Amide compounds for treatment of HIV

Abstract

To provide amide compounds for the treatment of HIV.SOLUTION: Compounds of formula (I) or salts thereof are disclosed. Also disclosed are pharmaceutical compositions comprising the compounds of formula I, processes for preparing the compounds of formula I, intermediates useful for preparing the compounds of formula I, and therapeutic methods for treating a Retroviridae viral infection including an infection caused by the HIV virus. Provided herein are compounds and methods for treating HIV (i.e., human immunodeficiency virus) infection.SELECTED DRAWING: None

Description

[Technical field]

[0001] therapeutic compounds CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 61 / 771,655, filed March 1, 2013, and U.S. Provisional Patent Application No. 61 / 857,636, filed July 23, 2013, the disclosures of each of which are hereby incorporated by reference in their entirety. [Background technology]

[0002] background Positive single-stranded RNA viruses, including the Retroviridae family, include those of the subfamily Orthoretrovirinae, as well as the genera Alpharetrovirus, Betaretrovirus, Gamaretrovirus, Deltaretrovirus, Epsilonretrovirus, Lentivirus, and Spumavirus, which cause many diseases in humans and animals. Among the Lentiviruses, human HIV-1 infection leads to the exhaustion of helper T cells 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 viral load and significantly slowing disease progression (Hammer, SM et al.; JAMA 2008, 300:555-570). However, these treatments may actually lead to the emergence of HIV strains that are resistant to current therapies (Taiwo, B., International Journal of Infectious Diseases 2009, vol. 13:552-559; Smith, RJ et al., Science 2010, vol. 327:697-701). Thus, there is an urgent need to discover new antiretroviral agents that are active against emerging drug-resistant HIV mutants. [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Hammer, SM et al. JAMA 2008, 300:555-570 [Non-Patent Document 2] Taiwo, B., International Journal of Infectious Diseases 2009, 13:552-559 [Non-Patent Document 3] Smith, RJ et al., Science 2010, 327:697-701 Summary of the Invention [Means for solving the problem]

[0004] overview Provided herein are compounds and methods for treating HIV (ie, human immunodeficiency virus) infection. One embodiment is a compound of formula IIId [ka] [In the formula, A 1 , CH, CZ 3 or nitrogen, A 2 is CH or nitrogen, R 1 is a 6- to 12-membered aryl, a 5- to 12-membered heteroaryl, or a 3- to 12-membered heterocycle; R 1 Any 6- to 12-membered aryl, 5- to 12-membered heteroaryl, or 3- to 12-membered heterocycle may be selected from the group consisting of 1, 2, 3, 4, or 5 Z 4 is optionally substituted with a group; 4 The groups are the same or different, R 3a and R 3b Each independently represents H or (C 1~C 3 ) alkyl, Z 1 is a 6- to 12-membered aryl, a 5- to 14-membered heteroaryl, or a 3- to 14-membered heterocycle; Z 1 Any 6- to 12-membered aryl, 5- to 14-membered heteroaryl, or 3- to 14-membered heterocycle may be selected from the group consisting of 1, 2, 3, 4, or 5 Z 1a or Z 1b and optionally substituted with Z 1a and Z 1b The groups are the same or different, each Z 1a are independently 3 ~C 7 ) Carbocycle, 5-12 membered heteroaryl, 3-12 membered heterocycle, halogen, -CN, -OR n1 , -OC(O)R p1 , -OC(O)NR q1 R r1 , -SR n1 , -S(O)R p1 , -S(O) 2 OH, -S(O) 2 R p1 , -S(O) 2 NR q1 R r1 , -NR q1 R r1 , -NR n1 COR p1 , -NR n1 CO 2 R p1 , -NR n1 CONR q1 R r1 , -NR n1 S(O) 2 R p1 , -NR n1 S(O) 2 OR p1 , -NR n1 S(O) 2 NR q1 R r1 , -C(O)R n1 , -C(O)OR n1 , -C(O)NR q1 R r1 and -S(O) 2 NR n1COR p1 and Z 1a Any (C 3 ~C 7 ) Carbocycle, 5-12 membered heteroaryl and 3-12 membered heterocycle are each independently selected from 1, 2, 3, 4 or 5 Z 1c or Z 1d is optionally substituted with a group; 1c and Z 1d The groups are the same or different, each Z 1b is optionally substituted with 1, 2, 3, 4 or 5 halogens, which are independently the same or different (C 1 ~C 8 ) alkyl, each Z 1c are independently halogen, -CN, -OH, -NH 2 , -C(O)NR q2 R r2 , or (C 1 ~C 8 ) heteroalkyl; each Z 1d are independently 1 ~C 8 ) alkyl or (C 1 ~C 8 ) haloalkyl; Each R n1 are independently, H, (C 1 ~C 8 ) alkyl, (C 3 ~C 7 ) a carbocycle, a 3- to 7-membered heterocycle, or a 5- to 6-membered monocyclic heteroaryl; R n1 Any (C 3 ~C 7 ) A carbocycle, a 3- to 7-membered heterocycle, or a 5- to 6-membered monocyclic heteroaryl is selected from the group consisting of 1, 2, 3, 4, or 5 Z 1c or Z 1d is optionally substituted with a group; 1c and Z 1d The groups may be the same or different, R n1 Any (C 1 ~C 8 ) alkyl is 1, 2, 3, 4 or 5 Z 1cis optionally substituted with a group; 1c The groups are the same or different, Each R p1 are independently 1 ~C 8 ) alkyl, (C 3 ~C 7 ) a carbocycle, a 3- to 7-membered heterocycle, or a 5- to 6-membered monocyclic heteroaryl; R p1 Any (C 3 ~C 7 )carbon A ring, a 3- to 7-membered heterocycle, or a 5- to 6-membered monocyclic heteroaryl may have 1, 2, 3, 4, or 5 Z 1c or Z 1d is optionally substituted with a group; 1c and Z 1d The groups may be the same or different, R p1 Any (C 1 ~C 8 ) alkyl is 1, 2, 3, 4 or 5 Z 1c is optionally substituted with a group; 1c The groups are the same or different, R q1 and R r1 are each independently H, (C 1 ~C 8 ) alkyl, (C 3 ~C 7 ) a carbocycle, a 3- to 7-membered heterocycle, or a 5- to 6-membered monocyclic heteroaryl; R q1 Or R r1 Any (C 3 ~C 7 ) A carbocycle, a 3- to 7-membered heterocycle, or a 5- to 6-membered monocyclic heteroaryl is selected from the group consisting of 1, 2, 3, 4, or 5 Z 1c Or Z 1d is optionally substituted with a group; 1c and Z 1d The groups may be the same or different, R q1 Or R r1 Any (C 1 ~C 8 ) alkyl is 1, 2, 3, 4 or 5 Z 1c is optionally substituted with a group;1c The groups may be the same or different, or R q1 and R r1 together with the nitrogen to which they are attached form a 5-, 6- or 7-membered heterocycle, the 5-, 6- or 7-membered heterocycle being bound to 1, 2, 3, 4 or 5 Z 1c Or Z 1d is optionally substituted with a group; 1c and Z 1d The groups may be the same or different, R q2 and R r2 are each independently H, (C 1 ~C 8 ) alkyl, (C 3 ~C 7 ) a carbocyclic ring or R q2 and R r2 together with the nitrogen to which they are attached form a 5-, 6-, or 7-membered heterocyclic ring; Z 2 is (C 2 ~C 8 ) alkenyl, (C 2 ~C 8 ) alkynyl, 6-12 membered aryl, 5-12 membered C-linked heteroaryl, 3-12 membered C-linked heterocycle, -C(O)R n3 or -C(O)NR q3 R r3 and Z 2 Any 6-12 membered aryl, 5-12 membered C-linked heteroaryl, or 3-12 membered C-linked heterocycle may be joined by 1, 2, 3, 4 or 5 Z 2b or Z 2c is optionally substituted with a group; 2b and Z 2c The groups may be the same or different, Z 2 Any (C 2 ~C 8 ) alkenyl or (C 2 ~C 8 ) Alkynyl is substituted with 1, 2, 3, 4 or 5 Z 2c is optionally substituted with a group; 2c The groups are the same or different, Each Rn3 are independently H or (C 1 ~C 4 ) alkyl, R q3 and R r3 Each independently represents H or (C 1 ~C 4 ) alkyl, each Z 2b are independently oxo, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 )heteroalkyl or (C 1 ~C 4 ) haloalkyl; each Z 2c are independently oxo, halogen, -CN, -OR n4 , -OC(O)R p4 , -OC(O)NR q4 R r4 , -SR n4 , -S(O)R p4 , -S(O) 2 OH, -S(O) 2 R p4 , -S(O) 2 NR q4 R r4 , -NR q4 R r4 , -NR n4 COR p4 , -NR n4 CO 2 R p4 , -NR n4 CONR q4 R r4 , -NR n4 S(O) 2 R p4 , -NR n4 S(O) 2 OR p4 , -NR n4 S(O) 2 NR q4 R r4 , -NO 2 , -C(O)R n4 , -C(O)OR n4 or -C(O)NR q4 R r4 and Each R n4 are independently, H, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 ) haloalkyl, or (C 1 ~C 4 ) heteroalkyl; Each R p4 are independently 1 ~C 8 ) alkyl, (C 1 ~C 4 ) haloalkyl, or (C 1 ~C 4 ) heteroalkyl; R q4 and R r4 are each independently H, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 ) haloalkyl, or (C 1 ~C 4 ) heteroalkyl; each Z 3 are independently 1 ~C 4 ) heteroalkyl; each Z 4 are independently oxo, (C 1 ~C 8 ) alkyl, (C 3 ~C 7 )Carbocycle, halogen, -CN, -OR n5 , -NR q5 R r5 , -NR n5 COR p5 , -NR n5 CO 2 R p5 , -C(O)R n5 , -C(O)OR n5 or -C(O)NR q5 R r5 and Z 4 Any (C 3 ~C 7 ) carbocyclic or (C 1 ~C 8 ) alkyl is 1, 2, 3, 4 or 5 Z 4ais optionally substituted with a group; 4a The groups are the same or different, each Z 4a are independently halogen, -CN, or -OR n6 and R n5 , R p5 , R q5 , R r5 , and R n6 Each independently represents H or (C 1 ~C 4 ) alkyl, each Z 5 are independently halogens which may be the same or different; n is 0, 1, 2 or 3. or a pharma- ceutically acceptable salt thereof.

[0005] One embodiment is a compound of formula III [ka] [In the formula, A is a 6-membered monocyclic heteroaryl having 1 or 2 nitrogen atoms, the 6-membered monocyclic heteroaryl being substituted with one Z at the indicated position. 1 group and one Z 2 group and one or two Z 3 is optionally substituted with a group; 3 The groups are the same or different, R 1 is a 6- to 12-membered aryl, a 5- to 12-membered heteroaryl, or a 3- to 12-membered heterocycle; R 1 Any 6- to 12-membered aryl, 5- to 12-membered heteroaryl, or 3- to 12-membered heterocycle may be selected from the group consisting of 1, 2, 3, 4, or 5 Z 4 is optionally substituted with a group; 4 The groups are the same or different, R 2is phenyl optionally substituted with 1, 2, 3, 4 or 5 halogens which are the same or different; R 3a and R 3b Each independently represents H or (C 1 ~C 3 ) alkyl, Z 1 is a 6- to 12-membered aryl, a 5- to 14-membered heteroaryl, or a 3- to 14-membered heterocycle; Z 1 Any 6- to 12-membered aryl, 5- to 14-membered heteroaryl, or 3- to 14-membered heterocycle may be selected from the group consisting of 1, 2, 3, 4, or 5 Z 1a or Z 1b and optionally substituted with Z 1a and Z 1b The groups are the same or different, each Z 1a are independently 3 ~C 7 ) Carbocycle, 5-12 membered heteroaryl, 3-12 membered heterocycle, halogen, -CN, -OR n1 , -OC(O)R p1 , -OC(O)NR q1 R r1 , -SR n1 , -S(O)R p1 , -S(O) 2 OH, -S(O) 2 R p1 , -S(O) 2 NR q1 R r1 , -NR q1 R r1 , -NR n1 COR p1 , -NR n1 CO 2 R p1 , -NR n1 CONR q1 R r1 , -NR n1 S(O) 2 R p1 , -NR n1 S(O) 2 OR p1 , -NR n1 S(O) 2 NR q1 Rr1 , -C(O)R n1 , -C(O)OR n1 , -C(O)NR q1 R r1 and -S(O) 2 NR n1 COR p1 and Z 1a Any (C 3 ~C 7 ) Carbocycle, 5-12 membered heteroaryl and 3-12 membered heterocycle are each independently selected from 1, 2, 3, 4 or 5 Z 1c or Z 1d is optionally substituted with a group; 1c and Z 1d The groups are the same or different, each Z 1b is optionally substituted with 1, 2, 3, 4 or 5 halogens, which are independently the same or different (C 1 ~C 8 ) alkyl, each Z 1c are independently halogen, -CN, -OH, -NH 2 , -C(O)NR q2 R r2 , or (C 1 ~C 8 ) heteroalkyl; each Z 1d are independently 1 ~C 8 ) alkyl or (C 1 ~C 8 ) haloalkyl; Each R n1 are independently, H, (C 1 ~C 8 ) alkyl, (C 3 ~C 7 ) a carbocycle, a 3- to 7-membered heterocycle, or a 5- to 6-membered monocyclic heteroaryl; R n1 Any (C 3 ~C 7 ) A carbocycle, a 3- to 7-membered heterocycle, or a 5- to 6-membered monocyclic heteroaryl is selected from the group consisting of 1, 2, 3, 4, or 5 Z 1c or Z 1d is optionally substituted with a group; 1c and Z1d The groups may be the same or different, R n1 Any (C 1 ~C 8 ) alkyl is 1, 2, 3, 4 or 5 Z 1c is optionally substituted with a group; 1c The groups are the same or different, Each R p1 are independently 1 ~C 8 ) alkyl, (C 3 ~C 7 ) a carbocycle, a 3- to 7-membered heterocycle, or a 5- to 6-membered monocyclic heteroaryl; R p1 Any (C 3 ~C 7 ) A carbocycle, a 3- to 7-membered heterocycle, or a 5- to 6-membered monocyclic heteroaryl is selected from the group consisting of 1, 2, 3, 4, or 5 Z 1c or Z 1d is optionally substituted with a group; 1c and Z 1d The groups may be the same or different, R p1 Any (C 1 ~C 8 ) alkyl is 1, 2, 3, 4 or 5 Z 1c is optionally substituted with a group; 1c The groups are the same or different, R q1 and R r1 are each independently H, (C 1 ~C 8 ) alkyl, (C 3 ~C 7 ) a carbocycle, a 3- to 7-membered heterocycle, or a 5- to 6-membered monocyclic heteroaryl; R q1 Or R r1 Any (C 3 ~C 7 ) A carbocycle, a 3- to 7-membered heterocycle, or a 5- to 6-membered monocyclic heteroaryl is selected from the group consisting of 1, 2, 3, 4, or 5 Z 1c Or Z 1d is optionally substituted with a group; 1c and Z 1d The groups may be the same or different, R q1 Or Rr1 Any (C 1 ~C 8 ) alkyl is 1, 2, 3, 4 or 5 Z 1c is optionally substituted with a group; 1c The groups may be the same or different, or R q1 and R r1 together with the nitrogen to which they are attached form a 5-, 6- or 7-membered heterocycle, the 5-, 6- or 7-membered heterocycle being bound to 1, 2, 3, 4 or 5 Z 1c Or Z 1d is optionally substituted with a group; 1c and Z 1d The groups may be the same or different, R q2 and R r2 are each independently H, (C 1 ~C 8 ) alkyl, (C 3 ~C 7 ) a carbocyclic ring or R q2 and R r2 together with the nitrogen to which they are attached form a 5-, 6-, or 7-membered heterocyclic ring; Z 2 is (C 2 ~C 8 ) alkenyl, (C 2 ~C 8 ) alkynyl, 6-12 membered aryl, 5-12 membered C-linked heteroaryl, 3-12 membered C-linked heterocycle, -C(O)R n3 or -C(O)NR q3 R r3 and Z 2 Any 6-12 membered aryl, 5-12 membered C-linked heteroaryl, or 3-12 membered C-linked heterocycle may be joined by 1, 2, 3, 4 or 5 Z 2b or Z 2c is optionally substituted with a group; 2b and Z 2c The groups may be the same or different, Z 2 Any (C 2 ~C 8 ) alkenyl or (C 2 ~C 8) Alkynyl is substituted with 1, 2, 3, 4 or 5 Z 2c is optionally substituted with a group; 2c The groups are the same or different, Each R n3 are independently H or (C 1 ~C 4 ) alkyl, R q3 and R r3 Each independently represents H or (C 1 ~C 4 ) alkyl, each Z 2b are independently oxo, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 ) heteroalkyl, or (C 1 ~C 4 ) haloalkyl; each Z 2c are independently oxo, halogen, -CN, -OR n4 , -OC(O)R p4 , -OC(O)NR q4 R r4 , -SR n4 , -S(O)R p4 , -S(O) 2 OH, -S(O) 2 R p4 , -S(O) 2 NR q4 R r4 , -NR q4 R r4 , -NR n4 COR p4 , -NR n4 CO 2 R p4 , -NR n4 CONR q4 R r4 , -NR n4 S(O) 2 R p4 , -NR n4 S(O) 2 OR p4 , -NR n4 S(O) 2 NR q4 R r4 , -NO 2, -C(O)R n4 , -C(O)OR n4 or -C(O)NR q4 R r4 and Each R n4 are independently, H, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 ) haloalkyl, or (C 1 ~C 4 ) heteroalkyl; Each R p4 are independently 1 ~C 8 ) alkyl, (C 1 ~C 4 ) haloalkyl, or (C 1 ~C 4 ) heteroalkyl; R q4 and R r4 are each independently H, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 ) haloalkyl, or (C 1 ~C 4 ) heteroalkyl; each Z 3 are independently 1 ~C 4 ) heteroalkyl or halogen; each Z 4 are independently oxo, (C 1 ~C 8 ) alkyl, (C 3 ~C 7 )Carbocycle, halogen, -CN, -OR n5 , -NR q5 R r5 , -NR n5 COR p5 , -NR n5 CO 2 R p5 , -C(O)R n5 , -C(O)OR n5 or -C(O)NR q5 R r5 and Z 4 Any (C3 ~C 7 ) carbocyclic or (C 1 ~C 8 ) alkyl is 1, 2, 3, 4 or 5 Z 4a is optionally substituted with a group; 4a The groups are the same or different, each Z 4a are independently halogen, -CN, or -OR n6 and R n5 , R p5 , R q5 , R r5 , and R n6 Each independently represents H or (C 1 ~C 4 ) alkyl] or a pharma- ceutically acceptable salt thereof.

[0006] One embodiment is a compound of formula I [ka] [In the formula, A is a 6-membered monocyclic heteroaryl having 1 or 2 nitrogen atoms, the 6-membered monocyclic heteroaryl being substituted with one Z at the indicated position. 1 group and one Z 2 group and one or more (e.g., one or two) Z 3 is optionally substituted with a group; R 1 is a 6- to 12-membered aryl, a 5- to 12-membered heteroaryl, or a 3- to 12-membered heterocycle; R 1 Any 6- to 12-membered aryl, 5- to 12-membered heteroaryl or 3- to 12-membered heterocycle may have one or more (e.g., 1, 2, 3, 4 or 5) Z 4 is optionally substituted with a group; R 2 is phenyl, 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl or (C 3 ~C7 ) carbocyclic ring, R 2 any phenyl, 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl or (C 3 ~C 7 ) The carbocycle may contain one or more (e.g., 1, 2, 3, 4 or 5) Z 5 is optionally substituted with a group; R 3a and R 3b are each independently H, halogen, (C 1 ~C 3 ) alkyl and (C 1 ~C 3 ) haloalkyl, or R 3a is H, (C 1 ~C 3 ) alkyl and (C 1 ~C 3 ) haloalkyl; R 3b is selected from -OH and -CN; Z 1 is selected from 6- to 12-membered aryl, 5- to 14-membered heteroaryl, and 3- to 14-membered heterocycle; Z 1 Any 6- to 12-membered aryl, 5- to 14-membered heteroaryl, and 3- to 14-membered heterocycle may have one or more (e.g., 1, 2, 3, 4, or 5) Z 1a or Z 1b and optionally substituted with each Z 1a are independently 3 ~C 7 ) Carbocycle, 6-12 membered aryl, 5-12 membered heteroaryl, 3-12 membered heterocycle, halogen, -CN, -OR n1 , -OC(O)R p1 , -OC(O)NR q1 R r1 , -SR n1 , -S(O)R p1 , -S(O) 2 OH, -S(O) 2 R p1 , -S(O) 2 NR q1 R r1 , -NR q1 Rr1 , -NR n1 COR p1 , -NR n1 CO 2 R p1 , -NR n1 CONR q1 R r1 , -NR n1 S(O) 2 R p1 , -NR n1 S(O) 2 OR p1 , -NR n1 S(O) 2 NR q1 R r1 , NO 2 , -C(O)R n1 , -C(O)OR n1 , -C(O)NR q1 R r1 and -S(O) 2 NR n1 COR p1 Selected from Z 1a Any (C 3 ~C 7 ) Carbocycle, 6- to 12-membered aryl, 5- to 12-membered heteroaryl and 3- to 12-membered heterocycle may each have one or more (e.g., 1, 2, 3, 4 or 5) Z 1c or Z 1d is optionally substituted with a group; each Z 1b are independently 1 ~C 8 ) alkyl, (C 2 ~C 8 ) alkenyl and (C 2 ~C 8 ) alkynyl; Z 1b Any (C 1 ~C 8 ) alkyl, (C 2 ~C 8 ) alkenyl and (C 2 ~C 8 ) Alkynyl is selected from the group consisting of one or more (e.g., 1, 2, 3, 4, or 5) Z 1c is optionally substituted with a group; each Z 1c are independently 3~C 7 ) Carbocycle, phenyl, 5-6 membered monocyclic heteroaryl, 3-7 membered heterocycle, halogen, -CN, -OR n2 , -OC(O)R p2 , -OC(O)NR q2 R r2 , -SR n2 , -S(O)R p2 , -S(O) 2 OH, -S(O) 2 R p2 , -S(O) 2 NR q2 R r2 , -NR q2 R r2 , -NR n2 COR p2 , -NR n2 CO 2 R p2 , -NR n2 CONR q2 R r2 , -NR n2 S(O) 2 R p2 , -NR n2 S(O) 2 OR p2 , -NR n2 S(O 2 NR q2 R r2 , NO 2 , -C(O)R n2 , -C(O)OR n2 , -C(O)NR q2 R r2 , halophenyl, 5-6 membered haloheteroaryl, 3-7 membered haloheterocycle and (C 1 ~C 8 ) heteroalkyl; each Z 1d are independently 1 ~C 8 ) alkyl, (C 2 ~C 8 ) alkenyl, (C 2 ~C 8 ) alkynyl and (C 1 ~C 8 ) haloalkyl; Each R n1are independently, H, (C 1 ~C 8 ) alkyl, (C 2 ~C 8 ) alkenyl, (C 2 ~C 8 ) alkynyl, (C 3 ~C 7 ) selected from carbocycle, 3- to 7-membered heterocycle, 5- to 6-membered monocyclic heteroaryl, and phenyl; R n1 Any (C 3 ~C 7 ) Carbocycle, 3- to 7-membered heterocycle, 5- to 6-membered monocyclic heteroaryl, and phenyl are each independently selected from one or more (e.g., 1, 2, 3, 4, or 5) Z 1c or Z 1d is optionally substituted with R n1 Any (C 1 ~C 8 ) alkyl, (C 2 ~C 8 ) alkenyl and (C 2 ~C 8 ) Alkynyl is selected from the group consisting of one or more (e.g., 1, 2, 3, 4, or 5) Z 1c is optionally substituted with a group; Each R p1 are independently 1 ~C 8 ) alkyl, (C 2 ~C 8 ) alkenyl, (C 2 ~C 8 ) alkynyl, (C 3 ~C 7 ) selected from carbocycle, 3- to 7-membered heterocycle, 5- to 6-membered monocyclic heteroaryl, and phenyl; R p1 Any (C 3 ~C 7 ) Carbocycle, 3- to 7-membered heterocycle, 5- to 6-membered monocyclic heteroaryl, and phenyl are each independently selected from one or more (e.g., 1, 2, 3, 4, or 5) Z 1c or Z 1d is optionally substituted with R p1 Any (C 1 ~C 8 ) alkyl, (C 2 ~C 8) alkenyl and (C 2 ~C 8 ) Alkynyl is selected from the group consisting of one or more (e.g., 1, 2, 3, 4, or 5) Z 1c is optionally substituted with a group; R q1 and R r1 are independently H, (C 1 ~C 8 ) alkyl, (C 2 ~C 8 ) alkenyl, (C 2 ~C 8 ) alkynyl, (C 3 ~C 7 ) selected from carbocycle, 3- to 7-membered heterocycle, 5- to 6-membered monocyclic heteroaryl, and phenyl; R q1 Or R r1 Any (C 3 ~C 7 ) Carbocycle, 3- to 7-membered heterocycle, 5- to 6-membered monocyclic heteroaryl, and phenyl are each independently selected from one or more (e.g., 1, 2, 3, 4, or 5) Z 1c Or Z 1d is optionally substituted with R q1 Or R r1 Any (C 1 ~C 8 ) alkyl, (C 2 ~C 8 ) alkenyl and (C 2 ~C 8 ) Alkynyl is one or more is multiple (e.g., 1, 2, 3, 4, or 5) Z 1c Optionally substituted with a group or R q1 and R r1 together with the nitrogen to which they are attached form a 5-, 6-, or 7-membered heterocycle, the 5-, 6-, or 7-membered heterocycle containing one or more (e.g., 1, 2, 3, 4, or 5) Z 1c Or Z 1d is optionally substituted with a group; Each R n2 are independently, H, (C 1 ~C 8 ) alkyl, (C 2 ~C8 ) alkenyl, (C 2 ~C 8 ) alkynyl, (C 3 ~C 7 ) carbocycle, 3- to 7-membered heterocycle, 5- to 6-membered monocyclic heteroaryl, phenyl, halophenyl, 5- to 6-membered monocyclic haloheteroaryl, 3- to 7-membered haloheterocycle, (C 1 ~C 8 ) haloalkyl and (C 1 ~C 8 ) heteroalkyl; Each R p2 are independently 1 ~C 8 ) alkyl, (C 2 ~C 8 ) alkenyl, (C 2 ~C 8 ) alkynyl, (C 3 ~C 7 ) carbocycle, 3- to 7-membered heterocycle, 5- to 6-membered monocyclic heteroaryl, phenyl, halophenyl, 5- to 6-membered monocyclic haloheteroaryl, 3- to 7-membered haloheterocycle, (C 1 ~C 8 ) haloalkyl and (C 1 ~C 8 ) heteroalkyl; R q2 and R r2 are independently H, (C 1 ~C 8 ) alkyl, (C 2 ~C 8 ) alkenyl, (C 2 ~C 8 ) alkynyl, (C 3 ~C 7 ) carbocycle, 3- to 7-membered heterocycle, 5- to 6-membered monocyclic heteroaryl, phenyl, halophenyl, 5- to 6-membered monocyclic haloheteroaryl, 3- to 7-membered haloheterocycle, (C 1 ~C 8 ) haloalkyl and (C 1 ~C 8 ) heteroalkyl; or R q2 and R r2 together with the nitrogen to which they are attached form a 5-, 6-, or 7-membered heterocyclic ring; Z 2 is (C 2 ~C 8 ) alkenyl, (C 2 ~C 8 ) alkynyl, 6-12 membered aryl, 5-12 membered C-linked heteroaryl, 3-12 membered C-linked heterocycle, -C(O)R n3 and -C(O)NR q3 R r3 Selected from Z 2 Any 6-12 membered aryl, 5-12 membered C-linked heteroaryl and 3-12 membered C-linked heterocycle may have one or more (e.g., 1, 2, 3, 4 or 5) Z 2b or Z 2c is optionally substituted with a group; 2 Any (C 2 ~C 8 ) alkenyl and (C 2 ~C 8 ) Alkynyl is selected from the group consisting of one or more (e.g., 1, 2, 3, 4, or 5) Z 2c is optionally substituted with a group; each Z 2a are independently 3 ~C 7 ) Carbocycle, 6-12 membered aryl, 5-12 membered heteroaryl, 3-12 membered heterocycle, halogen, -CN, -OR n4 , -OC(O)R p4 , -OC(O)NR q4 R r4 , -SR n4 , -S(O)R p4 , -S(O) 2 OH, -S(O) 2 R p4 , -S(O) 2 NR q4 R r4 , -NR q4 R r4 , -NR n4 COR p4 , -NR n4 CO 2 R p4 , -NR n4 CONR q4 R r4 , -NR n4 S(O)2 R p4 , -NR n4 S(O) 2 OR p4 , -NR n4 S(O) 2 NR q4 R r4 , NO 2 , -C(O)R n4 , -C(O)OR n4 and -C(O)NR q4 R r4 Selected from Z 2a Any (C 3 ~C 7 ) Carbocycle, 6- to 12-membered aryl, 5- to 12-membered heteroaryl and 3- to 12-membered heterocycle may each have one or more (e.g., 1, 2, 3, 4 or 5) Z 2b or Z 2c is optionally substituted with a group; each Z 2b are independently 1 ~C 4 ) alkyl, (C 1 ~C 4 )heteroalkyl and (C 1 ~C 4 ) haloalkyl; each Z 2c are independently halogen, -CN, -OR n4 , -OC(O)R p4 , -OC(O)NR q4 R r4 , -SR n4 , -S(O)R p4 , -S(O) 2 OH, -S(O) 2 R p4 , -S(O) 2 NR q4 R r4 , -NR q4 R r4 , -NR n4 COR p4 , -NR n4 CO 2 R p4 , -NR n4 CONR q4 R r4 , -NR n4 S(O)2 R p4 , -NR n4 S(O) 2 OR p4 , -NR n4 S(O) 2 NR q4 R r4 , NO 2 , -C(O)R n4 , -C(O)OR n4 and -C(O)NR q4 R r4 is selected from Each R n3 are independently, H, (C 1 ~C 4 ) alkyl, (C 2 ~C 4 ) alkenyl, (C 3 ~C 7 ) selected from carbocycle, 3- to 12-membered heterocycle, 5- to 12-membered heteroaryl, and 6- to 12-membered aryl; R n3 Any (C 3 ~C 7 ) Carbocyclic ring, 3-12 membered heterocyclic ring, 5 The 6- to 12-membered heteroaryl and the 6- to 12-membered aryl can each be selected from one or more (e.g., 1, 2, 3, 4, or 5) Z 2b or Z 2c is optionally substituted with R n3 Any (C 1 ~C 4 ) alkyl, (C 2 ~C 4 ) alkenyl and (C 2 ~C 4 ) Alkynyl is selected from the group consisting of one or more (e.g., 1, 2, 3, 4, or 5) Z 2a is optionally substituted with a group; R q3 and R r3 are independently H, (C 1 ~C 4 ) alkyl, (C 2 ~C 4 ) alkenyl, (C 3 ~C 7 ) selected from carbocycle, 3- to 12-membered heterocycle, 5- to 12-membered heteroaryl, and 6- to 12-membered aryl; Rq3 Or R r3 Any (C 3 ~C 7 ) Carbocycle, 3- to 12-membered heterocycle, 5- to 12-membered heteroaryl, and 6- to 12-membered aryl may each have one or more (e.g., 1, 2, 3, 4, or 5) Z 2b Or Z 2c is optionally substituted with R q3 Or R r3 Any (C 1 ~C 4 ) alkyl and (C 2 ~C 4 ) alkenyl is selected from one or more (e.g., 1, 2, 3, 4, or 5) Z 2a Optionally substituted with a group or R q3 and R r3 together with the nitrogen to which they are attached form a heterocycle or heteroaryl, the heterocycle or heteroaryl containing one or more (e.g., 1, 2, 3, 4, or 5) Z 2b Or Z 2c is optionally substituted with a group; Each R n4 are independently, H, (C 1 ~C 4 ) alkyl, (C 2 ~C 8 ) alkenyl, (C 2 ~C 8 ) alkynyl, (C 1 ~C 4 ) haloalkyl and (C 1 ~C 4 ) heteroalkyl; Each R p4 are independently 1 ~C 8 ) alkyl, (C 2 ~C 4 ) alkenyl, (C 2 ~C 4 ) alkynyl, (C 1 ~C 4 ) haloalkyl and (C 1 ~C 4 ) heteroalkyl; Rq4 and R r4 are independently H, (C 1 ~C 4 ) alkyl, (C 2 ~C 4 ) alkenyl, (C 2 ~C 4 ) alkynyl, (C 1 ~C 4 ) haloalkyl and (C 1 ~C 4 ) heteroalkyl; each Z 3 are independently halogen, (C 1 ~C 4 ) alkyl, -OH, -CN, (C 1 ~C 4 )heteroalkyl and (C 1 ~C 4 ) haloalkyl; each Z 4 are independently 1 ~C 8 ) alkyl, (C 2 ~C 8 ) alkenyl, (C 2 ~C 8 ) alkynyl, (C 3 ~C 7 )Carbocycle, halogen, -CN, -OR n5 , -OC(O)R p5 , -OC(O)NR q5 R r5 , -SR n5 , -S(O)R p5 , -S(O) 2 OH, -S(O) 2 R p5 , -S(O) 2 NR q5 R r5 , -NR q5 R r5 , -NR n5 COR p5 , -NR n5 CO 2 R p5 , -NR n5 CONR q5 R r5 , -NR n5 S(O) 2 Rp5 , -NR n5 S(O) 2 OR p5 , -NR n5 S(O) 2 NR q5 R r5 , NO 2 , -C(O)R n5 , -C(O)OR n5 and -C(O)NR q5 R r5 Selected from Z 4 Any (C 3 ~C 7 ) The carbocycle may contain one or more (e.g., 1, 2, 3, 4 or 5) Z 4a or Z 4b is optionally substituted with a group; 4 Any (C 1 ~C 8 ) alkyl, (C 2 ~C 8 ) alkenyl and (C 2 ~C 8 ) Alkynyl is selected from the group consisting of one or more (e.g., 1, 2, 3, 4, or 5) Z 4a is optionally substituted with a group; each Z 4a are independently halogen, -CN, -OR n6 , -OC(O)R p6 , -OC(O)NR q6 R r6 , -SR n6 , -S(O)R p6 , -S(O) 2 OH, -S(O) 2 R p6 , -S(O) 2 NR q6 R r6 , -NR q6 R r6 , -NR n6 COR p6 , -NR n6 CO 2 R p6 , -NR n6 CONR q6 R r6 , -NR n6 S(O) 2 R p6, -NR n6 S(O) 2 OR p6 , -NR n6 S(O) 2 NR q6 R r6 , NO 2 , -C(O)R n6 , -C(O)OR n6 and -C(O)NR q6 R r6 is selected from each Z 4b are independently 1 ~C 4 ) alkyl, (C 2 ~C 4 )Alkenyl (C 2 ~C 4 ) alkynyl and (C 1 ~C 4 ) haloalkyl; Each R n5 are independently, H, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 ) haloalkyl, (C 1 ~C 4 )heteroalkyl, (C 2 ~C 4 ) alkenyl and (C 2 ~C 4 ) alkynyl; Each R p5 are independently 1 ~C 4 ) alkyl, (C 1 ~C 4 ) haloalkyl, (C 1 ~C 4 )heteroalkyl, (C 2 ~C 4 ) alkenyl and (C 2 ~C 4 ) alkynyl; R q5 and R r5 are independently H, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 ) haloalkyl, (C1 ~C 4 ) heteroalkyl, (C 2 ~C 4 ) alkenyl and (C 2 ~C 4 ) alkynyl; Each R n6 are independently, H, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 ) haloalkyl, (C 1 ~C 4 )heteroalkyl, (C 2 ~C 4 ) alkenyl and (C 2 ~C 4 ) alkynyl; Each R p6 are independently 1 ~C 4 ) alkyl, (C 1 ~C 4 ) haloalkyl, (C 1 ~C 4 ) heteroalkyl, (C 2 ~C 4 ) alkenyl and (C 2 ~C 4 ) alkynyl; R q6 and R r6 are independently H, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 ) haloalkyl, (C 1 ~C 4 )heteroalkyl, (C 2 ~C 4 ) alkenyl and (C 2 ~C 4 ) alkynyl; each Z 5 are independently 1 ~C 6 ) Alkyl, halogen, -CN and -OR n7 Selected from Z 5 Any (C 1 ~C 6) alkyl is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) halogens; Each R n7 are independently, H, (C 1 ~C 3 ) alkyl, (C 1 ~C 3 ) haloalkyl and (C 3 ~C 7 ) carbocyclic rings] or a pharma- ceutically acceptable salt thereof.

