains at least one partially unsaturated ring, R 1 Any 8-12 member bicyclic heteroaryl or 8-12 member tricyclic heteroaryl can have 1, 2, 3, 4, or 5 Z 4 It is optionally substituted in the base.

[0263] In a particular embodiment, R 1 R is an 8-12 member tricyclic heteroaryl, and an 8-12 member tricyclic heteroaryl contains at least one partially unsaturated ring, 1 Any 8-12 member bicyclic heteroaryl or 8-12 member tricyclic heteroaryl can have 1, 2, 3, 4, or 5 Z 4 It is optionally substituted in the base.

[0264] In a particular embodiment of Equation III, R 1 R is an 8-12 membered bicyclic heteroaryl or an 8-12 membered tricyclic heteroaryl, and an 8-12 membered bicyclic heteroaryl or an 8-12 membered tricyclic heteroaryl has 4-9 carbon atoms and 1-5 heteroatoms in its ring system, 1 Any 8-12 member bicyclic heteroaryl or 8-12 member tricyclic heteroaryl can have 1, 2, 3, 4, or 5 Z 4 It is optionally substituted in the base.

[0265] In a particular embodiment, R 1 These are 8-12 membered bicyclic heteroaryls, and 8-12 membered bicyclic heteroaryls have 6-9 carbon atoms and 1-3 heteroatoms in the ring system. Having a child, R 1 Any 8-12 member bicyclic heteroaryl can have 1, 2, 3, 4, or 5 Z 4 It is optionally substituted in the base.

[0266] In a particular embodiment, R 1 R is an 8-12 membered bicyclic heteroaryl or an 8-12 membered tricyclic heteroaryl, and an 8-12 membered bicyclic heteroaryl or an 8-12 membered tricyclic heteroaryl has 6-9 carbon atoms and 1-3 heteroatoms in its ring system, 1 Any 8-12 member bicyclic heteroaryl or 8-12 member tricyclic heteroaryl can have 1, 2, 3, 4, or 5 Z 4 It is optionally substituted in the base.

[0267] In a particular embodiment of Equation III, R 1 It has the following equation IIa [ka] [In the formula, C, together with the two carbon atoms of the bonded ring B, forms a 3- to 7-membered monocyclic carbon ring, a 5- to 8-membered bicyclic carbon ring, a 3- to 7-membered monocyclic heterocycle, or a 5- to 8-membered bicyclic heterocycle, and any 3- to 7-membered monocyclic carbon ring, 5- to 8-membered bicyclic carbon ring, 3- to 7-membered monocyclic heterocycle, or 5- to 8-membered bicyclic heterocycle of C has 1, 2, 3, 4, or 5 Z 4 It is optionally substituted in the base, Z 4 The bases are the same or different. B is a 5-membered or 6-membered monocyclic heteroaryl having 1, 2, or 3 nitrogen atoms, and B has 1, 2, 3, 4, or 5 Z4 It is optionally substituted in the base, Z 4 The origins are the same or different.

[0268] In a particular embodiment of Equation III, R 1 The following equation IIb is obtained [ka] [In the formula, C, together with the two carbon atoms of the bonded ring B, forms a 3-7 member monocyclic carbon ring, a 5-8 member bicyclic carbon ring, a 3-7 member monocyclic heterocycle, or a 5-8 member bicyclic heterocycle of C. Elementary rings or biring heteroalgebras with 5 to 8 members are defined by 1, 2, 3, 4, or 5 Z 4 It is optionally substituted in the base, Z 4 The bases are the same or different. B is a 5-membered or 6-membered monocyclic heteroaryl having 1, 2, or 3 nitrogen atoms. V is either C or N, W is CZ 4c , NZ 4c or N, X is CZ 4c , NZ 4c or N, Y is CZ 4c Or it is N, or it does not exist. The dashed bonds are selected from single and double bonds, and the dashed bonds V, W, X, and Y are selected so that a 5-membered or 6-membered monocyclic heteroaryl B becomes aromatic. each Z 4c These are, independently, H or Z 4 Selected from, Z 4 The origins are the same or different.

[0269] In a particular embodiment of Equation III, R 1 The following equation IIc is obtained [ka] [In the formula, C, together with the two carbon atoms of the bonded ring B, forms a 3- to 7-membered monocyclic carbon ring, a 5- to 8-membered bicyclic carbon ring, a 3- to 7-membered monocyclic heterocycle, or a 5- to 8-membered bicyclic heterocycle, and any 3- to 7-membered monocyclic carbon ring, 5- to 8-membered bicyclic carbon ring, 3- to 7-membered monocyclic heterocycle, or 5- to 8-membered bicyclic heterocycle of C has 1, 2, 3, 4, or 5 Z 4 It is optionally substituted in the base, Z 4 The bases are the same or different. B is a 5-membered or 6-membered monocyclic heteroaryl having 1, 2, or 3 nitrogen atoms. V is either C or N, W is CZ 4c or N, X is CZ 4c , NZ 4c or N, Y is CZ 4c Or it is N, or it does not exist. The dashed bonds are selected from single and double bonds, and the dashed bonds V, W, X, and Y are selected so that a 5-membered or 6-membered monocyclic heteroaryl B becomes aromatic. each Z 4c These are, independently, H or Z 4 Selected from, Z 4 The origins are the same or different.

[0270] In a particular embodiment of Equation III, R 1 The following equation IId is obtained [ka] [In the formula, C, together with two bonded carbon atoms, forms a 3-7 member monocyclic carbon ring, a 5-9 member bicyclic carbon ring, a 3-7 member monocyclic heterocycle, or a 5-9 member bicyclic heterocycle, and any 3-7 member monocyclic carbon ring, 5-9 member bicyclic carbon ring, 3-7 member monocyclic heterocycle, or 5-9 member bicyclic heterocycle of C has 1, 2, 3, 4, or 5 Z 4 It is optionally substituted in the base, Z 4 The bases are the same or different. each Z 4c These are, independently, H or Z 4 Selected from, Z 4 The origins are the same or different.

[0271] In a particular embodiment of Equation III, R 1 The following equation is [ka] [In the formula, C, together with two bonded carbon atoms, forms a 3- to 7-membered monocyclic or 5- to 9-membered bicyclic carbocyclic ring, and any 3- to 7-membered monocyclic or 5- to 9-membered bicyclic carbocyclic ring of C contains 1, 2, 3, 4, or 5 Z atoms. 4 It is optionally substituted in the base, Z 4 The origins are the same or different.

[0272] In a particular embodiment of Equation III, R 1 The following equation [ka] It holds.

[0273] In certain embodiments of formula III, C, together with two bonded carbon atoms, forms a 5-7 member monocyclic or bicyclic carbon ring of C, and any 5-7 member monocyclic or bicyclic carbon ring of C contains 1, 2, 3, or 4 Z4 It is optionally substituted in the base, Z 4 The origins are either the same or different.

[0274] In a particular embodiment of Equation III, each Z 4 These are independently (C1-C8) alkyl, (C3-C7) carbon ring, halogen, -CN, and -NR. q5 R r5 , -NR n5 COR p5 , -NR n5 CO2R p5 , -C(O)OR n5 , or -C(O)NR q5 R r5 Z 4 Any (C3-C7) carbon ring or (C1-C8) alkyl group has 1, 2, 3, 4, or 5 Z 4a It is optionally substituted in the base.

[0275] In a particular embodiment, each Z 4 These are independently (C1-C6) alkyl or halogen, and Z 4 Any (C1-C6) alkyl group is optionally substituted with one, two, three, four, or five halogens, which may be the same or different. In certain embodiments, each Z 4 These are independently (C1-C4) alkyl or halogen, and Z 4 Any (C1-C6) alkyl group is optionally substituted with one, two, three, four, or five halogens, which may be the same or different. In certain embodiments, each Z 4 These are independently (C1-C3) alkyl or halogen, and Z 4 Any (C1-C3) alkyl group is optionally substituted with one, two, three, four, or five halogens, which may be the same or different.

[0276] In a particular embodiment, each Z 4 These are independently fluoromethyl, trifluoromethyl, or difluoromethyl.

[0277] In a particular embodiment of Equation III, 1, 2, 3, 4, or 5 Z 4 R is arbitrarily substituted in the base. 1 teeth, [ka] That is the case.

[0278] In a particular embodiment, there are 1, 2, 3, 4, or 5 Z 4 R is arbitrarily substituted in the base. 1 teeth, [ka] That is the case.

[0279] In a particular embodiment, there are 1, 2, 3, 4, or 5 Z 4 R is arbitrarily substituted in the base. 1 teeth, [ka] That is the case.

[0280] In a particular embodiment, there are 1, 2, 3, 4, or 5 Z 4 R is arbitrarily substituted in the base. 1 teeth, [ka] In certain embodiments, there are 1, 2, 3, 4, or 5 Z 4 R is arbitrarily substituted in the base. 1 teeth, [ka] That is the case.

[0281] In a particular embodiment, there are 1, 2, 3, 4, or 5 Z 4 R is arbitrarily substituted in the base. 1 teeth, [ka] In certain embodiments, there are 1, 2, 3, 4, or 5 Z 4 R is arbitrarily substituted in the base. 1 teeth, [ka] That is the case.

[0282] In a particular embodiment, there are 1, 2, 3, 4, or 5 Z 4 R is arbitrarily substituted in the base. 1 teeth, [ka] That is the case.

[0283] In a particular embodiment, R 1 This is 1, 2, 3, 4 or 5 Z 4 It is optionally substituted in the base. [ka] That is the case.

[0284] In a particular embodiment, R 1 This is 1, 2, 3, 4 or 5 Z 4 It is optionally substituted in the base. [ka] That is the case.

[0285] In a particular embodiment of Equation III, each Z 4 These are independently (C1-C6) alkyl or halogen, and Z 4 Any (C1-C6) alkyl group is optionally substituted with one, two, three, four, or five halogens, which may be the same or different.

[0286] In a particular embodiment, each Z 4 These are independently (C1-C6) alkyl, -CN, or halogen, and Z 4 Any (C1-C6) alkyl group is optionally substituted with one, two, three, four, or five halogens, which may be the same or different.

[0287] In a particular embodiment, each Z 4 These are independently fluoromethyl, trifluoromethyl, or difluoromethyl.

[0288] In a particular embodiment, each Z 4 These are independently fluoromethyl, trifluoromethyl, -CN, or difluoromethyl.

[0289] In a particular embodiment of Equation III, Z 1 Z is a phenyl, a 5-14 member heteroaryl, or a 3-14 member heterocycle. 1 Any phenyl, 5-14 membered heteroaryl, or 3-14 membered heterocycle can have 1, 2, 3, 4, or 5 Z 1a or Z 1b It is optionally substituted in the base.

[0290] In a particular embodiment, Z 1 Z is a phenyl, a 5-12 membered heteroaryl, or a 3-12 membered heterocycle. 1 Any phenyl, 5-12 membered heteroaryl, or 3-12 membered heterocycle can have 1, 2, 3, 4, or 5 Z 1a or Z1b It is optionally substituted in the base.

[0291] In a particular embodiment, Z 1 Z is a phenyl, a 5-14 member heteroaryl, or a 3-14 member heterocycle. 1 Any phenyl, 5-14 membered heteroaryl, or 3-14 membered heterocycle can have 1, 2, 3, 4, or 5 Z 1a It is optionally substituted in the base.

[0292] In a particular embodiment, Z 1 Z is a phenyl, a 5-12 membered heteroaryl, or a 3-12 membered heterocycle. 1 Any phenyl, 5-12 membered heteroaryl, or 3-12 membered heterocycle can have 1, 2, 3, 4, or 5 Z 1a It is optionally substituted in the base.

[0293] In a particular embodiment, Z 1 Z is a phenyl molecule, a 5-6 member monocyclic heteroaryl molecule, an 8-10 member bicyclic heteroaryl molecule, an 8-10 member bicyclic heterocycle, or a 9-12 member tricyclic heterocycle. 1 Any phenyl, 5-6 member monocyclic heteroaryl, 8-10 member bicyclic heteroaryl, 8-10 member bicyclic heterocycle, or 9-12 member tricyclic heterocycle may have 1, 2, 3, 4, or 5 Z 1a or Z 1b It is optionally substituted in the base.

[0294] In a particular embodiment, Z 1 Z is a phenyl molecule, a 5-6 member monocyclic heteroaryl molecule, an 8-10 member bicyclic heteroaryl molecule, an 8-10 member bicyclic heterocycle, or a 9-12 member tricyclic heterocycle. 1 Any phenyl, 5-6 member monocyclic heteroaryl, 8-10 member bicyclic heteroaryl, 8-10 member bicyclic heterocycle, or 9-12 member tricyclic heterocycle may have 1, 2, 3, 4, or 5 Z 1a It is optionally substituted in the base.

[0295] In a particular embodiment, Z 1 These are phenyl, a 5-6 member monocyclic heteroaryl, an 8-10 member bicyclic heteroaryl, an 8-10 member bicyclic heterocycle, or a 9-12 member tricyclic heterocycle, and the 5-6 member monocyclic heteroaryl, 8-10 member bicyclic heteroaryl, 8-10 member bicyclic heterocycle, or 9-12 member tricyclic heterocycle have 1-11 carbon atoms and 1-5 heteroatoms in the ring system, Z 1 Any phenyl, 5-6 member monocyclic heteroaryl, 8-10 member bicyclic heteroaryl, 8-10 member bicyclic heterocycle, or 9-12 member tricyclic heterocycle may have 1, 2, 3, 4, or 5 Z 1a or Z 1b It is optionally substituted in the base.

[0296] In a particular embodiment, Z 1 These are phenyl, a 5-6 member monocyclic heteroaryl, an 8-10 member bicyclic heteroaryl, an 8-10 member bicyclic heterocycle, or a 9-12 member tricyclic heterocycle, and the 5-6 member monocyclic heteroaryl, 8-10 member bicyclic heteroaryl, 8-10 member bicyclic heterocycle, or 9-12 member tricyclic heterocycle have 1-11 carbon atoms and 1-5 heteroatoms in the ring system, Z 1 Any phenyl, 5-6 member monocyclic heteroaryl, 8-10 member bicyclic heteroaryl, 8-10 member bicyclic heterocycle, or 9-12 member tricyclic heterocycle may have 1, 2, 3, 4, or 5 Z 1a It is optionally substituted in the base.

[0297] In a particular embodiment, Z 1 These are phenyl, a 5-6 member monocyclic heteroaryl, an 8-10 member bicyclic heteroaryl, an 8-10 member bicyclic heterocycle, or a 9-12 member tricyclic heterocycle, and the 5-6 member monocyclic heteroaryl, 8-10 member bicyclic heteroaryl, 8-10 member bicyclic heterocycle, or 9-12 member tricyclic heterocycle have 4-11 carbon atoms and 1-3 heteroatoms in the ring system, Z 1Any phenyl, 5-6 member monocyclic heteroaryl, 8-10 member bicyclic heteroaryl, 8-10 member bicyclic heterocycle, or 9-12 member tricyclic heterocycle may have 1, 2, 3, 4, or 5 Z 1a or Z 1b It is optionally substituted in the base.

[0298] In a particular embodiment, Z 1 It is phenyl, a 5-6 member monocyclic heteroaryl, 8- A 10-membered bicyclic heteroaryl, an 8-10 membered bicyclic heterocycle, or a 9-12 membered tricyclic heterocycle, while a 5-6 membered monocyclic heteroaryl, an 8-10 membered bicyclic heteroaryl, an 8-10 membered bicyclic heterocycle, or a 9-12 membered tricyclic heterocycle has 4-11 carbon atoms and 1-3 heteroatoms in its ring system, Z 1 Any phenyl, 5-6 member monocyclic heteroaryl, 8-10 member bicyclic heteroaryl, 8-10 member bicyclic heterocycle, or 9-12 member tricyclic heterocycle may have 1, 2, 3, 4, or 5 Z 1a It is optionally substituted in the base.

[0299] In a particular embodiment, Z 1 Z is an 8-10 membered bicyclic heteroaryl or 8-10 membered bicyclic heterocycle. 1 Any 8-10 member bicyclic heteroaryl or 8-10 member bicyclic heterocycle can have 1, 2, 3, 4, or 5 Z 1a or Z 1b It is optionally substituted in the base.

[0300] In a particular embodiment, Z 1 Z is an 8-10 membered bicyclic heteroaryl or 8-10 membered bicyclic heterocycle. 1 Any 8-10 member bicyclic heteroaryl or 8-10 member bicyclic heterocycle can have 1, 2, 3, 4, or 5 Z 1a It is optionally substituted in the base.

[0301] In a particular embodiment, Z 1Z is an 8-10 membered bicyclic heteroaryl or 8-10 membered bicyclic heterocycle, and an 8-10 membered bicyclic heteroaryl or 8-10 membered bicyclic heterocycle has 3-9 carbon atoms and 1-5 heteroatoms in its ring system. 1 Any 8-10 member bicyclic heteroaryl or 8-10 member bicyclic heterocycle can have 1, 2, 3, 4, or 5 Z 1a or Z 1b It is optionally substituted in the base.

[0302] In a particular embodiment, Z 1 Z is an 8-10 membered bicyclic heteroaryl or 8-10 membered bicyclic heterocycle, and an 8-10 membered bicyclic heteroaryl or 8-10 membered bicyclic heterocycle has 3-9 carbon atoms and 1-5 heteroatoms in its ring system. 1 Any 8-10 member bicyclic heteroaryl or 8-10 member bicyclic heterocycle can have 1, 2, 3, 4, or 5 Z 1a It is optionally substituted in the base.

[0303] In a particular embodiment of Equation III, Z 1 is, Z 1b It has not been replaced.

[0304] In a particular embodiment of Equation III, each Z 1a These are independently oxo, (C3~C7) carbon ring, halogen, -CN, -O-(C1~C8) alkyl, and -NR. q1 R r1 , -NR n1 COR p1 , -NR n1 CO2R p1 , -NR n1 CONR q1 R r1 , -NR n1 S(O)2R p1 , -NR n1 S(O)2NR q1 R r1 , or -C(O)NR q1 R r1 That is the case.

[0305] In a particular embodiment, each Z 1a -NR n1 S(O)2R p1 , -NR n1 S(O)2NR q1 R r1 , or halogen. In a particular embodiment, each Z 1a These can be used independently with halogen or -NR n1 S(O)2R p1 In a particular embodiment, each Z 1a These can be used independently with halogen or -NR n1 S(O)2NR q1 R r1 That is the case.

[0306] In a particular embodiment, Z 1 This is two Z 1a It is substituted with each Z 1a -NR n1 S(O)2R p1 , -NR n1 S(O)2NR q1 R r1 , or halogen.

[0307] In a particular embodiment, each Z 1a These can be used independently with halogen or -NR n1 S(O)2R p1 And each Z 1b These are (C1-C8) alkyl groups, which may be the same or different. That is the case.

[0308] In a particular embodiment, Z 1a -NR n1 S(O)2R p1 or -NR n1 S(O)2NR q1 R r1 In a particular embodiment, Z 1a is a halogen. In a particular embodiment, Z 1a -NR q1 R r1 , -NR n1 COR p1 , -NR n1CO2R p1 , or -NR n1 CONR q1 R r1 That is the case.

[0309] In a particular embodiment, Z 1a is halogen, -OR n1 , or -C(O)NR q1 R r1 That is the case.

[0310] In a particular embodiment, Z 1a is halogen or -C(O)NR q1 R r1 That is the case.

[0311] In a particular embodiment, Z 1a These are halogens, -OH, or -C(O)NH2.

[0312] In a particular embodiment, Z 1a It is fluoro, -OH, or -C(O)NH2.

[0313] In a particular embodiment, each Z 1b These are alkyl groups (C1-C8) that may be the same or different.

[0314] In a particular embodiment, each Z 1b These are independently methyl or difluoromethyl.

[0315] In a particular embodiment of Equation III, Z 1 This is 1, 2, 3, 4 or 5 Z 1a or Z 1b It is optionally replaced by [ka] That is the case.

[0316] In a particular embodiment, Z 1 teeth, [ka] And each Z 1w Z 1a , Z 1b Or H. In a particular embodiment, each Z 1a These are, independently, halogen, -CN, and -OR. n1 , -NR n1 S(O)2R p1 , -NR n1 S(O)2NR q1 R r1 , -NR q1 R r1 , -NR n1 COR p1 , -NR n1 CONR q1 R r1 , or -NR n1 CO2R p1 And each Z 1b These are independently (C1-C8 alkyl), and the (C1-C8 alkyl) is optionally substituted with one, two, or three halogens that are the same or different, Z 1w At least one of them is Z 1a or Z 1b In a particular embodiment, Z 1w At least two of them independently, Z 1a In a particular embodiment, each Z 1a These are, independently, halogen, -NR n1 S(O)2R p1 , or -NR n1 S(O)2NR q1 R r1 That is the case.

[0317] In a particular embodiment, Z 1 teeth, [ka] [In the formula, each Z 1a These are, independently, halogen, -NR n1S(O)2R p1 or -NR n1 S(O)2NR q1 R r1 It is.

[0318] In a particular embodiment, Z 1 is 1, 2, 3 or 4 Z 1a or Z 1b It is optionally replaced by [ka] That is the case.

[0319] In a particular embodiment, Z 1 teeth, [ka] That is the case.

[0320] In a particular embodiment, there are 1, 2, 3, 4, or 5 Z 1a or Z 1b Based on optional selection Selectively substituted Z 1 teeth, [ka] That is the case.

[0321] In a particular embodiment, there are 1, 2, 3, 4, or 5 Z 1a or Z 1b Z is arbitrarily substituted in the base. 1 teeth, [ka] That is the case.

[0322] In a particular embodiment, there are 1, 2, 3, 4, or 5 Z 1a or Z 1b Z is arbitrarily substituted in the base. 1 teeth, [ka] That is the case.

[0323] In a particular embodiment, there are 1, 2, 3, 4, or 5 Z 1a or Z 1b Z is arbitrarily substituted in the base. 1 teeth, [ka] That is the case.

[0324] In a particular embodiment, there are 1, 2, 3, 4, or 5 Z 1a or Z 1b Z is arbitrarily substituted in the base. 1 teeth, [ka] That is the case.

[0325] In a particular embodiment, Z 1 teeth, [ka] That is the case.

[0326] In a particular embodiment, Z 2 -AZ 1 teeth, [ka] That is the case.

[0327] In one variant of formula III, A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and R 1 These are 1, 2, 3, 4, or 5 Z which may be the same or different. 4 It is a 5- to 12-membered heteroaryl that is optionally substituted with a group. In another variant, A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and R 1 R is an 8-12 member bicyclic heteroaryl or an 8-12 member tricyclic heteroaryl, 1 Any 8-12 member bicyclic heteroaryl or 8-12 member tricyclic heteroaryl can have 1, 2, 3, 4, or 5 Z 4 The base is optionally substituted. In another variant, A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and R 1 R is an 8-12 member bicyclic heteroaryl or an 8-12 member tricyclic heteroaryl, 1 Any 8-12 member bicyclic heteroaryl or 8-12 member tricyclic heteroaryl can have 1, 2, 3, 4, or 5 Z 4 It is arbitrarily substituted at the base, and each Z 4 These are independently fluoromethyl, trifluoromethyl, or difluoromethyl.

[0328] In one variant of Equation III, A is pyridinyl, and R 1 R is an 8-12 member bicyclic heteroaryl or an 8-12 member tricyclic heteroaryl, 1 Any 8-12 member bicyclic heteroaryl or 8-12 member tricyclic heteroaryl may have 1, 2, 3, 4, or 5 Z, which may be the same or different. 4 It is optionally substituted in the base.

[0329] In one variant of formula III, A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and R 2is 3,5-difluorophenyl. In another variant, A is pyridinyl and R 2 is 3,5-difluorophenyl. In another variant, A is pyrimidinyl and R 2 is 3,5-difluorophenyl. In another variant, A is pyrazinyl and R 2 is 3,5-difluorophenyl. In another variant, A is pyridazinyl and R 2 It is 3,5-difluorophenyl.

[0330] In one variant of formula III, A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and Z 1 Z is a phenyl molecule, a 5-6 member monocyclic heteroaryl molecule, an 8-10 member bicyclic heteroaryl molecule, an 8-10 member bicyclic heterocycle, or a 9-12 member tricyclic heterocycle. 1 Any phenyl, 5-6 member monocyclic heteroaryl, 8-10 member bicyclic heteroaryl, 8-10 member bicyclic heterocycle, or 9-12 member tricyclic heterocycle may have 1, 2, 3, 4, or 5 Z, which may be the same or different. 1a The base is optionally substituted. In another variant, A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and Z 1 This is 1, 2, 3, 4 or 5 Z 1a It is a phenyl compound that is optionally substituted with a group. In another variant, A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridadinyl, and Z 1 These are monocyclic heteroaryl compounds with 5-6 members or bicyclic heteroaryl compounds with 8-10 members, and Z 1 Any 5-6 member monocyclic heteroaryl or 8-10 member bicyclic heteroaryl can have 1, 2, 3, 4, or 5 Z 1a The base is optionally substituted. In another variant, A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and Z 1 Z is a biring heteroalgebra with 8 to 10 members or a triring heteroalgebra with 9 to 12 members. 1Any 8-10 member biring complex or 9-12 member triring complex can be any 1, 2, 3, 4, or 5 Z 1a It is optionally substituted in the base.

[0331] In one variant of equation III, A is pyridinyl, and Z 1 Z is a phenyl molecule, a 5-6 member monocyclic heteroaryl molecule, an 8-10 member bicyclic heteroaryl molecule, an 8-10 member bicyclic heterocycle, or a 9-12 member tricyclic heterocycle. 1 Any phenyl, 5-6 member monocyclic heteroaryl, 8-10 member bicyclic heteroaryl, 8-10 member bicyclic heterocycle, or 9-12 member tricyclic heterocycle may have 1, 2, 3, 4, or 5 Z, which may be the same or different. 1a It is optionally substituted at the base. In another variant, A is pyridinyl Yes, Z 1 This is 1, 2, 3, 4 or 5 Z 1a It is a phenyl compound that is optionally substituted with a group. In another variant, A is pyridinyl and Z 1 These are monocyclic heteroaryl compounds with 5-6 members or bicyclic heteroaryl compounds with 8-10 members, and Z 1 Any 5-6 member monocyclic heteroaryl or 8-10 member bicyclic heteroaryl can have 1, 2, 3, 4, or 5 Z 1a It is optionally substituted at the base. In another variant, A is pyridinyl and Z 1 Z is a biring heteroalgebra with 8 to 10 members or a triring heteroalgebra with 9 to 12 members. 1 Any 8-10 member biring complex or 9-12 member triring complex can be any 1, 2, 3, 4, or 5 Z 1a It is optionally substituted in the base.

[0332] In one variant of formula III, A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and Z 2 These are (C2-C8) alkynyls, 6-12 membered aryls, 5-12 membered C-linked heteroaryls, 3-12 membered C-linked heterocycles, or -C(O)NR q3 R r3 Z2 Any 6-12 member aryl, 5-12 member C-linked heteroaryl, or 3-12 member C-linked heteroring may have 1, 2, 3, 4, or 5 Z, which may be the same or different. 2b or Z 2c It is optionally substituted in the base, Z 2 Any (C2-C8) alkynnyl can be one, two, three, four, or five Z which may be the same or different. 2c It is optionally substituted at the base. In another variant, A is pyridinyl and Z 2 These are (C2-C8) alkynyls, 6-12 membered aryls, 5-12 membered C-linked heteroaryls, 3-12 membered C-linked heterocycles, or -C(O)NR q3 R r3 Z 2 Any 6-12 member aryl, 5-12 member C-linked heteroaryl, or 3-12 member C-linked heteroring can have 1, 2, 3, 4, or 5 Z 2b or Z 2c It is optionally substituted in the base, Z 2 Any (C2-C8) alkynnyl has 1, 2, 3, 4, or 5 Z 2c It is optionally substituted at the base. In another variant, A is pyrimidinyl and Z 2 These are (C2-C8) alkynyls, 6-12 membered aryls, 5-12 membered C-linked heteroaryls, 3-12 membered C-linked heterocycles, or -C(O)NR q3 R r3 Z 2 Any 6-12 member aryl, 5-12 member C-linked heteroaryl, or 3-12 member C-linked heteroring can have 1, 2, 3, 4, or 5 Z 2b or Z 2c It is optionally substituted in the base, Z 2 Any (C2-C8) alkynnyl has 1, 2, 3, 4, or 5 Z 2c It is optionally substituted at the base. In another variant, A is pyrazinyl and Z 2 These are (C2-C8) alkynyls, 6-12 membered aryls, 5-12 membered C-linked heteroaryls, 3-12 membered C-linked heterocycles, or -C(O)NR q3R r3 Z 2 Any 6-12 member aryl, 5-12 member C-linked heteroaryl, or 3-12 member C-linked heteroring can have 1, 2, 3, 4, or 5 Z 2b or Z 2c It is optionally substituted in the base, Z 2 Any (C2-C8) alkynnyl has 1, 2, 3, 4, or 5 Z 2c It is optionally substituted at the base. In another variant, A is pyridazinyl and Z 2 These are (C2-C8) alkynyls, 6-12 membered aryls, 5-12 membered C-linked heteroaryls, 3-12 membered C-linked heterocycles, or -C(O)NR q3 R r3 Z 2 Any 6-12 member aryl, 5-12 member C-linked heteroaryl, or 3-12 member C-linked heteroring can have 1, 2, 3, 4, or 5 Z 2b or Z 2c It is optionally substituted in the base, Z 2 Any (C2-C8) alkynnyl has 1, 2, 3, 4, or 5 Z 2c It is optionally substituted in the base.

[0333] In one variation of Equation III, A is one Z 1 Part and one Z 2 It is partially replaced and Z 3 It is a pyridinyl that is not partially substituted (0 copies), Z 2 is (C2~C8) alkynyl or aryl, Z 2 This may be substituted at will, as shown by Equation III. In another variant, A is one Z 1 Part and one Z 2 It is partially replaced and Z 3 It is a pyridinyl that is not partially substituted (0 copies), Z 2 is (C2~C8)alkynyl, and Z 2 This may be optionally substituted, as shown by Equation III. In certain variants, A is one Z 1It is partially substituted, and there is one Z at the alpha position relative to the nitrogen atom of the pyridinyl ring. 2 portion It is replaced with and Z 3 It is a pyridinyl that is not partially substituted (0 copies), Z 2 is (C2~C8)alkynyl, and Z 2 This can be optionally substituted, as shown by Equation III.