[0007] One embodiment provides a pharmaceutical composition comprising a compound of Formula I, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier. Another embodiment provides a pharmaceutical composition comprising a compound detailed herein, including a compound of any one 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 pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0008] One embodiment provides a pharmaceutical composition comprising a compound of Formula I or a pharma- ceutically acceptable salt thereof and an additional therapeutic agent which is an HIV protease inhibitor compound, a non-nucleoside inhibitor of HIV reverse transcriptase, a nucleoside inhibitor of HIV reverse transcriptase, a nucleotide inhibitor of HIV reverse transcriptase, an HIV 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 inhibitor, and combinations thereof. Another embodiment provides a pharmaceutical composition comprising a compound of any one 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 pharma- ceutically acceptable salt thereof, and an additional therapeutic agent which is an HIV protease inhibitor compound, a non-nucleoside inhibitor of HIV reverse transcriptase, a nucleoside inhibitor of HIV reverse transcriptase, a nucleotide inhibitor of HIV reverse transcriptase, an HIV 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 inhibitor, and combinations thereof.

[0009] One embodiment provides a method of treating a Retroviridae viral infection (e.g., an HIV viral infection) in a mammal (e.g., a human) comprising administering to the mammal a compound of formula I or a pharma- ceutically acceptable salt thereof. Another embodiment provides a compound 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 a pharma- ceutically acceptable salt thereof. The present invention provides a method of treating a Retroviridae viral infection (e.g., an HIV viral infection) in a mammal (e.g., a human) comprising administering to the mammal a salt of the compound. Another embodiment provides a method of treating an HIV infection in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound detailed herein or a pharma- ceutically acceptable salt thereof.

[0010] One embodiment provides a method of inhibiting the growth of the HIV virus, treating AIDS, or delaying the onset of AIDS or ARC symptoms in a mammal (e.g., a human), comprising administering to the mammal a compound of formula I or a pharmaceutically acceptable salt thereof. Another embodiment provides a method of inhibiting the growth of the HIV virus, treating AIDS, or delaying the onset of AIDS or ARC symptoms in a mammal (e.g., a human), comprising administering to the mammal a compound detailed herein, including a compound of any one 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 of treating HIV infection in a mammal (e.g., a human) comprising administering to the mammal a compound of formula I or a pharma- ceutically acceptable salt thereof. Another embodiment provides a method of treating HIV infection in a mammal (e.g., a human) comprising administering to the mammal a compound detailed herein, including a compound of any one 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 pharma- ceutically acceptable salt thereof.

[0012] One embodiment provides a method of treating an HIV infection in a mammal (e.g., a human), comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of Formula I, or a pharma- ceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents selected from the group consisting of HIV protease inhibitor compounds, 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 of treating an HIV infection in a mammal (e.g., a human) comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of any one 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 pharma- ceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents selected from the group consisting of HIV protease inhibitor compounds, 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 of treating an HIV infection in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound as described herein, or a pharma- ceutically acceptable salt thereof, in combination with a therapeutically effective amount of an additional therapeutic agent which is an HIV protease inhibitor compound, a non-nucleoside inhibitor of HIV reverse transcriptase, a nucleoside inhibitor of HIV reverse transcriptase, a nucleotide inhibitor of HIV reverse transcriptase, an HIV 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, and combinations thereof.

[0013] One embodiment provides a method of treating an HIV infection in a mammal (e.g., a human), comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of Formula I, or a pharma- ceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents selected from the group consisting of HIV protease inhibitor compounds, 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 of treating an HIV infection in a mammal (e.g., a human) comprising administering to a mammal in need thereof a therapeutically effective amount of a compound detailed herein, including a compound of any one of Formulae I, Ia, Ib, Ic, Id, Ie, If, Ig, III, IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIi, IIIj and IIIk, or a pharma- ceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents selected from the group consisting of HIV protease inhibitor compounds, 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.

[0014] One embodiment provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in medical therapy (e.g., for use in treating a Retroviridae viral infection (e.g., HIV viral infection) or HIV viral proliferation or AIDS, or for delaying the onset of AIDS or ARC symptoms in a mammal (e.g., a human). Another embodiment provides a compound detailed herein, including a compound of any one 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, for use in medical therapy (e.g., for use in treating a Retroviridae viral infection (e.g., HIV viral infection) or HIV viral proliferation or AIDS, or for delaying the onset of AIDS or ARC symptoms in a mammal (e.g., a human).

[0015] One embodiment provides a compound of formula I or a pharma- ceutically acceptable salt thereof for use in the manufacture of a medicament for treating a Retroviridae viral infection (e.g., an HIV viral infection) or the proliferation of the HIV virus or AIDS, or for delaying the onset of AIDS or ARC symptoms in a mammal (e.g., a human). Another embodiment provides a compound detailed herein, including a compound of any one 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 pharma- ceutically acceptable salt thereof, for use in the manufacture of a medicament for treating a Retroviridae viral infection (e.g., an HIV viral infection) or the proliferation of the HIV virus or AIDS, or for delaying the onset of AIDS or ARC symptoms in a mammal (e.g., a human).

[0016] One embodiment provides a compound of formula I, or a pharma- ceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of Retroviridae viruses, HIV viral proliferation, or AIDS, or for use in therapeutic treatment to delay the onset of AIDS or ARC symptoms. Another embodiment provides a compound of formula I, or a pharma- ceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of Retroviridae viruses, HIV viral proliferation, or AIDS, or for use in therapeutic treatment to delay the onset of AIDS or ARC symptoms. The present invention provides compounds as detailed herein, including any one of compounds Ia, Ib, Ic, Id, Ie, If, Ig, III, IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIi, IIIj and IIIk, or a pharma- ceutically acceptable salt thereof.

[0017] One embodiment provides a compound of formula I or a pharma- ceutically acceptable salt thereof for use in the prophylactic or therapeutic treatment of a Retroviridae viral infection (e.g., an HIV viral infection). Another embodiment provides a compound detailed herein, including a compound of any one 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 pharma- ceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of a Retroviridae viral infection (e.g., an HIV viral infection).

[0018] One embodiment provides the use of a compound of formula I, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for a Retroviridae viral infection, such as an HIV viral infection, in a mammal (e.g., a human). Another embodiment provides a compound detailed herein, including a compound of any one 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 pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for a Retroviridae viral infection, such as an HIV viral infection, in a mammal (e.g., a human).

[0019] One embodiment provides processes and intermediates disclosed herein that are useful for preparing a compound of formula I, or a salt thereof. Another embodiment provides processes and intermediates disclosed herein that are useful for preparing a compound of any one 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 salt thereof.

[0020] Other embodiments, objects, features and advantages will be set forth in the following detailed description of the embodiments, and in part will be apparent from the following description, or may be learned by the practice of the invention as claimed. These objects and advantages will be realized and attained by the processes and compositions particularly pointed out in the written description and claims herein. The foregoing summary has been written with the understanding that it should be considered a summary 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 is not intended in any manner to limit the scope of the appended claims or the scope of equivalents to which they are lawfully entitled. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] Detailed Description The following description is written with the understanding that the present disclosure should be considered as an example of the claimed subject matter, and does not limit the scope of the appended claims to the specific embodiments illustrated. The headings used throughout this disclosure are provided merely for convenience and should not be construed to limit the scope of the claims in any manner. An embodiment illustrated under any heading can be combined with an embodiment illustrated under any other heading.

[0022] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. A dash at the beginning or end of a chemical group means The dashes are for convenience only. Chemical groups may be depicted with or without one or more dashes without loss of their ordinary meaning. Wavy lines drawn through a line in a structure indicate points of attachment of a group. Dashed lines indicate optional bonds. u~v " or (C u ~C v ) indicates that the following group has u to v carbon atoms. For example, "C 1~6 "Alkyl" indicates that the alkyl group has from 1 to 6 carbon atoms.

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

[0024] When trade names are used herein, applicants intend to independently include the trademarked product and the active pharmaceutical ingredient(s) of that trademarked product.

[0025] An "alkyl" is a straight or branched chain saturated hydrocarbon. For example, an alkyl group can be one to eight carbon atoms (i.e., (C 1 ~C 8 ) alkyl) or 1 to 6 carbon atoms (i.e., (C 1 ~C 6 alkyl) or 1 to 4 carbon atoms (i.e., (C1 ~C 4 Examples of suitable alkyl groups include methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, i-propyl, -CH(CH 3 ) 2 ), 1-Butyl (n-Bu, n-Butyl, -CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl (i-Bu, i-butyl, -CH 2 CH(CH 3 ) 2 ), 2-Butyl (s-Bu, s-Butyl, -CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH 3 ) 3 ), 1-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butyl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH3 )CH 2 CH 3 ), 1-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3-hexyl (-CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 )), 2-methyl-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (-CH(CH 3 )CH(CH 3 )CH 2 CH 3 ), 4-methyl-2-pentyl (-CH(CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3-pentyl (-C(CH 3 )(CH 2 CH 3 ) 2 ), 2-methyl-3-pentyl (-CH(CH 2 CH 3 )CH(CH 3 ) 2 ), 2,3-dimethyl-2-butyl (-C(CH 3 ) 2 CH(CH 3 ) 2 ), 3,3-dimethyl-2-butyl (-CH(CH 3 )C(CH 3 ) 3 , and octyl (-(CH 2 ) 7 CH 3 ), but are not limited to these.

[0026] "Alkenyl" means at least one carbon-carbon, sp 2 It is a straight or branched chain hydrocarbon with a double bond. For example, an alkenyl group is an alkyl group having 2 to 8 carbon atoms (i.e., C 2 ~C 8 alkenyl) or 2 to 6 carbon atoms (i.e., C 2 ~C 6 Examples of suitable alkenyl groups include ethylene or vinyl (-CH=CH 2 ), allyl (-CH 2 CH=CH 2 ) and 5-hexenyl (-CH 2 CH 2 CH 2 CH 2 CH=CH 2 ), but are not limited to these.

[0027] "Alkynyl" refers to a straight or branched chain hydrocarbon having at least one carbon-carbon, sp triple bond. For example, an alkynyl group can be an alkynyl group having 2 to 8 carbon atoms (i.e., C 2 ~C 8 alkynes) or 2–6 carbon atoms (i.e., C 2 ~C 6 Examples of suitable alkynyl groups include acetylenic (-C≡CH), propargyl (-CH 2 C≡CH), but not limited to these Not done.

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

[0029] The term "haloalkyl," as used herein, refers to an alkyl, as defined herein, in which one or more hydrogen atoms are each independently replaced by a halo substituent. For example, (C 1 ~C 6 )Haloalkyl is (C 1 ~C 6) one or more of the hydrogen atoms of the alkyl are replaced by a halo substituent (C 1 ~C 6 ) alkyl. Examples of haloalkyl include, but are not limited to, fluoromethyl, fluorochloromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, 1,1,1,trifluoroethyl, and pentafluoroethyl.

[0030] The term "heteroalkyl," as used herein, refers to an alkyl group, as defined herein, in which one or more of the carbon atoms is O, S, or NR q (Each R q are independently H or (C 1 ~C 6 ) alkyl) (or, if the carbon atom being replaced is a terminal carbon, OH, SH, or N(R q ) 2 Refers to an alkyl group that is substituted with (C 1 ~C 8 ) Heteroalkyl is an alkyl group consisting of 1 to 8 carbons and 1 or more heteroatoms (e.g., O, S, NR q , OH, SH or N(R q ) 2 ) heteroalkyl. Thus, for example, C 1 Heteroalkyl is, for example, -CH 2 -NH 2 Examples of heteroalkyl include, but are not limited to, methoxymethyl, ethoxymethyl, methoxy, 2-hydroxyethyl, and N,N'-dimethylpropylamine.

[0031] The term "aryl," as used herein, refers to a single all-carbon aromatic ring or multiple all-carbon fused ring systems in which at least one of the rings is aromatic. For example, in certain embodiments, aryl groups have from 6 to 20 carbon atoms, from 6 to 14 carbon atoms, or from 6 to 12 carbon atoms. Aryl includes phenyl radicals. Aryl also refers to multiple fused 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., carbocyclic). Such multiple condensed ring systems include aryls (e.g., ring systems containing 2, 3, or 4 rings). Such multiple condensed ring systems are optionally substituted with one or more (e.g., 1, 2, or 3) oxo groups on any carbocyclic portion of the multiple condensed ring system. The rings of the multiple condensed ring system may be connected to each other by fused, spiro, and bridged bonds, where valence requirements permit. It is understood that the attachment point of the multiple condensed ring system defined above may be at any position on the ring system, including the aromatic or carbocyclic portions of the ring. Also, when referring to a particular atom range of membered aryls (e.g., 6-12 membered aryls), it is understood that the atom range refers to the entire ring atoms of the aryl. For example, 6 membered aryls include phenyl, and 10 membered aryls include naphthyl and 1,2,3,4-tetrahydronaphthyl. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, and the like.

[0032] The term "heteroaryl" as used herein refers to a single aromatic ring having at least one atom other than carbon in the ring, which atom is selected from the group consisting of oxygen, nitrogen and sulfur. "Heteroaryl" also includes multiple condensed ring systems having at least one such aromatic ring, which are further described below. Thus, "heteroaryl" includes a single aromatic ring having about 1-6 carbon atoms and about 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. The sulfur and nitrogen atoms can also be present in oxidized form if the ring is aromatic. Exemplary heteroaryl ring systems include pyridyl, pyrimidinyl, oxazolyl or furyl, including but not limited to pyridyl, pyrimidinyl, oxazolyl or furyl. "Heteroaryl" also includes, but is not limited to, multiple condensed ring systems (e.g., ring systems containing 2, 3, or 4 rings) in which the heteroaryl group defined above is fused with one or more rings selected from heteroaryl (e.g., forming 1,8-naphthyridinyl), heterocycle (e.g., forming 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycle (e.g., forming 5,6,7,8-tetrahydroquinolyl), and aryl (e.g., forming indazolyl) to form multiple condensed ring systems. Thus, a heteroaryl (single aromatic ring or multiple condensed ring system) has about 1-20 carbon atoms and about 1-6 heteroatoms in the heteroaryl ring. Such multiple condensed ring systems may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups on the carbocyclic or heterocyclic portions of the fused rings. The rings of the multiple condensed ring system may be connected to each other by fused, spiro and bridged bonds, if valence requirements permit. It is understood that the individual rings of the multiple condensed ring system may be connected to each other in any order. It is understood that the attachment point of the multiple condensed ring system (as defined above for heteroaryl) may be at any position of the multiple condensed ring system, including the heteroaryl, heterocyclic, aryl or carbocyclic portion of the multiple condensed ring system. It is also understood that the attachment point of the heteroaryl or heteroaryl multiple condensed ring system may be at any suitable atom of the heteroaryl or heteroaryl multiple condensed ring system, including carbon atoms and heteroatoms (e.g., nitrogen). It is also understood that when referring to a particular atom range of membered heteroaryl (e.g., 5-14 membered heteroaryl), the atom range is in reference to the entire ring atoms of the heteroaryl, including carbon atoms and heteroatoms. For example, a 5-membered heteroaryl includes thiazolyl, and a 10-membered heteroaryl includes quinolinyl.Exemplary heteroaryls include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl benzofuranyl, benzimidazolyl, thianaphthenyl, 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 that is linked to the remainder of the compound of formula I at a carbon atom of the heteroaryl (e.g., a Z-linked heteroaryl that is attached to the A ring of formula I through a carbon atom of the C-linked heteroaryl). 2 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 atom other than carbon in the ring, which atom is selected from the group consisting of oxygen, nitrogen, and sulfur. The term also includes multiple condensed ring systems having at least one such saturated or partially unsaturated ring, which are further described below. Thus, the term includes a single saturated or partially unsaturated ring (e.g., a 3-, 4-, 5-, 6-, or 7-membered ring) having about 1-6 carbon atoms and about 1-3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur in the ring. The ring may be substituted with one or more (e.g., 1, 2, or 3) oxo groups, and the sulfur and nitrogen atoms may also be present in their oxidized forms. Exemplary heterocyclyls include, but are not limited to, azetidinyl, tetrahydrofuranyl, and piperidinyl. The term "heterocycle" also includes multiple fused ring systems (e.g., ring systems containing 2, 3 or 4 rings) in which a single heterocycle (as defined above) can be fused with one or more groups selected from heterocycles (e.g., to form 1,8-decahydronapthyridinyl), carbocycles (e.g., to form decahydroquinolyl), and aryl to form multiple fused ring systems. Thus, a heterocycle (a single saturated or single partially unsaturated ring, or a multiple condensed ring system) has about 2-20 carbon atoms and 1-6 heteroatoms in the heterocycle ring. Such multiple condensed ring systems may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups on the carbocyclic or heterocyclic portions of the multiple condensed ring. The rings of the multiple condensed ring system may be connected to each other by fused, spiro, and bridged bonds, where valence requirements permit. It is understood that the individual rings of the multiple condensed ring system may be connected to each other in any order. It is also understood that the attachment point of the multiple condensed ring system (as defined above for heterocycle) may be at any position of the multiple condensed ring system, including the heterocyclic, aryl, and carbocyclic portions of the ring. It is also understood that the attachment point of the heterocyclic ring or heterocyclic multiple condensed ring system can be at any suitable atom of the heterocyclic ring or heterocyclic multiple condensed ring system, including carbon atoms and heteroatoms (e.g., nitrogen). Also, when referring to a heterocyclic ring of a certain atom range (e.g., a 3- to 14-membered heterocyclic ring), it is understood that the atom range is for the entire ring atoms of the heterocyclic ring, including carbon atoms and heteroatoms. For example, a 3-membered heterocyclic ring includes aziridinyl, and a 10-membered heterocyclic ring includes 1,2,3,4-tetrahydroquinolyl. Exemplary heterocycles include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4-tetrahydroquinolyl, benzoxazinyl, dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, spiro[cyclopropane-1,1'-isoindolinyl]-3'-one, isoindolinyl-1-one, 2-oxa-6-azaspiro[3.3]heptanyl, imidazolidin-2-one, and pyrrolidin-2-one.

[0035] The term "C-linked heterocycle" (carbon-linked heterocycle), as used herein, refers to a heterocycle that is linked to the remainder of the compound of formula I at a carbon atom of the heterocycle (e.g., a Z-linked heterocycle that is bonded to the A-ring of formula I through a carbon atom of the C-linked heterocycle). 2 C-linked heterocycle.

[0036] The term "carbocycle" or "carbocyclyl" refers to a ring having 3 to 7 carbon atoms (i.e., (C 3 ~C 7) carbocycle), a single saturated (i.e., cycloalkyl) or a single partially unsaturated (e.g., cycloalkenyl, cycloalkadienyl, etc.) all-carbon ring. The term "carbocycle" or "carbocyclyl" also includes polycondensed, saturated and partially unsaturated all-carbon ring systems (e.g., ring systems containing 2, 3, or 4 carbocyclic rings). Thus, carbocycle includes polycyclic carbocycles, such as bicyclic carbocycles (e.g., bicyclic carbocycles having about 6-12 carbon atoms, such as bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane), and polycyclic carbocycles (e.g., tricyclic and tetracyclic carbocycles having up to about 20 carbon atoms). The rings of a polycondensed ring system may be connected to each other by fused, spiro, and bridged bonds, where valence requirements permit. For example, polycyclic carbocycles can be connected to each other through a single carbon atom to form a spiro connection (e.g., spiropentane, spiro[4,5]decane, etc.), connected to each other through two adjacent carbon atoms to form a fused connection (e.g., carbocycles such as decahydronaphthalene, norsabinane, norcarane), or connected to each other through two non-adjacent carbon atoms to form a bridged connection (e.g., norbornane, bicyclo[2.2.2]octane, etc.). A "carbocycle" or "carbocyclyl" may also be optionally substituted with one or more (e.g., 1, 2 or 3) oxo groups. Non-limiting examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl and 1-cyclohex-3-enyl.

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

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

[0039] The term "haloheterocycle" as used herein refers to a heterocycle in which one or more (e.g., 1, 2, 3, 4, or 5) hydrogen atoms of the heterocycle are each independently replaced by a halo substituent. Examples of haloheteroaryl include, but are not limited to, 2-fluoropiperidinyl, 2-chloro-3-fluoropiperazinyl, and 3-bromopyrrolidinyl.

[0040] Those skilled in the art will recognize that the substituents and other moieties of the compound of formula I should be selected to provide a compound that is sufficiently stable to provide a pharma- ceutically useful compound that can be formulated into an acceptably stable pharmaceutical composition. Compounds of formula I that have such stability are intended to be within the scope of the present invention. Similarly, those skilled in the art will recognize that the substituents and other moieties of the 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 pharma- ceutically acceptable salts thereof, should be selected to provide a compound that is sufficiently stable to provide a pharma- ceutical useful compound that can be formulated into an acceptably stable pharmaceutical composition. Compounds detailed herein that have such stability are intended to be within the scope of the present invention.

[0041] The modifier "about" used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (e.g., includes the degree of error associated with measurement of the particular quantity). The term "about" can also be symbolized by "~" in the context of chemical measurements (e.g., ~50 mg or pH~7).

[0042] The terms "treatment" or "treating", in relation to a disease or condition, include preventing the onset of the disease or condition, inhibiting the disease or condition, eliminating the disease or condition, and / or alleviating one or more symptoms of the disease or condition.

[0043] In one embodiment, "treatment" or "treating" includes one or more of the following: a) inhibiting a disease or condition (e.g., reducing one or more symptoms resulting from a disease or condition and / or lessening the severity of the disease or condition); b) slowing or halting the development of one or more symptoms associated with a disease or condition (e.g., stabilizing a disease or condition, delaying the worsening or progression of a disease or condition); and c) alleviating a disease or condition, e.g., causing regression of clinical symptoms, alleviating pathology, slowing the progression of a disease, improving quality of life, and / or prolonging survival.

[0044] stereoisomer The stereochemical definitions and conventions used herein are generally those set forth in the McGraw-Hill Dictionary of Chemical Te 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 has the property of not being superimposable on its mirror image partner, while the term "achiral" refers to a molecule that is superimposable on its mirror image partner.

[0046] The term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0047] "Diastereomer" refers to a stereoisomer having two or more centers or axes of chirality whose molecules are not mirror images of one another. Diastereomers typically have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can be separated by high-resolution analytical procedures, such as electrophoresis and chromatography.

[0048] "Enantiomers" refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0049] The compounds disclosed herein may have chiral centers, such as chiral carbon atoms. Thus, such compounds include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers. Furthermore, the compounds disclosed herein include optical isomers enriched or resolved 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 resolved at any or all asymmetric chiral atoms. In other words, the chiral centers evident from the depiction are provided as chiral isomers or racemic mixtures. Both racemic and diastereomeric mixtures, as well as isolated or synthesized individual optical isomers substantially free of their enantiomeric or diastereomeric partners, are all within the scope of the present invention. Racemic mixtures can be separated into their substantially optically pure individual isomers by well-known techniques, such as, for example, separation of diastereomeric salts formed with optically active auxiliaries (e.g., acids or bases) followed by conversion back to the optically active substances. Alternatively, the desired optical isomers can be synthesized beginning with the appropriate stereoisomer of the desired starting material by using stereospecific reactions.

[0050] The present invention includes any or all stereochemical forms, including any enantiomeric or diastereomeric forms and geometric isomers, or mixtures thereof, of the compounds described. Unless stereochemistry is explicitly indicated in a chemical structure or name, the structure or name is intended to include all possible stereoisomers, including the geometric isomers of the compound depicted. Also contemplated are compositions that include the compounds of the present invention, such as compositions of substantially pure compounds (including specific stereochemical forms, including their specific geometric isomers). Compositions that include mixtures of the compounds of the present invention in any ratio, including mixtures of two or more stereochemical forms of the compounds of the present invention in any ratio, are also encompassed by the present invention, thus including racemic, non-racemic, enantiomerically enriched, scalemic mixtures, or mixtures thereof, of the compounds.

[0051] For the compounds disclosed herein, bonds are depicted in a non-stereochemical fashion (e.g., flat). When a bond is depicted in a stereochemical fashion (e.g., bold, bold wedge, dotted, or dotted wedge), it is understood that the atom to which the stereochemical bond is attached has the stereochemistry shown unless otherwise indicated. Thus, in one embodiment, the compounds disclosed herein are greater than 50% single enantiomers. In another embodiment, the compounds disclosed herein are at least 80% single enantiomers. In another embodiment, the compounds disclosed herein are at least 90% single enantiomers. In another embodiment, the compounds disclosed herein are at least 98% single enantiomers. In another embodiment, the compounds disclosed herein are at least 99% single enantiomers. In another embodiment, the compounds disclosed herein are greater than 50% single diastereomers. In another embodiment, the compounds disclosed herein are at least 80% single diastereomers. In another embodiment, the compounds disclosed herein are at least 90% single diastereomers. In another embodiment, the compounds disclosed herein are at least 98% single diastereomers. In another embodiment, the compounds disclosed herein are at least 99% single diastereomers.

[0052] Thus, in one embodiment, the compositions disclosed herein are greater than 50% of a single enantiomer. In another embodiment, the compositions disclosed herein are at least 80% of a single enantiomer. In another embodiment, the compositions disclosed herein are at least 90% of a single enantiomer. In another embodiment, the compositions disclosed herein are at least 98% of a single enantiomer. In another embodiment, the compositions disclosed herein are at least 99% of a single enantiomer. In another embodiment, the compositions disclosed herein are greater than 50% of a single diastereomer. In another embodiment, the compositions disclosed herein are at least 80% of a single diastereomer. In another embodiment, the compositions disclosed herein are at least 90% of a single diastereomer. In another embodiment, the compositions disclosed herein are at least 98% of a single diastereomer. In another embodiment, the compositions disclosed herein are at least 99% of a single diastereomer.

[0053] In certain embodiments, the compounds disclosed herein exhibit atropisomerism resulting from steric hindrance that affects the rate of axial rotation around a single bond. In certain circumstances, the resulting conformers are observed as separate 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 atropisomer mixtures have been observed. However, detection of atropisomers depends on factors such as temperature, solvent, purification conditions, and time scale of spectroscopic techniques. The characterization data presented herein may not represent equilibrium conditions, depending on purification conditions, isolation conditions, handling conditions, solvents used, and temperatures.