[0334] In one variation of Equation III, R 1 These are 1, 2, 3, 4, or 5 Z which may be the same or different. 4 A 5-12 member heteroaryl that is optionally substituted at the base, Z 1 Z is a phenyl molecule, a 5-6 member monocyclic heteroaryl molecule, an 8-10 member bicyclic heteroaryl molecule, an 8-10 member bicyclic heterocycle, or a 9-12 member tricyclic heterocycle. 1 Any phenyl, 5-6 member monocyclic heteroaryl, 8-10 member bicyclic heteroaryl, 8-10 member bicyclic heterocycle, or 9-12 member tricyclic heterocycle may have 1, 2, 3, 4, or 5 Z, which may be the same or different. 1a It is optionally substituted in the base. In another variant, R 1 R is an 8-12 member bicyclic heteroaryl or an 8-12 member tricyclic heteroaryl, 1 Any 8-12 member bicyclic heteroaryl or 8-12 member tricyclic heteroaryl can have 1, 2, 3, 4, or 5 Z 4 It is optionally substituted in the base, Z 1 Z is a phenyl molecule, a 5-6 member monocyclic heteroaryl molecule, an 8-10 member bicyclic heteroaryl molecule, an 8-10 member bicyclic heterocycle, or a 9-12 member tricyclic heterocycle. 1 Any phenyl, 5-6 member monocyclic heteroaryl, 8-10 member bicyclic heteroaryl, 8-10 member bicyclic heterocycle, or 9-12 member tricyclic heterocycle may have 1, 2, 3, 4, or 5 Z 1a It is optionally substituted in the base.

[0335] In one variation of Equation III, R 1 R is an 8-12 member bicyclic heteroaryl or an 8-12 member tricyclic heteroaryl, 1 Any 8-12 member bicyclic heteroaryl or 8-12 member tricyclic heteroaryl may have 1, 2, 3, 4, or 5 Z, which may be the same or different. 4 It is optionally substituted in the base, Z 1 Z is an 8-10 membered bicyclic heteroaryl or 8-10 membered bicyclic heterocycle. 1 Any 8-10 member bicyclic heteroaryl or 8-10 member bicyclic heterocycle may have 1, 2, 3, 4, or 5 Z elements, which may be the same or different. 1a It is optionally substituted in the base.

[0336] In one variation of Equation III, R 1 These are 1, 2, 3, 4, or 5 Z which may be the same or different. 4 A 5-12 member heteroaryl that is optionally substituted at the base, Z 2 These are (C2-C8) alkynyls, 6-12 membered aryls, 5-12 membered C-linked heteroaryls, 3-12 membered C-linked heterocycles, or -C(O)NR q3 R r3 Z 2 Any 6-12 member aryl, 5-12 member C-linked heteroaryl, or 3-12 member C-linked heteroring can have 1, 2, 3, 4, or 5 Z 2b or Z 2c It is optionally substituted in the base, Z 2 Any (C2-C8) alkynnyl can be one, two, three, four, or five Z which may be the same or different. 2c It is optionally substituted in the base. In another variant, R 1 R is an 8-12 member bicyclic heteroaryl or an 8-12 member tricyclic heteroaryl, 1 Any 8-12 member bicyclic heteroaryl or 8-12 member tricyclic heteroaryl can have 1, 2, 3, 4, or 5 Z 4 It is optionally substituted in the base, Z 2These are (C2-C8) alkynyls, 6-12 membered aryls, 5-12 membered C-linked heteroaryls, 3-12 membered C-linked heterocycles, or -C(O)NR q3 R r3 Z 2 Any 6-12 member aryl, 5-12 member C-linked heteroaryl, or 3-12 member C-linked heteroring can have 1, 2, 3, 4, or 5 Z 2b or Z 2c It is optionally substituted in the base, Z 2 Any (C2-C8) alkynnyl has 1, 2, 3, 4, or 5 Z 2c It is optionally substituted in the base.

[0337] In one variant of Equation III, Z 1 Z is a phenyl molecule, a 5-6 member monocyclic heteroaryl molecule, an 8-10 member bicyclic heteroaryl molecule, an 8-10 member bicyclic heterocycle, or a 9-12 member tricyclic heterocycle. 1 Any phenyl, 5-6 member monocyclic heteroaryl, 8-10 member bicyclic heteroaryl, 8-10 member bicyclic heterocycle, or 9-12 member tricyclic heterocycle The elementary ring consists of 1, 2, 3, 4, or 5 Z elements, which may be the same or different. 1a It is optionally substituted in the base, Z 2 These are (C2-C8) alkynyls, 6-12 membered aryls, 5-12 membered C-linked heteroaryls, 3-12 membered C-linked heterocycles, or -C(O)NR q3 R r3 Z 2 Any 6-12 member aryl, 5-12 member C-linked heteroaryl, or 3-12 member C-linked heteroring may have 1, 2, 3, 4, or 5 Z, which may be the same or different. 2b or Z 2c It is optionally substituted in the base, Z 2 Any (C2-C8) alkynnyl can be one, two, three, four, or five Z which may be the same or different. 2c It is optionally substituted in the base.

[0338] In one variant of Equation III, Z 1These are 1, 2, 3, 4, or 5 Z which may be the same or different. 1a It is a bicyclic heteroaryl that is optionally substituted with Z 2 These are 1, 2, 3, 4, or 5 Z which may be the same or different. 2c These are (C2-C8) alkynyl groups that are optionally substituted at the base.

[0339] In one variation of Equation III, R 1 It is a 5-12 member heteroaryl, Z 1 Z is a phenyl molecule, a 5-6 member monocyclic heteroaryl molecule, an 8-10 member bicyclic heteroaryl molecule, an 8-10 member bicyclic heterocycle, or a 9-12 member tricyclic heterocycle. 1 Any phenyl, 5-6 member monocyclic heteroaryl, 8-10 member bicyclic heteroaryl, 8-10 member bicyclic heterocycle, or 9-12 member tricyclic heterocycle may have 1, 2, 3, 4, or 5 Z, which may be the same or different. 1a It is optionally substituted in the base, Z 2 These are (C2-C8) alkynyls, 6-12 membered aryls, 5-12 membered C-linked heteroaryls, 3-12 membered C-linked heterocycles, or -C(O)NR q3 R r3 Z 2 Any 6-12 member aryl, 5-12 member C-linked heteroaryl, or 3-12 member C-linked heteroring may have 1, 2, 3, 4, or 5 Z, which may be the same or different. 2b or Z 2c It is optionally substituted in the base, Z 2 Any (C2-C8) alkynnyl can be one, two, three, four, or five Z which may be the same or different. 2c It is optionally substituted in the base.

[0340] In a particular embodiment of Equation III, A is a six-membered monocyclic heteroaryl having one or two nitrogen atoms, and the six-membered monocyclic heteroaryl has one Z at the indicated position. 1 Substituted with a base, and one Z 2Substituting with the base, and one or two Z which may be the same or different 3 It is optionally substituted in the base, R 1 R is a 6-12 member aryl, a 5-12 member heteroaryl, or a 3-12 member heteroring. 1 Any 6- to 12-membered aryl, 5- to 12-membered heteroaryl, or 3- to 12-membered heteroring may have 1, 2, 3, 4, or 5 Z, which may be the same or different. 4 It is optionally substituted in the base, R 2 This is a phenyl compound that is optionally substituted with one, two, three, four, or five halogens, which may be the same or different. R 3a and R 3b Each of these is independently H or (C1-C3) alkyl, Z 1 Z is a 6-12 member aryl, a 5-14 member heteroaryl, or a 3-14 member heteroring. 1 Any 6- to 12-membered aryl, 5- to 14-membered heteroaryl, or 3- to 14-membered heteroring may have 1, 2, 3, 4, or 5 Z, which may be the same or different. 1a or Z 1b It is optionally replaced by each Z 1a These are independently oxo, (C3~C7) carbon ring, halogen, -CN, -O-(C1~C8) alkyl, and -OC(O)R p1 -OC(O)NR q1 R r1 , -NR q1 R r1 , -NR n1 COR p1 , -NR n1 CO2R p1 , -NR n1 CONR q1 R r1 , -NR n1 S(O)2R p1 , -NR n1 S(O)2NR q1 R r1 , -C(O)R n1 , -C(O)ORn1 , or -C(O)NR q1 R r1 And, each Z 1b These are 1, 2, 3, 4, or 5 independently, which may be the same or different. It is an alkyl group (C1-C8) that is optionally substituted with a logen. Each R n1 These are independently H or (C1-C8) alkyl, Each R p1 These are independently (C1-C8) alkyl, (C3-C7) carbon ring, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl, and R p1 Any (C3-C7) carbon ring, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 (C1-C8) alkyl groups, which may be the same or different. p1 Any (C1-C8) alkyl group may be the same or different 1, 2, 3, 4, or 5 halogens, hydroxyls, -O(C1-C8) alkyl groups, or -NR groups. q2 R r2 It is optionally replaced by R q1 and R r1 Each of them is independently H, (C1-C8) alkyl, (C3-C7) carbon ring, or a 3-7 membered heterocycle, R q1 Or R r1 Any (C1-C8) alkyl group is optionally substituted with one, two, three, four, or five halogens or -CN, which may be the same or different, or R q1 and R r1 These, together with the nitrogen atoms to which they are bonded, form a 5-membered, 6-membered, or 7-membered heterocycle, and the 5-membered, 6-membered, or 7-membered heterocycle is optionally substituted with one, two, three, four, or five (C1-C8) alkyl groups, which may be the same or different. R q2 and R r2 Each of them is independently either H, (C1-C8) alkyl, (C3-C7) carbon ring, or R q2 and Rr2 These, together with the nitrogen atoms to which they are bonded, form a 5-membered, 6-membered, or 7-membered heterocycle. Z 2 These include (C2-C8) alkenyls, (C2-C8) alkynyls, 6-12 membered aryls, 5-12 membered C-linked heteroaryls, 3-12 membered C-linked heterocycles, and -C(O)R n3 , or -C(O)NR q3 R r3 Z 2 Any 6-12 member aryl, 5-12 member C-linked heteroaryl, or 3-12 member C-linked heteroring may have 1, 2, 3, 4, or 5 Z, which may be the same or different. 2b or Z 2c It is optionally substituted in the base, Z 2 Any (C2-C8) alkenyl or (C2-C8) alkinyl may be the same or different of 1, 2, 3, 4, or 5 Z 2c It is optionally substituted in the base, Each R n3 These are independently H or (C1-C4) alkyl, R q3 and R r3 Each of these is independently H or (C1-C4) alkyl, each Z 2b These are independently oxo, (C1-C4) alkyl, (C1-C4) heteroalkyl, or (C1-C4) haloalkyl. each Z 2c These are independently oxo, halogen, -CN, and -OR. n4 , NR q4 R r4 , -NR n4 COR p4 , -NR n4 CO2R p4 , -NR n4 S(O)2R p4 , -C(O)R n4 , -C(O)OR n4 or -C(O)NR q4 R r4 And, Each R n4These are independently H, (C1-C4) alkyl, or (C1-C4) heteroalkyl. Each R p4 These are independently (C1-C8) alkyl groups, R q4 and R r4 Each of these is independently H, (C1-C4) alkyl, or (C1-C4) heteroalkyl. each Z 3 These are independently (C1-C4) heteroalkyl or halogen, each Z 4 These are independently oxo, (C1-C8) alkyl, (C3-C7) carbon ring, halogen, -CN, and -OR. n5 , -NR q5 R r5 , -NR n5 COR p5 , -NR n5 CO2R p5 , -C(O)R n5 , -C(O)OR n5 , or -C(O)NR q5 R r5 Z 4 Any (C3-C7) carbon ring or (C1-C8) alkyl group may be the same or different 1, 2, 3, 4, or 5 Z 4a It is optionally substituted in the base, each Z 4a These are, independently, halogen, -CN, or -OR n6 And, R n5 , R p5 , R q5 , R r5 , and R n6 Each of these is independently either H or (C1-C4) alkyl.

[0341] In a particular embodiment of Equation III, A 1 CH, CZ 3 , or nitrogen, A 2 is CH or nitrogen, R 1R is a 6-12 member aryl, a 5-12 member heteroaryl, or a 3-12 member heteroring. 1 Any 6- to 12-membered aryl, 5- to 12-membered heteroaryl, or 3- to 12-membered heteroring may have 1, 2, 3, 4, or 5 Z, which may be the same or different. 4 It is optionally substituted in the base, R 3a and R 3b Each of these is independently H or (C1-C3) alkyl, Z 1 Z is a 6-12 member aryl, a 5-14 member heteroaryl, or a 3-14 member heteroring. 1 Any 6- to 12-membered aryl, 5- to 14-membered heteroaryl, or 3- to 14-membered heteroring may have 1, 2, 3, 4, or 5 Z, which may be the same or different. 1a or Z 1b It is optionally replaced by each Z 1a These are independently oxo, (C3~C7) carbon ring, halogen, -CN, -O-(C1~C8) alkyl, and -OC(O)R p1 -OC(O)NR q1 R r1 , -NR q1 R r1 , -NR n1 COR p1 , -NR n1 CO2R p1 , -NR n1 CONR q1 R r1 , -NR n1 S(O)2R p1 , -NR n1 S(O)2NR q1 R r1 , -C(O)R n1 , -C(O)OR n1 , or -C(O)NR q1 R r1 And, each Z 1b These are (C1-C8) alkyl groups that are independently and optionally substituted with 1, 2, 3, 4, or 5 halogens, which may be the same or different. Each R n1These are independently H or (C1-C8) alkyl, Each R p1 These are independently (C1-C8) alkyl, (C3-C7) carbon ring, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl, and R p1 Any (C3-C7) carbon ring, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 (C1-C8) alkyl groups, which may be the same or different. p1 Any (C1-C8) alkyl group may be the same or different 1, 2, 3, 4, or 5 halogens, hydroxyls, -O(C1-C8) alkyl groups, or -NR groups. q2 R r2 It is optionally replaced by R q1 and R r1 Each of them is independently H, (C1-C8) alkyl, (C3-C7) carbon ring, or a 3-7 membered heterocycle, R q1 Or R r1 Any (C1-C8) alkyl group is optionally substituted with one, two, three, four, or five halogens or -CN, which may be the same or different, or R q1 and R r1 These, together with the nitrogen atoms to which they are bonded, form a 5-membered, 6-membered, or 7-membered heterocycle, and the 5-membered, 6-membered, or 7-membered heterocycle is optionally substituted with one, two, three, four, or five (C1-C8) alkyl groups, which may be the same or different. R q2 and R r2 Each of them is independently either H, (C1-C8) alkyl, (C3-C7) carbon ring, or R q2 and R r2 These, together with the nitrogen atoms to which they are bonded, form a 5-membered, 6-membered, or 7-membered heterocycle. Z 2 These include (C2-C8) alkenyls, (C2-C8) alkynyls, 6-12 membered aryls, 5-12 membered C-linked heteroaryls, 3-12 membered C-linked heterocycles, and -C(O)R n3 , or -C(O)NR q3R r3 Z 2 Any 6-12 member aryl, 5-12 member C-linked heteroaryl, or 3-12 member C-linked heteroring may have 1, 2, 3, 4, or 5 Z, which may be the same or different. 2b or Z 2c It is optionally substituted in the base, Z 2 Any (C2-C8) alkenyl or (C2-C8) alkinyl may be the same or different of 1, 2, 3, 4, or 5 Z 2c It is optionally substituted in the base, Each R n3 These are independently H or (C1-C4) alkyl, R q3 and R r3 Each of these is independently H or (C1-C4) alkyl, each Z 2b These are independently oxo, (C1-C4) alkyl, (C1-C4) heteroalkyl, or (C1-C4) haloalkyl. each Z 2c These are independently oxo, halogen, -CN, and -OR. n4 , NR q4 R r4 , -NR n4 COR p4 , -NR n4 CO2R p4 , -NR n4 S(O)2R p4 , -C(O)R n4 , -C(O)OR n4 or -C(O)NR q4 R r4 And, Each R n4 These are independently H, (C1-C4) alkyl, or (C1-C4) heteroalkyl. Each R p4 These are independently (C1-C8) alkyl groups, R q4 and R r4 Each of these is independently H, (C1-C4) alkyl, or (C1-C4) heteroalkyl. Z 3These are independently (C1-C4) heteroalkyl or halogen, each Z 4 These are independently oxo, (C1-C8) alkyl, (C3-C7) carbon ring, halogen, -CN, and -OR. n5 , -NR q5 R r5 , -NR n5 COR p5 , -NR n5 CO2R p5 , -C(O)R n5 , -C(O)OR n5 , or -C(O)NR q5 R r5 Z 4 Any (C3-C7) carbon ring or (C1-C8) alkyl group may be the same or different 1, 2, 3, 4, or 5 Z 4a It is optionally substituted in the base, each Z 4a These are, independently, halogen, -CN, or -OR n6 And, R n5 , R p5 , R q5 , R r5 , and R n6 Each of these is independently H or (C1-C4) alkyl, each Z 5 These are halogens that can be the same or different, independently. n is 0, 1, 2, or 3.

[0342] In one embodiment, the compound of formula I is [ka] [ka] [ka] Furthermore, a selection is made from their pharmaceutically acceptable salts.

[0343] In a particular embodiment, the compound is [ka] Or a pharmaceutically acceptable salt thereof.

[0344] In a particular embodiment, the compound is [ka] Or a pharmaceutically acceptable salt thereof.

[0345] In certain embodiments, the compound or a pharmaceutically acceptable salt thereof is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] That is the case.

[0346] In a particular embodiment, the compound is [ka] Or a pharmaceutically acceptable salt thereof.

[0347] In a particular embodiment, the compound is [ka] Or a pharmaceutically acceptable salt thereof.

[0348] In a particular embodiment, the compound is [ka] Or a pharmaceutically acceptable salt thereof.

[0349] In a particular embodiment, the compound is [ka] Or a pharmaceutically acceptable salt thereof.

[0350] In a particular embodiment, the compound is [ka] Or a pharmaceutically acceptable salt thereof.

[0351] In a particular embodiment, the compound is [ka] Or a pharmaceutically acceptable salt thereof.

[0352] General synthesis procedure The following scheme describes a method useful for preparing the compound of formula I. Similarly, the following scheme describes a method useful for preparing the compound of formula III. [ka]

[0353] Scheme 1 describes a common stereoselective route used to prepare the compound of formula I. This scheme is also used to prepare the compound of formula III. A heteroaryl acid of formula A1 (wherein X represents a diversifiable chemical group such as NH2, SH, or halogen, which is appropriately protected) is converted to the corresponding aldehyde and then condensed with a chiral auxiliary group that results in the stereoselective addition of a nucleophilic reagent. Scheme 1 illustrates the conversion of heteroaryl acid A1 containing two diversified functional groups (e.g., X and Br) to the corresponding aldehyde. Subsequently, aldehyde A3 is condensed with (S)tert-butanesulfinamide, and a Grignard reagent is added to obtain a mixture of A5 and A6 enriched with A5. Separation of this mixture by column chromatography on silica gel yields the pure diastereomer. Removal of the auxiliary group yields amines A7 and A8, which are coupled with various carboxylic acids to obtain the heteroaryl compounds of formulas A9 and A10. Diversification of A9 and A10 is achieved by various methods, including alkylation, acylation, cyanation, substitution of nucleophilic aromatics, and metal-catalyzed cross-coupling reactions, such as Suzuki coupling, Buchwald-Hartwig type coupling, and Sonogashira coupling.

[0354] Scheme 2 describes a general stereoselective route that can be used to prepare the compounds of formulas I and III. [ka]

[0355] Scheme 2 illustrates the protection of amine A7 to the compound of formula B1, followed by the conversion of Br to the corresponding boronic acid. Diversification of functional group X and the boronic acid is achieved by various methods, including alkylation, acylation, cyanation, substitution of nucleophilic aromatics, and metal-catalyzed cross-coupling reactions, such as Suzuki coupling, Buchwald-Hartwig type coupling, and Sonogashira coupling, yielding compounds of formulas B3 and B4. After deprotection, amides are formed using various carboxylic acids to obtain compounds of formula I.

[0356] Combination therapy In one embodiment, the present invention provides a method for treating HIV infection, comprising the step of administering to a patient in need of the therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof in combination with one or more additional therapeutic agents suitable for treating HIV infection.

[0357] The compounds disclosed herein (e.g., any compound of formulas I and III or a pharmaceutically acceptable salt thereof) can be combined with one or more additional therapeutic agents in any dosage of the compound (e.g., 50 mg to 300 mg of the compound).

[0358] In one embodiment, a method is provided for treating or preventing HIV infection in a person who has or is at risk of having an infection, comprising the step of administering to a person a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of one or more additional therapeutic agents.

[0359] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof in combination with at least one additional therapeutic agent and a pharmaceutically acceptable carrier. For example, the therapeutic agent used in combination with the compound disclosed herein may be any anti-HIV agent.

[0360] In one embodiment, a combination pharmaceutical agent is provided comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof in combination with one or more additional therapeutic agents.

[0361] One embodiment provides a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof in combination with at least one additional therapeutic agent and a pharmaceutically acceptable carrier. In one embodiment, the additional therapeutic agent may be an anti-HIV agent. For example, in some embodiments, additional therapeutic agents are selected from the group consisting of HIV protease inhibitors, non-nucleoside inhibitors of HIV reverse transcriptase, nucleoside inhibitors of HIV reverse transcriptase, nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic (or allosteric) integrase inhibitors, entry inhibitors (e.g., CCR5 inhibitors, gp41 inhibitors (i.e., fusion inhibitors) and CD4 adhesion inhibitors), CXCR4 inhibitors, gp120 inhibitors, G6PD and NADH-oxidase inhibitors, capsid polymerization inhibitors or capsid disrupting compounds, e.g., those described in US2013 / 0165489 (University of Pennsylvania) and WO2013 / 006792 (Pharma Resources), pharmacokinetic enhancers, and other drugs for treating HIV, as well as combinations thereof.

[0362] In further embodiments, additional therapeutic agents are (1) HIV protease inhibitors selected from the group consisting of amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, nelfinavir, saquinavir, tipranavir, brekanavir, darunavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649, KNI-272, DPC-681, DPC-684, GW640385X, DG17, PPL-100, DG35, and AG1859; (2) Non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase selected from the group consisting of caplavillin, emibirin, delaviridine, efavirenz, nevirapine, (+) calanolide A, etravirin, GW5634, DPC-083, DPC-961, DPC-963, MIV-150, TMC-120, rilpivirene, BILR355BS, VRX840773, relsivirin (UK-453061), RDEA806, KM023, and MK-1439; (3) HIV reverse transcriptase nucleoside inhibitors selected from the group consisting of zidovudine, emtricitabine, didanosine, stabudine, zalcitabine, lamivudine, abacavir, amdoxovir, erbucitabine, alovudine, MIV-210, ±-FTC, D-d4FC, emtricitabine, phosphazide, fodivudine tidoxil, apricitabine (AVX754), amdoxovir, KP-1461, GS-9131 (Gilead Sciences), and fosaluvudine tidoxil (formerly HDP99.0003); (4) Tenofovir, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir alafenamide, GS-7340 (Gilead Sciences), GS-9148 (Gilead Sciences), adefovir, adefovir dipivoxil, CMX-001 (Chimerix) or C Nucleotide inhibitors of HIV reverse transcriptase selected from the group consisting of MX-157 (Chimerix); (5) HIV integrase inhibitors selected from the group consisting of curcumin, curcumin derivatives, chicoric acid, chicoric acid derivatives, 3,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid derivatives, aurintricarboxylic acid, aurintricarboxylic acid derivatives, caffeate phenethyl ester, caffeate phenethyl ester derivatives, tyrofostine, tyrofostine derivatives, quercetin, quercetin derivatives, S-1360, AR-177, L-870812 and L-870810, raltegravir, BMS-538158, GSK364735C, BMS-707035, MK-2048, BA011, elvitegravir, dolutegravir and GSK-744; (6) HIV non-catalytic sites or allosteric integrase inhibitors (NCINIs), including, but not limited to, compounds disclosed in BI-224436, CX0516, CX05045, CX14442, WO2009 / 062285 (Boehringer Ingelheim), WO2010 / 130034 (Boehringer Ingelheim), WO2013 / 159064 (Gilead Sciences), WO2012 / 145728 (Gilead Sciences), WO2012 / 003497 (Gilead Sciences), and WO2012 / 003498 (Gilead Sciences) (each of these is incorporated herein by reference in whole); (7) gp41 inhibitors selected from the group consisting of enfuvirtide, sifuvirtide, albuvirtide, FB006M, and TRI-1144; (8) CXCR4 inhibitor AMD-070; (9) Invasion inhibitor SP01A; (10) gp120 inhibitor BMS-488043; (11) G6PD and NADH oxidase inhibitor immunotin; (12) A CCR5 inhibitor selected from the group consisting of apraviroc, bicriviroc, maraviroc, senicliviroc, PRO-140, INCB15050, PF-232798 (Pfizer), and CCR5mAb004; (13) CD4 adhesion inhibitors selected from the group consisting of ibalizumab (TMB-355) and BMS-068 (BMS-663068); (14) Pharmacokinetic enhancers selected from the group consisting of cobicistat, ritonavir, and SPI-452; and (15) Other drugs for treating HIV, selected from the group consisting of BAS-100, SPI-452, REP9, SP-01A, TNX-355, DES6, ODN-93, ODN-112, VGV-1, PA-457 (bevirimumab), HRG214, VGX-410, KD-247, AMZ0026, CYT99007A-221HIV, DEBIO-025, BAY50-4798, MDX010 (ipilimumab), PBS119, ALG889, and PA-1050040 (PA-040). Select one or more from the options provided.

[0363] In certain embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with two, three, four, or more than four additional therapeutic agents. In certain embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with two additional therapeutic agents. In other embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with three additional therapeutic agents. In further embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with four additional therapeutic agents. The two, three, four, or more than four additional therapeutic agents may be different therapeutic agents selected from the same class or may be selected from different classes of therapeutic agents. In one embodiment, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with nucleotide inhibitors of HIV reverse transcriptase and non-nucleoside inhibitors of HIV reverse transcriptase. In another specific embodiment, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with nucleotide inhibitors of HIV reverse transcriptase and HIV protease inhibitor compounds. In a further embodiment, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with nucleotide inhibitors of HIV reverse transcriptase, non-nucleoside inhibitors of HIV reverse transcriptase, and HIV protease inhibitor compounds. In a further embodiment, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with nucleotide inhibitors of HIV reverse transcriptase, non-nucleoside inhibitors of HIV reverse transcriptase, and pharmacokinetic enhancers.

[0364] In one specific embodiment, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with tenofovir, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In another specific embodiment, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir alafenamide. In one specific embodiment, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with emtricitabine, abacavir, or lamivudine.

[0365] In a specific embodiment, one of the compounds disclosed herein or a pharmaceutically acceptable salt thereof is combined with tenofovir, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and one of emtricitabine, abacavir, or lamivudine.

[0366] In some embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with 5 to 30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. In some embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with 5 to 10 mg, 5 to 15 mg, 5 to 20 mg, 5 to 25 mg, 25 to 30 mg, 20 to 30 mg, 15 to 30 mg, or 10 to 30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. In some embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. In some embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. The compounds disclosed herein (e.g., any of the compounds of formulas I and III or pharmaceutically acceptable salts thereof) may be combined with the agents presented herein in any dosage of the compound (e.g., 50 mg to 300 mg of the compound), as if each dosage combination were specifically enumerated individually.

[0367] In some embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are 2 00-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil is combined with 200 mg of emtricitabine. In some embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with 200 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil in amounts of 200-250 mg, 200-300 mg, 200-350 mg, 250-350 mg, 250-400 mg, 350-400 mg, 300-400 mg, or 250-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In some embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with 300 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg of emtricitabine. The compounds disclosed herein (e.g., any of the compounds of formulas I and III or pharmaceutically acceptable salts thereof) may be combined with the agents presented herein in any dosage of the compound (e.g., 50 mg to 300 mg of the compound), as if each dosage combination were specifically enumerated individually.

[0368] In some embodiments, one or more of the compounds disclosed herein are combined with one or more other active therapeutic agents in unit dosage forms for simultaneous or sequential administration to a patient. In certain embodiments, a pharmaceutical composition is provided comprising one or more of the compounds disclosed herein in combination with one or more other active therapeutic agents. In certain embodiments, the compounds disclosed herein are combined with one or more other active therapeutic agents in solid dosage forms. The combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more doses.

[0369] In some embodiments, one or more of the compounds disclosed herein are co-administered with one or more other active therapeutic agents. Co-administration of the compounds disclosed herein and one or more other active therapeutic agents generally means administering the compounds disclosed herein and one or more other active therapeutic agents simultaneously or sequentially so that therapeutically effective amounts of both are present in the patient's body.

[0370] In yet another embodiment, the present application provides a method for treating HIV infection, comprising the step of administering to a patient in need a therapeutically effective amount of one or more additional therapeutic agents, such as those disclosed above, in combination with a therapeutically effective amount of one or more additional therapeutic agents, such as those disclosed above.

[0371] Pharmaceutical preparations The compounds disclosed herein are formulated using conventional carriers (e.g., inert components or additive materials) typically selected in accordance with common practice. Tablets contain additives, including flow enhancers, fillers, binders, etc. Aqueous formulations are prepared in sterile form and are generally isotonic when intended for delivery by means other than oral administration. All formulations are described in the Handbook of The formulation optionally contains additives such as those described in Pharmaceutical Excipients (1986). Examples of additives include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, and stearic acid. One embodiment provides the formulation in solid dosage forms, including a solid oral dosage form. The pH of the formulation is in the range of about 3 to about 11, but is usually about 7 to 10.

[0372] While it is possible to administer the active ingredients alone, it is sometimes preferable to provide them as a pharmaceutical formulation (composition). The formulations of the present invention for both veterinary and human use comprise at least one of the previously defined active ingredients, one or more acceptable carriers, and optionally other therapeutic ingredients. The carrier(s) are compatible with the other components of the formulation. It must be "acceptable" in the sense that it is physiologically harmless to the recipient of the formulation.

[0373] The formulations include those suitable for the above-mentioned routes of administration. The formulations may, conveniently, be given in unit dosage forms and may be prepared by any method well known in the pharmaceutical field. The techniques and formulations are generally found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pennsylvania). Such methods involve the step of associating the active ingredient with one or more inactive components (e.g., carriers, pharmaceutical excipients, etc.) constituting auxiliary components. Generally, formulations are prepared by homogeneously and thoroughly associating the active ingredient with a liquid carrier or a finely ground solid carrier or both, and then, if necessary, shaping the product.

[0374] The oral formulations described herein may be provided as separate units, including but not limited to capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient.

[0375] The pharmaceutical formulations disclosed herein comprise one or more of the compounds disclosed herein, together with one or more pharmaceutically acceptable carriers or excipients, and optionally other therapeutic agents. Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration. When used for oral use, for example, tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known in the art of pharmaceutical composition production, and such compositions may contain one or more agents, including sweeteners, flavorings, colorings, and preservatives, to provide a palatable preparation. Tablets containing the active ingredient as a miscion with non-toxic, pharmaceutically acceptable excipients suitable for tablet production are acceptable. These additives may include, for example, inert excipients such as calcium carbonate or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium phosphate or sodium phosphate; granulators and disintegrants such as corn starch or alginic acid; binders such as cellulose, microcrystalline cellulose, starch, gelatin or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or coated by known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract, thereby providing a sustained effect over a long period. For example, time-delaying materials such as glyceryl monostearate or glyceryl distearate may be used alone or in combination with wax.