[0054] Tautomers The compounds disclosed herein may also exist as tautomers in certain cases. Although only one delocalized resonance structure may be illustrated, all such forms are intended to be within the scope of the present invention. For example, in purine, pyrimidine, imidazole, guanidine, amidine, and tetrazole systems, ene-amine tautomers may exist, and all their possible tautomeric forms are within the scope of the present invention. Another non-limiting example includes keto-enol tautomers of heteroaryls. Such tautomers are exemplified by T1 / T1', T2 / T2', and T3 / T3'. All such tautomeric forms are also within the scope of the present invention. [ka]

[0055] protecting group "Protective group" refers to a moiety of a compound that masks or alters the properties of a functional group or the properties of 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. Protective groups are often utilized to mask the reactivity of certain functional groups and aid in the efficiency of desired chemical reactions, for example, to create and break chemical bonds in an ordered and planned manner. Protection of a functional group of a compound alters the reactivity of the protected functional group as well as other physical properties, such as polarity, lipophilicity (hydrophobicity), and other properties that can be measured by common analytical tools. Chemically protected intermediates may themselves be biologically active or inactive.

[0056] Salts and hydrates "Pharmaceutically acceptable salt" refers to a salt of a compound that is pharmaceutically acceptable and has (or can be converted into a form that has) the desired pharmacological activity of the parent compound. Pharmaceutically acceptable salts are generally considered to be safe and suitable for use without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio. Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein include salts of suitable bases, such as alkali metals (e.g., sodium), alkaline earth metals (e.g., magnesium), ammonium, and NX. 4 + (X is C 1 ~C 4 The pharmaceutically acceptable salts of nitrogen atoms or amino groups include, for example, salts derived from organic carboxylic acids such as acetic acid, benzoic acid, camphorsulfonic 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-napththalenesulfonic 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. The pharmaceutically acceptable salts of hydroxy groups of the compounds include, for example, salts of suitable cations such as Na + and NX 4 + (X is independently H or C 1 ~C 4The term "pharmaceutically acceptable salts" includes the anion of the compound in combination with an alkyl group (selected from an alkyl group). Pharmaceutically acceptable salts also include salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as either an alkali metal ion, an alkaline earth ion, or an aluminum ion, or coordinates with an organic base, such as diethanolamine, triethanolamine, N-methylglucamine, and the like. Also included in this definition are ammonium and substituted or quaternized ammonium salts. A representative, non-limiting list of pharmaceutically acceptable salts can be found in SM Berge et al., J. Am. Soc., 1999, 143:131-135, 19 ... Pharma Sci., Vol. 66(1), pp. 1-19 (1977), and Remington: The Science and Practice of Pharmacy, edited by R. Hendrickson, 21st ed., Lippincott, Williams & Wilkins, Philadelphia, PA, (2005), p. 732, table 38-5, both of which are hereby incorporated by reference herein.

[0057] For therapeutic use, the salt of the active ingredient of the compound disclosed herein is typically pharmaceutically acceptable, i.e., derived from physiologically acceptable acid or base.However, the salt of non-pharmaceutically acceptable acid or base may also be useful, for example, in the preparation or purification of the compound of formula I or other compounds disclosed herein.All salts, whether derived from physiologically acceptable acid or base or not, are included in the scope of the present invention.

[0058] Metal salts are typically prepared by reacting the metal hydroxide with a compound disclosed herein. Examples of metal salts thus prepared are Li + , Na + and K. + A less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the appropriate metal compound.

[0059] Additionally, salts can be prepared from certain organic and inorganic acids, e.g., HCl, HBr, H 2 SO 4 , H 3 PO 4 Or organic sulfonic acids can be formed by acid addition to basic centers, such as amines. Finally, it is to be understood that the compositions herein include the compounds disclosed herein in their non-ionized forms, as well as zwitterionic forms and in combination with stoichiometric amounts of water, such as hydrates.

[0060] Often, crystallization produces a solvate of the compound of the present invention. As used herein, the term "solvate" refers to an aggregate that contains 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 compound of the present invention may exist as a hydrate, including monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, etc., as well as the corresponding solvated forms. The compound of the present invention may be a true solvate, while in other cases, the compound of the present invention may simply retain incidental water or may be a mixture of water and incidental solvent.

[0061] Isotopes The present invention also includes the use of one or more isotopes in any or all atoms beyond the naturally occurring isotope ratio, such as, but not limited to, deuterium ( 2 It will be understood by one of ordinary skill in the art that the present invention includes any of the claimed compounds that may be enriched with -H or D. As a non-limiting example, in certain embodiments, -CH 3 The group is -CD 3 can be replaced with.

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

[0063] Compounds of Formula I A specific group of compounds of formula I are compounds of formula Ia [ka] or a pharma- ceutically acceptable salt thereof.

[0064] Another specific group of compounds of formula I is the compound of formula Ib [ka] or a pharma- ceutically acceptable salt thereof.

[0065] Another specific group of compounds of formula I is the compound of formula Ic [ka] or a pharma- ceutically acceptable salt thereof.

[0066] Another specific group of compounds of formula I is the compound of formula Id [ka] or a pharma- ceutically acceptable salt thereof.

[0067] Another specific group of compounds of formula I is the compound of formula Ie [ka] or a pharma- ceutically acceptable salt thereof.

[0068] Another specific group of compounds of formula I is the compound of formula If [ka] or a pharma- ceutically acceptable salt thereof.

[0069] Another specific group of compounds of formula I is the compound of formula Ig [ka] or a pharma- ceutically acceptable salt thereof.

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

[0071] Specific values ​​recited for compounds of formula I, where applicable, can be equally applied to compounds of formula III and all related formulas (e.g., formulas IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIi, IIIj and IIIk). For example, specific values ​​of ring A of formula I can be equally applied to ring A of formula III, provided that ring A of formula III includes the specific value within its range. It is also understood that any combination of variables of compounds of formula I, where applicable, can be equally applied to compounds of formula III and all related formulas (e.g., formulas IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIi, IIIj and IIIk), as if every combination were specifically and individually recited. For example, rings A and Z can be equally applied to compounds of formula III and all related formulas (e.g., formulas IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIi, IIIj and IIIk), as if every combination were specifically and individually recited. 1 Specific values ​​of AZ in formula III are 1 A-Z of formula III, provided that the moiety range includes specific values. 1 The provisions of this Act can be applied equally to all parts.

[0072] A specific group of compounds of formula I are 3a and R 3b are each independently H, halogen, (C 1 ~C 3 ) alkyl, and (C 1 ~C 3 ) haloalkyl.

[0073] A specific group of compounds of formula I are 3a and R 3b are each independently H, (C 1 ~C 3 ) alkyl, and (C 1 ~C 3 ) haloalkyl.

[0074] A specific group of compounds of formula I are 3a and R 3b each independently represents H and (C 1 ~C 3 ) alkyl.

[0075] A specific group of compounds of formula I are 3a and R 3b are each independently selected from H, methyl and ethyl.

[0076] A specific group of compounds of formula I are 3a and R 3b are each independently selected from H and methyl.

[0077] A specific group of compounds of formula I are 3a is H and R 3b But (C 1 ~C 3 ) alkyl.

[0078] A specific group of compounds of formula I are 3a is H and R 3b is methyl or ethyl.

[0079] A specific group of compounds of formula I are 3a is H and R 3b is methyl.

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

[0081] R 2 A specific value for is phenyl or 5-membered monocyclic heteroaryl, 2 Any phenyl or 5-membered monocyclic heteroaryl may have one or more (e.g., 1, 2, 3, 4, or 5) Z 5 is optionally substituted with a group.

[0082] R 2 A specific value for is phenyl or 5-membered monocyclic heteroaryl, 2 Any phenyl or 5-membered monocyclic heteroaryl may have one or more (e.g., 1, 2, 3, 4, or 5) Z 5is substituted with a group.

[0083] R 2 Specific values ​​for are one or more (e.g., 1, 2, 3, 4, or 5) Z 5 and n is 0, 1 or 2. It is preferably phenyl optionally substituted with a group.

[0084] R 2 Specific values ​​for are one or more (e.g., 1, 2, 3, 4, or 5) Z 5 It is a phenyl substituted with a group.

[0085] Z 5 A specific value for is a halogen.

[0086] Z 5 A specific value for is fluoro.

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

[0088] A specific value for A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and any pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl of A may be selected from the group consisting of one Z at the indicated position. 1 group and one Z 2 group and one or more (e.g., one or two) Z 3 is optionally substituted with a group.

[0089] A specific value for A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and any pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl of A may be selected from the group consisting of one Z at the indicated position. 1 group and one Z 2 is substituted with a group.

[0090] A specific value for A is pyridinyl, where any pyridinyl for A is at the position shown. One Z in 1group and one Z 2 group and one or more (e.g., one or two) Z 3 is optionally substituted with a group.

[0091] A specific value for A is pyridinyl, where any pyridinyl of A is selected from the group consisting of one Z 1 group and one Z 2 is substituted with a group.

[0092] The specific value of A is: [ka] Each Z 3a are independently H and Z 3 is selected from.

[0093] The specific value of A is: [ka] Each Z 3a are independently H and Z 3 is selected from.

[0094] The specific value of A is: [ka] Each Z 3a are independently H and Z 3 is selected from.

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

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

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

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

[0099] Z 1 Specific values ​​for are selected from phenyl, 5-14 membered heteroaryl, and 3-14 membered heterocycle; Z 1 Any phenyl, 5- to 14-membered heteroaryl, and 3- to 14-membered heterocycle may have one or more (e.g., 1, 2, 3, 4, or 5) Z 1a or Z 1 b is optionally substituted with a group.

[0100] Z 1 Specific values ​​for are selected from phenyl, 5-12 membered heteroaryl, and 3-12 membered heterocycle; Z 1 Any phenyl, 5- to 12-membered heteroaryl, and 3- to 12-membered heterocycle may have one or more (e.g., 1, 2, 3, 4, or 5) Z 1a or Z 1bis optionally substituted with a group.

[0101] Z 1 Specific values ​​for are selected from phenyl, 5-14 membered heteroaryl, and 3-14 membered heterocycle; Z 1 Any phenyl, 5- to 14-membered heteroaryl, and 3- to 14-membered heterocycle may have one or more (e.g., 1, 2, 3, 4, or 5) Z 1a is optionally substituted with a group.

[0102] Z 1 Specific values ​​for are selected from phenyl, 5-12 membered heteroaryl, and 3-12 membered heterocycle; Z 1 Any phenyl, 5- to 12-membered heteroaryl, and 3- to 12-membered heterocycle may have one or more (e.g., 1, 2, 3, 4, or 5) Z 1a is optionally substituted with a group.

[0103] Z 1 Specific values ​​for are selected from phenyl, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 8- to 10-membered bicyclic heterocycle, and 9- to 12-membered tricyclic heterocycle; Z 1 Any phenyl, 5-6 membered monocyclic heteroaryl, 8-10 membered bicyclic heteroaryl, 8-10 membered bicyclic heterocycle, and 9-12 membered tricyclic heterocycle may be selected from the group consisting of one or more (e.g., 1, 2, 3, 4, or 5) Z 1a or Z 1b is optionally substituted with a group.

[0104] Z 1 Specific values ​​for are selected from phenyl, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 8- to 10-membered bicyclic heterocycle, and 9- to 12-membered tricyclic heterocycle; Z 1 Any phenyl, 5-6 membered monocyclic heteroaryl, 8-10 membered bicyclic heteroaryl, 8-10 membered bicyclic heterocycle, and 9-12 membered tricyclic heterocycle may be selected from the group consisting of one or more (e.g., 1, 2, 3, 4, or 5) Z 1a is optionally substituted with a group.

[0105] Z 1 Specific values ​​for are selected from phenyl, 5-6 membered monocyclic heteroaryl, 8-10 membered bicyclic heteroaryl, 8-10 membered bicyclic heterocycle, and 9-12 membered tricyclic heterocycle, wherein the 5-6 membered monocyclic heteroaryl, 8-10 membered bicyclic heteroaryl, 8-10 membered bicyclic heterocycle, and 9-12 membered tricyclic heterocycle have 1-11 carbon atoms and 1-5 heteroatoms in the ring system, and Z 1 Any phenyl, 5-6 membered monocyclic heteroaryl, 8-10 membered bicyclic heteroaryl, 8-10 membered bicyclic heterocycle, and 9-12 membered tricyclic heterocycle may be selected from the group consisting of one or more (e.g., 1, 2, 3, 4, or 5) Z 1a or Z 1b Groups are optionally substituted.

[0106] Z 1 Specific values ​​for are selected from phenyl, 5-6 membered monocyclic heteroaryl, 8-10 membered bicyclic heteroaryl, 8-10 membered bicyclic heterocycle, and 9-12 membered tricyclic heterocycle, wherein the 5-6 membered monocyclic heteroaryl, 8-10 membered bicyclic heteroaryl, 8-10 membered bicyclic heterocycle, and 9-12 membered tricyclic heterocycle have 1-11 carbon atoms and 1-5 heteroatoms in the ring system, and Z 1 Any phenyl, 5-6 membered monocyclic heteroaryl, 8-10 membered bicyclic heteroaryl, 8-10 membered bicyclic heterocycle, and 9-12 membered tricyclic heterocycle may be selected from the group consisting of one or more (e.g., 1, 2, 3, 4, or 5) Z 1a Groups are optionally substituted.

[0107] Z 1 Specific values ​​of are phenyl, 5-6 membered monocyclic heteroaryl, 8-10 membered bicyclic and Z is selected from the group consisting of a 5- to 6-membered monocyclic heteroaryl, an 8- to 10-membered bicyclic heterocycle, and a 9- to 12-membered tricyclic heterocycle, wherein the 5- to 6-membered monocyclic heteroaryl, the 8- to 10-membered bicyclic heterocycle, and the 9- to 12-membered tricyclic heterocycle have 4 to 11 carbon atoms and 1 to 3 heteroatoms in the ring system. 1Any phenyl, 5-6 membered monocyclic heteroaryl, 8-10 membered bicyclic heteroaryl, 8-10 membered bicyclic heterocycle, and 9-12 membered tricyclic heterocycle may be selected from the group consisting of one or more (e.g., 1, 2, 3, 4, or 5) Z 1a or Z 1b is optionally substituted with a group.

[0108] Z 1 Specific values ​​for are selected from phenyl, 5-6 membered monocyclic heteroaryl, 8-10 membered bicyclic heteroaryl, 8-10 membered bicyclic heterocycle, and 9-12 membered tricyclic heterocycle, wherein the 5-6 membered monocyclic heteroaryl, 8-10 membered bicyclic heteroaryl, 8-10 membered bicyclic heterocycle, and 9-12 membered tricyclic heterocycle have 4-11 carbon atoms and 1-3 heteroatoms in the ring system, and Z 1 Any phenyl, 5-6 membered monocyclic heteroaryl, 8-10 membered bicyclic heteroaryl, 8-10 membered bicyclic heterocycle, and 9-12 membered tricyclic heterocycle may be selected from the group consisting of one or more (e.g., 1, 2, 3, 4, or 5) Z 1a is optionally substituted with a group.

[0109] Z 1 Particular values ​​of are selected from 8-10 membered bicyclic heteroaryl and 8-10 membered bicyclic heterocycle; Z 1 Any 8-10 membered bicyclic heteroaryl and 8-10 membered bicyclic heterocycle may be selected from the group consisting of one or more Z 1a or Z 1b is optionally substituted with a group.

[0110] Z 1 Particular values ​​of are selected from 8-10 membered bicyclic heteroaryl and 8-10 membered bicyclic heterocycle; Z 1 Any 8-10 membered bicyclic heteroaryl and 8-10 membered bicyclic heterocycle may be selected from the group consisting of one or more Z 1a is optionally substituted with a group.

[0111] Z 1Particular values ​​of are selected from 8-10 membered bicyclic heteroaryl and 8-10 membered bicyclic heterocycle, the 8-10 membered bicyclic heteroaryl and 8-10 membered bicyclic heterocycle having 3-9 carbon atoms and 1-5 heteroatoms in the ring system, and Z 1 Any 8-10 membered bicyclic heteroaryl and 8-10 membered bicyclic heterocycle may be selected from the group consisting of one or more Z 1a or Z 1b Groups are optionally substituted.

[0112] Z 1 Particular values ​​of are selected from 8-10 membered bicyclic heteroaryl and 8-10 membered bicyclic heterocycle, the 8-10 membered bicyclic heteroaryl and 8-10 membered bicyclic heterocycle having 3-9 carbon atoms and 1-5 heteroatoms in the ring system, and Z 1 Any 8-10 membered bicyclic heteroaryl and 8-10 membered bicyclic heterocycle may be selected from the group consisting of one or more Z 1a Groups are optionally substituted.

[0113] Z 1 Specific values ​​of 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-oxo-pyridinyl, and 2,4-dioxo-1,2,3,4-tetrahydroquinazolinyl; Z 1 Any of phenyl, 1H-pyrrolo[2,3-b]pyridinyl, 1-oxoisoindolinyl, 4-oxo-3,4-dihydroquinazolinyl, 3-oxospiro[cyclopropane-1,1'-isoindolin]-yl, 1H-2-oxo-pyridinyl and 2,4-dioxo-1,2,3,4-tetrahydroquinazolinyl may be selected from the group consisting of one or more (e.g., one, two, three, four or five) Z 1a or Z 1b is optionally substituted with a Z group. 1 A specific value for is 1H-indazol-7-yl, Z 1 is one or more Z1a or Z 1b Groups are optionally substituted.

[0114] Z 1 Specific values ​​of 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-oxo-pyridinyl, and 2,4-dioxo-1,2,3,4-tetrahydroquinazolinyl, as represented by the formula: [ka] Z 1 Any of phenyl, 1H-pyrrolo[2,3-b]pyridinyl, 1-oxoisoindolinyl, 4-oxo-3,4-dihydroquinazolinyl, 3-oxospiro[cyclopropane-1,1'-isoindolin]-yl, 1H-2-oxo-pyridinyl and 2,4-dioxo-1,2,3,4-tetrahydroquinazolinyl may be selected from the group consisting of one or more (e.g., one, two, three, four or five) Z 1a or Z 1b is optionally substituted with a Z group. 1 The specific value of is: [ka] It is. 1 The specific value of is: [ka] It is.

[0115] Z 1Specific values ​​of 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 selected from the group consisting of one or more (e.g., one, two, three, four or five) Z 1a or Z 1b Groups are optionally substituted.

[0116] Z 1 Specific values ​​of 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-oxo-pyridinyl, and 2,4-dioxo-1,2,3,4-tetrahydroquinazolinyl; Z 1 Any of phenyl, 1H-pyrrolo[2,3-b]pyridinyl, 1-oxoisoindolinyl, 4-oxo-3,4-dihydroquinazolinyl, 3-oxospiro[cyclopropane-1,1'-isoindolin]-yl, 1H-2-oxo-pyridinyl and 2,4-dioxo-1,2,3,4-tetrahydroquinazolinyl may be selected from the group consisting of one or more (e.g., one, two, three, four or five) Z 1a Groups are optionally substituted.

[0117] Z 1 Specific values ​​of 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 selected from the group consisting of one or more (e.g., one, two, three, four or five) Z 1aGroups are optionally substituted.

[0118] Z 1 Specific values ​​of are selected from phenyl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1-oxoisoindolin-5-yl, 1-oxoisoindolin-4-yl, 4-oxo-3,4-dihydroquinazolin-8-yl, 3′-oxospiro[cyclopropane-1,1′-isoindolin]-5′-yl, 1H-2-oxo-pyridin-4-yl, and 2,4-dioxo-1,2,3,4-tetrahydroquinazolin-8-yl; Z 1 Any phenyl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1-oxoisoindolin-5-yl, 1-oxoisoindolin-4-yl, 4-oxo-3,4-dihydroquinazolin-8-yl, 3'-oxospiro[cyclopropane-1,1'-isoindolin]-5'-yl, 1H-2-oxo-pyridin-4-yl and 2,4-dioxo-1,2,3,4-tetrahydroquinazolin-8-yl may be selected from the group consisting of one or more (e.g., 1, 2, 3, 4 or 5) Z 1a or Z 1b Groups are optionally substituted.

[0119] Z 1 Specific values ​​of are selected from phenyl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1-oxoisoindolin-5-yl, 1-oxoisoindolin-4-yl, 3'-oxospiro[cyclopropane-1,1'-isoindolin]-5'-yl, pyridin-4-yl and quinazolin-8-yl; Z 1 Any phenyl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1-oxoisoindolin-5-yl, 1-oxoisoindolin-4-yl, 3'-oxospiro[cyclopropane-1,1'-isoindolin]-5'-yl, pyridin-4-yl and quinazolin-8-yl may be selected from the group consisting of one or more (e.g., one, two, three, four or five) Z 1a or Z 1b Groups are optionally substituted.

[0120] Z 1Specific values ​​of are selected from phenyl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1-oxoisoindolin-5-yl, 1-oxoisoindolin-4-yl, 4-oxo-3,4-dihydroquinazolin-8-yl, 3'-oxospiro[cyclopropane-1,1'-isoindolin]-5'-yl, 1H-2-oxo-pyridin-4-yl, and 2,4-dioxo-1,2,3,4-tetrahydroquinazolin-8-yl, as represented by the formula: [ka] Z 1 Any phenyl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1-oxoisoindolin-5-yl, 1-oxoisoindolin-4-yl, 4-oxo-3,4-dihydroquinazolin-8-yl, 3'-oxospiro[cyclopropane-1,1'-isoindolin]-5'-yl, 1H-2-oxo-pyridin-4-yl and 2,4-dioxo-1,2,3,4-tetrahydroquinazolin-8-yl may be selected from the group consisting of one or more (e.g., 1, 2, 3, 4 or 5) Z 1a or Z 1b is optionally substituted with a Z group. 1 The specific value of is: [ka] It is. 1 The specific value of is: [ka] It is.

[0121] Z 1Specific values ​​of are selected from phenyl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1-oxoisoindolin-5-yl, 1-oxoisoindolin-4-yl, 4-oxo-3,4-dihydroquinazolin-8-yl, 3′-oxospiro[cyclopropane-1,1′-isoindolin]-5′-yl, 1H-2-oxo-pyridin-4-yl, and 2,4-dioxo-1,2,3,4-tetrahydroquinazolin-8-yl; Z 1 Any phenyl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1-oxoisoindolin-5-yl, 1-oxoisoindolin-4-yl, 4-oxo-3,4-dihydroquinazolin-8-yl, 3'-oxospiro[cyclopropane-1,1'-isoindolin]-5'-yl, 1H-2-oxo-pyridin-4-yl and 2,4-dioxo-1,2,3,4-tetrahydroquinazolin-8-yl may be selected from the group consisting of one or more (e.g., 1, 2, 3, 4 or 5) Z 1a is optionally substituted with a group.

[0122] Z 1 Specific values ​​of are selected from phenyl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1-oxoisoindolin-5-yl, 1-oxoisoindolin-4-yl, 3'-oxospiro[cyclopropane-1,1'-isoindolin]-5'-yl, pyridin-4-yl and quinazolin-8-yl; Z 1 Any phenyl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1-oxoisoindolin-5-yl, 1-oxoisoindolin-4-yl, 3'-oxospiro[cyclopropane-1,1'-isoindolin]-5'-yl, pyridin-4-yl and quinazolin-8-yl may be selected from the group consisting of one or more (e.g., one, two, three, four or five) Z 1a is optionally substituted with a group.

[0123] A specific group of compounds of formula I is 1 But, Z 1b is a compound that is not substituted with

[0124] each Z 1aThe specific values ​​of are independently halogen, -OR n1 and -C(O)NR q1 R r1 is selected from.

[0125] each Z 1a Specific values ​​of are independently selected from halogen and -C(O)NR q1 R r1 is selected from.

[0126] Each R n1 , each R q1 and each R r1 The specific value of each is H.

[0127] each Z 1a Specific values ​​of are independently halogen, -OH and -C(O)NH 2 is selected from.

[0128] each Z 1a Specific values ​​of are independently fluoro, -OH and -C(O)NH 2 is selected from.

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

[0130] each Z 1a Specific values ​​of are independently halogen and -NR n1 S(O) 2 R p1 is selected from.

[0131] each Z 1b The specific values ​​of may be the same or different (C 1 ~C 8 ) alkyl.

[0132] In certain embodiments, each Z 1a are independently halogen and -NR n1 S(O) 2 R p1 Each Z 1bmay be the same or different (C 1 ~C 8 )a It's Rukiru.

[0133] Z 1 The specific value of is: [ka] is selected from.

[0134] Z 1 The specific value of is: [ka] It is. 1 The specific value of is: [ka] It is.

[0135] Z 2 The specific value of is (C 2 ~C 8 ) alkynyl, 6-12 membered aryl, 5-12 membered C-linked heteroaryl, 3-12 membered C-linked heterocycle and -C(O)NR q3 R r3 Selected from Z 2 Any 6-12 membered aryl, 5-12 membered C-linked heteroaryl and 3-12 membered C-linked heterocycle may have one or more (e.g., 1, 2, 3, 4 or 5) Z 2b or Z 2c is optionally substituted with a group; 2 Any (C 2 ~C 8 ) Alkynyl is selected from the group consisting of one or more (e.g., 1, 2, 3, 4, or 5) Z 2c is optionally substituted with a group.

[0136] Z 2 The specific value of is (C 2 ~C 8 ) alkynyl, 6-12 membered aryl, 5-12 membered C-linked heteroaryl, 3-12 membered C-linked heterocycle and -C(O)NR q3 R r3 Selected from Z 2 Any 6-12 membered aryl, 5-12 membered C-linked heteroaryl and 3-12 membered C-linked heterocycle may have one or more (e.g., 1, 2, 3, 4 or 5) Z 2c is optionally substituted with a group; 2 Any (C 2 ~C 8 ) Alkynyl is selected from the group consisting of one or more (e.g., 1, 2, 3, 4, or 5) Z 2c is optionally substituted with a group.

[0137] Z 2 The specific value of is (C 2 ~C 8 ) alkynyl, phenyl, 5-6 membered C-linked monocyclic heteroaryl, 8-10 membered C-linked bicyclic heteroaryl, 8-10 membered C-linked bicyclic heterocycle and -C(O)NR q3 R r3 Selected from Z 2 Any phenyl, 5-6 membered C-linked monocyclic heteroaryl, 8-10 membered C-linked bicyclic heteroaryl and 8-10 membered C-linked bicyclic heterocycle may be joined by one or more (e.g., 1, 2, 3, 4 or 5) Z 2b or Z 2c is optionally substituted with a group; 2 Any (C 2 ~C 8 ) Alkynyl is selected from the group consisting of one or more (e.g., 1, 2, 3, 4, or 5) Z 2c is optionally substituted with a group.

[0138] Z 2 The specific value of is (C 2 ~C 8) alkynyl, phenyl, 5-6 membered C-linked monocyclic heteroaryl, 8-10 membered C-linked bicyclic heteroaryl, 8-10 membered C-linked bicyclic heterocycle and -C(O)NR q3 R r3 Selected from Z 2 Any phenyl, 5-6 membered C-linked monocyclic heteroaryl, 8-10 membered C-linked bicyclic heteroaryl and 8-10 membered C-linked bicyclic heterocycle may be joined by one or more (e.g., 1, 2, 3, 4 or 5) Z 2c is optionally substituted with a group; 2 Any (C 2 ~C 8 ) Alkynyl is selected from the group consisting of one or more (e.g., 1, 2, 3, 4, or 5) Z 2c is optionally substituted with a group.

[0139] Z 2 The specific value of is (C 2 ~C 8 ) alkynyl, phenyl, 5-6 membered C-linked monocyclic heteroaryl, 8-10 membered C-linked bicyclic heteroaryl, 8-10 membered C-linked bicyclic heterocycle and -C(O)NR q3 R r3 wherein the 5-6 membered C-linked monocyclic heteroaryl, the 8-10 membered C-linked bicyclic heteroaryl and the 8-10 membered C-linked bicyclic heterocycle have 1-9 carbon atoms and 1-4 heteroatoms in the ring system, and Z 2 Any phenyl, 5-6 membered C-linked monocyclic heteroaryl, 8-10 membered C-linked bicyclic heteroaryl and 8-10 membered C-linked bicyclic heterocycle may be joined by one or more (e.g., 1, 2, 3, 4 or 5) Z 2b or Z 2c is optionally substituted with a group; 2 Any (C 2 ~C 8 ) Alkynyl is selected from the group consisting of one or more (e.g., 1, 2, 3, 4, or 5) Z 2c is optionally substituted with a group.

[0140] Z 2 The specific value of is (C 2 ~C8 ) alkynyl, phenyl, 5-6 membered C-linked monocyclic heteroaryl, 8-10 membered C-linked bicyclic heteroaryl, 8-10 membered C-linked bicyclic heterocycle and -C(O)NR q3 R r3 wherein the 5-6 membered C-linked monocyclic heteroaryl, the 8-10 membered C-linked bicyclic heteroaryl and the 8-10 membered C-linked bicyclic heterocycle have 1-9 carbon atoms and 1-4 heteroatoms in the ring system, and Z 2 Any phenyl, 5-6 membered C-linked monocyclic heteroaryl, 8-10 membered C-linked bicyclic heteroaryl and 8-10 membered C-linked bicyclic heterocycle may be joined by one or more (e.g., 1, 2, 3, 4 or 5) Z 2c is optionally substituted with a group; 2 Any (C 2 ~C 8 ) Alkynyl is selected from the group consisting of one or more (e.g., 1, 2, 3, 4, or 5) Z 2c is optionally substituted with a group.

[0141] Z 2 Specific values ​​are 4-methylpentynyl, phenyl, pyridinyl, 1H-2-oxo -o-pyridinyl, triazolyl, 1-oxoisoindolinyl, 1H-pyrrolo[2,3-b]pyridinyl and -C(O)NR q3 R r3 Selected from Z 2 Any phenyl, pyridinyl, 1H-2-oxo-pyridinyl, triazolyl, 1-oxoisoindolinyl and 1H-pyrrolo[2,3-b]pyridinyl may have one or more (e.g., 1, 2, 3, 4 or 5) Z 2b or Z 2c is optionally substituted with a group; 2 Any 4-methylpentynyl may have one or more (e.g., 1, 2, 3, 4, or 5) Z 2c is optionally substituted with a group.

[0142] Z 2Specific values ​​of are 4-methylpentynyl, phenyl, pyridinyl, 1H-2-oxo-pyridinyl, triazolyl, 1-oxoisoindolinyl, 1H-pyrrolo[2,3-b]pyridinyl, and -C(O)NR q3 R r3 Selected from Z 2 Any of the phenyl, pyridinyl, 2-oxopyridinyl, triazolyl, 1-oxoisoindolinyl and 1H-pyrrolo[2,3-b]pyridinyl may have one or more (e.g., 1, 2, 3, 4 or 5) Z 2c is optionally substituted with a group; 2 Any 4-methylpentynyl may have one or more (e.g., 1, 2, 3, 4, or 5) Z 2c is optionally substituted with a group.

[0143] Z 2 Specific values ​​of are 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 Selected from Z 2 Any phenyl, pyridin-4-yl, 1H-2-oxo-pyridin-2-yl, triazol-4-yl, 1-oxoisoindolin-6-yl and 1H-pyrrolo[2,3-b]pyridin-5-yl may have one or more (e.g., 1, 2, 3, 4 or 5) Z 2b or Z 2c is optionally substituted with a group; 2 Any 4-methylpentyn-1-yl may have one or more (e.g., 1, 2, 3, 4, or 5) Z 2c is optionally substituted with a group.

[0144] Z 2Specific values ​​of are 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 Selected from Z 2 Any phenyl, pyridin-4-yl, 1H-2-oxo-pyridin-2-yl, triazol-4-yl, 1-oxoisoindolin-6-yl and 1H-pyrrolo[2,3-b]pyridin-5-yl may have one or more (e.g., 1, 2, 3, 4 or 5) Z 2c is optionally substituted with a group; 2 Any 4-methylpentyn-1-yl may have one or more (e.g., 1, 2, 3, 4, or 5) Z 2c is optionally substituted with a group.