[0376] The amount of active ingredient combined with an inactive ingredient to produce a dosage form varies depending on the host being treated and the specific mode of administration. For example, in some embodiments, a dosage form for oral administration to humans contains approximately 1 to 1000 mg of active ingredient, which is formulated using an appropriate and convenient amount of carrier material (e.g., an inactive ingredient or excipient material). In some embodiments, the dosage form (for example, a dosage form for oral administration to humans) contains 10 mg to 1000 mg or 50 mg to 1000 mg or 100 mg to 1000 mg or 200 mg to 1000 mg or 300 mg to 1000 mg or 10 mg to 800 mg or 10 mg to 600 mg or 10 mg to 500 mg or 10 mg to 400 mg or 10 mg to 300 mg or 50 mg to 800 mg or 100 mg to 600 mg or 150 mg to 500 mg or 200 mg to 400 mg or 50 mg to 500 mg or 10 mg to 300 mg or 50 mg to 300 mg or 10 mg to 200 mg or 50 mg to 200 mg or 100 mg to 300 mg or 100 mg to 200 mg or 200 mg to 300 mg of the active material (for example, a compound of formula I or III). part In some embodiments, the dosage form for oral administration to humans is at least 10 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, or 300 mg, and contains 500 mg, 800 mg, or 1000 mg or less of the active material (for example, at least 50 mg to 500 mg or less). In some embodiments, the dosage form for oral administration to humans contains at least 10 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, or 300 mg, or 500 mg, 800 mg, or 1000 mg or less of the active material. In some embodiments, dosage forms for oral administration to humans contain any of the following active ingredients: 10 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg. It is understood that the dosage forms in amounts presented herein can be administered to a patient (e.g., a person in need of it) according to the administration regimes presented herein, such as once, twice, or three times a day. In one embodiment, the administration regimen provides for administering at least 10 mg and no more than 1,000 mg of the active material (e.g., a compound of formula I or III) per day, and the amount is understood to be provided in any suitable dosage form and quantity (e.g., 500 mg twice daily or 1,000 mg once daily provides the same 1,000 mg daily dose). The present invention encompasses administering a dosage form of a compound (e.g., a compound of formula I or III) containing at least 50 mg and no more than 300 mg of the compound once daily to an individual (e.g., a human being in need of it). In certain embodiments, the carrier material varies in weight from about 5% to about 95% of the total composition.

[0377] The formulations of the present invention may, in addition to the components described above, include other agents conventional in the art, taking into consideration the type of formulation. For example, formulations suitable for oral administration may include flavoring agents.

[0378] The present invention further provides a veterinary composition comprising at least one of the previously defined active ingredients together with a veterinary carrier.

[0379] Veterinary carriers are materials useful for administering compositions and may be solid, liquid, or gaseous materials that are otherwise inert or acceptable in the veterinary field and compatible with the active ingredients. These veterinary compositions may be administered orally, parenterally, or by any other preferred route.

[0380] The effective dose of the active ingredient is determined by the clinician using conventional dose-escalation studies, and depends at least on the nature of the condition being treated, its toxicity, whether the compound is used prophylactically (at lower doses), the method of delivery, and the pharmaceutical formulation.

[0381] Route of administration One or more compounds disclosed herein (referred to herein as active ingredients) are administered by any route suitable for the condition being treated. Suitable routes include oral, rectal, nasal, topical (including oral buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It is understood that the preferred route may vary, for example, with the recipient's condition. An advantage of the compounds disclosed herein is that they are orally bioavailable and can be administered orally.

[0382] Administration regimen Compounds such as either compound I or III are administered according to an effective dosing regimen for the desired time or period, for example, at least about 1 month, at least about 2 months, at least about The compound may be administered to an individual for a period of 3 months, at least about 6 months, at least about 12 months, or longer. In one variant, the compound is administered daily or intermittently over the lifespan of the individual.

[0383] The dosage or frequency of administration of any of the compounds in formulas I and III may be adjusted during the course of treatment, for example, based on the judgment of the administering physician.

[0384] The compound may be administered to an individual (e.g., a human) in an effective dose. In one embodiment, the compound is administered once daily. In one embodiment, the compound is administered twice daily. In one embodiment, the compound is administered three times daily. The compound may be administered in any dose provided herein, such as doses providing at least 10 mg per day and doses of 1,000 mg or less per day. Oral administration once daily is included, such as administering a dosage form containing 50 mg to 300 mg of the compound.

[0385] The antiviral properties of the compound of the present invention can be determined using Test A described below.

[0386] Study A: Antiviral assay in MT4 cells In the antiviral assay, 40 μL of a 3-fold serial dilution of the compound, at the concentration required to achieve the final effective 1× test concentration, was added to each well of a 384-well plate in a quad-twin configuration (10 different concentrations) in culture medium containing 10% FBS. MT-4 cells were then mixed with HIV-IIIb at 0.003 moi for 1 hour, followed by the immediate addition of 35 μL of virus / cell mixture (2000 cells) to each well containing 40 μL of the diluted compound. The plates were then incubated at 37°C for 5 days. After 5 days of incubation, 25 μL of 2-fold concentrated CellTiter-Glo® reagent (catalog no. G7571, Promega Biosciences, Inc., Madison, Wisconsin) was added to each well containing MT-4 cells. Cell lysis was performed by incubation at room temperature for 10 minutes, followed by readings of chemiluminescence. The EC50 value was calculated as the compound concentration that caused a 50% decrease in the luminescence signal, a measure of HIV-1 replication. The inhibition rates of virus-induced cell death calculated from dose-response curves at drug concentrations of 2 μM and 0.2 μM are shown in the table below.

[0387] Test B: Cytotoxic Assay The cytotoxicity of the compounds and their corresponding CC50 values ​​were determined using the same protocol as described in the antiviral assay (Test A), except that uninfected cells were used.

[0388] The compounds of the present invention demonstrate antiviral activity as shown in the table below (Test A). Below, the values ​​corresponding to CC50 and the inhibition rate of virus-induced cell death in the presence of drug concentrations of 2 μM and 0.2 μM are shown. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6]

[0389] The data above represents the time-course average for each assay for each compound. For a particular compound, multiple assays were performed over the duration of the project. Therefore, the data recorded in the table includes data recorded in the priority documents as well as data from assays performed during the intervening period. In the table above, if the inhibition rate calculation resulted in a value greater than 100, the inhibition rate value was normalized to 100%.

[0390] In one embodiment, the compound demonstrates >10% inhibition at 2 μM. In one embodiment, the compound demonstrates >30% inhibition at 2 μM. In one embodiment, the compound demonstrates >50% inhibition at 2 μM. In one embodiment, the compound demonstrates >70% inhibition at 2 μM. In one embodiment, the compound demonstrates >75% inhibition at 2 μM. In one embodiment, the compound demonstrates >80% inhibition at 2 μM. In one embodiment, the compound demonstrates >85% inhibition at 2 μM. In one embodiment, the compound demonstrates >90% inhibition at 2 μM. In one embodiment, the compound demonstrates >95% inhibition at 2 μM. It should be understood that the compounds disclosed herein can be classified according to their inhibition rates (%) as described above.

[0391] In one embodiment, the compound demonstrates >10% inhibition at 0.2 μM. In one embodiment, the compound demonstrates >30% inhibition at 0.2 μM. In one embodiment, the compound demonstrates >50% inhibition at 0.2 μM. In one embodiment, the compound demonstrates >70% inhibition at 0.2 μM. In one embodiment, the compound demonstrates >75% inhibition at 0.2 μM. In one embodiment, the compound demonstrates >80% inhibition at 0.2 μM. In one embodiment, the compound demonstrates >85% inhibition at 0.2 μM. In one embodiment, the compound demonstrates >90% inhibition at 0.2 μM. In one embodiment, the compound demonstrates >95% inhibition at 0.2 μM. It should be understood that the compounds disclosed herein can be classified according to their inhibition rates (%) as described above.

[0392] In one variant, the compound is a compound of any formula presented herein, and the compound exhibits 85% to 100% inhibition of virus-induced cell death at a concentration of 2 μM. In another variant, the compound is a compound of any formula presented herein, and the compound exhibits 85% to 100% inhibition of virus-induced cell death at a concentration of 0.2 μM. In other embodiments, the compound is a compound of any formula presented herein, and the compound exhibits 50-100%, 60-100%, 70-100%, 80-100%, or 90-100% inhibition of virus-induced cell death at a concentration of 2 μM or 0.2 μM.

[0393] The inhibition rate (%) is understood to be assessable by techniques known in the art. In certain variant forms, the compound is any compound of any of the formulas presented herein, and the compound exhibits 85% to 110% inhibition of virus-induced cell death at 2 μM or 0.2 μM, as measured by the methods presented in the sections of Test A and Test B discussed above.

[0394] Furthermore, the inhibition rate was calculated for a specific compound by comparing it with a previously published compound (WO2013 / 006738), and is shown below. The inhibition rates of virus-induced cell death at 2 μM and 0.2 μM were measured using the methods presented in the sections of Test A and Test B discussed earlier. [Table 2]

[0395] The specific pharmacological responses observed may vary depending on the selected active compound, the presence or absence of a pharmaceutical carrier and / or pharmaceutically active compound, and the type of formulation and mode of administration used, and such variations or differences in expected results are intended in accordance with the implementation of the present invention.

[0396] The examples presented herein describe the synthesis of the compounds disclosed herein, as well as the intermediates used to prepare the compounds. The individual steps described herein are combined Please understand that they can be combined. Also, please understand that separate batches of compounds can be combined and then carried over to the next synthesis step. [Examples]

[0397] (Example 1) [ka] Synthesis of (S)-5-bromo-6-(1-(2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazole-1-yl)acetamide)-2-(3,5-difluorophenyl)ethyl)picolinamide (1A): Compound 5F (100 mg, 0.15 mmol) and CuCN (16 mg, 0.18 mmol) were dissolved in DMF (0.3 mL). The reaction mixture was heated overnight at 100 °C. After cooling to room temperature, it was diluted with water and extracted with ethyl acetate. The organic phase was dried (Na₂SO₄), filtered, and concentrated. The crude material was purified by reverse-phase HPLC eluting with acetonitrile and water (containing 0.1% TFA) to obtain (S)-N-(1-(3-bromo-6-cyanopyridine-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazole-1-yl)acetamide and the title product (1A). MS (m / z) 640.05 [M+H] + . Synthesis of (S)-6-(1-(2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazole-1-yl)acetamide)-2-(3,5-difluorophenyl)ethyl)-5-(1H-pyrrolo[2,3-b]pyridine-5-yl)picolinamide (1B):

[0398] Using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine and 1A, the title compound (1B) was prepared according to the method described for the synthesis of compound 4H in Example 4. [ka] MS (m / z) 678.08 [M+H] + . (Example 2) [ka] Synthesis of 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)-N-((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbuta-1-in-1-yl)-3-(4-oxo-3,4-dihydroquinazolin-8-yl)pyridine-2-yl)ethyl)acetamide (2):

[0399] Using (4-oxo-3,4-dihydroquinazolin-8-yl)boronic acid and 14D, the title compound (2) was prepared according to the method described for the synthesis of compound 4H in Example 4. [ka] MS (m / z) 725.14 [M+H] + . (Example 3) [ka] Synthesis of 3'-Oxospiro[cyclopropane-1,1'-isoindoline]-5'-yltrifluoromethanesulfonate (3B):

[0400] A mixture of compound 3A (1 g, 5.7 mmol, prepared according to the method described in Tetrahedron Letters Vol. 50 (2009), pp. 1267-1269), DCM (20 mL), and Et3N (0.9 mL, 6.8 mmol) was cooled to 0°C using an ice / water bath. Trifluoromethanesulfonyl chloride (0.91 mL, 8.5 mmol) was added dropwise by syringe. The mixture was then stirred at ambient temperature for 1 hour. Further trifluoromethanesulfonyl chloride (0.8 mL) was added, and the mixture was stirred at ambient temperature for another 1 hour. The mixture was then diluted with DCM (150 mL) and washed with 1.0 N HCl (50 mL), saturated sodium bicarbonate aqueous solution (1 × 50 mL), and saturated sodium chloride aqueous solution (1 × 50 mL). The organic layer was dehydrated with MgSO4, filtered through Celite®, and concentrated under vacuum to obtain the title product (3B). MS (m / z) 308.29 [M+H] + . Synthesis of 5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclopropane-1,1'-isoindoline]-3'-one (3C):

[0401] 3B (200 mg, 0.65 mmol), bis(pinacolato)diborone (330 mg, 1.3 mmol), potassium acetate (191 mg, 1.95 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14 mg, 0.02 mmol), and 1,4-dioxane (8 mL) were charged into a microwave tube. The mixture was heated in a microwave synthesizer at 150°C for 20 minutes. Upon completion, the solution was diluted with SiO2, the organic layer was washed with water and saturated NaCl solution, dehydrated with MgSO4, and concentrated under vacuum to obtain the title compound as a dark brown solid. Half of the product was purified by silica gel chromatography eluted with SiO2 / hexane to obtain the title product. MS (m / z) 286.23 [M+H] + . Synthesis of 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)-N-((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbuta-1-in-1-yl)-3-(3'-oxospiro[cyclopropane-1,1'-isoindoline]-5'-yl)pyridine-2-yl)ethyl)acetamide (3D):

[0402] 14D (33 mg, 0.05 mmol), 3C (21 mg, 0.075 mmol), LiCl (6 mg, 0.15 mmol), K2CO3 (21 mg, 0.15 mmol), Pd(PPh3)2Cl2 (3 mg), and Pd(dppf)Cl2 (3 mg) were charged into a microwave tube. DME (1 mL) and H2O (0.2 mL) were added to the mixture. The mixture was heated in a microwave synthesizer at 165°C for 12 minutes. After cooling and filtration through a syringe filter, the product was purified by reverse-phase HPLC elution with acetonitrile and water (containing 0.1% TFA) to obtain the title product. [ka] MS (m / z) 738.15 [M+H] + . (Example 4) [ka] Synthesis of (S)-N-((3,5-dibromopyridine-2-yl)methylene)-2-methylpropane-2-sulfinamide (4B):

[0403] (S)-2-methylpropane-2-sulfinamide (870 mg, 7.17 mmol) and CuSO4 (2.29 g, 14.3 mmol) were added to 3,5-dibromopicoline aldehyde (1.9 g, 7.17 mmol) in DCM (30 mL). The reaction mixture was stirred for 15 hours. The solid was filtered through Celite. The solvent was removed under vacuum, and the residue was purified by silica column chromatography to obtain 2.6 g of the title compound. MS (m / z) 368.9 [M+H] + . Synthesis of (S)-N-((S)-1-(3,5-dibromopyridine-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (4C):

[0404] (S)-N-((3,5-dibromopyridine-2-yl)methylene)-2-methylpropane-2-sulfinamide (2.6 g, 7.1 mmol) dissolved in THF (24 mL). The mixture was cooled to -78°C. (3,5-difluorobenzyl)magnesium bromide (34 mL, 0.25 M in Et2O) was added dropwise. The reaction mixture was stirred at -78°C for 3 hours, then heated to 0°C and quenched. The reaction mixture was partitioned between HCl and NH4Cl aqueous solution. Organic matter was separated, dried, and removed under vacuum. The residue was purified by silica column chromatography to obtain the title compound. MS (m / z) 496.6 [M + H] + . Synthesis of (S)-1-(3,5-dibromopyridine-2-yl)-2-(3,5-difluorophenyl)ethanamine (4D):