[0145] A particular group of compounds of formula I is 2 But, Z 2b is a compound that is not substituted with

[0146] A particular group of compounds of formula I is 2 But one or more Z 2c The compound is optionally substituted with a group.

[0147] each Z 2c The specific values ​​of are independently halogen, -OR n4 and -C(O)NR q4 R r4 is selected from.

[0148] A specific group of compounds of formula I are n4 is H or methyl, and R q4 and R r4 are H.

[0149] R n4 A specific value for is H or methyl.

[0150] Each Rq4 and each R r4 A specific value of is H.

[0151] Z 2 The specific value of is: [ka] is selected from.

[0152] A-Z 1 The specific value of is: [ka] [ka] is selected from.

[0153] A-Z 1 The specific value of is: [ka] is selected from.

[0154] R 1 A specific value for is 5-12 membered heteroaryl, R 1 Any 5 to 12 members Heteroaryl is one or more (e.g., 1, 2, 3, 4, or 5) Z 4 is optionally substituted with a group.

[0155] R 1 A specific value for is 8-12 membered bicyclic heteroaryl or 8-12 membered tricyclic heteroaryl; 1Any 8-12 membered bicyclic heteroaryl or 8-12 membered tricyclic heteroaryl may have one or more (e.g., 1, 2, 3, 4, or 5) Z 4 is optionally substituted with a group.

[0156] R 1 A specific value for is an 8-12 membered bicyclic heteroaryl or an 8-12 membered tricyclic heteroaryl having 4-10 carbon atoms and 1-5 heteroatoms in the ring system; 1 Any 8-12 membered bicyclic heteroaryl or 8-12 membered tricyclic heteroaryl may have one or more (e.g., 1, 2, 3, 4, or 5) Z 4 is optionally substituted with a group.

[0157] R 1 A specific value for is an 8-12 membered bicyclic heteroaryl or an 8-12 membered tricyclic heteroaryl, wherein the 8-12 membered bicyclic heteroaryl or the 8-12 membered tricyclic heteroaryl contains at least one partially unsaturated ring, and R 1 Any 8-12 membered bicyclic heteroaryl or 8-12 membered tricyclic heteroaryl may have one or more (e.g., 1, 2, 3, 4, or 5) Z 4 is optionally substituted with a group.

[0158] R 1 A specific value of has the following formula IIa [ka] [In the formula, C, together with the two carbon atoms of ring B to which it is attached, forms a 3- to 7-membered monocyclic carbocycle, a 5- to 8-membered bicyclic carbocycle, a 3- to 7-membered monocyclic heterocycle, or a 5- to 8-membered bicyclic heterocycle, and any 3- to 7-membered monocyclic carbocycle, 5- to 8-membered bicyclic carbocycle, 3- to 7-membered monocyclic heterocycle, or 5- to 8-membered bicyclic heterocycle of C may be joined by one or more (e.g., 1, 2, 3, 4, or 5) Z 4 is optionally substituted with a group; B is a 5- or 6-membered monocyclic heteroaryl having 1, 2, or 3 nitrogen atoms, and B is selected from the group consisting of one or more (e.g., 1, 2, 3, 4, or 5) Z 4 group.

[0159] R 1 The specific value of has the following IIb [ka] [In the formula, C, together with the two carbon atoms of ring B to which it is attached, forms a 3- to 7-membered monocyclic carbocycle, a 5- to 8-membered bicyclic carbocycle, a 3- to 7-membered monocyclic heterocycle, or a 5- to 8-membered bicyclic heterocycle, and any 3- to 7-membered monocyclic carbocycle, 5- to 8-membered bicyclic carbocycle, 3- to 7-membered monocyclic heterocycle, or 5- to 8-membered bicyclic heterocycle of C may be joined by one or more (e.g., 1, 2, 3, 4, or 5) Z 4 is optionally substituted with a group; B is a 5- or 6-membered monocyclic heteroaryl having 1, 2 or 3 nitrogen atoms; V is C or N; W is for CZ 4c , N.Z. 4c or N, X is for CZ 4c , N.Z. 4c or N, Y is CZ 4c or N or absent, the dashed bond is selected from a single bond and a double bond, and the dashed bond, V, W, X and Y are selected such that the 5- or 6-membered monocyclic heteroaryl B is aromatic; each Z 4c are independently H or Z 4 [Selected from].

[0160] R 1 Specific values ​​of have the following formula IIc [ka] [In the formula, C, together with the two carbon atoms of ring B to which it is attached, forms a 3- to 7-membered monocyclic carbocycle, a 5- to 8-membered bicyclic carbocycle, a 3- to 7-membered monocyclic heterocycle, or a 5- to 8-membered bicyclic heterocycle, and any 3- to 7-membered monocyclic carbocycle, 5- to 8-membered bicyclic carbocycle, 3- to 7-membered monocyclic heterocycle, or 5- to 8-membered bicyclic heterocycle of C may be joined by one or more (e.g., 1, 2, 3, 4, or 5) Z 4 is optionally substituted with a group; B is a 5- or 6-membered monocyclic heteroaryl having 1, 2 or 3 nitrogen atoms; V is C or N; W is for CZ 4c or N, X is for CZ 4c , N.Z. 4c or N, Y is CZ 4c or N or absent, the dashed bond is selected from a single bond and a double bond, and the dashed bond, V, W, X and Y are selected such that the 5- or 6-membered monocyclic heteroaryl B is aromatic; each Z 4c are independently H or Z 4 [Selected from].

[0161] R 1 Specific values ​​of have the following formula IId: [ka] [In the formula, C, together with the two carbon atoms to which it is attached, forms a 3- to 7-membered monocyclic carbocycle, a 5- to 9-membered bicyclic carbocycle, a 3- to 7-membered monocyclic heterocycle, or a 5- to 9-membered bicyclic heterocycle, and any 3- to 7-membered monocyclic carbocycle, 5- to 9-membered bicyclic carbocycle, 3- to 7-membered monocyclic heterocycle, or 5- to 9-membered bicyclic heterocycle of C may be joined by one or more (e.g., 1, 2, 3, 4, or 5) Z 4 is optionally substituted with a group; each Z 4c are independently H or Z 4 [Selected from].

[0162] each Z 4 The specific values ​​of are, independently, (C 1 ~C 6 ) alkyl and halogen; Z 4 Any (C 1 ~C 6 ) The alkyl is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) halogen.

[0163] each Z 4 Particular values ​​for are independently selected from fluoro, trifluoromethyl, and difluoromethyl.

[0164] R 1 The specific value of is: [ka] is selected from.

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

[0166] R 1 The specific value of is: [ka] R 1 The specific value of is: [ka] It is.

[0167] R 1 A specific value for is an 8-12 membered bicyclic heteroaryl or an 8-12 membered tricyclic heteroaryl having 4-9 carbon atoms and 1-5 heteroatoms in the ring system; 1 Any 8-12 membered bicyclic heteroaryl or 8-12 membered tricyclic heteroaryl may have one or more (e.g., 1, 2, 3, 4 or 5) Z 4 Groups are optionally substituted.

[0168] R 1 A specific value for is an 8-12 membered bicyclic heteroaryl having 6-9 carbon atoms and 1-3 heteroatoms in the ring system; 1 Any 8-12 membered bicyclic heteroaryl may have one or more (e.g., 1, 2, 3, 4 or 5) Z 4 Groups are optionally substituted.

[0169] R 1 A specific value for is an 8-12 membered bicyclic heteroaryl or an 8-12 membered tricyclic heteroaryl having 6-9 carbon atoms and 1-3 heteroatoms in the ring system, and R 1Any 8-12 membered bicyclic heteroaryl or 8-12 membered tricyclic heteroaryl of A rule may contain one or more (e.g., 1, 2, 3, 4, or 5) Z 4 is optionally substituted with a group.

[0170] R 1 A 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 have one or more (e.g., 1, 2, 3, 4 or 5) Z 4 is optionally substituted with a group.

[0171] R 1 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 have one or more (e.g., 1, 2, 3, 4 or 5) Z 4 is optionally substituted with a group.

[0172] R 1 A specific value of is selected from indol-3-yl and 4,5,6,7-tetrahydro-1H-indazol-1-yl; R 1 Any indol-3-yl and 4,5,6,7-tetrahydro-1H-indazol-1-yl may have one or more (e.g., 1, 2, 3, 4, or 5) Z 4 is optionally substituted with a group.

[0173] R 1Specific values ​​of are selected from indol-3-yl, 4,5,6,7-tetrahydro-1H-indazol-1-yl, 3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl and 1,4,5,5a,6,6a-hexahydrocyclopropa[g]indazol-1-yl; R 1 Any of the indol-3-yl, 4,5,6,7-tetrahydro-1H-indazol-1-yl, 3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl and 1,4,5,5a,6,6a-hexahydrocyclopropa[g]indazol-1-yl may have one or more (e.g., 1, 2, 3, 4 or 5) Z 4 is optionally substituted with a group.

[0174] each Z 4 The specific values ​​of are, independently, (C 1 ~C 6 ) alkyl and halogen; Z 4 Any (C 1 ~C 6 ) The alkyl is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) halogen.

[0175] each Z 4 The specific values ​​of are, independently, (C 1 ~C 6 ) alkyl, -CN and halogen; Z 4 Any (C 1 ~C 6 ) The alkyl is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) halogen.

[0176] each Z 4 Particular values ​​for are independently selected from fluoro, trifluoromethyl, and difluoromethyl.

[0177] each Z 4Particular values ​​for are independently selected from fluoro, trifluoromethyl, -CN, and difluoromethyl.

[0178] R 1 The specific value of is: [ka] is selected from.

[0179] R 1 The specific value of is: [ka] is selected from.

[0180] R 1 The specific value of is: [ka] is selected from.

[0181] R 1 The specific value of is: [ka] R 1 The specific value of is: [ka] It is.

[0182] In one variation of formula I, A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl and R 1is 1, 2, 3, 4 or 5 Z, which may be the same or different 4 In another variation, A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl and R 1 is an 8-12 membered bicyclic heteroaryl or an 8-12 membered tricyclic heteroaryl; R 1 Any 8-12 membered bicyclic heteroaryl or 8-12 membered tricyclic heteroaryl may be selected from the group consisting of 1, 2, 3, 4 or 5 Z 4 In another variation, A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl and R 1 is an 8-12 membered bicyclic heteroaryl or an 8-12 membered tricyclic heteroaryl; R 1 Any 8-12 membered bicyclic heteroaryl or 8-12 membered tricyclic heteroaryl may have 1, 2, 3, 4 or 5 Z 4 groups, and each Z 4 is independently fluoro, trifluoromethyl or difluoromethyl.

[0183] In one variation of Formula I, A is pyridinyl and R 1 is an 8-12 membered bicyclic heteroaryl or an 8-12 membered tricyclic heteroaryl; R 1 Any 8-12 membered bicyclic heteroaryl or 8-12 membered tricyclic heteroaryl may have 1, 2, 3, 4 or 5 Z 4 Groups are optionally substituted.

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

[0185] In one variation of formula I, A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl; Z 1 is phenyl, a 5- to 6-membered monocyclic heteroaryl, an 8- to 10-membered bicyclic heteroaryl, an 8- to 10-membered bicyclic heterocycle, or a 9- to 12-membered tricyclic heterocycle. Z 1 Any phenyl, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 8- to 10-membered bicyclic heterocycle, or 9- to 12-membered tricyclic heterocycle may be joined by 1, 2, 3, 4, or 5 Z 1a In another variation, A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl and Z is optionally substituted with a group. 1 can contain 1, 2, 3, 4 or 5 Z's 1a In another variation, A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl and Z is phenyl optionally substituted with a group. 1 is a 5- to 6-membered monocyclic heteroaryl or an 8- to 10-membered bicyclic heteroaryl; Z 1 Any 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl may be selected from the group consisting of 1, 2, 3, 4 or 5 Z 1a In another variation, A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl and Z is optionally substituted with a group. 1 is an 8- to 10-membered bicyclic heterocycle or a 9- to 12-membered tricyclic heterocycle; Z 1 Any 8- to 10-membered bicyclic heterocycle or 9- to 12-membered tricyclic heterocycle may contain 1, 2, 3, 4 or 5 Z 1a is optionally substituted with a group.

[0186] In one variation of Formula I, A is pyridinyl and Z 1is phenyl, a 5- to 6-membered monocyclic heteroaryl, an 8- to 10-membered bicyclic heteroaryl, an 8- to 10-membered bicyclic heterocycle, or a 9- to 12-membered tricyclic heterocycle; Z 1 Any phenyl, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 8- to 10-membered bicyclic heterocycle, or 9- to 12-membered tricyclic heterocycle may be joined by 1, 2, 3, 4, or 5 Z 1a In another variation, A is pyridinyl and Z is optionally substituted with a 1 can contain 1, 2, 3, 4 or 5 Z's 1a In another variation, A is pyridinyl and Z is phenyl optionally substituted with a group. 1 is a 5- to 6-membered monocyclic heteroaryl or an 8- to 10-membered bicyclic heteroaryl; Z 1 Any 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl may be selected from the group consisting of 1, 2, 3, 4 or 5 Z 1a In another variation, A is pyridinyl and Z is optionally substituted with a 1 is an 8- to 10-membered bicyclic heterocycle or a 9- to 12-membered tricyclic heterocycle; Z 1 Any 8- to 10-membered bicyclic heterocycle or 9- to 12-membered tricyclic heterocycle may contain 1, 2, 3, 4 or 5 Z 1a Groups are optionally substituted.

[0187] In one variation of formula I, A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl; Z 2 is (C 2 ~C 8 ) alkynyl, 6-12 membered aryl, 5-12 membered C-linked heteroaryl, 3-12 membered C-linked heterocycle, or -C(O)NR q3 R r3 and Z 2 Any 6-12 membered aryl, 5-12 membered C-linked heteroaryl, or 3-12 membered C-linked heterocycle may be joined by 1, 2, 3, 4 or 5 Z 2b or Z 2c is optionally substituted with a group; 2 Any (C 2 ~C8 ) Alkynyl is substituted with 1, 2, 3, 4 or 5 Z 2c In another variation, A is pyridinyl and Z is optionally substituted with a 2 is (C 2 ~C 8 ) alkynyl, 6-12 membered aryl, 5-12 membered C-linked heteroaryl, 3-12 membered C-linked heterocycle, or -C(O)NR q3 R r3 and Z 2 Any 6-12 membered aryl, 5-12 membered C-linked heteroaryl, or 3-12 membered C-linked heterocycle may be joined by 1, 2, 3, 4 or 5 Z 2b or Z 2c is optionally substituted with a group; 2 Any (C 2 ~C 8 ) Alkynyl is substituted with 1, 2, 3, 4 or 5 Z 2c In another variation, A is pyrimidinyl and Z is optionally substituted with a substituted aryl group. 2 is (C 2 ~C 8 ) alkynyl, 6-12 membered aryl, 5-12 membered C-linked heteroaryl, 3-12 membered C-linked heterocycle, or -C(O)NR q3 R r3 and Z 2 Any 6-12 membered aryl, 5-12 membered C-linked heteroaryl, or 3-12 membered C-linked heterocycle may be joined by 1, 2, 3, 4 or 5 Z 2b or Z 2c is optionally substituted with a group; 2 Any (C 2 ~C 8 ) Alkynyl is substituted with 1, 2, 3, 4 or 5 Z 2c In another variation, A is pyrazinyl and Z is optionally substituted with a substituted aryl group. 2 is (C 2 ~C 8 ) alkynyl, 6-12 membered aryl, 5-12 membered C-linked heteroaryl, 3-12 membered C-linked heterocycle, or -C(O)NR q3 R r3 and , Z 2Any 6-12 membered aryl, 5-12 membered C-linked heteroaryl, or 3-12 membered C-linked heterocycle may be joined by 1, 2, 3, 4 or 5 Z 2b or Z 2c is optionally substituted with a group; 2 Any (C 2 ~C 8 ) Alkynyl is substituted with 1, 2, 3, 4 or 5 Z 2c In another variation, A is pyridazinyl and Z is optionally substituted with a group. 2 is (C 2 ~C 8 ) alkynyl, 6-12 membered aryl, 5-12 membered C-linked heteroaryl, 3-12 membered C-linked heterocycle, or -C(O)NR q3 R r3 and Z 2 Any 6-12 membered aryl, 5-12 membered C-linked heteroaryl, or 3-12 membered C-linked heterocycle may be joined by 1, 2, 3, 4 or 5 Z 2b or Z 2c is optionally substituted with a group; 2 Any (C 2 ~C 8 ) Alkynyl is substituted with 1, 2, 3, 4 or 5 Z 2c is optionally substituted with a group.

[0188] In one variation of Formula I, A is one Z 1 Part and 1 Z 2 is substituted with a moiety and Z 3 pyridinyl that is not substituted with any (0) moiety; 2 is (C 2 ~C 8 ) alkynyl or aryl; Z 2 is optionally substituted as provided by formula I. In another variation, A is selected from one Z 1 Part and 1 Z 2 is substituted with a moiety and Z 3 pyridinyl that is not substituted with any (0) moiety; 2 is (C 2 ~C 8 ) alkynyl, and Z2 is optionally substituted as provided by formula I. In certain variations, A is selected from one Z 1 and one Z moiety alpha to the nitrogen atom of the pyridinyl ring. 2 is substituted with a moiety, and Z 3 pyridinyl that is not substituted with any (0) moiety; 2 is (C 2 ~C 8 ) alkynyl, and Z 2 is optionally substituted as provided by Formula I.

[0189] In one variation of Formula I, R 1 is 1, 2, 3, 4 or 5 Z, which may be the same or different 4 is a 5- to 12-membered heteroaryl optionally substituted with a group; Z 1 is phenyl, a 5- to 6-membered monocyclic heteroaryl, an 8- to 10-membered bicyclic heteroaryl, an 8- to 10-membered bicyclic heterocycle, or a 9- to 12-membered tricyclic heterocycle; Z 1 Any phenyl, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 8- to 10-membered bicyclic heterocycle, or 9- to 12-membered tricyclic heterocycle may be joined by 1, 2, 3, 4, or 5 Z 1a In another variation, R 1 is an 8-12 membered bicyclic heteroaryl or an 8-12 membered tricyclic heteroaryl; R 1 Any 8-12 membered bicyclic heteroaryl or 8-12 membered tricyclic heteroaryl may have 1, 2, 3, 4 or 5 Z 4 is optionally substituted with a group; 1 is phenyl, a 5- to 6-membered monocyclic heteroaryl, an 8- to 10-membered bicyclic heteroaryl, an 8- to 10-membered bicyclic heterocycle, or a 9- to 12-membered tricyclic heterocycle; Z 1 Any phenyl, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 8- to 10-membered bicyclic heterocycle, or 9- to 12-membered tricyclic heterocycle may be joined by 1, 2, 3, 4, or 5 Z 1aGroups are optionally substituted.

[0190] In one variation of Formula I, R 1 is an 8-12 membered bicyclic heteroaryl or an 8-12 membered tricyclic heteroaryl; R 1 Any 8-12 membered bicyclic heteroaryl or 8-12 membered tricyclic heteroaryl may have 1, 2, 3, 4 or 5 Z 4 is optionally substituted with a group; 1 is an 8-10 membered bicyclic heteroaryl or an 8-10 membered bicyclic heterocycle; Z 1 Any 8-10 membered bicyclic heteroaryl or 8-10 membered bicyclic heterocycle may have 1, 2, 3, 4 or 5 Z 1a Groups are optionally substituted.

[0191] In one variation of Formula I, R 1 is 1, 2, 3, 4 or 5 Z, which may be the same or different 4 is a 5- to 12-membered heteroaryl optionally substituted with a group; Z 2 is (C 2 ~C 8 ) alkynyl, 6-12 membered aryl, 5-12 membered C-linked heteroaryl aryl, 3-12 membered C-linked heterocycle, or -C(O)NR q3 R r3 and Z 2 Any 6-12 membered aryl, 5-12 membered C-linked heteroaryl, or 3-12 membered C-linked heterocycle may be joined by 1, 2, 3, 4 or 5 Z 2b or Z 2c is optionally substituted with a group; 2 Any (C 2 ~C 8 ) Alkynyl is substituted with 1, 2, 3, 4 or 5 Z 2c In another variation, R 1 is an 8-12 membered bicyclic heteroaryl or an 8-12 membered tricyclic heteroaryl; R 1Any 8-12 membered bicyclic heteroaryl or 8-12 membered tricyclic heteroaryl may have 1, 2, 3, 4 or 5 Z 4 is optionally substituted with a group; 2 is (C 2 ~C 8 ) alkynyl, 6-12 membered aryl, 5-12 membered C-linked heteroaryl, 3-12 membered C-linked heterocycle, or -C(O)NR q3 R r3 and Z 2 Any 6-12 membered aryl, 5-12 membered C-linked heteroaryl, or 3-12 membered C-linked heterocycle may be joined by 1, 2, 3, 4 or 5 Z 2b or Z 2c is optionally substituted with a group; 2 Any (C 2 ~C 8 ) Alkynyl is substituted with 1, 2, 3, 4 or 5 Z 2c is optionally substituted with a group.

[0192] In one variation of Formula I, Z 1 is phenyl, a 5- to 6-membered monocyclic heteroaryl, an 8- to 10-membered bicyclic heteroaryl, an 8- to 10-membered bicyclic heterocycle, or a 9- to 12-membered tricyclic heterocycle; Z 1 Any phenyl, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 8- to 10-membered bicyclic heterocycle, or 9- to 12-membered tricyclic heterocycle may be joined by 1, 2, 3, 4, or 5 Z 1a is optionally substituted with a group; 2 is (C 2 ~C 8 ) alkynyl, 6-12 membered aryl, 5-12 membered C-linked heteroaryl, 3-12 membered C-linked heterocycle, or -C(O)NR q3 R r3 and Z 2 Any 6-12 membered aryl, 5-12 membered C-linked heteroaryl, or 3-12 membered C-linked heterocycle may be joined by 1, 2, 3, 4 or 5 Z 2b or Z 2c is optionally substituted with a group; 2 Any (C 2 ~C8 ) Alkynyl is substituted with 1, 2, 3, 4 or 5 Z 2c Groups are optionally substituted.

[0193] In one variation of Formula I, Z 1 can contain 1, 2, 3, 4 or 5 Z's 1a is a bicyclic heteroaryl optionally substituted with a group; Z 2 can contain 1, 2, 3, 4 or 5 Z's 2c Optionally substituted with a group (C 2 ~C 8 ) alkynyl.

[0194] In one variation of Formula I, R 1 is a 5-12 membered heteroaryl; Z 1 is phenyl, a 5- to 6-membered monocyclic heteroaryl, an 8- to 10-membered bicyclic heteroaryl, an 8- to 10-membered bicyclic heterocycle, or a 9- to 12-membered tricyclic heterocycle; Z 1 Any phenyl, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 8- to 10-membered bicyclic heterocycle, or 9- to 12-membered tricyclic heterocycle may be joined by 1, 2, 3, 4, or 5 Z 1a is optionally substituted with a group; 2 is (C 2 ~C 8 ) alkynyl, 6-12 membered aryl, 5-12 membered C-linked heteroaryl, 3-12 membered C-linked heterocycle, or -C(O)NR q3 R r3 and Z 2 Any 6-12 membered aryl, 5-12 membered C-linked heteroaryl, or 3-12 membered C-linked heterocycle may be joined by 1, 2, 3, 4 or 5 Z 2b or Z 2c is optionally substituted with a group; 2 Any (C 2 ~C 8 ) Alkynyl is substituted with 1, 2, 3, 4 or 5 Z 2c Groups are optionally substituted.

[0195] Compound of Formula III The present disclosure relates to a compound of formula III [ka] [In the formula, A is a 6-membered monocyclic heteroaryl having 1 or 2 nitrogen atoms, the 6-membered monocyclic heteroaryl being substituted with one Z at the indicated position. 1 group and one Z 2 group and one or two Z 3 is optionally substituted with a group; 3 The groups are the same or different, R 1 is a 6- to 12-membered aryl, a 5- to 12-membered heteroaryl, or a 3- to 12-membered heterocycle; R 1 Any 6- to 12-membered aryl, 5- to 12-membered heteroaryl, or 3- to 12-membered heterocycle may be selected from the group consisting of 1, 2, 3, 4, or 5 Z 4 is optionally substituted with a group; 4 The groups are the same or different, R 2 is phenyl optionally substituted with 1, 2, 3, 4 or 5 halogens which are the same or different; R 3a and R 3b Each independently represents H or (C 1 ~C 3 ) alkyl, Z 1 is a 6- to 12-membered aryl, a 5- to 14-membered heteroaryl, or a 3- to 14-membered heterocycle; Z 1 Any 6- to 12-membered aryl, 5- to 14-membered heteroaryl, or 3- to 14-membered heterocycle may be selected from the group consisting of 1, 2, 3, 4, or 5 Z 1a or Z 1b and optionally substituted with Z 1a and Z 1b The groups are the same or different, each Z 1a are independently 3 ~C 7) Carbocycle, 5-12 membered heteroaryl, 3-12 membered heterocycle, halogen, -CN, -OR n1 , -OC(O)R p1 , -OC(O)NR q1 R r1 , -SR n1 , -S(O)R p1 , -S(O) 2 OH, -S(O) 2 R p1 , -S(O) 2 NR q1 R r1 , -NR q1 R r1 , -NR n1 COR p1 , -NR n1 CO 2 R p1 , -NR n1 CONR q1 R r1 , -NR n1 S(O) 2 R p1 , -NR n1 S(O) 2 OR p1 , -NR n1 S(O) 2 NR q1 R r1 , -C(O)R n1 , -C(O)OR n1 , -C(O)NR q1 R r1 and -S(O) 2 NR n1 COR p1 and Z 1a Any (C 3 ~C 7 ) Carbocycle, 5-12 membered heteroaryl and 3-12 membered heterocycle are each independently selected from 1, 2, 3, 4 or 5 Z 1c or Z 1d is optionally substituted with a group; 1c and Z 1d The groups are the same or different, each Z 1b is optionally substituted with 1, 2, 3, 4 or 5 halogens, which are independently the same or different (C 1 ~C 8) alkyl, each Z 1c are independently halogen, -CN, -OH, -NH 2 , -C(O)NR q2 R r2 , or (C 1 ~C 8 ) heteroalkyl; each Z 1d are independently 1 ~C 8 ) alkyl or (C 1 ~C 8 ) haloalkyl; Each R n1 are independently, H, (C 1 ~C 8 ) alkyl, (C 3 ~C 7 ) a carbocycle, a 3- to 7-membered heterocycle, or a 5- to 6-membered monocyclic heteroaryl; R n1 Any (C 3 ~C 7 ) A carbocycle, a 3- to 7-membered heterocycle, or a 5- to 6-membered monocyclic heteroaryl is selected from the group consisting of 1, 2, 3, 4, or 5 Z 1c or Z 1d is optionally substituted with a group; 1c and Z 1d The groups may be the same or different, R n1 Any (C 1 ~C 8 ) alkyl is 1, 2, 3, 4 or 5 Z 1c is optionally substituted with a group; 1c The groups are the same or It is different, Each R p1 are independently 1 ~C 8 ) alkyl, (C 3 ~C 7 ) a carbocycle, a 3- to 7-membered heterocycle, or a 5- to 6-membered monocyclic heteroaryl; R p1 Any (C 3 ~C 7 ) A carbocycle, a 3- to 7-membered heterocycle, or a 5- to 6-membered monocyclic heteroaryl is selected from the group consisting of 1, 2, 3, 4, or 5 Z 1c or Z 1dis optionally substituted with a group; 1c and Z 1d The groups may be the same or different, R p1 Any (C 1 ~C 8 ) alkyl is 1, 2, 3, 4 or 5 Z 1c is optionally substituted with a group; 1c The groups are the same or different, R q1 and R r1 are each independently H, (C 1 ~C 8 ) alkyl, (C 3 ~C 7 ) a carbocycle, a 3- to 7-membered heterocycle, or a 5- to 6-membered monocyclic heteroaryl; R q1 Or R r1 Any (C 3 ~C 7 ) A carbocycle, a 3- to 7-membered heterocycle, or a 5- to 6-membered monocyclic heteroaryl is selected from the group consisting of 1, 2, 3, 4, or 5 Z 1c Or Z 1d is optionally substituted with a group; 1c and Z 1d The groups may be the same or different, R q1 Or R r1 Any (C 1 ~C 8 ) alkyl is 1, 2, 3, 4 or 5 Z 1c is optionally substituted with a group; 1c The groups may be the same or different, or R q1 and R r1 together with the nitrogen to which they are attached form a 5-, 6- or 7-membered heterocycle, the 5-, 6- or 7-membered heterocycle being bound to 1, 2, 3, 4 or 5 Z 1c Or Z 1d is optionally substituted with a group; 1c and Z 1d The groups may be the same or different, R q2 and R r2 are each independently H, (C 1 ~C 8 ) alkyl, (C3 ~C 7 ) a carbocyclic ring or R q2 and R r2 together with the nitrogen to which they are attached form a 5-, 6-, or 7-membered heterocyclic ring; Z 2 is (C 2 ~C 8 ) alkenyl, (C 2 ~C 8 ) alkynyl, 6-12 membered aryl, 5-12 membered C-linked heteroaryl, 3-12 membered C-linked heterocycle, -C(O)R n3 or -C(O)NR q3 R r3 and Z 2 Any 6-12 membered aryl, 5-12 membered C-linked heteroaryl, or 3-12 membered C-linked heterocycle may be joined by 1, 2, 3, 4 or 5 Z 2b or Z 2c is optionally substituted with a group; 2b and Z 2c The groups may be the same or different, Z 2 Any (C 2 ~C 8 ) alkenyl or (C 2 ~C 8 ) Alkynyl is substituted with 1, 2, 3, 4 or 5 Z 2c is optionally substituted with a group; 2c The groups are the same or different, Each R n3 are independently H or (C 1 ~C 4 ) alkyl, R q3 and R r3 Each independently represents H or (C 1 ~C 4 ) alkyl, each Z 2b are independently oxo, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 ) heteroalkyl, or (C 1 ~C 4 ) haloalkyl; each Z2c are independently oxo, halogen, -CN, -OR n4 , -OC(O)R p4 , -OC(O)NR q4 R r4 , -SR n4 , -S(O)R p4 , -S(O) 2 OH, -S(O) 2 R p4 , -S(O) 2 NR q4 R r4 , -NR q4 R r4 , -NR n4 COR p4 , -NR n4 CO 2 R p4 , -NR n4 CONR q4 R r4 , -NR n4 S(O) 2 R p4 , -NR n4 S(O) 2 OR p4 , -NR n4 S(O) 2 NR q4 R r4 , -NO 2 , -C(O)R n4 , -C(O)OR n4 or -C(O)NR q4 R r4 and Each R n4 are independently, H, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 ) haloalkyl, or (C 1 ~C 4 ) heteroalkyl; Each R p4 are independently 1 ~C 8 ) alkyl, (C 1 ~C 4 ) haloalkyl, or (C 1 ~C 4 ) heteroalkyl; R q4 and Rr4 are each independently H, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 ) haloalkyl, or (C 1 ~C 4 ) heteroalkyl; each Z 3 are independently 1 ~C 4 ) heteroalkyl or halogen; each Z 4 are independently oxo, (C 1 ~C 8 ) alkyl, (C 3 ~C 7 )Carbocycle, halogen, -CN, -OR n5 , -NR q5 R r5 , -NR n5 COR p5 , -NR n5 CO 2 R p5 , -C(O)R n5 , -C(O)OR n5 or -C(O)NR q5 R r5 and , Z 4 Any (C 3 ~C 7 ) carbocyclic or (C 1 ~C 8 ) alkyl is 1, 2, 3, 4 or 5 Z 4a is optionally substituted with a group; 4a The groups are the same or different, each Z 4a are independently halogen, -CN, or -OR n6 and R n5 , R p5 , R q5 , R r5 , and R n6 Each independently represents H or (C 1 ~C 4 ) alkyl] or a pharma- ceutically acceptable salt thereof.