[0405] (S)-N-((S)-1-(3,5-dibromopyridine-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (650 mg) was dissolved in DCM (3 mL), to which 4N HCl (4 mL) in dioxane was added. The reaction mixture was stirred at ambient temperature for 2 hours. The solvent was removed under vacuum, and the crude desired product was used without further purification. MS (m / z) 393.0 [M+H] + . Synthesis of (S)-tert-butyl 1-(3,5-dibromopyridine-2-yl)-2-(3,5-difluorophenyl)ethylcarbamate (4E):

[0406] (S)-1-(3,5-dibromopyridine-2-yl)-2-(3,5-difluorophenyl)ethanamine (780 mg, 1.84 mmol) was combined with di-tert-butyl dicarbonate (400 mg, 1.84 mmol) and TEA (515 μL, 3.7 mmol) in DCM (9 mL). The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was partitioned between siRNA and H2O. Organic matter was separated, dried, and removed under vacuum. The residue was purified by silica column chromatography to obtain the title compound. MS (m / z) 492.9 [M+H] + . Synthesis of (S)-tert-butyl 1-(3-bromo-5-(3-hydroxy-3-methylbuta-1-inyl)pyridine-2-yl)-2-(3,5-difluorophenyl)ethylcarbamate (4F):

[0407] (S)-tert-butyl 1-(3,5-dibromopyridine-2-yl)-2-(3,5-difluorophenyl)ethyl carbamate (140 mg, 0.29 mmol) was added to THF (18 mL) with 2-methylbuta-3-in-2-ol (42 μL, 0.43 mmol), TEA (0.9 mL), Pd(PPh3)2Cl2 (30 mg), and CuI (16 mg). The reaction mixture was stirred at ambient temperature for 2 hours, then partitioned between ELISA and H2O. Organic matter was separated, dried, and removed under vacuum. The residue was purified by silica column chromatography to obtain the title compound as a mixture with 4E, which was used in the next step. MS (m / z) 496.7 [M+H] + . Synthesis of (S)-N-(1-(3-bromo-5-(3-hydroxy-3-methylbuta-1-inyl)pyridine-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazole-1-yl)acetamide (4G):

[0408] A mixture of (S)-tert-butyl 1-(3-bromo-5-(3-hydroxy-3-methylbuta-1-inyl)pyridine-2-yl)-2-(3,5-difluorophenyl)ethyl carbamate and (S)-tert-butyl 1-(3,5-dibromopyridine-2-yl)-2-(3,5-difluorophenyl)ethyl carbamate (105 mg) obtained from the previous step was dissolved in DCM (3 mL) and treated with 4N HCl (4 mL) in dioxane. The reaction mixture was stirred for 2 hours, and then the solvent was removed under vacuum. The residue was purified by silica column chromatography to obtain (S)-4-(6-(1-amino-2-(3,5-difluorophenyl)ethyl)-5-bromopyridine-3-yl)-2-methylbuta-3-in-2-ol (MS (m / z) 395.0 [M+H] + )18 mg was obtained. (S)-4-(6-(1-amino-2-(3,5-difluoro) in DMF (1 mL). Phenyl)ethyl)-5-bromopyridine-3-yl)-2-methylbuta-3-in-2-ol (18 mg, 0.046 mmol) was mixed with 2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazole-1-yl)acetic acid (15 mg, 0.05 mmol), iPr2NEt (17 μL, 0.1 mmol), and HATU (26 mg, 0.07 mmol). The reaction mixture was stirred for 30 minutes, then partitioned between butyl and H2O. Organic matter was separated, dried, and removed under vacuum. The crude product was used directly in the next reaction. MS (m / z) 679.2 [M+H] + . Synthesis of (S)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazole-1-yl)-N-(2-(3,5-difluorophenyl)-1-(5-(3-hydroxy-3-methylbuta-1-inyl)-3-(3-oxoisoindorin-5-yl)pyridine-2-yl)ethyl)acetamide(4H):

[0409] (S)-N-(1-(3-bromo-5-(3-hydroxy-3-methylbuta-1-inyl)pyridine-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazole-1-yl)acetamide (16 mg, 0.02 mmol) was mixed with 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindorin-1-one (7 mg, 0.03 mmol), Pd(PPh3)2Cl2 (2 mg), LiCl (1 mg), and 2M K2CO3 aqueous solution (30 μL). The reaction mixture was heated in a microwave reactor at 150°C for 20 minutes. The reaction mixture was purified by RP HPLC to obtain the desired product. [ka] MS (m / z) 732.1 [M+H] + . (Example 5) [ka] Synthesis of 3,6-dibromo-2-(dibromomethyl)pyridine (5A)

[0410] To a solution of 3,6-dibromo-2-methylpyridine (5.2 g, 21 mmol) in CCl4 (50 mL), N-bromosuccinimide (7.57 g, 42 mmol) and 2,2'-azobis(2-methylpropionitrile) (0.70 g, 4.3 mmol) were added. The mixture was heated overnight at 80°C and cooled to room temperature. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure. After elution with 0-10 percent siRNA in hexane (7.36 g) by flash chromatography, product (5A) was obtained. MS (m / z): 409.66 [M+H] + Synthesis of 3,6-dibromopicolinealdehyde (5B)

[0411] A solution of silver nitrate (7.6 g, 45 mmol) in water (24 mL) was added dropwise to a solution of 5A (7.36 g, 18 mmol) in EtOH (90 mL) under reflux. The mixture was stirred at 80°C for 5 hours. After cooling the mixture to room temperature, it was diluted with water (100 mL), extracted with SiO3 (3 times), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product (5B, 4.6 G) was used directly in the next step. MS(m / z):265.96.[M+H] + Synthesis of (S,Z)-N-((3,6-dibromopyridine-2-yl)methylene)-2-methylpropane-2-sulfinamide (5C)

[0412] The title compound (5C) was prepared using 5B according to the method described for the synthesis of compound 4B in Example 4. MS(m / z)368.86[M+H] + Synthesis of (S)-N-((S)-1-(3,6-dibromopyridine-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (5D)

[0413] The title compound (5D) was prepared using 5C according to the method described for the synthesis of compound 4C in Example 4. MS(m / z)496.99[M+H] + Synthesis of (S)-1-(3,6-dibromopyridine-2-yl)-2-(3,5-difluorophenyl)ethanamine hydrochloride (5E):

[0414] Using 5D, the title compound (5E) was prepared according to the method described for the synthesis of compound 4D in Example 4. MS(m / z)393.29[M+H] + Synthesis of (S)-N-(1-(3,6-dibromopyridine-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazole-1-yl)acetamide (5F):

[0415] Using 5E, the title compound (5F) was prepared according to the method described for the synthesis of compound 10A in Example 10. MS(m / z)676.96[M+H] + . Synthesis of (S)-5,5'-(6-(1-(2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazole-1-yl)acetamide)-2-(3,5-difluorophenyl)ethyl)pyridine-2,5-diyl)bis(2-fluorobenzamide)(5G):

[0416] 5F (100 mg, 0.15 mmol), (3-carbamoyl-4-fluorophenyl)boronic acid (81 mg, 0.45 mmol), LiCl (19 mg, 0.45 mmol), Na2CO3 (50 mg, 0.6 mmol), and Pd(PPh3)2Cl2 (5 mg) were charged into a microwave tube. 1.4 mL of 1,4-dioxane / methanol / H2O(5 / 1 / 1) was added to the mixture. The mixture was heated in a microwave synthesizer at 170°C for 15 minutes. After cooling and filtration through a syringe filter, the product was purified by reverse-phase HPLC elution with acetonitrile and water (containing 0.1% TFA) to obtain the title compound. [ka] MS (m / z) 793.19 [M+H] + . (Example 6) [ka] Synthesis of (S)-N-(1-(3,6-bis(3-oxoisoindolin-5-yl)pyridine-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazole-1-yl)acetamide (6):

[0417] Using 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindorin-1-one and 5F, the title compound (6) was prepared according to the method described for the synthesis of compound 5G in Example 5. [ka] MS(m / z)781.02[M+H] + . (Example 7) [ka] (S)-N-(1-(3,6-bis(1H-pyrrolo[2,3-b]pyridine-5-yl)pyridine-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(di Synthesis of fluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazole-1-yl)acetamide (7):

[0418] Using 6 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine and 5F, the title compound (7) was prepared according to the method described for the synthesis of compound 5G in Example 5. [ka] MS (m / z) 751.22 [M+H] + . (Example 8) [ka] Synthesis of (S)-N-(1-(5-bromo-2'-methoxy-[2,4'-bipyridine]-6-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazole-1-yl)acetamide (8A) and (S)-N-(1-(2',5'-di(methoxy-[2,4'-bipyridine]-6-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazole-1-yl)acetamide (8B):

[0419] Using 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2 equivalents) and 5F, the compound 5G of Example 5 was synthesized. The title compounds (8A and 8B) were prepared according to the method described below. Synthesis of (S)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazole-1-yl)-N-(2-(3,5-difluorophenyl)-1-(2'-methoxy-5-(3-oxoisoindorin-5-yl)-[2,4'-bipyridine]-6-yl)ethyl)acetamide (8C):

[0420] Using 8A, the title compound (8C) was prepared according to the method described for the synthesis of compound 4H in Example 4. [ka] MS (m / z) 757.25 [M+H] + . (Example 9) [ka] Synthesis of (S)-N-(1-(3-bromo-6-(3-hydroxy-3-methylbuta-1-in-1-yl)pyridine-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazole-1-yl)acetamide (9A):

[0421] Using 2-methylbuta-3-in-2-ol and 5F, the title compound (9A) was prepared according to the method described for the synthesis of compound 4F in Example 4. MS(m / z)681.17[M+H] + . Synthesis of (S)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazole-1-yl)-N-(2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbuta-1-in-1-yl)-3-(3-oxoisoindorin-5-yl)pyridine-2-yl)ethyl)acetamide (9B):

[0422] Using 9A, the title compound (9B) was prepared according to the method described for the synthesis of compound 4H in Example 4. [ka] MS (m / z) 732.23 [M+H] + . (Example 10) [ka] Synthesis of (S)-N-(1-(3,5-dibromopyridine-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazole-1-yl)acetamide (10A):

[0423] (S)-1-(3,5-dibromopyridine-2-yl)-2-(3,5-difluorophenyl)ethanamine (380 mg, 0.97 mmol) was dissolved in DMF (10 mL), to which iPr2NEt (350 μL, 2 mmol) and 2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazole-1-yl)acetic acid (293 mg, 0.97 mmol) were added. HATU (442 mg, 1.16 mmol) was added, and the reaction mixture was stirred for 30 minutes. The reaction mixture was partitioned between HCl and H2O. Organic matter was separated, dried, and removed under vacuum. The residue was sterilized with silica. The title compound was obtained by purification by column chromatography. MS (m / z) 677.1 [M+H] + . Synthesis of (S)-N-(1-(3,5-bis(3-oxoisoindolin-5-yl)pyridine-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazole-1-yl)acetamide (10B):

[0424] (S)-N-(1-(3,5-dibromopyridine-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazole-1-yl)acetamide (50 mg, 0.074 mmol) was mixed with 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindorin-1-one (48 mg, 0.19 mmol), Pd(PPh3)2Cl2 (5 mg), LiCl (2 mg), and 110 μL of 2M K2CO3 aqueous solution. The reaction mixture was heated in a microwave reactor at 150°C for 20 minutes. The reaction mixture was purified by RP HPLC to obtain the desired product. [ka] MS (m / z) 798.1 [M+H] + . (Example 11)

Chemical Structure

[0425] Using 10A and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine, the synthesis of 10B in Example 10 was performed The title compound was prepared according to the method presented for the synthesis.

Chemical Structure

Chemical Structure

[0426] (S)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazole-1-yl)-N-(2-(3,5-difluorophenyl)-1-(2'-methoxy-5-(3-oxoisoindolin-5-yl)-[2,4'-bipyridine]-6-yl)ethyl)acetamide (8C, 5 mg), HCl (4N, 0.3 mL) and ethanol (0.3 mL) in 1,4-dioxane were charged into a microwave tube. The mixture was heated in a microwave synthesizer at 100°C for 20 minutes. After cooling, the solvent was removed, and the residue was purified by reverse-phase HPLC elution with acetonitrile and water (containing 0.1% TFA) to obtain the title product. [ka] MS (m / z) 742.99 [M+H] + . (Example 13) [ka] Synthesis of (S)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazole-1-yl)-N-(2-(3,5-difluorophenyl)-1-(2,2''-dioxo-1,1'',2,2''-tetrahydro-[4,2':5',4''-terpyridine]-6'-yl)ethyl)acetamide (13):

[0427] Using 8B, the title compound (13) was prepared according to the method described for the synthesis of compound 12 in Example 12. [ka] MS(m / z)705.00[M+H] + . (Example 14) [ka] Synthesis of (S)-tert-butyl 1-(3,6-dibromopyridine-2-yl)-2-(3,5-difluorophenyl)ethylcarbamate (14A):

[0428] Using 5E, the title compound was prepared according to the method described for the synthesis of compound 4E in Example 4. Synthesis of (S)-tert-butyl(1-(3-bromo-6-(3-hydroxy-3-methylbuta-1-in-1-yl)pyridine-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (14B):

[0429] The title compound (14B) was prepared using 2-methylbuta-3-in-2-ol and (S)-tert-butyl(1-(3,6-dibromopyridine-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate, according to the method described for the synthesis of compound 4F in Example 4. MS(m / z)496.90[M+H] + . Synthesis of the (1:1) hydrochloride salt (14C) of the compound (14C) of 2-methylbuta-3-in-2-ol and (S)-4-(6-(1-amino-2-(3,5-difluorophenyl)ethyl)-5-bromopyridine-2-yl)-2-methylbuta-3-in-2-ol:

[0430] Using 14B, the title compound (14C) was prepared according to the method described for the synthesis of compound 4G in Example 4. MS(m / z)397.09[M+H] + . Synthesis of N-((S)-1-(3-bromo-6-(3-hydroxy-3-methylbuta-1-in-1-yl)pyridine-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetamide(14D):

[0431] Synthesis of compound 4G in Example 4 using 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetic acid and 14C The title compound (14D) was prepared according to the method described. MS(m / z) 659.23[M+H] + . Synthesis of 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)-N-((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbuta-1-in-1-yl)-3-(1-oxoisoindorin-4-yl)pyridine-2-yl)ethyl)acetamide (14E):

[0432] Using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine and 14D, the title compound (14E) was prepared according to the method described for the synthesis of compound 4H in Example 4. [ka] MS (m / z) 697.28 [M+H] + . (Example 15) [ka] Synthesis of 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)-N-((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbuta-1-in-1-yl)-3-(1-oxoisoindorin-4-yl)pyridine-2-yl)ethyl)acetamide (15):

[0433] Using 14D and 2,3-dihydro-1H-isoindole-1-one-4-boronic acid pinacol ester, the title compound (15) was prepared according to the method described for the synthesis of compound 4H in Example 4. [ka] MS (m / z) 712.18 [M+H] + . (Example 16) [ka] Synthesis of (S)-N-(1-(3-bromo-6-((trimethylsilyl)ethynyl)pyridine-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazole-1-yl)acetamide (16A):

[0434] Using ethynyltrimethylsilane and 5F, the title compound (16A) was prepared according to the method described for the synthesis of compound 4F in Example 4. MS(m / z)694.59[M+H] + . Synthesis of (S)-N-(1-(3-(1H-pyrrolo[2,3-b]pyridine-5-yl)-6-((trimethylsilyl)ethynyl)pyridine-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazole-1-yl)acetamide (16B):

[0435] Using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine and 16A, the compound 4H of Example 4 The title compound (16B) was prepared according to the synthesis method described. MS(m / z)731.22[M+H] + . Synthesis of (S)-N-(1-(3-(1H-pyrrolo[2,3-b]pyridine-5-yl)-6-(1H-1,2,3-triazole-4-yl)pyridine-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazole-1-yl)acetamide (16C):

[0436] Compound 16B (75 mg, 0.1 mmol), NaN3 (13 mg, 0.2 mmol), and NH4Cl (5 mg, 0.1 mmol) were dissolved in DMF (0.5 mL) and stirred overnight at 100°C. The reaction mixture was cooled to room temperature, diluted with water, and extracted with phenylethylamine. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude material was purified by reverse-phase HPLC eluting with acetonitrile and water (containing 0.1% TFA) to obtain the title product. [ka] MS(m / z)702.02[M+H] + . (Example 17) [ka] Synthesis of 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)-N-((S)-2-(3,5-difluorophenyl)-1-(3-(2,4-dioxo-1,2,3,4-tetrahydroquinazoline-8-yl)-6-(3-hydroxy-3-methylbuta-1-inyl)pyridine-2-yl)ethyl)acetamide (17):

[0437] The title compound was prepared using 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline-2,4(1H,3H)-dione and 14D, according to the method described for the synthesis of compound 4F in Example 4. [ka] MS (m / z) 741.1 [M+H] + . (Example 18) [ka] Synthesis of 5-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetamide)-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbuta-1-in-1-yl)pyridine-3-yl)-2-fluorobenzamide (18):

[0438] The title compound was prepared using (3-carbamoyl-4-fluorophenyl)boronic acid and 14D, according to the method described for the synthesis of compound 4F in Example 4. [ka] MS (m / z) 718.2 [M+H] + . (Example 19) [ka] Synthesis of 7-bromo-4-chloro-1-methyl-1H-indazole-3-amine (19B):

[0439] Methylhydrazine (9 ml, 171 mmol) was added to 3-bromo-6-chloro-2-fluorobenzonitrile (10 g, 42.7 mmol) in EtOH (100 mL). The reaction mixture was stirred at 110 °C for 4 hours. The reaction mixture was slowly cooled over 4 hours, and the solid was filtered off. The mixture was used without further purification to obtain 7 g of the title compound (including small amounts of other positional isomers). MS (m / z) 262.0 [M+H] + . Synthesis of 4-chloro-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-3-amine (19C):

[0440] 7-bromo-4-chloro-1-methyl-1H-indazole-3-amine (3g, 11.5 mmol) in dioxane (40 mL) and DMF (25 mL) contains bis(pinaco Lato-diborane (8.8 g, 34.6 mmol), potassium acetate (3.4 g, 34.6 mmol), and trans-dichlorobis(triphenylphosphine)palladium(II) (486.35 mg, 0.69 mmol) were added. The reaction mixture was stirred at 130°C for 3 hours. The reaction mixture was cooled, diluted with phenylethylamine, and the solid was filtered off with phenylethylamine and silica gel. The mixture was concentrated and purified by flash column chromatography to obtain 1.8 g of the title compound. MS (m / z) 308.3 [M+H] + . Synthesis of N-(4-chloro-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-3-yl)methanesulfonamide (19D):

[0441] 7-bromo-4-chloro-1-methyl-1H-indazole-3-amine (2.6 g, 8.5 mmol) in DCM (30 mL) was mixed with N,N-diisopropylethylamine (5.9 ml, 33.8 mmol). The reaction mixture was then cooled in an ice bath, and methanesulfonyl chloride (2 ml, 25.4 mmol) was added. The reaction mixture was stirred at 0°C for 20 minutes. The reaction mixture was diluted with water and extracted twice with DCM. The organic layer was dehydrated with sodium sulfate and concentrated. The resulting mixture was dissolved in EtOH (30 ml) and 10N NaOH (8 ml) was added. The reaction mixture was tracked by LC / MS once (10 minutes), diluted with water, and quenched with concentrated HCl to pH 2. The mixture was extracted three times with DCM. The organic layer was dehydrated with sodium sulfate and concentrated until solid precipitation began. Next, the mixture was cooled in a brine / ice bath for 20 minutes, filtered, and the desired product was collected in two lots. These lots were used without further purification to obtain 2.1 g of the title compound. MS(m / z) 386.4[M+H] + . Synthesis of (S)-tert-butyl1-(3-(4-chloro-1-methyl-3-(methylsulfonamide)-1H-indazole-7-yl)-6-(3-hydroxy-3-methylbuta-1-inyl)pyridine-2-yl)-2-(3,5-difluorophenyl)ethylcarbamate (19E):

[0442] N-(4-chloro-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-3-yl)methanesulfonamide (39 mg, 0.1 mmol) in dioxane (5 mL) and DMF (0.3 mL) was mixed with 14B (50 mg, 0.1 mmol), 1N sodium bicarbonate (0.9 mL, 0.9 mmol), and dichlorobis(tricyclohexylphosphine)palladium(II) (1.9 mg, 0.003 mmol). The reaction mixture was stirred at 140 °C for 4 hours. The reaction mixture was cooled and diluted with HCl and brine. The mixture was extracted twice with HCl, the organic layer was dehydrated with sodium sulfate, concentrated, and purified by flash column chromatography to obtain 30 mg of the title compound. MS (m / z) 674.7 [M+H] + . Synthesis of (S)-N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbuta-1-inyl)pyridine-3-yl)-4-chloro-1-methyl-1H-indazole-3-yl)methanesulfonamide TFA salt (19F):

[0443] (S)-tert-butyl 1-(3-(4-chloro-1-methyl-3-(methylsulfonamide)-1H-indazole-7-yl)-6-(3-hydroxy-3-methylbuta-1-inyl)pyridine-2-yl)-2-(3,5-difluorophenyl)ethyl carbamate (30 mg, 0.04 mmol) in DCM (4 mL) was mixed with TFA (2 mL). The reaction mixture was stirred at room temperature for 0.5 hours. The reaction product was concentrated and used without further purification to obtain the title compound. MS (m / z) 574.4 [M+H] + . (S)-N-(1-(3-(4-chloro-1-methyl-3-(methylsulfonamide)-1H-indazole-7-yl)-6-(3-hydroxy-3-methylbuta-1-inyl)pyridine-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b Synthesis of S,4aR)-5,5-difluoro-3-(difluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetamide (19G):

[0444] Using 2-((3bS,4aR)-5,5-difluoro-3-(difluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetic acid and (S)-N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbuta-1-inyl)pyridine-3-yl)-4-chloro-1-methyl-1H-indazole-3-yl)methanesulfonamide, the title compound (19G) was prepared according to the method described for the synthesis of compound 4G in Example 4, yielding 20 mg of the title compound. [ka]

[0445] MS (m / z) 820.8 [M+H] + . (Example 20) [ka] Synthesis of (S)-N-(1-(3-(1-methyl-3-(methylsulfonamide)-1H-indazole-7-yl)-6-(3-hydroxy-3-methylbuta-1-inyl)pyridine-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(difluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetamide (20):

[0446] The title compound was prepared using N-(1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-3-yl)methanesulfonamide and compound 14B, according to the method described for the synthesis of compound 19G. [ka]

[0447] MS (m / z) 786.1 [M+H] + . (Example 21) [ka] Synthesis of 5-bromo-N-methoxy-N-methyl-2-(methylthio)pyrimidine-4-carboxamide (21A):

[0448] A mixture of 5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid (5 g, 20 mmol), N,O-dimethylhydroxylamine hydrochloride (2.9 g, 30 mmol), and HATU (9.1 g, 24 mmol) in CH2Cl2 (100 mL) was mixed with N,N-diisopropylethylamine (17.4 mL, 100 mmol) at 0°C. The reaction mixture was stirred at 0°C for 30 minutes and then diluted with CH2Cl2. This was washed with water and semi-brine. The organic layer was separated, dehydrated with MgSO4, filtered, and concentrated. The crude product was purified by silica gel chromatography to obtain the title compound 21A. MS (m / z) 292.16 [M+H] + . Synthesis of 5-bromo-2-(methylthio)pyrimidine-4-carbaldehyde (21B):

[0449] A solution of 5-bromo-N-methoxy-N-methyl-2-(methylthio)pyrimidine-4-carboxamide (21A, 8.2 g, 28 mmol) in THF (120 mL) was added dropwise to a suspension of lithium aluminum hydride (1.06 g, 28 mmol) and THF (120 mL) at -78 °C. After the addition was complete, the mixture was stirred for 10 minutes. H₂O (1.06 mL), 15% NaOH aqueous solution (1.06 mL), and H₂O (3.18 mL) were added very slowly and sequentially to the mixture at 0 °C. The resulting precipitate was filtered and washed with THF. The filtrate was concentrated under vacuum to obtain the crude product of the title compound. MS (m / z): 233.14, [M+H] + . Synthesis of (S)-N-((5-bromo-2-(methylthio)pyrimidine-4-yl)methylene)-2-methylpropane-2-sulfinamide (21C):

[0450] Anhydrous copper(II) sulfate (8.9 g, 56 mmol) was added to a solution of 5-bromo-2-(methylthio)pyrimidine-4-carbaldehyde (21B, approximately 28 mmol) and (S)-2-methylpropane-2-sulfinamide (3.4 g, 28 mmol) in CH2Cl2 (100 mL). The suspension was stirred at room temperature for 3 days. The reaction product was filtered and washed with CH2Cl2 (3 × 20 mL). The filtrate was concentrated. The crude product was purified by silica gel chromatography to obtain the title compound 21C. MS (m / z) 337.7 [M + H] + Synthesis of (S)-N-((S)-1-(5-bromo-2-(methylthio)pyrimidine-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (21D):

[0451] To a solution of (S)-N-((5-bromo-2-(methylthio)pyrimidine-4-yl)methylene)-2-methylpropane-2-sulfinamide (21C, 2.97g, 8.8 mmol) cooled to -78°C in THF (18 mL), 3,5-difluorobenzylmagnesium bromide (53 mL, 0.25 M in ether, 13.3 mmol) was added dropwise. After stirring at -78°C for 10 minutes, NH4Cl (saturated aqueous solution) (10 mL) was added to the reaction mixture, and the mixture was warmed to ambient temperature. Extraction with SiO2 was performed, and the organic layer was dehydrated with Na2SO4 (solid). After removing the solvent, the residue was purified by silica gel chromatography to obtain the title compound 21D (1.44 g). MS (m / z) 465.87 [M+H] + Synthesis of (S)-1-(5-bromo-2-(methylthio)pyrimidine-4-yl)-2-(3,5-difluorophenyl)ethanamine hydrochloride (21E):

[0452] Compound 21D (8 g, 17.23 mmol) was dissolved in 35 mL of methanol and cooled to 0°C. 4N HCl / 1,4-dioxane (10.7 mL) was added. The reaction mixture was stirred for 20 minutes, and diethyl ether was added. The resulting precipitate was collected by vacuum filtration and then dried to obtain the title product 21E. MS (m / z) 362.02[ M+H] + . Synthesis of (S)-N-(1-(5-bromo-2-(methylthio)pyrimidine-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazole-1-yl)acetamide (21F):

[0453] A mixture of 2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazole-1-yl)acetic acid (604 mg, 2 mmol), compound 21E (793 mg, 2 mmol), and HATU (912 mg, 2.4 mmol) in DMF (10 mL) was cooled to 0°C. N,N-diisopropylethylamine (1.05 mL, 6 mmol) was added dropwise. The reaction mixture was stirred at 0°C for 10 minutes, and then slowly poured into ice water while stirring. The resulting precipitate was collected by vacuum filtration and then dried to obtain the title product 21F. MS (m / z) 644.22 [M+H] + . Synthesis of (S)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazole-1-yl)-N-(2-(3,5-difluorophenyl)-1-(2-(methylthio)-5-(3-oxoisoindorin-5-yl)pyrimidine-4-yl)ethyl)acetamide (21G):

[0454] Compound 21F (300 mg, 0.47 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindorin-1-one (181 mg, 0.7 mmol), and PdCl2[P(Cy)3]2 (17 mg, 0.023 mmol) were charged into a microwave tube. 10 mL of 1,4-dioxane and 1.4 mL of 1M sodium bicarbonate aqueous solution were added to the mixture. The mixture was heated in a microwave synthesizer at 155°C for 25 minutes. After cooling to room temperature, it was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, then dehydrated with MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain the title compound 21G. MS(m / z) 697.32[M+H] + . Synthesis of (S)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazole-1-yl)-N-(2-(3,5-difluorophenyl)-1-(2-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-(3-oxoisoindorin-5-yl)pyrimidine-4-yl)ethyl)acetamide (21H):

[0455] A mixture of solid CuI (3.3 mg, 0.017 mmol), Pd(dppf)Cl2 (7 mg, 0.009 mmol), 2-methylbuta-3-in-2-ol (22 mg, 0.26 mmol), and compound 21G (60 mg, 0.086 mmol) was mixed with THF (1 mL) and Et3N (0.06 mL, 0.4 mmol). The reaction mixture was heated in a microwave at 160°C for 20 minutes. After cooling to room temperature, it was diluted with SiO2. Si-thiol (130 mg, 1.37 mmol / g) was added, and the mixture was stirred at 40°C for 1 hour. This was then filtered, and the filtrate was washed with 10% NH4OH aqueous solution, water, and brine. The organic layer was dehydrated with MgSO4, filtered, concentrated, and purified by reverse-phase HPLC to obtain the title compound (21H). [ka] MS (m / z): 732.99 [M+H] + . (Example 22) [ka] Synthesis of N-((S)-1-(5-bromo-2-(methylthio)pyrimidine-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetamide (22A):

[0456] Using 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetic acid and compound 21E, the title compound (22A) was prepared according to the method described for the synthesis of compound 21F in Example 21. MS(m / z) 624.13[M+H] + . Synthesis of 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)-N-((S)-2-(3,5-difluorophenyl)-1-(2-(methylthio)-5-(3-oxoisoindorin-5-yl)pyrimidine-4-yl)ethyl)acetamide (22B):

[0457] Using compound 22A and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindorin-1-one, the title compound (22B) was prepared according to the method described for the synthesis of compound 21G in Example 21. MS(m / z)677.05[M+H] + . 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)-N-((S)-2-(3,5-difluorophenyl)-1- Synthesis of (2-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-(3-oxoisoindolin-5-yl)pyrimidine-4-yl)ethyl)acetamide (22C):

[0458] Using compound 22B and 2-methylbuta-3-in-2-ol, the title compound (22C) was prepared according to the method described for the synthesis of compound 21H in Example 21. [ka] MS(m / z)713.01[M+H] + . (Example 23) [ka] Synthesis of 5-(4-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetamide)-2-(3,5-difluorophenyl)ethyl)-2-(methylthiopyrimidine-5-yl)-2-fluorobenzamide (23A):

[0459] Using compound 22A and 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide, the title compound (23A) was prepared according to the method described for the synthesis of compound 21G in Example 21. MS(m / z)683.06[M+H] + . 5-(4-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-( Synthesis of difluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetamide)-2-(3,5-difluorophenyl)ethyl)-2-(3-hydroxy-3-methylbuta-1-in-1-yl)pyrimidine-5-yl)-2-fluorobenzamide (23B):