[0196] In certain embodiments, the compound of formula III is a compound of formula IIIa [ka] or a pharma- ceutically acceptable salt thereof.

[0197] In certain embodiments, the compound of formula III is a compound of formula IIIb [ka] or a pharma- ceutically acceptable salt thereof.

[0198] In certain embodiments, the compound of formula III is a compound of formula IIIc [ka] or a pharma- ceutically acceptable salt thereof.

[0199] The present disclosure relates to a compound of formula IIId [ka] [In the formula, A 1 , CH, CZ 3 or nitrogen, A 2 is CH or nitrogen, R 1 is a 6- to 12-membered aryl, a 5- to 12-membered heteroaryl, or a 3- to 12-membered heterocycle; R 1 Any 6- to 12-membered aryl, 5- to 12-membered heteroaryl, or 3- to 12-membered heterocycle may be selected from the group consisting of 1, 2, 3, 4, or 5 Z 4 is optionally substituted with a group;4 The groups are the same or different, R 3a and R 3b Each independently represents H or (C 1 ~C 3 ) alkyl, Z 1 is a 6- to 12-membered aryl, a 5- to 14-membered heteroaryl, or a 3- to 14-membered heterocycle; Z 1 Any 6- to 12-membered aryl, 5- to 14-membered heteroaryl, or 3- to 14-membered heterocycle may be selected from the group consisting of 1, 2, 3, 4, or 5 Z 1a or Z 1b and optionally substituted with Z 1a and Z 1b The groups are the same or different, each Z 1a are independently 3 ~C 7 ) Carbocycle, 5-12 membered heteroaryl, 3-12 membered heterocycle, halogen, -CN, -OR n1 , -OC(O)R p1 , -OC(O)NR q1 R r1 , -SR n1 , -S(O)R p1 , -S(O) 2 OH, -S(O) 2 R p1 , -S(O) 2 NR q1 R r1 , -NR q1 R r1 , -NR n1 COR p1 , -NR n1 CO 2 R p1 , -NR n1 CONR q1 R r1 , -NR n1 S(O) 2 R p1 , -NR n1 S(O) 2 OR p1 , -NR n1 S(O) 2 NR q1 R r1 , -C(O)Rn1 , -C(O)OR n1 , -C(O)NR q1 R r1 and -S(O) 2 NR n1 COR p1 and Z 1a Any (C 3 ~C 7 ) Carbocycle, 5-12 membered heteroaryl and 3-12 membered heterocycle are each independently selected from 1, 2, 3, 4 or 5 Z 1c or Z 1d is optionally substituted with a group; 1c and Z 1d The groups are the same or different, each Z 1b is optionally substituted with 1, 2, 3, 4 or 5 halogens, which are independently the same or different (C 1 ~C 8 ) alkyl, each Z 1c are independently halogen, -CN, -OH, -NH 2 , -C(O)NR q2 R r2 , or (C 1 ~C 8 ) heteroalkyl; each Z 1d are independently 1 ~C 8 ) alkyl or (C 1 ~C 8 ) haloalkyl; Each R n1 are independently, H, (C 1 ~C 8 ) alkyl, (C 3 ~C 7 ) a carbocycle, a 3- to 7-membered heterocycle, or a 5- to 6-membered monocyclic heteroaryl; R n1 Any (C 3 ~C 7 ) A carbocycle, a 3- to 7-membered heterocycle, or a 5- to 6-membered monocyclic heteroaryl is selected from the group consisting of 1, 2, 3, 4, or 5 Z 1c or Z 1d is optionally substituted with a group; 1c and Z1d The groups may be the same or different, R n1 Any (C 1 ~C 8 ) alkyl is 1, 2, 3, 4 or 5 Z 1c is optionally substituted with a group; 1c The groups are the same or different, Each R p1 are independently 1 ~C 8 ) alkyl, (C 3 ~C 7 ) a carbocycle, a 3- to 7-membered heterocycle, or a 5- to 6-membered monocyclic heteroaryl; R p1 Any (C 3 ~C 7 ) A carbocycle, a 3- to 7-membered heterocycle, or a 5- to 6-membered monocyclic heteroaryl is selected from the group consisting of 1, 2, 3, 4, or 5 Z 1c or Z 1d is optionally substituted with a group; 1c and Z 1d The groups may be the same or different, R p1 Any (C 1 ~C 8 ) alkyl is 1, 2, 3, 4 or 5 Z 1c is optionally substituted with a group; 1c The groups are the same or different, R q1 and R r1 are each independently H, (C 1 ~C 8 ) alkyl, (C 3 ~C 7 ) a carbocycle, a 3- to 7-membered heterocycle, or a 5- to 6-membered monocyclic heteroaryl; R q1 Or R r1 Any (C 3 ~C 7 ) A carbocycle, a 3- to 7-membered heterocycle, or a 5- to 6-membered monocyclic heteroaryl is selected from the group consisting of 1, 2, 3, 4, or 5 Z 1c Or Z 1d is optionally substituted with a group; 1c and Z 1d The groups may be the same or different, R q1 Or Rr1 Any (C 1 ~C 8 ) alkyl is 1, 2, 3, 4 or 5 Z 1c is optionally substituted with a group; 1c The groups may be the same or different, or R q1 and R r1 together with the nitrogen to which they are attached form a 5-, 6- or 7-membered heterocycle, the 5-, 6- or 7-membered heterocycle being bound to 1, 2, 3, 4 or 5 Z 1c Or Z 1d is optionally substituted with a group; 1c and Z 1d The groups may be the same or different, R q2 and R r2 are each independently H, (C 1 ~C 8 ) alkyl, (C 3 ~C 7 ) a carbocyclic ring or R q2 and R r2 together with the nitrogen to which they are attached form a 5-, 6-, or 7-membered heterocyclic ring; Z 2 is (C 2 ~C 8 ) alkenyl, (C 2 ~C 8 ) alkynyl, 6-12 membered aryl, 5-12 membered C-linked heteroaryl, 3-12 membered C-linked heterocycle, -C(O)R n3 or -C(O)NR q3 R r3 and Z 2 Any 6-12 membered aryl, 5-12 membered C-linked heteroaryl, or 3-12 membered C-linked heterocycle may be joined by 1, 2, 3, 4 or 5 Z 2b or Z 2c is optionally substituted with a group; 2b and Z 2c The groups may be the same or different, Z 2 Any (C 2 ~C 8 ) alkenyl or (C 2 ~C 8) Alkynyl is substituted with 1, 2, 3, 4 or 5 Z 2c is optionally substituted with a group; 2c The groups are the same or different, Each R n3 are independently H or (C 1 ~C 4 ) alkyl, R q3 and R r3 Each independently represents H or (C 1 ~C 4 ) alkyl, each Z 2b are independently oxo, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 )heteroalkyl or (C 1 ~C 4 ) haloalkyl; each Z 2c are independently oxo, halogen, -CN, -OR n4 , -OC(O)R p4 , - OC(O)NR q4 R r4 , -SR n4 , -S(O)R p4 , -S(O) 2 OH, -S(O) 2 R p4 , -S(O) 2 NR q4 R r4 , -NR q4 R r4 , -NR n4 COR p4 , -NR n4 CO 2 R p4 , -NR n4 CONR q4 R r4 , -NR n4 S(O) 2 R p4 , -NR n4 S(O) 2 OR p4 , -NR n4 S(O) 2 NR q4 R r4, -NO 2 , -C(O)R n4 , -C(O)OR n4 or -C(O)NR q4 R r4 and Each R n4 are independently, H, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 ) haloalkyl, or (C 1 ~C 4 ) heteroalkyl; Each R p4 are independently 1 ~C 8 ) alkyl, (C 1 ~C 4 ) haloalkyl, or (C 1 ~C 4 ) heteroalkyl; R q4 and R r4 are each independently H, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 ) haloalkyl, or (C 1 ~C 4 ) heteroalkyl; each Z 3 are independently 1 ~C 4 ) heteroalkyl; each Z 4 are independently oxo, (C 1 ~C 8 ) alkyl, (C 3 ~C 7 )Carbocycle, halogen, -CN, -OR n5 , -NR q5 R r5 , -NR n5 COR p5 , -NR n5 CO 2 R p5 , -C(O)R n5 , -C(O)OR n5 or -C(O)NR q5 R r5 and Z 4Any (C 3 ~C 7 ) carbocyclic or (C 1 ~C 8 ) alkyl is 1, 2, 3, 4 or 5 Z 4a is optionally substituted with a group; 4a The groups are the same or different, each Z 4a are independently halogen, -CN, or -OR n6 and R n5 , R p5 , R q5 , R r5 , and R n6 Each independently represents H or (C 1 ~C 4 ) alkyl, each Z 5 are independently halogens which may be the same or different; n is 0, 1, 2 or 3. or a pharma- ceutically acceptable salt thereof.

[0200] In certain embodiments, the compound of formula IIId is a compound of formula IIIe [ka] or a pharma- ceutically acceptable salt thereof.

[0201] The present disclosure relates to a compound of formula IIIf [ka] [In the formula, A 1 , CH, CZ 3 or nitrogen, A 2 is CH or nitrogen, R 1is a 6- to 12-membered aryl, a 5- to 12-membered heteroaryl, or a 3- to 12-membered heterocycle; R 1 Any 6- to 12-membered aryl, 5- to 12-membered heteroaryl, or 3- to 12-membered heterocycle may be selected from the group consisting of 1, 2, 3, 4, or 5 Z 4 is optionally substituted with a group; 4 The groups are the same or different, R 3a and R 3b Each independently represents H or (C 1 ~C 3 ) alkyl, Z 1 is a 6- to 12-membered aryl, a 5- to 14-membered heteroaryl, or a 3- to 14-membered heterocycle; Z 1 Any 6- to 12-membered aryl, 5- to 14-membered heteroaryl, or 3- to 14-membered heterocycle may be selected from the group consisting of 1, 2, 3, 4, or 5 Z 1a or Z 1b and optionally substituted with Z 1a and Z 1b The groups are the same or different, each Z 1a are independently 3 ~C 7 ) Carbocycle, 5-12 membered heteroaryl, 3-12 membered heterocycle, halogen, -CN, -OR n1 , -OC(O)R p1 , -OC(O)NR q1 R r1 , -SR n1 , -S(O)R p1 , -S(O) 2 OH, -S(O) 2 R p1 , -S(O) 2 NR q1 R r1 , -NR q1 R r1 , -NR n1 COR p1 , -NR n1 CO 2 R p1 , -NR n1 CONR q1 R r1 , -NR n1 S(O)2 R p1 , -NR n1 S(O) 2 OR p1 , -NR n1 S(O) 2 NR q1 R r1 , -C(O)R n1 , -C(O)OR n1 , -C(O)NR q1 R r1 and -S(O) 2 NR n1 COR p1 and Z 1a Any (C 3 ~C 7 ) Carbocycle, 5-12 membered heteroaryl and 3-12 membered heterocycle are each independently selected from 1, 2, 3, 4 or 5 Z 1c or Z 1d is optionally substituted with a group; 1c and Z 1d The groups are the same or different, each Z 1b is optionally substituted with 1, 2, 3, 4 or 5 halogens, which are independently the same or different (C 1 ~C 8 ) alkyl, each Z 1c are independently halogen, -CN, -OH, -NH 2 , -C(O)NR q2 R r2 , or (C 1 ~C 8 ) heteroalkyl; each Z 1d are independently 1 ~C 8 ) alkyl or (C 1 ~C 8 ) haloalkyl; Each R n1 are independently, H, (C 1 ~C 8 ) alkyl, (C 3 ~C 7 ) a carbocycle, a 3- to 7-membered heterocycle, or a 5- to 6-membered monocyclic heteroaryl; R n1 Any (C 3~C 7 ) A carbocycle, a 3- to 7-membered heterocycle, or a 5- to 6-membered monocyclic heteroaryl is selected from the group consisting of 1, 2, 3, 4, or 5 Z 1c or Z 1d is optionally substituted with a group; 1c and Z 1d The groups may be the same or different, R n1 Any (C 1 ~C 8 ) alkyl is 1, 2, 3, 4 or 5 Z 1c is optionally substituted with a group; 1c The groups are the same or different, Each R p1 are independently 1 ~C 8 ) alkyl, (C 3 ~C 7 )Carbocyclic, 3-7 membered heterocyclic ring, or 5-6 membered monocyclic heteroaryl; R p1 Any (C 3 ~C 7 ) A carbocycle, a 3- to 7-membered heterocycle, or a 5- to 6-membered monocyclic heteroaryl is selected from the group consisting of 1, 2, 3, 4, or 5 Z 1c or Z 1d is optionally substituted with a group; 1c and Z 1d The groups may be the same or different, R p1 Any (C 1 ~C 8 ) alkyl is 1, 2, 3, 4 or 5 Z 1c is optionally substituted with a group; 1c The groups are the same or different, R q1 and R r1 are each independently H, (C 1 ~C 8 ) alkyl, (C 3 ~C 7 ) a carbocycle, a 3- to 7-membered heterocycle, or a 5- to 6-membered monocyclic heteroaryl; R q1 Or R r1 Any (C 3 ~C 7) A carbocycle, a 3- to 7-membered heterocycle, or a 5- to 6-membered monocyclic heteroaryl is selected from the group consisting of 1, 2, 3, 4, or 5 Z 1c Or Z 1d is optionally substituted with a group; 1c and Z 1d The groups may be the same or different, R q1 Or R r1 Any (C 1 ~C 8 ) alkyl is 1, 2, 3, 4 or 5 Z 1c is optionally substituted with a group; 1c The groups may be the same or different, or R q1 and R r1 together with the nitrogen to which they are attached form a 5-, 6- or 7-membered heterocycle, the 5-, 6- or 7-membered heterocycle being bound to 1, 2, 3, 4 or 5 Z 1c Or Z 1d is optionally substituted with a group; 1c and Z 1d The groups may be the same or different, R q2 and R r2 are each independently H, (C 1 ~C 8 ) alkyl, (C 3 ~C 7 ) a carbocyclic ring or R q2 and R r2 together with the nitrogen to which they are attached form a 5-, 6-, or 7-membered heterocyclic ring; Z 2 is (C 2 ~C 8 ) alkenyl, (C 2 ~C 8 ) alkynyl, 6-12 membered aryl, 5-12 membered C-linked heteroaryl, 3-12 membered C-linked heterocycle, -C(O)R n3 or -C(O)NR q3 R r3 and Z 2 Any 6-12 membered aryl, 5-12 membered C-linked heteroaryl, or 3-12 membered C-linked heterocycle may be joined by 1, 2, 3, 4 or 5 Z 2b or Z2c is optionally substituted with a group; 2b and Z 2c The groups may be the same or different, Z 2 Any (C 2 ~C 8 ) alkenyl or (C 2 ~C 8 ) Alkynyl is substituted with 1, 2, 3, 4 or 5 Z 2c is optionally substituted with a group; 2c The groups are the same or different, Each R n3 are independently H or (C 1 ~C 4 ) alkyl, R q3 and R r3 Each independently represents H or (C 1 ~C 4 ) alkyl, each Z 2b are independently oxo, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 )heteroalkyl or (C 1 ~C 4 ) haloalkyl; each Z 2c are independently oxo, halogen, -CN, -OR n4 , -OC(O)R p4 , -OC(O)NR q4 R r4 , -SR n4 , -S(O)R p4 , -S(O) 2 OH, -S(O) 2 R p4 , -S(O) 2 NR q4 R r4 , -NR q4 R r4 , -NR n4 COR p4 , -NR n4 CO 2 R p4 , -NR n4 CONR q4 R r4 , -NR n4S(O) 2 R p4 , -NR n4 S(O) 2 OR p4 , -NR n4 S(O) 2 NR q4 R r4 , -NO 2 , -C(O)R n4 , -C(O)OR n4 or -C(O)NR q4 R r4 and Each R n4 are independently, H, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 ) haloalkyl, or (C 1 ~C 4 ) heteroalkyl; Each R p4 are independently 1 ~C 8 ) alkyl, (C 1 ~C 4 ) haloalkyl, or (C 1 ~C 4 ) heteroalkyl; R q4 and R r4 are each independently H, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 ) haloalkyl, or (C 1 ~C 4 ) heteroalkyl; each Z 3 are independently 1 ~C 4 ) heteroalkyl; each Z 4 are independently oxo, (C 1 ~C 8 ) alkyl, (C 3 ~C 7 )Carbocycle, halogen, -CN, -OR n5 , -NR q5 R r5 , -NR n5 COR p5 , -NRn5 CO 2 R p5 , -C(O)R n5 , -C(O)OR n5 or -C(O)NR q5 R r5 and Z 4 Any (C 3 ~C 7 ) carbocyclic or (C 1 ~C 8 ) alkyl is 1, 2, 3, 4 or 5 Z 4a is optionally substituted with a group; 4a The groups may be the same or different. And, each Z 4a are independently halogen, -CN, or -OR n6 and R n5 , R p5 , R q5 , R r5 , and R n6 Each independently represents H or (C 1 ~C 4 ) alkyl, each Z 5 are independently halogens which may be the same or different; n is 0, 1, 2 or 3. or a pharma- ceutically acceptable salt thereof.

[0202] In certain embodiments, the compound of formula IIIf is a compound of formula IIIg [ka] or a pharma- ceutically acceptable salt thereof.

[0203] The present disclosure relates to a compound of formula IIIh [ka] [In the formula, A 1 , CH, CZ 3 or nitrogen, A 2 is CH or nitrogen, C, together with the two carbon atoms to which it is attached, forms a 3- to 7-membered monocyclic carbocyclic ring or a 5- to 9-membered bicyclic heterocyclic ring, and any 3- to 7-membered monocyclic carbocyclic ring or 5- to 9-membered bicyclic heterocyclic ring of C may be joined by 1, 2, 3, 4 or 5 Z 4 is optionally substituted with a group; 4 The groups are the same or different, each Z 1w are independently 1a , Z 1b or H, each Z 1a are independently 3 ~C 7 ) Carbocycle, 5-12 membered heteroaryl, 3-12 membered heterocycle, halogen, -CN, -OR n1 , -OC(O)R p1 , -OC(O)NR q1 R r1 , -SR n1 , -S(O)R p1 , -S(O) 2 OH, -S(O) 2 R p1 , -S(O) 2 NR q1 R r1 , -NR q1 R r1 , -NR n1 COR p1 , -NR n1 CO 2 R p1 , -NR n1 CONR q1 R r1 , -NR n1 S(O) 2 R p1 , -NR n1 S(O) 2 OR p1 , -NR n1 S(O) 2 NR q1 R r1 , -C(O)R n1 , -C(O)OR n1, -C(O)NR q1 R r1 and -S(O) 2 NR n1 COR p1 and Z 1a Any (C 3 ~C 7 ) Carbocycle, 5-12 membered heteroaryl and 3-12 membered heterocycle are each independently selected from 1, 2, 3, 4 or 5 Z 1c or Z 1d is optionally substituted with a group; 1c and Z 1d The groups are the same or different, each Z 1b is optionally substituted with 1, 2, 3, 4 or 5 halogens, which are independently the same or different (C 1 ~C 8 ) alkyl, each Z 1c are independently halogen, -CN, -OH, -NH 2 , -C(O)NR q2 R r2 , or (C 1 ~C 8 ) heteroalkyl; each Z 1d are independently 1 ~C 8 ) alkyl or (C 1 ~C 8 ) haloalkyl; Each R n1 are independently, H, (C 1 ~C 8 ) alkyl, (C 3 ~C 7 ) a carbocycle, a 3- to 7-membered heterocycle, or a 5- to 6-membered monocyclic heteroaryl; R n1 Any (C 3 ~C 7 ) A carbocycle, a 3- to 7-membered heterocycle, or a 5- to 6-membered monocyclic heteroaryl is selected from the group consisting of 1, 2, 3, 4, or 5 Z 1c or Z 1d is optionally substituted with a group; 1c and Z 1d The groups may be the same or different, R n1 Any (C1 ~C 8 ) alkyl is 1, 2, 3, 4 or 5 Z 1c is optionally substituted with a group; 1c The groups are the same or different, Each R p1 are independently 1 ~C 8 ) alkyl, (C 3 ~C 7 ) a carbocycle, a 3- to 7-membered heterocycle, or a 5- to 6-membered monocyclic heteroaryl; R p1 Any (C 3 ~C 7 ) A carbocycle, a 3- to 7-membered heterocycle, or a 5- to 6-membered monocyclic heteroaryl is selected from the group consisting of 1, 2, 3, 4, or 5 Z 1c or Z 1d is optionally substituted with a group; 1c and Z 1d The groups may be the same or different, R p1 Any (C 1 ~C 8 ) alkyl is 1, 2, 3, 4 or 5 Z 1c is optionally substituted with a group; 1c The groups are the same or different, R q1 and R r1 are each independently H, (C 1 ~C 8 ) alkyl, (C 3 ~C 7 ) a carbocycle, a 3- to 7-membered heterocycle, or a 5- to 6-membered monocyclic heteroaryl; R q1 Or R r1 Any (C 3 ~C 7 ) A carbocycle, a 3- to 7-membered heterocycle, or a 5- to 6-membered monocyclic heteroaryl is selected from the group consisting of 1, 2, 3, 4, or 5 Z 1c Or Z 1d is optionally substituted with a group; 1c and Z 1d The groups may be the same or different, R q1 Or R r1 Any (C 1 ~C 8) alkyl is 1, 2, 3, 4 or 5 Z 1c is optionally substituted with a group; 1c The groups may be the same or different, or R q1 and R r1 together with the nitrogen to which they are attached form a 5-, 6- or 7-membered heterocycle, the 5-, 6- or 7-membered heterocycle being bound to 1, 2, 3, 4 or 5 Z 1c Or Z 1d is optionally substituted with a group; 1c and Z 1d The groups may be the same or different, R q2 and R r2 are each independently H, (C 1 ~C 8 ) alkyl, (C 3 ~C 7 ) a carbocyclic ring or R q2 and R r2 together with the nitrogen to which they are attached form a 5-, 6-, or 7-membered heterocyclic ring; Z 2 is (C 2 ~C 8 ) alkenyl, (C 2 ~C 8 ) alkynyl, 6-12 membered aryl, 5-12 membered C-linked heteroaryl, 3-12 membered C-linked heterocycle, -C(O)R n3 or -C(O)NR q3 R r3 and Z 2 Any 6-12 membered aryl, 5-12 membered C-linked heteroaryl, or 3-12 membered C-linked heterocycle may be joined by 1, 2, 3, 4 or 5 Z 2b or Z 2c is optionally substituted with a group; 2b and Z 2c The base is Same or different, Z 2 Any (C 2 ~C 8 ) alkenyl or (C 2 ~C 8 ) Alkynyl is substituted with 1, 2, 3, 4 or 5 Z 2cis optionally substituted with a group; 2c The groups are the same or different, Each R n3 are independently H or (C 1 ~C 4 ) alkyl, R q3 and R r3 Each independently represents H or (C 1 ~C 4 ) alkyl, each Z 2b are independently oxo, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 )heteroalkyl or (C 1 ~C 4 ) haloalkyl; each Z 2c are independently oxo, halogen, -CN, -OR n4 , -OC(O)R p4 , -OC(O)NR q4 R r4 , -SR n4 , -S(O)R p4 , -S(O) 2 OH, -S(O) 2 R p4 , -S(O) 2 NR q4 R r4 , -NR q4 R r4 , -NR n4 COR p4 , -NR n4 CO 2 R p4 , -NR n4 CONR q4 R r4 , -NR n4 S(O) 2 R p4 , -NR n4 S(O) 2 OR p4 , -NR n4 S(O) 2 NR q4 R r4 , -NO 2 , -C(O)R n4 , -C(O)ORn4 or -C(O)NR q4 R r4 and Each R n4 are independently, H, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 ) haloalkyl, or (C 1 ~C 4 ) heteroalkyl; Each R p4 are independently 1 ~C 8 ) alkyl, (C 1 ~C 4 ) haloalkyl, or (C 1 ~C 4 ) heteroalkyl; R q4 and R r4 are each independently H, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 ) haloalkyl, or (C 1 ~C 4 ) heteroalkyl; Z 3 are independently 1 ~C 4 ) heteroalkyl; each Z 4 are independently oxo, (C 1 ~C 8 ) alkyl, (C 3 ~C 7 )Carbocycle, halogen, -CN, -OR n5 , -NR q5 R r5 , -NR n5 COR p5 , -NR n5 CO 2 R p5 , -C(O)R n5 , -C(O)OR n5 or -C(O)NR q5 R r5 and Z 4 Any (C 3 ~C 7 ) carbocyclic or (C1 ~C 8 ) alkyl is 1, 2, 3, 4 or 5 Z 4a is optionally substituted with a group; 4a The groups are the same or different, each Z 4a are independently halogen, -CN, or -OR n6 and R n5 , R p5 , R q5 , R r5 , and R n6 Each independently represents H or (C 1 ~C 4 ) alkyl, Z 5a is H or a halogen. or a pharma- ceutically acceptable salt thereof.

[0204] In certain embodiments, the compound of formula IIIh is a compound of formula IIIi [ka] or a pharma- ceutically acceptable salt thereof.

[0205] The present disclosure relates to a compound 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 (C 1 ~C 8 ) alkyl, Z 1y -NR n1 S(O) 2 R p1 , -NRn1 S(O) 2 NR q1 R r1 , -NR q1 R r1 , -NR n1 COR p1 , -NR n1 CONR q1 R r1 , or -NR n1 CO 2 R p1 and Z 1z is H, halogen, -CN, -OR n1 , (C 1 ~C 8 ) alkyl, (C 1 ~C 8 ) alkyl is optionally substituted with 1, 2 or 3 halogens which may be the same or different; Each R n1 are independently H or (C 1 ~C 8 ) alkyl, Each R p1 are independently 1 ~C 8 ) alkyl, R q1 and R r1 Each independently represents H or (C 1 ~C 8 ) alkyl, Z 3 is (C 1 ~C 4 ) heteroalkyl; Z 2 can contain 1, 2, 3, 4 or 5 Z's 2c Optionally substituted with a group (C 2 ~C 8 ) alkynyl, and Z 2c The groups may be the same or different, Z 2c are independently halogen, -OR n4 , -NR n4 CO 2 R p4 , -C(O)OR n4 , or -NR q4 R r4 and Each R n4 are independently H or (C 1 ~C 4 ) alkyl, Each R p4 are independently 1 ~C 4 ) alkyl, R q4 and R r4 are each independently H, (C 1 ~C 4 ) alkyl, or (C 1 ~C 4 ) heteroalkyl; Z 4 is hydrogen, (C 1 ~C 8 )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 (C 3 ~C 7 ) carbocyclic ring, Z 4 Any (C 3 ~C 7 ) carbocyclic or (C 1 ~C 8 ) alkyl is optionally substituted with halogen or hydroxyl; Each R n5 are independently H or (C 1 ~C 4 ) alkyl, Each R p5 are independently H or (C 1 ~C 4 ) alkyl, R q5 and R r5 Each independently represents H or (C 1 ~C 4 ) alkyl, Z 5a is H or a halogen. or a pharma- ceutically acceptable salt thereof.

[0206] In certain embodiments, the compound of formula IIIj is a compound of formula IIIk [ka] or a pharma- ceutically acceptable salt thereof.

[0207] The specific values ​​listed below, where applicable, 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). For example, the following values, when applied to formula III, apply equally to all related formulas of formula III that allow such variables to be present (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. Thus, 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 every combination of variables were specifically and individually listed. For example, the R values ​​detailed herein for compounds of formula III can be combined with any other variable in a compound of formula III as if every combination of variables were specifically and individually listed. 1 Any specific value of is independently selected from the variables A, Z, and Z of formula III as if every combination were specifically and individually recited. 1 , R 2 , R 3a or R 3b It is understood that the above values ​​may be combined with one or more of any other specific values.

[0208] In certain embodiments of formula III, A 1 is CH. In certain embodiments, A 1 is CZ 3 In certain embodiments, A 1 is nitrogen.

[0209] In certain embodiments of formula III, A 2 is CH. In certain embodiments, A 2 is nitrogen.

[0210] In certain embodiments of formula III, A 1 is CH and A 2 is CH. In certain embodiments, A 1 is CZ 3 And A 2 is CH. In certain embodiments, A 1 is nitrogen, A 2 is CH.

[0211] In certain embodiments of formula III, A 1 is CH and A 2 is nitrogen. In certain embodiments, A 1 is CZ 3 And A 2 is nitrogen. In certain embodiments, A 1 is nitrogen, A 2 is nitrogen.

[0212] In certain embodiments of formula III, Z 5 is F. In certain embodiments of formula III, n is 1. In certain embodiments, n is 2. In certain embodiments of formula III, In an embodiment, n is 1 and Z 5 is F. In certain embodiments, n is 2 and each Z 5 is F.

[0213] In certain embodiments of formula III, Z 5a is H. In certain embodiments, Z 5a is F.

[0214] In certain embodiments of formula III, each Z 1w are independently 1a or Z 1b and Z 1a and Z 1bThe groups can be the same or different. In certain embodiments, each Z 1w may be independently the same or different (C 1 ~C 8 ) alkyl, halogen, or -NR n1 S(O) 2 R p1 It is.

[0215] In certain embodiments of formula III, Z 1x is H. In certain embodiments, Z 1x is (C 1 ~C 8 ) alkyl. In certain embodiments, Z 1x is (C 1 ~C 4 ) alkyl. In certain embodiments, Z 1x is (C 1 ~C 3 ) alkyl. In certain embodiments, Z 1x is methyl.

[0216] In certain embodiments of formula III, Z 1y -NR n1 S(O) 2 R p1 , -NR n1 S(O) 2 NR q1 R r1 , or -NR q1 R r1 In certain embodiments, Z 1y -NR n1 S(O) 2 R p1 or -NR n1 S(O) 2 NR q1 R r1 In certain embodiments, Z 1y -NR n1 S(O) 2 R p1 In certain embodiments, Z 1y -NR n1 S(O) 2 NR q1 Rr1 In certain embodiments, Z 1y -NR q1 R r1 It is.

[0217] In certain embodiments of formula III, Z 1z is H or halogen. In certain embodiments, Z 1z is H. In certain embodiments, Z 1z is halogen. In certain embodiments, Z 1z is Cl. In certain embodiments, Z 1z is F. In certain embodiments, Z 1z is Br.

[0218] In certain embodiments of formula III, Z 1y -NR n1 S(O) 2 R p1 or -NR n1 S(O) 2 NR q1 R r1 and Z 1z is halogen. In certain embodiments, Z 1y -NR n1 S(O) 2 R p1 and Z 1z is halogen. In certain embodiments, Z 1x is (C 1 ~C 4 ) alkyl, Z 1y -NR n1 S(O) 2 R p1 or -NR n1 S(O) 2 NR q1 R r1 and Z 1z is halogen. In certain embodiments, Z 1x is (C 1 ~C 4 ) alkyl, Z 1y -NR n1 S(O) 2 R p1and Z 1z is a halogen.

[0219] In certain embodiments of formula III, A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and any pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl of A can be selected from one Z at the indicated position. 1 group and one Z 2 group and one or two Z 3 In certain embodiments, A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and any pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl of A is optionally substituted with one Z group at the indicated position. 1 group and one Z 2 group and one Z 3 is optionally substituted with a group.

[0220] In certain embodiments, A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and any pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl of A is selected from the group consisting of one Z 1 group and one Z 2 In one embodiment, A is substituted with a Z group. 3 is not substituted with a group.

[0221] In certain embodiments, A is pyridinyl, and any pyridinyl of A is selected from one Z 1 group and one Z 2 group and one or two Z 3 In certain embodiments, A is pyridinyl, and any pyridinyl of A is optionally substituted with one Z group at the indicated position. 1 group and one Z 2 group and one Z 3 is optionally substituted with a group.

[0222] In certain embodiments, A is pyridinyl, and any pyridinyl of A is selected from one Z 1 group and one Z 2 In one embodiment, Z is substituted with 2 In a further aspect, A is Z 3 is not substituted with a group.

[0223] In certain embodiments, A is pyrimidinyl, and any pyridinyl of A is selected from one Z 1 group and one Z 2 group and one or two Z 3 In certain embodiments, A is pyrimidinyl, and any pyridinyl of A is optionally substituted with one Z group at the indicated position. 1 group and one Z 2 group and one Z 3 Groups are optionally substituted.

[0224] In certain embodiments, A is pyrimidinyl, and any pyridinyl of A is selected from one Z 1 group and one Z 2 In one embodiment, A is substituted with a Z group. 3 is not substituted with a group.

[0225] In certain embodiments, A is pyrazinyl, and any pyridinyl of A is selected from one Z 1 group and one Z 2 group and one or two Z 3 In certain embodiments, A is pyrazinyl, and any pyridinyl of A is optionally substituted with one Z group at the indicated position. 1 group and one Z 2 group and one Z 3is optionally substituted with a group.

[0226] In certain embodiments, A is pyrazinyl, and any pyridinyl of A is selected from one Z 1 group and one Z 2 In one embodiment, A is substituted with a Z group. 3 is not substituted with a group.

[0227] In certain embodiments, A is [ka] It is.

[0228] In certain embodiments, A is [ka] It is.

[0229] In certain embodiments, A is [ka] It is.

[0230] In certain embodiments, A is [ka] It is.

[0231] In certain embodiments, A is [ka] It is.

[0232] In certain embodiments of formula III, R 2 is phenyl optionally substituted with 1, 2 or 3 halogens, which may be the same or different. In certain embodiments, R 2 is phenyl optionally substituted with 1 or 2 halogens, which may be the same or different. In certain embodiments, R 2 is phenyl optionally substituted with two halogens, which may be the same or different. In certain embodiments, R 2 is phenyl optionally substituted with one halogen.

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

[0234] In certain embodiments, the moiety [ka] teeth, [ka] In the formula, Z 5a is H or a halogen.

[0235] In certain embodiments of formula III, each Z 3 is, when present, independently methoxy, dimethylamino, or methylamino. In certain embodiments, Z 3 When present, Z is methoxy.3 When present, it is dimethylamino. In certain embodiments, Z 3 When present, it is methylamino. In certain embodiments, Z 3 When present, Z is halogen. 3 When present, Z is fluoro. 3 When present, Z is chloro. 3 is bromo, if present.

[0236] In certain embodiments of formula III, each R 3a and each R 3b are each H. In certain embodiments, R 3a is methyl, R 3b is H.

[0237] In certain embodiments of formula III, Z 2 is (C 2 ~C 8 ) alkynyl, 6-12 membered aryl, 5-12 membered C-linked heteroaryl, 3-12 membered C-linked heterocycle, or -C(O)NR q3 R r3 and Z 2 Any 6-12 membered aryl, 5-12 membered C-linked heteroaryl, or 3-12 membered C-linked heterocycle may be joined by 1, 2, 3, 4 or 5 Z 2b or Z 2c is optionally substituted with a group; 2 Any (C 2 ~C 8 ) Alkynyl is substituted with 1, 2, 3, 4 or 5 Z 2c is optionally substituted with a group.

[0238] In certain embodiments, Z 2 is (C 2 ~C 8 ) alkynyl, 6-12 membered aryl, 5-12 membered C-linked heteroaryl, 3-12 membered C-linked heterocycle, or -C(O)NR q3 Rr3 and Z 2 Any 6-12 membered aryl, 5-12 membered C-linked heteroaryl, or 3-12 membered C-linked heterocycle may be joined by 1, 2, 3, 4 or 5 Z 2c is optionally substituted with a group; 2 Any (C 2 ~C 8 ) Alkynyl is substituted with 1, 2, 3, 4 or 5 Z 2c is optionally substituted with a group.

[0239] In certain embodiments, Z 2 is (C 2 ~C 8 ) alkynyl, phenyl, 5-6 membered C-linked monocyclic heteroaryl, 8-10 membered C-linked bicyclic heteroaryl, 8-10 membered C-linked bicyclic heterocycle, or -C(O)NR q3 R r3 and Z 2 Any phenyl, 5-6 membered C-linked monocyclic heteroaryl, 8-10 membered C-linked bicyclic heteroaryl or 8-10 membered C-linked bicyclic heterocycle may be joined by 1, 2, 3, 4 or 5 Z 2b or Z 2c is optionally substituted with a group; 2 Any (C 2 ~C 8 ) Alkynyl is substituted with 1, 2, 3, 4 or 5 Z 2c is optionally substituted with a group.

[0240] In certain embodiments, Z 2 is (C 2 ~C 8 ) alkynyl, phenyl, 5-6 membered C-linked monocyclic heteroaryl, 8-10 membered C-linked bicyclic heteroaryl, 8-10 membered C-linked bicyclic heterocycle, or -C(O)NR q3 R r3 and Z 2 Any phenyl, 5-6 membered C-linked monocyclic heteroaryl, 8-10 membered C-linked bicyclic heteroaryl or 8-10 membered C-linked bicyclic heterocycle may be joined by 1, 2, 3, 4 or 5 Z 2c is optionally substituted with a group;2 Any (C 2 ~C 8 ) Alkynyl is substituted with 1, 2, 3, 4 or 5 Z 2c Groups are optionally substituted.

[0241] In certain embodiments, Z 2 is (C 2 ~C 8 ) alkynyl, phenyl, 5-6 membered C-linked monocyclic heteroaryl, 8-10 membered C-linked bicyclic heteroaryl, 8-10 membered C-linked bicyclic heterocycle, or -C(O)NR q3 R r3 wherein the 5-6 membered C-linked monocyclic heteroaryl, 8-10 membered C-linked bicyclic heteroaryl or 8-10 membered C-linked bicyclic heterocycle has 1-9 carbon atoms and 1-4 heteroatoms in the ring system, and Z 2 Any phenyl, 5-6 membered C-linked monocyclic heteroaryl, 8-10 membered C-linked bicyclic heteroaryl, and 8-10 membered C-linked bicyclic heterocycle may be joined by 1, 2, 3, 4 or 5 Z 2b or Z 2c is optionally substituted with a group; 2 Any (C 2 ~C 8 ) Alkynyl is substituted with 1, 2, 3, 4 or 5 Z 2c Groups are optionally substituted.

[0242] In certain embodiments, Z 2 is (C 2 ~C 8 ) alkynyl, phenyl, 5-6 membered C-linked monocyclic heteroaryl, 8-10 membered C-linked bicyclic heteroaryl, 8-10 membered C-linked bicyclic heterocycle, or -C(O)NR q3 R r3 wherein the 5-6 membered C-linked monocyclic heteroaryl, 8-10 membered C-linked bicyclic heteroaryl or 8-10 membered C-linked bicyclic heterocycle has 1-9 carbon atoms and 1-4 heteroatoms in the ring system, and Z 2Any phenyl, 5-6 membered C-linked monocyclic heteroaryl, 8-10 membered C-linked bicyclic heteroaryl, and 8-10 membered or C-linked bicyclic heterocycle may be joined by 1, 2, 3, 4 or 5 Z 2c is optionally substituted with a group; 2 Any (C 2 ~C 8 ) Alkynyl is substituted with 1, 2, 3, 4 or 5 Z 2c is optionally substituted with a group.

[0243] In certain embodiments of formula III, Z 2 can contain 1, 2, 3, 4 or 5 Z's 2c Optionally substituted with a group (C 2 ~C 8 ) alkynyl. In certain embodiments, Z 2 can contain 1, 2, 3 or 4 Z's 2c Optionally substituted with a group (C 2 ~C 8 ) alkynyl. In certain embodiments, Z 2 can contain one, two or three Z 2c Based on Optionally substituted (C 2 ~C 8 ) alkynyl. In certain embodiments, Z 2 1 or 2 Z 2c Optionally substituted with a group (C 2 ~C 8 ) alkynyl.

[0244] In certain embodiments, Z 2 is the formula [ka] and Z 2 (C 1 ~C 4 Each alkyl moiety, when present, is selected from 1, 2 or 3 Z 2c is optionally substituted with a group; 2bThe groups can be the same or different.

[0245] In certain embodiments, Z 2 is the formula [ka] and Z 2 (C 1 ~C 4 ) each alkyl moiety may have one, two or three Z 2c is optionally substituted with a group; 2b The groups can be the same or different.

[0246] In certain embodiments, Z 2 is the formula [ka] and Z 2 (C 1 ~C 4 ) each alkyl moiety may have one, two or three Z 2c is optionally substituted with a group; 2b The groups can be the same or different.

[0247] In certain embodiments of formula III, Z 2 can contain 1, 2, 3 or 4 Z's 2b or Z 2c is substituted with a Z 2b and Z 2c The groups may be the same or different. In certain embodiments, Z 2 can contain one, two or three Z 2b or Z 2c is substituted with a Z 2b and Z 2c The groups may be the same or different. In certain embodiments, Z 2 1 or 2 Z2b or Z 2c is substituted with a Z 2b and Z 2c The groups may be the same or different. In certain embodiments, Z 2 is one Z 2b or Z 2c is substituted with a group.

[0248] In certain embodiments of formula III, Z 2 can contain one, two or three Z 2b or Z 2c is optionally substituted with a group; 2b and Z 2c The groups may be the same or different. In certain embodiments, Z 2 is one Z 2b or Z 2c In certain embodiments, Z 2 is two Z 2b or Z 2c is substituted with a Z 2b and Z 2c The groups may be the same or different. In certain embodiments, Z 2 is 3 Z 2b or Z 2c is substituted with a Z 2b and Z 2c The groups can be the same or different.

[0249] In certain embodiments of formula III, Z 2 can contain 1, 2, 3 or 4 Z's 2c is substituted with a Z 2c The groups may be the same or different. In certain embodiments, Z 2 can contain one, two or three Z 2c is substituted with a Z 2c The groups may be the same or different. In certain embodiments, Z 2 1 or 2 Z 2c is substituted with a Z 2c The groups may be the same or different. In certain embodiments, Z2 is one Z 2c is substituted with a group.

[0250] In certain embodiments of formula III, Z 2 can contain one, two or three Z 2c is optionally substituted with a group; 2c The groups may be the same or different. In certain embodiments, Z 2 is one Z 2c In certain embodiments, Z 2 is two Z 2c is substituted with a Z 2c The groups may be the same or different. In certain embodiments, Z 2 is 3 Z 2c is substituted with a Z 2c The groups can be the same or different.

[0251] In certain embodiments, each Z 2c are independently halogen, -OR n4 , N.R. q4 R r4 , -NR n4 CO 2 R p4 , -C(O)OR n4 or -C(O)NR q4 R r4 In certain embodiments, each Z 2c are independently halogen or -OR n4 It is.

[0252] In certain embodiments, 1, 2, 3, 4, or 5 Z 2b or Z 2c Z optionally substituted with a group 2 teeth, [ka] It is.

[0253] In certain embodiments, 1, 2, 3, 4, or 5 Z 2b or Z 2c Z optionally substituted with a group 2 teeth, [ka] It is.

[0254] In certain embodiments, 1, 2, 3, 4, or 5 Z 2b or Z 2c Z optionally substituted with a group 2 teeth, [ka] It is.

[0255] In certain embodiments, 1, 2, 3, 4, or 5 Z 2b or Z 2c Z optionally substituted with a group 2 teeth, [ka] It is.

[0256] In certain embodiments, 1, 2, 3, 4, or 5 Z 2b or Z 2c Z optionally substituted with a group 2 teeth, [ka] It is.

[0257] In certain embodiments, 1, 2, 3, 4, or 5 Z 2b or Z 2cZ optionally substituted with a group 2 teeth, [ka] It is.

[0258] In certain embodiments of formula III, R 1 is a 5-12 membered heteroaryl; R 1 Any 5-12 membered heteroaryl may have 1, 2, 3, 4 or 5 Z 4 Groups are optionally substituted.

[0259] In certain embodiments of formula III, R 1 is an 8-12 membered bicyclic heteroaryl or an 8-12 membered tricyclic heteroaryl; R 1 Any 8-12 membered bicyclic heteroaryl or 8-12 membered tricyclic heteroaryl may have 1, 2, 3, 4 or 5 Z 4 Groups are optionally substituted.

[0260] In certain embodiments, R 1 is an 8-12 membered tricyclic heteroaryl; R 1 The 8-12 membered tricyclic heteroaryl may have 1, 2, 3, 4 or 5 Z 4 Groups are optionally substituted.

[0261] In certain embodiments, R 1 is an 8-12 membered bicyclic heteroaryl or an 8-12 membered tricyclic heteroaryl having 4-10 carbon atoms and 1-5 heteroatoms in the ring system; R 1 Any 8-12 membered bicyclic heteroaryl or 8-12 membered tricyclic heteroaryl may have 1, 2, 3, 4 or 5 Z 4 Groups are optionally substituted.

[0262] In certain embodiments, R 1 is an 8-12 membered bicyclic heteroaryl or an 8-12 membered tricyclic heteroaryl, the 8-12 membered bicyclic heteroaryl or the 8-12 membered tricyclic heteroaryl containing at least one partially unsaturated ring; R 1 Any 8-12 membered bicyclic heteroaryl or 8-12 membered tricyclic heteroaryl may have 1, 2, 3, 4 or 5 Z 4 is optionally substituted with a group.

[0263] In certain embodiments, R 1 is an 8-12 membered tricyclic heteroaryl, the 8-12 membered tricyclic heteroaryl containing at least one partially unsaturated ring; R 1 Any 8-12 membered bicyclic heteroaryl or 8-12 membered tricyclic heteroaryl may have 1, 2, 3, 4 or 5 Z 4 is optionally substituted with a group.

[0264] In certain embodiments of formula III, R 1 is an 8-12 membered bicyclic heteroaryl or an 8-12 membered tricyclic heteroaryl having 4-9 carbon atoms and 1-5 heteroatoms in the ring system; R 1 Any 8-12 membered bicyclic heteroaryl or 8-12 membered tricyclic heteroaryl may have 1, 2, 3, 4 or 5 Z 4 is optionally substituted with a group.

[0265] In certain embodiments, R 1 is an 8-12 membered bicyclic heteroaryl; A 2-membered bicyclic heteroaryl has 6-9 carbon atoms and 1-3 heteroatoms in the ring system, and R 1 Any 8-12 membered bicyclic heteroaryl may have 1, 2, 3, 4 or 5 Z 4 is optionally substituted with a group.

[0266] In certain embodiments, R 1 is an 8-12 membered bicyclic heteroaryl or an 8-12 membered tricyclic heteroaryl having 6-9 carbon atoms and 1-3 heteroatoms in the ring system; R 1 Any 8-12 membered bicyclic heteroaryl or 8-12 membered tricyclic heteroaryl may have 1, 2, 3, 4 or 5 Z 4 Groups are optionally substituted.

[0267] In certain embodiments of formula III, R 1 has the following formula IIa [ka] [In the formula, C, together with the two carbon atoms of ring B to which it is attached, forms a 3- to 7-membered monocyclic carbocycle, a 5- to 8-membered bicyclic carbocycle, a 3- to 7-membered monocyclic heterocycle, or a 5- to 8-membered bicyclic heterocycle, and any 3- to 7-membered monocyclic carbocycle, 5- to 8-membered bicyclic carbocycle, 3- to 7-membered monocyclic heterocycle, or 5- to 8-membered bicyclic heterocycle of C may be joined by 1, 2, 3, 4, or 5 Z 4 is optionally substituted with a group; 4 The groups are the same or different, B is a 5- or 6-membered monocyclic heteroaryl having 1, 2 or 3 nitrogen atoms; B is a 5- or 6-membered monocyclic heteroaryl having 1, 2, 3, 4 or 5 Z 4 is optionally substituted with a group; 4 the groups may be the same or different.

[0268] In certain embodiments of formula III, R 1 has the formula IIb [ka] [In the formula, C, together with the two carbon atoms of ring B to which it is attached, forms a 3- to 7-membered monocyclic carbocycle, a 5- to 8-membered bicyclic carbocycle, a 3- to 7-membered monocyclic heterocycle, or a 5- to 8-membered bicyclic heterocycle; and any 3- to 7-membered monocyclic carbocycle, 5- to 8-membered bicyclic carbocycle, 3- to 7-membered monocyclic heterocycle or 5- to 8-membered bicyclic heterocycle of C is substituted with 1, 2, 3, 4 or 5 Z 4 is optionally substituted with a group; 4 The groups are the same or different, B is a 5- or 6-membered monocyclic heteroaryl having 1, 2 or 3 nitrogen atoms; V is C or N; W is for CZ 4c , N.Z. 4c or N, X is for CZ 4c , N.Z. 4c or N, Y is CZ 4c or N or absent, the dashed bond is selected from a single bond and a double bond, and the dashed bond, V, W, X and Y are selected such that the 5- or 6-membered monocyclic heteroaryl B is aromatic; each Z 4c are independently H or Z 4 Selected from Z 4 the groups may be the same or different.

[0269] In certain embodiments of formula III, R 1 has the formula IIc [ka] [In the formula, C, together with the two carbon atoms of ring B to which it is attached, forms a 3- to 7-membered monocyclic carbocycle, a 5- to 8-membered bicyclic carbocycle, a 3- to 7-membered monocyclic heterocycle, or a 5- to 8-membered bicyclic heterocycle, and any 3- to 7-membered monocyclic carbocycle, 5- to 8-membered bicyclic carbocycle, 3- to 7-membered monocyclic heterocycle, or 5- to 8-membered bicyclic heterocycle of C may be joined by 1, 2, 3, 4, or 5 Z4 is optionally substituted with a group; 4 The groups are the same or different, B is a 5- or 6-membered monocyclic heteroaryl having 1, 2 or 3 nitrogen atoms; V is C or N; W is for CZ 4c or N, X is for CZ 4c , N.Z. 4c or N, Y is CZ 4c or N or absent, the dashed bond is selected from a single bond and a double bond, and the dashed bond, V, W, X and Y are selected such that the 5- or 6-membered monocyclic heteroaryl B is aromatic; each Z 4c are independently H or Z 4 Selected from Z 4 the groups may be the same or different.

[0270] In certain embodiments of formula III, R 1 has the formula IId [ka] [In the formula, C together with the two carbon atoms to which it is attached forms a 3- to 7-membered monocyclic carbocycle, a 5- to 9-membered bicyclic carbocycle, a 3- to 7-membered monocyclic heterocycle, or a 5- to 9-membered bicyclic heterocycle, and any 3- to 7-membered monocyclic carbocycle, 5- to 9-membered bicyclic carbocycle, 3- to 7-membered monocyclic heterocycle, or 5- to 9-membered bicyclic heterocycle of C may be optionally joined by 1, 2, 3, 4, or 5 Z 4 is optionally substituted with a group; 4 The groups are the same or different, each Z 4c are independently H or Z 4 Selected from Z 4 the groups may be the same or different.

[0271] In certain embodiments of formula III, R 1 has the formula [ka] [In the formula, C, together with the two carbon atoms to which it is attached, forms a 3- to 7-membered monocyclic carbocycle or a 5- to 9-membered bicyclic carbocycle, and any 3- to 7-membered monocyclic carbocycle or 5- to 9-membered bicyclic carbocycle of C may be joined by 1, 2, 3, 4 or 5 Z 4 is optionally substituted with a group; 4 the groups may be the same or different.

[0272] In certain embodiments of formula III, R 1 is expressed as follows: [ka] has.

[0273] In certain embodiments of formula III, C, together with the two carbon atoms to which it is attached, forms a 5-7 membered monocyclic carbocycle or a 5-7 membered bicyclic carbocycle, and any 5-7 membered monocyclic carbocycle or 5-7 membered bicyclic carbocycle of C can be joined by 1, 2, 3, or 4 Z 4 is optionally substituted with a group; 4 The groups may be the same or different.

[0274] In certain embodiments of formula III, each Z 4 are independently 1 ~C 8 ) alkyl, (C 3 ~C 7 )Carbocycle, halogen, -CN, -NR q5 R r5 , -NR n5 COR p5 , -NR n5 CO 2 R p5 , -C(O)ORn5 or -C(O)NR q5 R r5 and Z 4 Any (C 3 ~C 7 ) carbocyclic or (C 1 ~C 8 ) alkyl is 1, 2, 3, 4 or 5 Z 4a Groups are optionally substituted.

[0275] In certain embodiments, each Z 4 are independently 1 ~C 6 ) alkyl or halogen; Z 4 Any (C 1 ~C 6 ) alkyl is optionally substituted with 1, 2, 3, 4 or 5 halogens, which may be the same or different. In certain embodiments, each Z 4 are independently 1 ~C 4 ) alkyl or halogen; Z 4 Any (C 1 ~C 6 ) alkyl is optionally substituted with 1, 2, 3, 4 or 5 halogens, which may be the same or different. In certain embodiments, each Z 4 are independently 1 ~C 3 ) alkyl or halogen; Z 4 Any (C 1 ~C 3 ) The alkyl is optionally substituted with 1, 2, 3, 4 or 5 halogens which may be the same or different.

[0276] In certain embodiments, each Z 4 is independently fluoro, trifluoromethyl or difluoromethyl.

[0277] In certain embodiments of formula III, 1, 2, 3, 4 or 5 Z 4 R optionally substituted with a group 1 teeth, [ka] It is.

[0278] In certain embodiments, 1, 2, 3, 4, or 5 Z 4 R optionally substituted with a group 1 teeth, [ka] It is.

[0279] In certain embodiments, 1, 2, 3, 4, or 5 Z 4 R optionally substituted with a group 1 teeth, [ka] It is.

[0280] In certain embodiments, 1, 2, 3, 4, or 5 Z 4 R optionally substituted with a group 1 teeth, [ka] In certain embodiments, 1, 2, 3, 4, or 5 Z 4 R optionally substituted with a group 1 teeth, [ka] It is.

[0281] In certain embodiments, 1, 2, 3, 4, or 5 Z 4 R optionally substituted with a group1 teeth, [ka] In certain embodiments, 1, 2, 3, 4, or 5 Z 4 R optionally substituted with a group 1 teeth, [ka] It is.

[0282] In certain embodiments, 1, 2, 3, 4, or 5 Z 4 R optionally substituted with a group 1 teeth, [ka] It is.

[0283] In certain embodiments, R 1 can contain 1, 2, 3, 4 or 5 Z's 4 Optionally substituted with a group [ka] It is.

[0284] In certain embodiments, R 1 can contain 1, 2, 3, 4 or 5 Z's 4 Optionally substituted with a group [ka] It is.

[0285] In certain embodiments of formula III, each Z 4 are independently 1 ~C 6 ) alkyl or halogen; Z 4 Any (C 1 ~C 6 ) The alkyl is optionally substituted with 1, 2, 3, 4 or 5 halogens which may be the same or different.

[0286] In certain embodiments, each Z 4 are independently 1 ~C 6 ) alkyl, -CN or halogen; Z 4 Any (C 1 ~C 6 ) The alkyl is optionally substituted with 1, 2, 3, 4 or 5 halogens which may be the same or different.

[0287] In certain embodiments, each Z 4 is independently fluoro, trifluoromethyl, or difluoromethyl.

[0288] In certain embodiments, each Z 4 is independently fluoro, trifluoromethyl, —CN, or difluoromethyl.

[0289] In certain embodiments of formula III, Z 1 is phenyl, a 5- to 14-membered heteroaryl, or a 3- to 14-membered heterocycle; Z 1 Any phenyl, 5- to 14-membered heteroaryl, or 3- to 14-membered heterocycle may be selected from the group consisting of 1, 2, 3, 4, or 5 Z 1a or Z 1b is optionally substituted with a group.

[0290] In certain embodiments, Z 1 is phenyl, a 5- to 12-membered heteroaryl, or a 3- to 12-membered heterocycle; Z 1Any phenyl, 5- to 12-membered heteroaryl, or 3- to 12-membered heterocycle may be selected from the group consisting of 1, 2, 3, 4, or 5 Z 1a or Z 1b is optionally substituted with a group.

[0291] In certain embodiments, Z 1 is phenyl, a 5- to 14-membered heteroaryl, or a 3- to 14-membered heterocycle; Z 1 Any phenyl, 5- to 14-membered heteroaryl, or 3- to 14-membered heterocycle may be selected from the group consisting of 1, 2, 3, 4, or 5 Z 1a is optionally substituted with a group.

[0292] In certain embodiments, Z 1 is phenyl, a 5- to 12-membered heteroaryl, or a 3- to 12-membered heterocycle; Z 1 Any phenyl, 5- to 12-membered heteroaryl, or 3- to 12-membered heterocycle may be selected from the group consisting of 1, 2, 3, 4, or 5 Z 1a is optionally substituted with a group.

[0293] In certain embodiments, Z 1 is phenyl, a 5- to 6-membered monocyclic heteroaryl, an 8- to 10-membered bicyclic heteroaryl, an 8- to 10-membered bicyclic heterocycle, or a 9- to 12-membered tricyclic heterocycle; Z 1 Any phenyl, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 8- to 10-membered bicyclic heterocycle, or 9- to 12-membered tricyclic heterocycle may be joined by 1, 2, 3, 4, or 5 Z 1a or Z 1b is optionally substituted with a group.

[0294] In certain embodiments, Z 1 is phenyl, a 5- to 6-membered monocyclic heteroaryl, an 8- to 10-membered bicyclic heteroaryl, an 8- to 10-membered bicyclic heterocycle, or a 9- to 12-membered tricyclic heterocycle; Z 1Any phenyl, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 8- to 10-membered bicyclic heterocycle, or 9- to 12-membered tricyclic heterocycle may be joined by 1, 2, 3, 4, or 5 Z 1a is optionally substituted with a group.

[0295] In certain embodiments, Z 1 is phenyl, 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, wherein the 5-6 membered monocyclic heteroaryl, the 8-10 membered bicyclic heteroaryl, the 8-10 membered bicyclic heterocycle, or the 9-12 membered tricyclic heterocycle has 1-11 carbon atoms and 1-5 heteroatoms in the ring system; and Z 1 Any phenyl, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 8- to 10-membered bicyclic heterocycle, or 9- to 12-membered tricyclic heterocycle may be joined by 1, 2, 3, 4, or 5 Z 1a or Z 1b is optionally substituted with a group.

[0296] In certain embodiments, Z 1 is phenyl, 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, wherein the 5-6 membered monocyclic heteroaryl, the 8-10 membered bicyclic heteroaryl, the 8-10 membered bicyclic heterocycle, or the 9-12 membered tricyclic heterocycle has 1-11 carbon atoms and 1-5 heteroatoms in the ring system; and Z 1 Any phenyl, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 8- to 10-membered bicyclic heterocycle, or 9- to 12-membered tricyclic heterocycle may be joined by 1, 2, 3, 4, or 5 Z 1a is optionally substituted with a group.

[0297] In certain embodiments, Z 1is phenyl, 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, wherein the 5-6 membered monocyclic heteroaryl, the 8-10 membered bicyclic heteroaryl, the 8-10 membered bicyclic heterocycle, or the 9-12 membered tricyclic heterocycle has 4-11 carbon atoms and 1-3 heteroatoms in the ring system; and Z 1 Any phenyl, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 8- to 10-membered bicyclic heterocycle, or 9- to 12-membered tricyclic heterocycle may be joined by 1, 2, 3, 4, or 5 Z 1a or Z 1b Groups are optionally substituted.

[0298] In certain embodiments, Z 1 is phenyl, 5-6 membered monocyclic heteroaryl, 8- a 10-membered bicyclic heteroaryl, an 8-10-membered bicyclic heterocycle, or a 9-12-membered tricyclic heterocycle, wherein the 5-6-membered monocyclic heteroaryl, the 8-10-membered bicyclic heteroaryl, the 8-10-membered bicyclic heterocycle, or the 9-12-membered tricyclic heterocycle has 4-11 carbon atoms and 1-3 heteroatoms in the ring system, and Z 1 Any phenyl, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 8- to 10-membered bicyclic heterocycle, or 9- to 12-membered tricyclic heterocycle may be joined by 1, 2, 3, 4, or 5 Z 1a Groups are optionally substituted.

[0299] In certain embodiments, Z 1 is an 8-10 membered bicyclic heteroaryl or an 8-10 membered bicyclic heterocycle; Z 1 Any 8-10 membered bicyclic heteroaryl or 8-10 membered bicyclic heterocycle may have 1, 2, 3, 4 or 5 Z 1a or Z 1b Groups are optionally substituted.

[0300] In certain embodiments, Z 1is an 8-10 membered bicyclic heteroaryl or an 8-10 membered bicyclic heterocycle; Z 1 Any 8-10 membered bicyclic heteroaryl or 8-10 membered bicyclic heterocycle may have 1, 2, 3, 4 or 5 Z 1a Groups are optionally substituted.

[0301] In certain embodiments, Z 1 is an 8-10 membered bicyclic heteroaryl or an 8-10 membered bicyclic heterocycle having 3-9 carbon atoms and 1-5 heteroatoms in the ring system; Z 1 Any 8-10 membered bicyclic heteroaryl or 8-10 membered bicyclic heterocycle may have 1, 2, 3, 4 or 5 Z 1a or Z 1b Groups are optionally substituted.

[0302] In certain embodiments, Z 1 is an 8-10 membered bicyclic heteroaryl or an 8-10 membered bicyclic heterocycle having 3-9 carbon atoms and 1-5 heteroatoms in the ring system; Z 1 Any 8-10 membered bicyclic heteroaryl or 8-10 membered bicyclic heterocycle may have 1, 2, 3, 4 or 5 Z 1a Groups are optionally substituted.

[0303] In certain embodiments of formula III, Z 1 is Z 1b is not replaced by

[0304] In certain embodiments of formula III, each Z 1a are independently oxo, (C 3 ~C 7 )Carbocycle, halogen, -CN, -O-(C 1 ~C 8 ) alkyl, -NR q1 R r1 , -NR n1 COR p1 , -NRn1 CO 2 R p1 , -NR n1 CONR q1 R r1 , -NR n1 S(O) 2 R p1 , -NR n1 S(O) 2 NR q1 R r1 or -C(O)NR q1 R r1 It is.

[0305] In certain embodiments, each Z 1a are independently, -NR n1 S(O) 2 R p1 , -NR n1 S(O) 2 NR q1 R r1 or halogen. In certain embodiments, each Z 1a are independently halogen or -NR n1 S(O) 2 R p1 In certain embodiments, each Z 1a are independently halogen or -NR n1 S(O) 2 NR q1 R r1 It is.

[0306] In certain embodiments, Z 1 is two Z 1a groups, each Z 1a are independently, -NR n1 S(O) 2 R p1 , -NR n1 S(O) 2 NR q1 R r1 , or a halogen.

[0307] In certain embodiments, each Z 1a are independently halogen or -NR n1 S(O) 2 R p1 And each Z1b may be the same or different (C 1 ~C 8 ) Alkyl It is.

[0308] In certain embodiments, Z 1a -NR n1 S(O) 2 R p1 or -NR n1 S(O) 2 NR q1 R r1 In certain embodiments, Z 1a is halogen. In certain embodiments, Z 1a -NR q1 R r1 , -NR n1 COR p1 , -NR n1 CO 2 R p1 , or -NR n1 CONR q1 R r1 It is.

[0309] In certain embodiments, Z 1a is halogen, -OR n1 or -C(O)NR q1 R r1 It is.