[0460] Using compound 23A and 2-methylbuta-3-in-2-ol, the title compound (23B) was prepared according to the method described for the synthesis of compound 21H in Example 21. [ka] MS (m / z) 719.06 [M+H] + . (Example 24) [ka] Synthesis of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline-1(2H)-one (24A):

[0461] 5-bromoisoquinoline-1(2H)-one (40 mg, 0.18 mmol) was added to dioxane (1 mL) with bis(pinacorato)diborone (63 mg, 0.25 mmol) and PdCl2[P(Ph)3]2 (6 mg, 0.01 mmol). The reaction mixture was sealed and heated at 100°C for 1 hour. The reaction mixture was cooled to room temperature and used directly in the next reaction. MS(m / z) 272.3[M+H] + . 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)-N-((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbuta-1-in-1-yl)-3-(1-oxo-1,2-dihydroisoquinoline-5-yl)pyridine-2-yl)ethyl)acetamide Synthesis of (24B):

[0462] To a reaction vial containing 24A (0.18 mmol), 14D (50 mg, 0.07 mmol), PdCl2[P(Ph)3]2 (5 mg, 0.01 mmol), LiCl (11 mg, 0.22 mmol), and 1 M NaHCO3 aqueous solution (0.22 mL, 0.22 mmol) were added. The reaction mixture was sealed and heated in a microwave reactor at 160°C for 20 minutes. Upon cooling, the reaction mixture was diluted with RINKAN and washed three times with brine. The organic layer was dehydrated with Na2SO4, filtered, concentrated under vacuum, and purified by reverse-phase HPLC to obtain the title compound 24B as a mixture of atrop isomers. MS(m / z)724.2[M+H] + HPLC retention times of 6.95 min and 7.09 min (concentration gradient of 8.5 min on a Phenomonex Kinetex C18 column with 2-98% acetonitrile containing 0.1% trifluoroacetic acid:water). (Example 25) [ka] Synthesis of N-((S)-1-(3-(3-amino-1-methyl-1H-indazole-7-yl)-6-(3-hydroxy-3-methylbuta-1-in-1-yl)pyridine-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetamide (25):

[0463] Using 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetic acid and 37A, the title compound (25) was prepared as a mixture of atrop isomers according to the method presented for the synthesis of compound 33F in Example 33. [ka] MS (m / z) 726.2 [M+H] + . (Example 26) [ka] Synthesis of 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)-N-((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbuta-1-in-1-yl)-3-(3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-6-yl)pyridine-2-yl)ethyl)acetamide (26):

[0464] Using 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one, the title compound (26) was prepared according to the method described for the synthesis of compound 24B in Example 24. MS(m / z)714.1[M+H] + HPLC retention time 6.58 min (concentration gradient 8.5 min on a Phenomonex Kinetex C18 column with 2-98% acetonitrile containing 0.1% trifluoroacetic acid:water). (Example 27) [ka] Synthesis of 3-bromo-6-hydrazinyl-2-methylpyridine (27B):

[0465] Hydrazine hydrate (1.8 ml, 37 mmol) was added to 3-bromo-6-chloro-2-methylpyridine (1.53 g, 7.41 mmol) in dioxane (4.5 ml). The reaction mixture was heated in a microwave reactor at 160°C for 55 minutes. After cooling to ambient temperature, the reaction mixture was partitioned between ethyl acetate and saturated NaCl aqueous solution. Organic matter was separated and evaporated under vacuum. The product was used directly in the following steps. MS (m / z) 202.0 [M+H] + . Synthesis of 6-bromo-5-methyl-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one (27C):

[0466] 3-Bromo-6-hydrazinyl-2-methylpyridine (4.55 g, 22.52 mmol) was dissolved in DCE (35 ml), and trichloromethyl chloroformate (2.72 ml, 22.52 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 hour. Hexane (15 ml) was added, and the solid was filtered to obtain the desired product. The volume of the eluate was reduced, and the precipitate was isolated as a second crop. The combined solid was used without further purification. MS (m / z) 228.0 [M+H] + . Synthesis of 5-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one(27D):

[0467] 6-Bromo-5-methyl-[1,2,4]triazolo[4,3-a]pyridine-3(2 H)-one (3.62 g, 15.87 mmol) was combined with bis(pinacorato)diborone (6.05 g, 23.81 mmol), KOAc (3.12 g, 31.75 mmol), and PdCl2(PCy3)2 (0.23 g, 0.32 mmol) in dioxane (80 ml). Argon was blown into the reaction solution for 15 minutes. The reaction mixture was then heated at 85°C for 15 hours. An additional PdCl2(PCy3)2 (250 mg) was added, and the temperature was raised to 125°C and heated for 15 hours. After cooling to ambient temperature, the reaction mixture was partitioned between butyl and water. Organic matter was separated, dried, and removed under vacuum. The residue was suspended in butyl (50 ml), and the resulting solid was filtered to obtain the title compound. MS (m / z) 276.2 [M + H] + . Synthesis of (S)-tert-butyl(2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbuta-1-in-1-yl)-3-(5-methyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-6-yl)pyridine-2-yl)ethyl)carbamate (27E):

[0468] In a microwave reaction vessel, 14B (66 mg, 0.13 mmol) and 5-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one (55 mg, 0.2 mmol) were dissolved in dioxane (2 mL) and treated with 1 M NaHCO3 aqueous solution (0.4 mL) and PdCl2(PCy3)2 (10 mg). The mixture was heated at 150°C for 20 minutes. After cooling to ambient temperature, the reaction product was partitioned between ethyl acetate and water. Organic matter was separated, dried, and removed under vacuum. The residue was purified by silica column chromatography to obtain the title compound as a mixture of atropisomers. MS (m / z) 563.8 [M+H] + . Synthesis of (S)-6-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbuta-1-in-1-yl)pyridine-3-yl)-5-methyl-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one(27F):

[0469] Using 27E, the title compound (27F) was prepared as a mixture of atrop isomers according to the method described for the synthesis of 19F in Example 19. MS(m / z)464.1[M+H] + . Synthesis of 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)-N-((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbuta-1-in-1-yl)-3-(5-methyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3a]pyridine-6-yl)pyridine-2-yl)ethyl)acetamide (27G):

[0470] Using 27F and 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetic acid, the title compound (27G) was prepared as a mixture of atrop isomers according to the method presented for the synthesis of 37E in Example 37. [ka] MS (m / z) 728.0 [M+H] + . (Example 28) [ka] Synthesis of (S)-5-(2-(1-(2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazole-1-yl)acetamide)-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbuta-1-in-1-yl)pyridine-3-yl)-2-fluorobenzamide (28):

[0471] Using (3-carbamoyl-4-fluorophenyl)boronic acid and 2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazole-1-yl)acetic acid, the title compound (28) was prepared according to the method described for the synthesis of compound 33F in Example 33. [ka] MS (m / z) 738.2 [M+H] + . (Example 29) [ka] Synthesis of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-3-amine (29A):

[0472] 7-bromo-1H-indazole-3-amine (75 mg, 0.35 mmol) was added to dioxane (3 mL) with bis(pinacorato)diborone (126 mg, 0.5 mmol) and PdCl2[P(Ph)3]2 (12 mg, 0.01 mmol). The reaction mixture was sealed and heated at 100°C for 16 hours. The reaction mixture was cooled to room temperature and used directly in the next reaction. MS(m / z)260.2[M+H] + . Synthesis of N-((S)-1-(3-(3-amino-1H-indazole-7-yl)-6-(3-hydroxy-3-methylbuta-1-in-1-yl)pyridine-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetamide (29B):

[0473] Using 29A, the title compound (29) was prepared according to the method described for the synthesis of compound 24B in Example 24. MS(m / z)712.4[M+H] + PLC retention time 6.02 min (concentration gradient 8.5 min on a Phenomonex Kinetex C18 column with 2-98% acetonitrile containing 0.1% trifluoroacetic acid:water). (Example 30) [ka] Synthesis of 5-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetamide)-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbuta-1-in-1-yl)pyridine-3-yl)-2,3-difluorobenzamide (30):

[0474] Using 5-bromo-2,3-difluorobenzamide and 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetic acid, the title compound (30) was prepared according to the method described for the synthesis of compound 33F in Example 33. [ka] MS (m / z) 736.1 [M+H] + . (Example 31) [ka] Synthesis of (S)-N-(1-(3-(3-amino-1-methyl-1H-indazole-7-yl)-6-(3-hydroxy-3-methylbuta-1-in-1-yl)pyridine-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazole-1-yl)acetamide (31):

[0475] Using 37A and 2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazole-1-yl)acetic acid, the title compound (31) was prepared as a mixture of atrop isomers according to the method presented for the synthesis of compound 33F in Example 33. [ka] MS (m / z) 746.2 [M+H] + . (Example 32) [ka] Synthesis of N-((S)-1-(3-(3-amino-1-methyl-1H-indazole-7-yl)-6-(3-hydroxy-3-methylbuta-1-in-1-yl)pyridine-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetamide (32):

[0476] Using 37A, the title compound (32) was prepared as a mixture of atrop isomers according to the method described for the synthesis of compound 33F in Example 33. [ka] MS (m / z) 708.2 [M+H] + . (Example 33) [ka] Synthesis of 7-bromo-1-methyl-1H-indazole-3-amine (33A):

[0477] A solution of 3-bromo-2-fluorobenzonitrile (2 g, 10 mmol) in ethanol (10 mL) was treated with methylhydrazine (2.1 mL, 40 mmol) in a microwave vial, sealed, and heated in a microwave reactor at 120°C for 35 minutes. The reaction mixture was concentrated under vacuum, the crude product was dissolved in pharmaceutically acceptable solution (30 mL) and washed with water (30 mL), then with 2 M NaCl (aqueous solution, 30 mL). The organic matter was dried over Na₂SO₄, filtered, and concentrated. The product was purified by silica chromatography to obtain the title compound. MS (m / z) 227.1 [M + H] + . Synthesis of N-(7-bromo-1-methyl-1H-indazole-3-yl)methanesulfonamide (33B):

[0478] To a stirred solution of 33A (500 mg, 2.21 mmol), 4-dimethylaminopyridine (13.5 mg, 0.11 mmol), and N,N-diisopropylethylamine (714.6 mg, 5.53 mmol) in DCM (20 ml), methanesulfonyl chloride (532.0 mg, 4.64 mmol) was added dropwise at 0°C. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was washed with water, dried over Na₂SO₄, filtered, and concentrated. The crude product was dissolved in EtOH (10 mL) and treated with 8N NaOH (1.65 ml). The reaction mixture was heated at 60°C for 0.5 hours. Ethanol was removed under vacuum, the pH was adjusted to approximately 2 with 1.0 HCl, and then extracted with ELISA. The organic matter was dried over Na₂SO₄, filtered, and concentrated. The product was purified by silica chromatography to obtain the title compound. MS (m / z) 305.9 [M+H] + . Synthesis of N-(1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-3-yl)methanesulfonamide (33C):

[0479] To 33B (1.2 g, 3.9 mmol) in dioxane (15 mL), bis(pinacorato)diborone (1.9 mg, 5.5 mmol) and PdCl2[P(Ph)3]2 (138 mg, 0.19 mmol) were added. The reaction mixture was sealed and heated at 100°C for 1 hour. The reaction mixture was cooled to room temperature and filtered through Celite using ethyl acetate, and the pad was rinsed. The collected organic phase was concentrated under vacuum and purified by silica gel chromatography to obtain the title compound. MS(m / z) 352.1[M+H] + . Synthesis of (S)-tert-butyl(2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbuta-1-in-1-yl)-3-(1-methyl-3-(methylsulfonamide)-1H-indazole-7-yl)pyridine-2-yl)ethyl)carbamate (33D):

[0480] To 14B (250 mg, 0.5 mmol) in dioxane (12 mL), N-(1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-3-yl)methanesulfonamide (33C, 253 mg, 0.72 mmol), PdCl2[P(Ph)3]2 (35 mg, 0.05 mmol), and 1 M NaHCO3 aqueous solution (1.5 mL, 1.5 mmol) were added. The reaction mixture was sealed and heated in a microwave reactor at 150°C for 20 minutes. Upon cooling, the reaction mixture was diluted with  and washed three times with brine. The organic layer was dehydrated with Na2SO4, filtered, concentrated under vacuum, and purified by silica gel column chromatography eluted with 0-100%  in hexane to obtain the title compound 33D as a mixture of atropisomers. Synthesis of (S)-N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbuta-1-in-1-yl)pyridine-3-yl)-1-methyl-1H-indazole-3-yl)methanesulfonamide (33E):

[0481] To a solution of 33D (47 mg, 0.07 mmol) in DCM, 4M HCl in dioxane (0.7 mL, 2.9 mmol) was added. The reaction mixture was stirred at room temperature for 0.5 hours. After the Boc protecting group had been completely removed, the reaction mixture was concentrated under vacuum to obtain the title compound 33E as a mixture of atrop isomers. Synthesis of 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)-N-((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbuta-1-in-1-yl)-3-(1-methyl-3-(methylsulfonamide)-1H-indazole-7-yl)pyridine-2-yl)ethyl)acetamide (33F):

[0482] To a solution of 33E (70 mg) in DMA (3 mL), triethylamine (0.046 mL, 0.32 mmol) was added, followed by 2-((3bS,4aR)-3-(trifluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetic acid (31 mg, 0.1 mmol) and HATU (46 mg, 0.12 mmol). After stirring for 30 minutes, the reaction mixture was filtered and purified by reverse-phase HPLC to obtain product 33F as a mixture of atrop isomers. [ka] MS(m / z)804.1[M+H] + . (Example 34) [ka] Synthesis of N-((S)-1-(3-(3-amino-1-methyl-1H-indazole-7-yl)-6-(3-hydroxy-3-methylbuta-1-in-1-yl)pyridine-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazole-1(4H)-yl)acetamide (34):

[0483] 37A and 2-(3-(difluoromethyl)-5,5a,6,6a-tetrahydromethyl Using clopropa[g]indazole-1(4H)-yl)acetic acid (WO2013006738), the title compound (34) was prepared as a mixture of atrop isomers according to the method described for the synthesis of compound 33F in Example 33. [ka] MS(m / z)686.2[M+H] + . (Example 35) [ka] Synthesis of 6-bromo-N-(oxetane-3-yl)imidazo[1,2-a]pyridine-8-carboxamide (35B):

[0484] 6-Bromoimidazo[1,2-a]pyridine-8-carboxylic acid hydrochloride (235 mg, 0.85 mmol) and HATU (386.16 mg, 1.02 mmol) were combined in DMF (4 ml) and treated with iPr2NEt (0.37 ml, 2.12 mmol). 3-Oxetamine hydrochloride (92.31 mg, 0.85 mmol) was added, and the reaction mixture was stirred at ambient temperature for 1 hour. Upon addition of water (2 ml), a solid precipitate formed. The solid was collected by filtration to obtain the desired product. MS (m / z) 296.0 [M+H] + . Synthesis of (8-(oxetane-3-ylcarbamoyl)imidazo[1,2-a]pyridine-6-yl)boronic acid (35C):

[0485] Using 35B, the boronic acid ester was hydrolyzed according to the method described for the synthesis of 27D in Example 27 to prepare the title compound (35C), and the corresponding boronic acid was isolated. MS(m / z) 262.1[M+H] + . [ka] Synthesis of 6-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trif...

Claims

[Claim 1] The antiviral properties of the compound.

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