[0310] In certain embodiments, Z 1a is halogen or -C(O)NR q1 R r1 It is.

[0311] In certain embodiments, Z 1a is a halogen, -OH, or -C(O)NH 2 It is.

[0312] In certain embodiments, Z 1a is fluoro, -OH, or -C(O)NH 2 It is.

[0313] In certain embodiments, each Z1b may be the same or different (C 1 ~C 8 ) alkyl.

[0314] In certain embodiments, each Z 1b is independently methyl or difluoromethyl.

[0315] In certain embodiments of formula III, Z 1 can contain 1, 2, 3, 4 or 5 Z's 1a or Z 1b is optionally substituted with [ka] It is.

[0316] In certain embodiments, Z 1 teeth, [ka] And each Z 1w are independently 1a , Z 1b or H. In certain embodiments, each Z 1a are independently halogen, -CN, -OR n1 , -NR n1 S(O) 2 R p1 , -NR n1 S(O) 2 NR q1 R r1 , -NR q1 R r1 , -NR n1 COR p1 , -NR n1 CONR q1 R r1 , or -NR n1 CO 2 R p1 And each Z 1b are independently 1 ~C8 alkyl), and (C 1 ~C 8 alkyl) is optionally substituted with 1, 2 or 3 halogens which may be the same or different; Z 1w At least one of the following is Z 1a or Z 1b In certain embodiments, Z 1w At least two of the following are independently 1a In certain embodiments, each Z 1a are independently halogen, -NR n1 S(O) 2 R p1 , or -NR n1 S(O) 2 NR q1 R r1 It is.

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

[0318] In certain embodiments, Z 1 can contain 1, 2, 3 or 4 Z's 1a or Z 1b is optionally substituted with [ka] It is.

[0319] In certain embodiments, Z 1 teeth, [ka] It is.

[0320] In certain embodiments, 1, 2, 3, 4, or 5 Z 1a or Z 1b Z optionally substituted with a group 1 teeth, [ka] It is.

[0321] In certain embodiments, 1, 2, 3, 4, or 5 Z 1a or Z 1b Z optionally substituted with a group 1 teeth, [ka] It is.

[0322] In certain embodiments, 1, 2, 3, 4, or 5 Z 1a or Z 1b Z optionally substituted with a group 1 teeth, [ka] It is.

[0323] In certain embodiments, 1, 2, 3, 4, or 5 Z 1a or Z 1b Z optionally substituted with a group 1 teeth, [ka] It is.

[0324] In certain embodiments, 1, 2, 3, 4, or 5 Z 1a or Z 1b Z optionally substituted with a group 1 teeth, [ka] It is.

[0325] In certain embodiments, Z 1 teeth, [ka] It is.

[0326] In certain embodiments, Z 2 -A-Z 1 teeth, [ka] It is.

[0327] In one variation of Formula III, A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl; R 1 is 1, 2, 3, 4 or 5 Z, which may be the same or different 4 In another variation, A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl and R 1 is an 8-12 membered bicyclic heteroaryl or an 8-12 membered tricyclic heteroaryl; R 1 Any 8-12 membered bicyclic heteroaryl or 8-12 membered tricyclic heteroaryl may have 1, 2, 3, 4 or 5 Z 4In another variation, A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl and R 1 is an 8-12 membered bicyclic heteroaryl or an 8-12 membered tricyclic heteroaryl; R 1 Any 8-12 membered bicyclic heteroaryl or 8-12 membered tricyclic heteroaryl may have 1, 2, 3, 4 or 5 Z 4 groups, and each Z 4 is independently fluoro, trifluoromethyl or difluoromethyl.

[0328] In one variation of Formula III, A is pyridinyl and R 1 is an 8-12 membered bicyclic heteroaryl or an 8-12 membered tricyclic heteroaryl; R 1 Any 8-12 membered bicyclic heteroaryl or 8-12 membered tricyclic heteroaryl may have 1, 2, 3, 4 or 5 Z 4 Groups are optionally substituted.

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

[0330] In one variation of Formula III, A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl; Z 1is phenyl, a 5- to 6-membered monocyclic heteroaryl, an 8- to 10-membered bicyclic heteroaryl, an 8- to 10-membered bicyclic heterocycle, or a 9- to 12-membered tricyclic heterocycle; Z 1 Any phenyl, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 8- to 10-membered bicyclic heterocycle, or 9- to 12-membered tricyclic heterocycle may have 1, 2, 3, 4, or 5 Z 1a In another variation, A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl and Z is optionally substituted with a group. 1 can contain 1, 2, 3, 4 or 5 Z's 1a In another variation, A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl and Z is phenyl optionally substituted with a group. 1 is a 5- to 6-membered monocyclic heteroaryl or an 8- to 10-membered bicyclic heteroaryl; Z 1 Any 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl may be selected from the group consisting of 1, 2, 3, 4 or 5 Z 1a In another variation, A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl and Z is optionally substituted with a group. 1 is an 8- to 10-membered bicyclic heterocycle or a 9- to 12-membered tricyclic heterocycle; Z 1 Any 8- to 10-membered bicyclic heterocycle or 9- to 12-membered tricyclic heterocycle may contain 1, 2, 3, 4 or 5 Z 1a Groups are optionally substituted.

[0331] In one variation of Formula III, A is pyridinyl and Z 1 is phenyl, a 5- to 6-membered monocyclic heteroaryl, an 8- to 10-membered bicyclic heteroaryl, an 8- to 10-membered bicyclic heterocycle, or a 9- to 12-membered tricyclic heterocycle; Z 1 Any phenyl, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 8- to 10-membered bicyclic heterocycle, or 9- to 12-membered tricyclic heterocycle may have 1, 2, 3, 4, or 5 Z 1aIn another variation, A is optionally substituted with a pyridinyl group. Yes, Z 1 can contain 1, 2, 3, 4 or 5 Z's 1a In another variation, A is pyridinyl and Z is phenyl optionally substituted with a group. 1 is a 5- to 6-membered monocyclic heteroaryl or an 8- to 10-membered bicyclic heteroaryl; Z 1 Any 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl may be selected from the group consisting of 1, 2, 3, 4 or 5 Z 1a In another variation, A is pyridinyl and Z is optionally substituted with a substituted aryl group. 1 is an 8- to 10-membered bicyclic heterocycle or a 9- to 12-membered tricyclic heterocycle; Z 1 Any 8- to 10-membered bicyclic heterocycle or 9- to 12-membered tricyclic heterocycle may contain 1, 2, 3, 4 or 5 Z 1a Groups are optionally substituted.

[0332] In one variation of Formula III, A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl; Z 2 is (C 2 ~C 8 ) alkynyl, 6-12 membered aryl, 5-12 membered C-linked heteroaryl, 3-12 membered C-linked heterocycle, or -C(O)NR q3 R r3 and Z 2 Any 6-12 membered aryl, 5-12 membered C-linked heteroaryl, or 3-12 membered C-linked heterocycle may have 1, 2, 3, 4 or 5 Z 2b or Z 2c is optionally substituted with a group; 2 Any (C 2 ~C 8 Alkynyl may have 1, 2, 3, 4 or 5 Z, which may be the same or different. 2c In another variation, A is pyridinyl and Z is optionally substituted with a 2 is (C 2 ~C 8) alkynyl, 6-12 membered aryl, 5-12 membered C-linked heteroaryl, 3-12 membered C-linked heterocycle, or -C(O)NR q3 R r3 and Z 2 Any 6-12 membered aryl, 5-12 membered C-linked heteroaryl, or 3-12 membered C-linked heterocycle may be joined by 1, 2, 3, 4 or 5 Z 2b or Z 2c is optionally substituted with a group; 2 Any (C 2 ~C 8 ) Alkynyl is substituted with 1, 2, 3, 4 or 5 Z 2c In another variation, A is pyrimidinyl and Z is optionally substituted with a 2 is (C 2 ~C 8 ) alkynyl, 6-12 membered aryl, 5-12 membered C-linked heteroaryl, 3-12 membered C-linked heterocycle, or -C(O)NR q3 R r3 and Z 2 Any 6-12 membered aryl, 5-12 membered C-linked heteroaryl, or 3-12 membered C-linked heterocycle may be joined by 1, 2, 3, 4 or 5 Z 2b or Z 2c is optionally substituted with a group; 2 Any (C 2 ~C 8 ) Alkynyl is substituted with 1, 2, 3, 4 or 5 Z 2c In another variation, A is pyrazinyl and Z is optionally substituted with a 2 is (C 2 ~C 8 ) alkynyl, 6-12 membered aryl, 5-12 membered C-linked heteroaryl, 3-12 membered C-linked heterocycle, or -C(O)NR q3 R r3 and Z 2 Any 6-12 membered aryl, 5-12 membered C-linked heteroaryl, or 3-12 membered C-linked heterocycle may be joined by 1, 2, 3, 4 or 5 Z 2b or Z 2c is optionally substituted with a group; 2 Any (C 2~C 8 ) Alkynyl is substituted with 1, 2, 3, 4 or 5 Z 2c In another variation, A is pyridazinyl and Z is optionally substituted with a 2 is (C 2 ~C 8 ) alkynyl, 6-12 membered aryl, 5-12 membered C-linked heteroaryl, 3-12 membered C-linked heterocycle, or -C(O)NR q3 R r3 and Z 2 Any 6-12 membered aryl, 5-12 membered C-linked heteroaryl, or 3-12 membered C-linked heterocycle may be joined by 1, 2, 3, 4 or 5 Z 2b or Z 2c is optionally substituted with a group; 2 Any (C 2 ~C 8 ) Alkynyl is substituted with 1, 2, 3, 4 or 5 Z 2c Groups are optionally substituted.

[0333] In one variation of Formula III, A is one Z 1 Part and 1 Z 2 is substituted with a moiety and Z 3 pyridinyl that is not substituted with any (0) moiety; 2 is (C 2 ~C 8 ) alkynyl or aryl; Z 2 is optionally substituted as provided by formula III. In another variation, A is selected from one Z 1 Part and 1 Z 2 is substituted with a moiety and Z 3 pyridinyl that is not substituted with any (0) moiety; 2 is (C 2 ~C 8 ) alkynyl, and Z 2 is optionally substituted as provided by formula III. In certain variations, A is selected from the group consisting of one Z 1 and one Z moiety alpha to the nitrogen atom of the pyridinyl ring. 2 portion and is replaced by Z 3 pyridinyl that is not substituted with any (0) moiety; 2 is (C 2 ~C 8 ) alkynyl, and Z 2 may be optionally substituted as provided by formula III.

[0334] In one variation of Formula III, R 1 is 1, 2, 3, 4 or 5 Z, which may be the same or different 4 is a 5- to 12-membered heteroaryl optionally substituted with a group; Z 1 is phenyl, a 5- to 6-membered monocyclic heteroaryl, an 8- to 10-membered bicyclic heteroaryl, an 8- to 10-membered bicyclic heterocycle, or a 9- to 12-membered tricyclic heterocycle; Z 1 Any phenyl, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 8- to 10-membered bicyclic heterocycle, or 9- to 12-membered tricyclic heterocycle may have 1, 2, 3, 4, or 5 Z 1a In another variation, R 1 is an 8-12 membered bicyclic heteroaryl or an 8-12 membered tricyclic heteroaryl; R 1 Any 8-12 membered bicyclic heteroaryl or 8-12 membered tricyclic heteroaryl may have 1, 2, 3, 4 or 5 Z 4 is optionally substituted with a group; 1 is phenyl, a 5- to 6-membered monocyclic heteroaryl, an 8- to 10-membered bicyclic heteroaryl, an 8- to 10-membered bicyclic heterocycle, or a 9- to 12-membered tricyclic heterocycle; Z 1 Any phenyl, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 8- to 10-membered bicyclic heterocycle, or 9- to 12-membered tricyclic heterocycle may be joined by 1, 2, 3, 4, or 5 Z 1a Groups are optionally substituted.

[0335] In one variation of Formula III, R 1is an 8-12 membered bicyclic heteroaryl or an 8-12 membered tricyclic heteroaryl; R 1 Any 8-12 membered bicyclic heteroaryl or 8-12 membered tricyclic heteroaryl may have 1, 2, 3, 4 or 5 Z 4 is optionally substituted with a group; 1 is an 8-10 membered bicyclic heteroaryl or an 8-10 membered bicyclic heterocycle; Z 1 Any 8-10 membered bicyclic heteroaryl or 8-10 membered bicyclic heterocycle may have 1, 2, 3, 4 or 5 Z 1a Groups are optionally substituted.

[0336] In one variation of Formula III, R 1 is 1, 2, 3, 4 or 5 Z, which may be the same or different 4 is a 5- to 12-membered heteroaryl optionally substituted with a group; Z 2 is (C 2 ~C 8 ) alkynyl, 6-12 membered aryl, 5-12 membered C-linked heteroaryl, 3-12 membered C-linked heterocycle, or -C(O)NR q3 R r3 and Z 2 Any 6-12 membered aryl, 5-12 membered C-linked heteroaryl, or 3-12 membered C-linked heterocycle may be joined by 1, 2, 3, 4 or 5 Z 2b or Z 2c is optionally substituted with a group; 2 Any (C 2 ~C 8 Alkynyl may have 1, 2, 3, 4 or 5 Z, which may be the same or different. 2c In another variation, R 1 is an 8-12 membered bicyclic heteroaryl or an 8-12 membered tricyclic heteroaryl; R 1 Any 8-12 membered bicyclic heteroaryl or 8-12 membered tricyclic heteroaryl may have 1, 2, 3, 4 or 5 Z 4 is optionally substituted with a group;2 is (C 2 ~C 8 ) alkynyl, 6-12 membered aryl, 5-12 membered C-linked heteroaryl, 3-12 membered C-linked heterocycle, or -C(O)NR q3 R r3 and Z 2 Any 6-12 membered aryl, 5-12 membered C-linked heteroaryl, or 3-12 membered C-linked heterocycle may be joined by 1, 2, 3, 4 or 5 Z 2b or Z 2c is optionally substituted with a group; 2 Any (C 2 ~C 8 ) Alkynyl is substituted with 1, 2, 3, 4 or 5 Z 2c is optionally substituted with a group.

[0337] In one variation of Formula III, Z 1 is phenyl, a 5- to 6-membered monocyclic heteroaryl, an 8- to 10-membered bicyclic heteroaryl, an 8- to 10-membered bicyclic heterocycle, or a 9- to 12-membered tricyclic heterocycle; Z 1 any of phenyl, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 8- to 10-membered bicyclic heterocycle, or 9- to 12-membered tricyclic heteroaryl; The ring may have 1, 2, 3, 4 or 5 Z 1a is optionally substituted with a group; 2 is (C 2 ~C 8 ) alkynyl, 6-12 membered aryl, 5-12 membered C-linked heteroaryl, 3-12 membered C-linked heterocycle, or -C(O)NR q3 R r3 and Z 2 Any 6-12 membered aryl, 5-12 membered C-linked heteroaryl, or 3-12 membered C-linked heterocycle may have 1, 2, 3, 4 or 5 Z 2b or Z 2c is optionally substituted with a group; 2 Any (C 2 ~C 8Alkynyl may have 1, 2, 3, 4 or 5 Z, which may be the same or different. 2c Groups are optionally substituted.

[0338] In one variation of Formula III, Z 1 is 1, 2, 3, 4 or 5 Z, which may be the same or different 1a is a bicyclic heteroaryl optionally substituted with a group; Z 2 is 1, 2, 3, 4 or 5 Z, which may be the same or different 2c Optionally substituted with a group (C 2 ~C 8 ) alkynyl.

[0339] In one variation of Formula III, R 1 is a 5-12 membered heteroaryl; Z 1 is phenyl, a 5- to 6-membered monocyclic heteroaryl, an 8- to 10-membered bicyclic heteroaryl, an 8- to 10-membered bicyclic heterocycle, or a 9- to 12-membered tricyclic heterocycle; Z 1 Any phenyl, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 8- to 10-membered bicyclic heterocycle, or 9- to 12-membered tricyclic heterocycle may have 1, 2, 3, 4, or 5 Z 1a is optionally substituted with a group; 2 is (C 2 ~C 8 ) alkynyl, 6-12 membered aryl, 5-12 membered C-linked heteroaryl, 3-12 membered C-linked heterocycle, or -C(O)NR q3 R r3 and Z 2 Any 6-12 membered aryl, 5-12 membered C-linked heteroaryl, or 3-12 membered C-linked heterocycle may have 1, 2, 3, 4 or 5 Z 2b or Z 2c is optionally substituted with a group; 2 Any (C 2 ~C 8 Alkynyl may have 1, 2, 3, 4 or 5 Z, which may be the same or different.2c is optionally substituted with a group.

[0340] In certain embodiments of formula III, A is a 6-membered monocyclic heteroaryl having 1 or 2 nitrogen atoms, the 6-membered monocyclic heteroaryl being substituted with one Z at the indicated position. 1 group and one Z 2 group and one or two Z 3 is optionally substituted with a group; R 1 is a 6- to 12-membered aryl, a 5- to 12-membered heteroaryl, or a 3- to 12-membered heterocycle; R 1 Any 6- to 12-membered aryl, 5- to 12-membered heteroaryl, or 3- to 12-membered heterocycle may have 1, 2, 3, 4, or 5 Z 4 is optionally substituted with a group; R 2 is phenyl optionally substituted with 1, 2, 3, 4 or 5 halogens which may be the same or different; R 3a and R 3b Each independently represents H or (C 1 ~C 3 ) alkyl, Z 1 is a 6- to 12-membered aryl, a 5- to 14-membered heteroaryl, or a 3- to 14-membered heterocycle; Z 1 Any 6- to 12-membered aryl, 5- to 14-membered heteroaryl, or 3- to 14-membered heterocycle may have 1, 2, 3, 4, or 5 Z 1a or Z 1b and optionally substituted with each Z 1a are independently oxo, (C 3 ~C 7 )Carbocycle, halogen, -CN, -O-(C 1 ~C 8 ) alkyl, -OC(O)R p1 , -OC(O)NR q1 Rr1 , -NR q1 R r1 , -NR n1 COR p1 , -NR n1 CO 2 R p1 , -NR n1 CONR q1 R r1 , -NR n1 S(O) 2 R p1 , -NR n1 S(O) 2 NR q1 R r1 , -C(O)R n1 , -C(O)OR n1 or -C(O)NR q1 R r1 and each Z 1b are independently 1, 2, 3, 4 or 5 halo groups which may be the same or different. Optionally substituted with halogen (C 1 ~C 8 ) alkyl, Each R n1 are independently H or (C 1 ~C 8 ) alkyl, Each R p1 are independently 1 ~C 8 ) alkyl, (C 3 ~C 7 ) a carbocycle, a 3- to 7-membered heterocycle, or a 5- to 6-membered monocyclic heteroaryl; R p1 Any (C 3 ~C 7 ) carbocycle, 3- to 7-membered heterocycle, or 5- to 6-membered monocyclic heteroaryl may have 1, 2, 3, 4, or 5 (C 1 ~C 8 ) optionally substituted with alkyl; R p1 Any (C 1 ~C 8 )Alkyl may contain 1, 2, 3, 4 or 5 halogens, hydroxyl, -O(C 1 ~C 8) alkyl, or -NR q2 R r2 and optionally substituted with R q1 and R r1 are each independently H, (C 1 ~C 8 ) alkyl, (C 3 ~C 7 ) a carbocyclic ring or a 3- to 7-membered heterocyclic ring, R q1 Or R r1 Any (C 1 ~C 8 ) alkyl is optionally substituted with 1, 2, 3, 4 or 5 halogens or -CN, which may be the same or different, or R q1 and R r1 together with the nitrogen to which they are attached form a 5-, 6- or 7-membered heterocycle, the 5-, 6- or 7-membered heterocycle containing 1, 2, 3, 4 or 5 (C 1 ~C 8 ) optionally substituted with alkyl; R q2 and R r2 are each independently H, (C 1 ~C 8 ) alkyl, (C 3 ~C 7 ) a carbocyclic ring or R q2 and R r2 together with the nitrogen to which they are attached form a 5-, 6-, or 7-membered heterocyclic ring; Z 2 is (C 2 ~C 8 ) alkenyl, (C 2 ~C 8 ) alkynyl, 6-12 membered aryl, 5-12 membered C-linked heteroaryl, 3-12 membered C-linked heterocycle, -C(O)R n3 or -C(O)NR q3 R r3 and Z 2 Any 6-12 membered aryl, 5-12 membered C-linked heteroaryl, or 3-12 membered C-linked heterocycle may have 1, 2, 3, 4 or 5 Z2b or Z 2c is optionally substituted with a group; 2 Any (C 2 ~C 8 ) alkenyl or (C 2 ~C 8 Alkynyl may have 1, 2, 3, 4 or 5 Z, which may be the same or different. 2c is optionally substituted with a group; Each R n3 are independently H or (C 1 ~C 4 ) alkyl, R q3 and R r3 Each independently represents H or (C 1 ~C 4 ) alkyl, each Z 2b are independently oxo, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 )heteroalkyl or (C 1 ~C 4 ) haloalkyl; each Z 2c are independently oxo, halogen, -CN, -OR n4 , N.R. q4 R r4 , -NR n4 COR p4 , -NR n4 CO 2 R p4 , -NR n4 S(O) 2 R p4 , -C(O)R n4 , -C(O)OR n4 or -C(O)NR q4 R r4 and Each R n4 are independently, H, (C 1 ~C 4 ) alkyl, or (C 1 ~C 4 ) heteroalkyl; Each R p4 are independently 1 ~C8 ) alkyl, R q4 and R r4 are each independently H, (C 1 ~C 4 ) alkyl, or (C 1 ~C 4 ) heteroalkyl; each Z 3 are independently 1 ~C 4 ) heteroalkyl or halogen; each Z 4 are independently oxo, (C 1 ~C 8 ) alkyl, (C 3 ~C 7 )Carbocycle, halogen, -CN, -OR n5 , -NR q5 R r5 , -NR n5 COR p5 , -NR n5 CO 2 R p5 , -C(O)R n5 , -C(O)OR n5 or -C(O)NR q5 R r5 and Z 4 Any (C 3 ~C 7 ) carbocyclic or (C 1 ~C 8 ) Alkyl may have 1, 2, 3, 4 or 5 Z 4a is optionally substituted with a group; each Z 4a are independently halogen, -CN, or -OR n6 and R n5 , R p5 , R q5 , R r5 , and R n6 Each independently represents H or (C 1 ~C 4 ) alkyl.

[0341] In certain embodiments of formula III, A1 , CH, CZ 3 , or nitrogen, A 2 is CH or nitrogen, R 1 is a 6- to 12-membered aryl, a 5- to 12-membered heteroaryl, or a 3- to 12-membered heterocycle; R 1 Any 6- to 12-membered aryl, 5- to 12-membered heteroaryl, or 3- to 12-membered heterocycle may have 1, 2, 3, 4, or 5 Z 4 is optionally substituted with a group; R 3a and R 3b Each independently represents H or (C 1 ~C 3 ) alkyl, Z 1 is a 6- to 12-membered aryl, a 5- to 14-membered heteroaryl, or a 3- to 14-membered heterocycle; Z 1 Any 6- to 12-membered aryl, 5- to 14-membered heteroaryl, or 3- to 14-membered heterocycle may have 1, 2, 3, 4, or 5 Z 1a or Z 1b and optionally substituted with each Z 1a are independently oxo, (C 3 ~C 7 )Carbocycle, halogen, -CN, -O-(C 1 ~C 8 ) alkyl, -OC(O)R p1 , -OC(O)NR q1 R r1 , -NR q1 R r1 , -NR n1 COR p1 , -NR n1 CO 2 R p1 , -NR n1 CONR q1 R r1 , -NR n1 S(O) 2 R p1 , -NR n1 S(O) 2 NR q1 Rr1 , -C(O)R n1 , -C(O)OR n1 or -C(O)NR q1 R r1 and each Z 1b is optionally substituted with 1, 2, 3, 4 or 5 halogens, which may be the same or different (C 1 ~C 8 ) alkyl, Each R n1 are independently H or (C 1 ~C 8 ) alkyl, Each R p1 are independently 1 ~C 8 ) alkyl, (C 3 ~C 7 ) a carbocycle, a 3- to 7-membered heterocycle, or a 5- to 6-membered monocyclic heteroaryl; R p1 Any (C 3 ~C 7 ) carbocycle, 3- to 7-membered heterocycle, or 5- to 6-membered monocyclic heteroaryl may have 1, 2, 3, 4, or 5 (C 1 ~C 8 ) optionally substituted with alkyl; R p1 Any (C 1 ~C 8 )Alkyl may contain 1, 2, 3, 4 or 5 halogens, hydroxyl, -O(C 1 ~C 8 ) alkyl, or -NR q2 R r2 and optionally substituted with R q1 and R r1 are each independently H, (C 1 ~C 8 ) alkyl, (C 3 ~C 7 ) a carbocyclic ring or a 3- to 7-membered heterocyclic ring, R q1 Or R r1 Any (C 1 ~C 8) alkyl is optionally substituted with 1, 2, 3, 4 or 5 halogens or -CN, which may be the same or different, or R q1 and R r1 together with the nitrogen to which they are attached form a 5-, 6- or 7-membered heterocycle, the 5-, 6- or 7-membered heterocycle containing 1, 2, 3, 4 or 5 (C 1 ~C 8 ) optionally substituted with alkyl; R q2 and R r2 are each independently H, (C 1 ~C 8 ) alkyl, (C 3 ~C 7 ) a carbocyclic ring or R q2 and R r2 together with the nitrogen to which they are attached form a 5-, 6-, or 7-membered heterocyclic ring; Z 2 is (C 2 ~C 8 ) alkenyl, (C 2 ~C 8 ) alkynyl, 6-12 membered aryl, 5-12 membered C-linked heteroaryl, 3-12 membered C-linked heterocycle, -C(O)R n3 or -C(O)NR q3 R r3 and Z 2 Any 6-12 membered aryl, 5-12 membered C-linked heteroaryl, or 3-12 membered C-linked heterocycle may have 1, 2, 3, 4 or 5 Z 2b or Z 2c is optionally substituted with a group; 2 Any (C 2 ~C 8 ) alkenyl or (C 2 ~C 8 Alkynyl may have 1, 2, 3, 4 or 5 Z, which may be the same or different. 2c is optionally substituted with a group; Each R n3 are independently H or (C 1 ~C4 ) alkyl, R q3 and R r3 Each independently represents H or (C 1 ~C 4 ) alkyl, each Z 2b are independently oxo, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 )heteroalkyl or (C 1 ~C 4 ) haloalkyl; each Z 2c are independently oxo, halogen, -CN, -OR n4 , N.R. q4 R r4 , -NR n4 COR p4 , -NR n4 CO 2 R p4 , -NR n4 S(O) 2 R p4 , -C(O)R n4 , -C(O)OR n4 or -C(O)NR q4 R r4 and Each R n4 are independently, H, (C 1 ~C 4 ) alkyl, or (C 1 ~C 4 ) heteroalkyl; Each R p4 are independently 1 ~C 8 ) alkyl, R q4 and R r4 are each independently H, (C 1 ~C 4 ) alkyl, or (C 1 ~C 4 ) heteroalkyl; Z 3 are independently 1 ~C 4 ) heteroalkyl or halogen; each Z 4 are independently oxo, (C 1 ~C 8 ) alkyl, (C 3 ~C 7 )Carbocycle, halogen, -CN, -OR n5 , -NR q5 R r5 , -NR n5 COR p5 , -NR n5 CO 2 R p5 , -C(O)R n5 , -C(O)OR n5 or -C(O)NR q5 R r5 and Z 4 Any (C 3 ~C 7 ) carbocyclic or (C 1 ~C 8 ) Alkyl may have 1, 2, 3, 4 or 5 Z 4a is optionally substituted with a group; each Z 4a are independently halogen, -CN, or -OR n6 and R n5 , R p5 , R q5 , R r5 , and R n6 Each independently represents H or (C 1 ~C 4 ) alkyl, each Z 5 are independently halogen, which may be the same or different; n is 0, 1, 2 or 3.

[0342] In one embodiment, the compound of formula I is [ka] [ka] [ka] and pharma- ceutically acceptable salts thereof.

[0343] In certain embodiments, the compound is [ka] or a pharma- ceutically acceptable salt thereof.

[0344] In certain embodiments, the compound is [ka] or a pharma- ceutically acceptable salt thereof.

[0345] In certain embodiments, the compound or a pharma- ceutically acceptable salt thereof is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] It is.

[0346] In certain embodiments, the compound is [ka] or a pharma- ceutically acceptable salt thereof.

[0347] In certain embodiments, the compound is [ka] or a pharma- ceutically acceptable salt thereof.

[0348] In certain embodiments, the compound is [ka] or a pharma- ceutically acceptable salt thereof.

[0349] In certain embodiments, the compound is [ka] or a pharma- ceutically acceptable salt thereof.

[0350] In certain embodiments, the compound is [ka] or a pharma- ceutically acceptable salt thereof.

[0351] In certain embodiments, the compound is [ka] or a pharma- ceutically acceptable salt thereof.

[0352] General synthetic procedure The following schemes describe methods useful for preparing compounds of formula I. Similarly, the following schemes describe methods useful for preparing compounds of formula III. [ka]

[0353] Scheme 1 describes a general stereoselective route used to prepare compounds of formula I. This scheme is also used to prepare compounds of formula III. Heteroaryl acids of formula A1, where X is a suitably protected NH 2 The heteroaryl acid A1, which contains two diverse functional groups (e.g., X and Br), is converted to the corresponding aldehyde, which is then condensed with a chiral auxiliary that results in the stereoselective addition of nucleophiles. Scheme 1 illustrates the conversion of the heteroaryl acid A1, which contains two diverse functional groups (e.g., X and Br), to the corresponding aldehyde. Subsequent condensation of the aldehyde A3 with (S) tert-butanesulfinamide and addition of a Grignard reagent gives a mixture of A5 and A6, enriched in A5. This mixture is separated by column chromatography on silica gel to give the pure diastereomers. Removal of the auxiliary gives the amines A7 and A8, which are coupled with various carboxylic acids to give the heteroaryl compounds of formula A9 and A10. Diversification of A9 and A10 is achieved by a variety of methods including alkylation, acylation, cyanation, nucleophilic aromatic displacement, 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 compounds of Formula I and III. [ka]

[0355] Scheme 2 illustrates the protection of amine A7 to compounds of formula B1, followed by conversion of Br to the corresponding boronic acid. Diversification of functional groups X and boronic acids can be achieved by a variety of methods, including alkylation, acylation, cyanation, nucleophilic aromatic displacement, and metal-catalyzed cross-coupling reactions, such as Suzuki coupling, Buchwald-Hartwig type coupling, and Sonogashira coupling, to give compounds of formula B3 and B4. Deprotection followed by amide formation with a variety of carboxylic acids gives compounds of formula I.

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

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

[0358] In one embodiment, there is provided a method of treating or preventing HIV infection in a human having or at risk of having an infection, comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharma- ceutically 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 pharma- ceutically acceptable salt thereof in combination with at least one additional therapeutic agent, and a pharma- ceutically acceptable carrier. For example, the therapeutic agent used in combination with the compound disclosed herein can be any anti-HIV agent.

[0360] In one embodiment, a combination pharmaceutical agent is provided that includes a compound disclosed herein, or a pharma- ceutically 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 pharma- ceutically acceptable salt thereof in combination with at least one additional therapeutic agent, and a pharma- ceutically acceptable carrier. In one embodiment, the additional therapeutic agent can be an anti-HIV agent. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of HIV protease inhibitor compounds (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 site (or allosteric) integrase inhibitors, entry inhibitors (e.g., CCR5 inhibitors, gp41 inhibitors (i.e., fusion inhibitors) and CD4 attachment inhibitors), CXCR4 inhibitors, gp120 inhibitors, G6PD and NADH-oxidase inhibitors, capsid polymerization inhibitors or capsid disrupting compounds, such as those described in US 2013 / 0165489 (University of Pennsylvania) and WO 2013 / 006792 (Pharma Resources), pharmacokinetic enhancers, and other drugs for treating HIV, and combinations thereof.

[0362] In a further embodiment, the additional therapeutic agent is (1) an HIV protease inhibitor selected from the group consisting of amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, nelfinavir, saquinavir, tipranavir, brecanavir, 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) a non-nucleoside or non-nucleotide inhibitor of HIV reverse transcriptase selected from the group consisting of capravirine, emivirine, delaviridine, efavirenz, nevirapine, (+)calanolide A, etravirine, GW5634, DPC-083, DPC-961, DPC-963, MIV-150, TMC-120, rilpivirene, BILR355BS, VRX840773, lersivirine (UK-453061), RDEA806, KM023 and MK-1439; (3) a nucleoside inhibitor of HIV reverse transcriptase selected from the group consisting of zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, abacavir, amdoxovir, elvucitabine, alovudine, MIV-210, ±-FTC, D-d4FC, emtricitabine, phosphazide, fodivudine tidoxyl, apricitabine (AVX754), amdoxovir, KP-1461, GS-9131 (Gilead Sciences), and fosalvudine tidoxyl (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 a nucleotide inhibitor of HIV reverse transcriptase selected from the group consisting of MX-157 (Chimerix); (5) HIV integrase inhibitors selected from the group consisting of curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrophostin, derivatives of tyrophostin, quercetin, derivatives of quercetin, 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 site or allosteric integrase inhibitors (NCINI), including but not limited to BI-224436, CX0516, CX05045, CX14442, compounds disclosed in WO2009 / 062285 (Boehringer Ingelheim), WO2010 / 130034 (Boehringer Ingelheim), WO2013 / 159064 (Gilead Sciences), WO2012 / 145728 (Gilead Sciences), WO2012 / 003497 (Gilead Sciences), WO2012 / 003498 (Gilead Sciences), each of which is incorporated herein by reference in its entirety; (7) a gp41 inhibitor selected from the group consisting of enfuvirtide, sifuvirtide, albuvirtide, FB006M and TRI-1144; (8) CXCR4 inhibitor AMD-070; (9) entry inhibitor SP01A; (10) gp120 inhibitor BMS-488043; (11) G6PD and NADH-oxidase inhibitor immunitin; (12) a CCR5 inhibitor selected from the group consisting of aplaviroc, vicriviroc, maraviroc, cenicriviroc, PRO-140, INCB15050, PF-232798 (Pfizer) and CCR5mAb004; (13) a CD4 adhesion inhibitor selected from the group consisting of ibalizumab (TMB-355) and BMS-068 (BMS-663068); (14) a pharmacokinetic enhancer 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 (Bevirimat), HRG214, VGX-410, KD-247, AMZ0026, CYT99007A-221HIV, DEBIO-025, BAY50-4798, MDX010 (ipilimumab), PBS119, ALG889 and PA-1050040 (PA-040). is selected from one or more of:

[0363] In certain embodiments, a compound disclosed herein or a pharma- ceutically acceptable salt thereof is combined with two, three, four or more than four additional therapeutic agents. In certain embodiments, a compound disclosed herein or a pharma- ceutically acceptable salt thereof is combined with two additional therapeutic agents. In other embodiments, a compound disclosed herein or a pharma- ceutically acceptable salt thereof is combined with three additional therapeutic agents. In further embodiments, a compound disclosed herein or a pharma- ceutically acceptable salt thereof is 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 of therapeutic agents or may be selected from different classes of therapeutic agents. Specific In one embodiment, the compound disclosed herein or a pharma- ceutically acceptable salt thereof is combined with a nucleotide inhibitor of HIV reverse transcriptase and a non-nucleoside inhibitor of HIV reverse transcriptase. In another specific embodiment, the compound disclosed herein or a pharma- ceutically acceptable salt thereof is combined with a nucleotide inhibitor of HIV reverse transcriptase and an HIV protease inhibitor compound. In a further embodiment, the compound disclosed herein or a pharma- ceutically acceptable salt thereof is combined with a nucleotide inhibitor of HIV reverse transcriptase, a non-nucleoside inhibitor of HIV reverse transcriptase, and an HIV protease inhibitor compound. In a further embodiment, the compound disclosed herein or a pharma- ceutically acceptable salt thereof is combined with a nucleotide inhibitor of HIV reverse transcriptase, a non-nucleoside inhibitor of HIV reverse transcriptase, and a pharmacokinetic enhancer.

[0364] In a specific embodiment, the compound 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. In another specific embodiment, the compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir alafenamide. In a specific embodiment, the compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with emtricitabine, abacavir, or lamivudine.

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

[0366] In some embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 5-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. In some embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 5-10 mg, 5-15 mg, 5-20 mg, 5-25 mg, 25-30 mg, 20-30 mg, 15-30 mg, or 10-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. In some embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. In some embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. A compound disclosed herein (e.g., a compound of any of formulas I and III or a pharmaceutically acceptable salt thereof) may be combined with an agent presented herein at any dosage of the compound (e.g., 50 mg to 300 mg of the compound), as if each combination of dosages were specifically listed individually.

[0367] In some embodiments, the compounds disclosed herein, or pharma- ceutically acceptable salts thereof, are In some embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 200 mg of emtricitabine. In some embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 200 mg of emtricitabine. In some embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 200 mg of emtricitabine. In some embodiments, a compound disclosed herein or a pharma- ceutically acceptable salt thereof is combined with 300 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg of emtricitabine. A compound disclosed herein (e.g., a compound of any of formulas I and III, or a pharma- ceutically acceptable salt thereof) may be combined with an agent presented herein at any dosage of the compound (e.g., 50 mg to 300 mg of compound), as if each combination of dosages were specifically recited individually.

[0368] In some embodiments, one or more of the compounds disclosed herein are combined with one or more other active therapeutic agents in a unit dosage form for simultaneous or sequential administration to patients.In certain embodiments, a pharmaceutical composition is provided that includes 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 a solid dosage form.Combination therapy can be administered as a simultaneous or sequential regimen.When administered sequentially, the combination can be administered in two or more administrations.

[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 a compound disclosed herein with one or more other active therapeutic agents generally refers to the simultaneous or sequential administration of a compound disclosed herein and one or more other active therapeutic agents such that a therapeutically effective amount of both the compound disclosed herein and the one or more other active therapeutic agents is present in the patient's body.

[0370] In yet another embodiment, the present application provides a method of treating HIV infection, comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, 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 with conventional carriers (e.g., inactive ingredients or excipient materials) selected in accordance with normal practice. Tablets contain excipients, including glidants, fillers, binders, and the like. Aqueous formulations are prepared in sterile form and, if intended for delivery by other than oral administration, are generally isotonic. All formulations are prepared in accordance with the Handbook of The formulations optionally contain additives such as those listed in Pharmaceutical Excipients (1986). Additives include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, and the like. One embodiment provides the formulation as a solid dosage form, including a solid oral dosage form. The pH of the formulation ranges from about 3 to about 11, but is typically about 7 to 10.

[0372] While it is possible for the active ingredients to be administered alone, it may be preferable to present them as pharmaceutical formulations (compositions). The formulations of the invention, both for veterinary and human use, comprise at least one active ingredient as defined above, together with one or more acceptable carriers, and optionally other therapeutic ingredients. The carrier(s) must be compatible with the other ingredients of the formulation. It must be "acceptable" in the sense of being compatible with the intended use and physiologically harmless to the recipient of the formulation.

[0373] Formulations include those suitable for the above-mentioned routes of administration. Formulations may conveniently be provided in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art. Techniques and formulations are generally found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with inactive ingredients (e.g., carriers, pharmaceutical excipients, etc.) which constitute one or more accessory ingredients. In general, formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

[0374] Formulations suitable for oral administration described herein may be presented as discrete units including, but not limited to, capsules, cachets or tablets, each containing a predetermined amount of the active ingredient.

[0375] The pharmaceutical preparations disclosed herein comprise one or more compounds disclosed herein, together with one or more pharma- ceutically acceptable carriers or excipients, and optionally other therapeutic agents.The pharmaceutical preparations containing active ingredient can be in any form suitable for the intended administration method.When used for oral use, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs can be prepared.The compositions intended for oral use can be prepared according to any method known in the art of manufacturing pharmaceutical compositions, and such compositions can contain one or more agents, including sweeteners, flavorings, colorings, and preservatives, to provide a palatable preparation.Tablets containing active ingredient in admixture with non-toxic pharma-ceutically acceptable excipients suitable for tablet manufacture are acceptable. These additives can be, for example, inert excipients such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents 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. Tablets can be uncoated or coated by known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract, thereby providing a sustained action over a long period of time. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate can be used alone or with a wax.

[0376] The amount of active ingredient combined with the inactive ingredient to produce a dosage form varies depending on the host treated and the particular mode of administration. For example, in some embodiments, a dosage form for oral administration to humans contains approximately 1-1000 mg of active ingredient, formulated with an appropriate and convenient amount of carrier material (e.g., inactive ingredient or additive material). In some embodiments, the dosage form (e.g., 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 active material (e.g., a compound of either Formula I or III). part In some embodiments, dosage forms for oral administration to humans contain at least 10 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, or 300 mg, and up to 500 mg, 800 mg, or 1000 mg of active ingredient (e.g., at least 50 mg to 500 mg). In some embodiments, dosage forms for oral administration to humans contain at least 10 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, or 300 mg, and up to 500 mg, 800 mg, or 1000 mg of active ingredient. In some embodiments, dosage forms for oral administration to humans contain any of 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 of active ingredient. It is understood that dosage forms in the amounts provided herein can be administered to a patient (e.g., a human in need thereof) according to the dosing regimes provided herein, such as once, twice, or three times daily. In one aspect, the dosing regimen provides for the administration of at least 10 mg and no more than 1,000 mg of active material (e.g., a compound of either Formula I or III) per day, it being understood that the amount can be provided in any suitable dosage form and amount (e.g., 500 mg twice a day or 1,000 mg once a day would provide the same 1,000 mg dose per day). The invention encompasses the administration of a dosage form of a compound (e.g., a compound of either Formula I or III) containing at least 50 mg and no more than 300 mg of the compound once a day to an individual (e.g., a human in need thereof). In certain embodiments, the carrier material varies from about 5 to about 95% (weight:weight) of the total composition.

[0377] It will be understood that the formulations of the present invention may include, in addition to the ingredients particularly mentioned above, other agents conventional in the art having regard to the type of formulation in question; for example, formulations suitable for oral administration may include flavoring agents.

[0378] The present invention further provides veterinary compositions comprising at least one active ingredient as above defined, together with a veterinary carrier.

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

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

[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 to be treated.Suitable routes include oral, rectal, nasal, topical (including oral buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), etc.It is understood that preferred routes may vary, for example, with the condition of the recipient.The advantage of the compounds disclosed herein is that they are orally bioavailable and can be administered orally.

[0382] Dosing regimen A compound, such as a compound of any of Formulas I and III, can be administered in accordance with an effective dosing regimen for a 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 the individual for 3 months, at least about 6 months, or at least about 12 months, or longer. In one variation, the compound is administered on a daily or intermittent schedule for the life of the individual.

[0383] The dosage or frequency of administration of a compound of either Formula I or III may be adjusted during the course of treatment, eg, based on the judgment of the administering physician.

[0384] The compound may be administered to an individual (e.g., a human) in an effective amount. In one embodiment, the compound is administered once a day. In one embodiment, the compound is administered twice a day. In one embodiment, the compound is administered three times a day. It is understood that the compound may be administered in any dosage amount provided herein, such as a dosage amount that provides a dosage of at least 10 mg per day and a dosage of no more than 1,000 mg per day. Oral administration once a day is included, such as administering a dosage form containing 50 mg to 300 mg of the compound.

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

[0386] Test A: Antiviral assay in MT4 cells For the antiviral assay, 40 μL of 3-fold serially diluted compounds at the concentrations required to achieve a final effective 1× test concentration in culture medium containing 10% FBS were added in quadruplicate to each well of a 384-well plate (10 concentrations). MT-4 cells were then mixed with HIV-IIIb at an moi of 0.003 for 1 hour, after which 35 μL of virus / cell mixture (2000 cells) was immediately added to each well containing 40 μL of diluted compound. The plates were then incubated at 37° C. for 5 days. After the 5-day incubation, 25 μl of 2-fold concentrated CellTiter-Glo™ Reagent (catalog number G7571, Promega Biosciences, Inc., Madison, Wis.) was added to each well containing MT-4 cells. Cell lysis was performed by incubating at room temperature for 10 minutes, and then chemiluminescence was read. EC50 values ​​were calculated as the compound concentration that caused a 50% reduction in the luminescence signal, a measure of HIV-1 replication. The percentage inhibition of virus-induced cell killing calculated from dose-response curves at drug concentrations of 2 μM and 0.2 μM is shown in the table below.

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

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

[0389] The above data represent averages over time for each assay per compound. For a given compound, multiple assays were performed over the life of the project. Thus, the data recorded in the table include data recorded in the priority document as well as data from assays performed during the intervening period. In the above table, where percent inhibition calculations yielded values ​​greater than 100, the percent inhibition values ​​have been 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 is understood that the compounds disclosed herein may be classified according to their percent inhibition 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 is understood that the compounds disclosed herein may be classified according to their percent inhibition as described above.

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

[0393] It is understood that the percent inhibition can be evaluated by techniques known in the art. In certain variations, the compound is a compound of any formula provided herein, and the compound exhibits 85%-110% inhibition of virus-induced cell death at 2 μM or 0.2 μM as measured by the methods provided in Test A and Test B sections discussed above.

[0394] The inhibition rate was also calculated for a particular compound in comparison with a previously published compound (WO2013 / 006738), and is shown below: The inhibition rate of virus-induced cell death at 2 μM and 0.2 μM was measured by the method presented in the Test A and Test B sections discussed above. [Table 2]

[0395] The specific pharmacological response observed may vary depending on the particular active compound selected, and whether or not a pharmaceutical carrier and / or pharma- ceutical active compound is present, as well as the formulation type and mode of administration used, and thus variations or differences in expected results are contemplated in accordance with the practice of the invention.

[0396] The examples presented herein describe the synthesis of the compounds disclosed herein, as well as intermediates used to prepare the compounds. It is understood that separate batches of a compound may be combined and then carried forward to the next synthetic 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-indazol-1-yl)acetamido)-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 at 100° C. overnight. After cooling to room temperature, it was diluted with water and extracted with EtOAc. The organic phase was dried (Na 2 SO 4 ), filtered and concentrated. The crude material was purified by reverse phase HPLC eluting with acetonitrile and water (containing 0.1% TFA) to give (S)-N-(1-(3-bromo-6-cyanopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-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-indazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-5-(1H-pyrrolo[2,3-b]pyridin-5-yl)picolinamide (1B):

[0398] The title compound (1B) was prepared following the procedure provided for the synthesis of compound 4H in Example 4 utilizing 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine and 1A. [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]pyrazol-1-yl)-N-((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(4-oxo-3,4-dihydroquinazolin-8-yl)pyridin-2-yl)ethyl)acetamide (2):

[0399] The title compound (2) was prepared utilizing (4-oxo-3,4-dihydroquinazolin-8-yl)boronic acid and 14D following the procedure provided 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'-yl trifluoromethanesulfonate (3B):

[0400] Compound 3A (1 g, 5.7 mmol, prepared according to the method presented in Tetrahedron Letters, Vol. 50 (2009) pp. 1267-1269), DCM (20 mL) and Et 3 A mixture of N (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 via syringe. The mixture was then stirred at ambient temperature for 1 h. More trifluoromethanesulfonyl chloride (0.8 mL) was added and the mixture was stirred at ambient temperature for an additional 1 h. It was then diluted with DCM (150 mL) and washed with 1.0 N HCl (50 mL), saturated aqueous sodium bicarbonate (1 x 50 mL) and saturated aqueous sodium chloride (1 x 50 mL). The organic layer was diluted with MgSO 4 The mixture was dried at 40° C., filtered through Celite®, and concentrated in vacuo to give 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'-isoindolin]-3'-one (3C):

[0401] A microwave tube was charged with 3B (200 mg, 0.65 mmol), bis(pinacolato)diboron (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). The mixture was heated to 150 °C in a microwave synthesizer for 20 min. Upon completion, the solution was diluted in EtOAc and the organic layer was washed with water and saturated NaCl solution and diluted with MgSO. 4The mixture was dried at 40° C. and concentrated in vacuo to give the title compound as a dark brown solid. Half of the product was purified by silica gel chromatography eluting with EtOAc / hexanes to give 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]pyrazol-1-yl)-N-((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(3'-oxospiro[cyclopropane-1,1'-isoindoline]-5'-yl)pyridin-2-yl)ethyl)acetamide (3D):

[0402] In a microwave tube, 14D (33 mg, 0.05 mmol), 3C (21 mg, 0.075 mmol), LiCl (6 mg, 0.15 mmol), K 2 CO 3 (21 mg, 0.15 mmol), Pd(PPh 3 ) 2 Cl 2 (3 mg) and Pd(dppf)Cl 2 (3 mg). The mixture was added with DME (1 mL) and H 2 O (0.2 mL) was added. The mixture was heated to 165° C. in a microwave synthesizer for 12 min. After cooling and filtration through a syringe filter, it was purified by reverse phase HPLC eluting with acetonitrile and water (containing 0.1% TFA) to give the title product. [ka] MS(m / z)738.15[M+H] + . Example 4 [ka] Synthesis of (S)-N-((3,5-dibromopyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (4B):

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

[0404] (S)-N-((3,5-dibromopyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (2.6 g, 7.1 mmol) was dissolved in THF (24 mL). The mixture was cooled to -78°C. (3,5-difluorobenzyl)magnesium bromide (34 mL, Et 2 Aqueous hexanes (0.25M in 0) was added dropwise. The reaction was stirred at -78 °C for 3 h and then warmed to 0 °C and quenched. The reaction was diluted with EtOAc and NH 4 Partitioned between aqueous Cl. The organics were separated, dried and removed in vacuo. The residue was purified by column chromatography on silica to give the title compound. MS (m / z) 496.6 [M+H] + . Synthesis of (S)-1-(3,5-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethanamine (4D):

[0405] To (S)-N-((S)-1-(3,5-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (650 mg) dissolved in DCM (3 mL) was added 4N HCl in dioxane (4 mL). The reaction was stirred at ambient temperature for 2 h. The solvent was removed in vacuo 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-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamate (4E):

[0406] (S)-1-(3,5-dibromopyridin-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 was stirred at ambient temperature for 2 h. The reaction was diluted with EtOAc and H 2 Partitioned between 0.25 ml and 100 ml of ethyl acetate. The organics were separated, dried and removed in vacuo. The residue was purified by column chromatography on silica to give the title compound. MS (m / z) 492.9 [M+H] + . Synthesis of (S)-tert-butyl 1-(3-bromo-5-(3-hydroxy-3-methylbut-1-ynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamate (4F):

[0407] To a solution of (S)-tert-butyl 1-(3,5-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamate (140 mg, 0.29 mmol) in THF (18 mL), 2-methylbut-3-yn-2-ol (42 μL, 0.43 mmol), TEA (0.9 mL), Pd(PPh 3 ) 2 Cl 2 (30 mg) and CuI (16 mg) were added. The reaction was stirred at ambient temperature for 2 h and then diluted with EtOAc and H 2Partitioned between 0 and 100 mL of 1,2-dichloromethane. The organics were separated, dried and removed in vacuo. The residue was purified by column chromatography on silica to give 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-methylbut-1-ynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide (4G):

[0408] A mixture of (S)-tert-butyl 1-(3-bromo-5-(3-hydroxy-3-methylbut-1-ynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamate and (S)-tert-butyl 1-(3,5-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamate (105 mg) obtained from the previous step was dissolved in DCM (3 mL) and treated with 4N HCl in dioxane (4 mL). The reaction was stirred for 2 h and then the solvent was removed in vacuo. The residue was purified by column chromatography on silica to give (S)-4-(6-(1-amino-2-(3,5-difluorophenyl)ethyl)-5-bromopyridin-3-yl)-2-methylbut-3-yn-2-ol (MS (m / z) 395.0 [M+H] + 18 mg of (S)-4-(6-(1-amino-2-(3,5-difluoro)phenyl) in DMF (1 mL) was obtained. phenyl)ethyl)-5-bromopyridin-3-yl)-2-methylbut-3-yn-2-ol (18 mg, 0.046 mmol), 2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid (15 mg, 0.05 mmol), iPr 2 NEt (17 μL, 0.1 mmol) and HATU (26 mg, 0.07 mmol) were added. The reaction was stirred for 30 min and then diluted with EtOAc and H 2Partitioned between 0 and 100. The organics were separated, dried and removed in vacuo. 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-indazol-1-yl)-N-(2-(3,5-difluorophenyl)-1-(5-(3-hydroxy-3-methylbut-1-ynyl)-3-(3-oxoisoindolin-5-yl)pyridin-2-yl)ethyl)acetamide (4H):

[0409] To a solution of (S)-N-(1-(3-bromo-5-(3-hydroxy-3-methylbut-1-ynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide (16 mg, 0.02 mmol) in DME (0.7 mL), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (7 mg, 0.03 mmol), Pd(PPh 3 ) 2 Cl 2 (2 mg), LiCl (1 mg) and 2M K 2 CO 3 Aqueous solution (30 μL) was added. The reaction was heated to 150° C. in a microwave reactor for 20 min. The reaction was purified by RP HPLC to give the desired product. [ka] MS(m / z)732.1[M+H] + . Example 5 [ka] Synthesis of 3,6-dibromo-2-(dibromomethyl)pyridine (5A)

[0410] 3,6-Dibromo-2-methylpyridine (5.2 g, 21 mmol) CCl 4 To the (50 mL) solution was added N-bromosuccinimide (7.57 g, 42 mmol) and 2,2'-azobis(2-methylpropionitrile) (0.70 g, 4.3 mmol). The mixture was heated at 80° C. overnight and cooled to room temperature. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The product (5A) was obtained after flash chromatography eluting with 0-10 percent EtOAc in hexanes (7.36 g). MS (m / z): 409.66 [M+H] + Synthesis of 3,6-dibromopicolinaldehyde (5B)

[0411] A solution of silver nitrate (7.6 g, 45 mmol) in water (24 mL) was added dropwise to a refluxing solution of 5A (7.36 g, 18 mmol) in EtOH (90 mL). The mixture was stirred at 80° C. for 5 h. After the mixture was cooled to room temperature, it was diluted with water (100 mL), extracted with EtOAc (3×), and concentrated with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The crude product (5B, 4.6G) was used directly in the next step. MS (m / z): 265.96. [M+H] + Synthesis of (S,Z)-N-((3,6-dibromopyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (5C)

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

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

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

[0415] The title compound (5F) was prepared using 5E according to the method presented 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-indazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridine-2,5-diyl)bis(2-fluorobenzamide) (5G):

[0416] In a microwave tube, 5F (100 mg, 0.15 mmol), (3-carbamoyl-4-fluorophenyl)boronic acid (81 mg, 0.45 mmol), LiCl (19 mg, 0.45 mmol), Na 2 CO 3 (50 mg, 0.6 mmol) and Pd(PPh 3 ) 2 Cl 2 (5 mg). The mixture was diluted with 1,4-dioxane / methanol / H 21.4 mL of O (5 / 1 / 1) was added. The mixture was heated to 170° C. in a microwave synthesizer for 15 min. After cooling and filtration through a syringe filter, it was purified by reverse phase HPLC eluting with acetonitrile and water (containing 0.1% TFA) to give 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)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide (6):

[0417] The title compound (6) was prepared following the method provided for the synthesis of compound 5G in Example 5 utilizing 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one and 5F. [ka] MS(m / z)781.02[M+H] + . Example 7 [ka] (S)-N-(1-(3,6-bis(1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluorophenyl)ethyl) Synthesis of fluoromethyl-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide (7):

[0418] 6 The title compound (7) was prepared following the procedure provided for the synthesis of compound 5G in Example 5 utilizing 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine and 5F. [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-indazol-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-indazol-1-yl)acetamide (8B):

[0419] 2-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2 equivalents) and 5F were used to synthesize compound 5G of Example 5. The title compounds (8A and 8B) were prepared according to the methods presented. Synthesis of (S)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)-N-(2-(3,5-difluorophenyl)-1-(2'-methoxy-5-(3-oxoisoindolin-5-yl)-[2,4'-bipyridin]-6-yl)ethyl)acetamide (8C):

[0420] Utilizing 8A, the title compound (8C) was prepared following the method presented 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-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide (9A):

[0421] The title compound (9A) was prepared utilizing 2-methylbut-3-yn-2-ol and 5F following the procedure presented 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-indazol-1-yl)-N-(2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(3-oxoisoindolin-5-yl)pyridin-2-yl)ethyl)acetamide (9B):

[0422] Utilizing 9A, the title compound (9B) was prepared following the method presented 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-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide (10A):

[0423] (S)-1-(3,5-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethanamine (380 mg, 0.97 mmol) dissolved in DMF (10 mL) was treated with iPr 2 NEt (350 μL, 2 mmol) and 2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid (293 mg, 0.97 mmol) were added. HATU (442 mg, 1.16 mmol) was added and the reaction was stirred for 30 min. The reaction was diluted with EtOAc and H 2 The organics were separated, dried and removed in vacuo. The residue was washed with silica. The title compound was obtained by purification by column chromatography on 100° C. MS(m / z) 677.1[M+H] + . Synthesis of (S)-N-(1-(3,5-bis(3-oxoisoindolin-5-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide (10B):

[0424] To (S)-N-(1-(3,5-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide (50 mg, 0.074 mmol) in DME (0.8 mL) and DMF (0.2 mL), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (48 mg, 0.19 mmol), Pd(PPh 3 ) 2 Cl 2 (5 mg), LiCl (2 mg) and 2M K 2 CO 3 Aqueous solution (110 μL) was added. The reaction was heated to 150° C. in a microwave reactor for 20 min. The reaction was purified by RP HPLC to give the desired product. [ka] MS(m / z)798.1[M+H] + . Example 11 [ka] Synthesis of (S)-N-(1-(3,5-di(1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide (11):

[0425] Synthesis of 10B in Example 10 was carried out using 10A and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine. The title compound was prepared according to the method provided for synthesis. [ka] MS(m / z)751.1[M+H] + . Example 12 [ka] Synthesis of (S)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)-N-(2-(3,5-difluorophenyl)-1-(2'-oxo-5-(3-oxoisoindolin-5-yl)-1',2'-dihydro-[2,4'-bipyridin]-6-yl)ethyl)acetamide (12):

[0426] A microwave tube was charged with (S)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)-N-(2-(3,5-difluorophenyl)-1-(2'-methoxy-5-(3-oxoisoindolin-5-yl)-[2,4'-bipyridin]-6-yl)ethyl)acetamide (8C, 5 mg), HCl in 1,4-dioxane (4N, 0.3 mL) and ethanol (0.3 mL). The mixture was heated to 100°C in a microwave synthesizer for 20 min. After cooling, the solvent was removed and the residue was purified by reverse phase HPLC eluting with acetonitrile and water (containing 0.1% TFA) to give 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-indazol-1-yl)-N-(2-(3,5-difluorophenyl)-1-(2,2″-dioxo-1,1″,2,2″-tetrahydro-[4,2′:5′,4″-terpyridin]-6′-yl)ethyl)acetamide (13):

[0427] Utilizing 8B, the title compound (13) was prepared according to the method presented 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-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamate (14A):

[0428] Utilizing 5E, the title compound was prepared following the method presented for the synthesis of compound 4E in Example 4. Synthesis of (S)-tert-butyl (1-(3-bromo-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (14B):

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

[0430] Utilizing 14B, the title compound (14C) was prepared according to the method presented 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-methylbut-1-yn-1-yl)pyridin-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]pyrazol-1-yl)acetamide (14D):

[0431] Synthesis of compound 4G of Example 4 using 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid and 14C The title compound (14D) was prepared according to the method described for. 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]pyrazol-1-yl)-N-((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(1-oxoisoindolin-4-yl)pyridin-2-yl)ethyl)acetamide (14E):

[0432] The title compound (14E) was prepared following the procedure provided for the synthesis of compound 4H in Example 4 utilizing 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine and 14D. [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]pyrazol-1-yl)-N-((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(1-oxoisoindolin-4-yl)pyridin-2-yl)ethyl)acetamide (15):

[0433] The title compound (15) was prepared following the procedure provided for the synthesis of compound 4H in Example 4 utilizing 14D and 2,3-dihydro-1H-isoindol-1-one-4-boronic acid pinacol ester. [ka] MS(m / z)712.18[M+H] + . Example 16 [ka] Synthesis of (S)-N-(1-(3-bromo-6-((trimethylsilyl)ethynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide (16A):

[0434] The title compound (16A) was prepared following the procedure presented for the synthesis of compound 4F in Example 4, utilizing ethynyltrimethylsilane and 5F. MS (m / z) 694.59 [M+H] + . Synthesis of (S)-N-(1-(3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-6-((trimethylsilyl)ethynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide (16B):

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

[0436] Compound 16B (75 mg, 0.1 mmol), NaN 3 (13 mg, 0.2 mmol) and NH 4 Cl (5 mg, 0.1 mmol) was dissolved in DMF (0.5 mL) and stirred at 100° C. overnight. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The organic phase was dried (Na 2 SO 4 ), filtered and concentrated. The crude material was purified by reverse phase HPLC eluting with acetonitrile and water (containing 0.1% TFA) to give 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]pyrazol-1-yl)-N-((S)-2-(3,5-difluorophenyl)-1-(3-(2,4-dioxo-1,2,3,4-tetrahydroquinazolin-8-yl)-6-(3-hydroxy-3-methylbut-1-ynyl)pyridin-2-yl)ethyl)acetamide (17):

[0437] The title compound was prepared following the method provided for the synthesis of compound 4F in Example 4 utilizing 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline-2,4(1H,3H)-dione and 14D. [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]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-2-fluorobenzamide (18):

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

[0439] To 3-bromo-6-chloro-2-fluorobenzonitrile (10 g, 42.7 mmol) in EtOH (100 mL) was added methylhydrazine (9 ml, 171 mmol). The reaction mixture was stirred at 110° C. for 4 h. The reaction was allowed to cool slowly over 4 h, then the solid was filtered off and used without further purification to give the title compound 7 g (containing small amounts of other regioisomers). 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-indazol-3-amine (19C):

[0440] To 7-bromo-4-chloro-1-methyl-1H-indazol-3-amine (3 g, 11.5 mmol) in dioxane (40 mL) and DMF (25 ml), bis(pinaco) To the mixture was added trans-dichlorobis(triphenylphosphine)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). The reaction mixture was stirred at 130° C. for 3 h. The reaction was cooled and diluted with EtOAc, then the solids were filtered off through Celite and silica gel eluting with EtOAc. The mixture was concentrated and purified by flash column chromatography to give 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-indazol-3-yl)methanesulfonamide (19D):

[0441] To 7-bromo-4-chloro-1-methyl-1H-indazol-3-amine (2.6 g, 8.5 mmol) in DCM (30 mL) was added N,N-diisopropylethylamine (5.9 ml, 33.8 mmol), then the reaction was 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 min. The reaction was diluted with water and extracted twice with DCM. The organic layer was dried over sodium sulfate and concentrated. The resulting mixture was dissolved in EtOH (30 ml) and 10N NaOH (8 ml) was added. The reaction was followed by LC / MS and once run (10 min), the reaction was diluted with water and quenched with concentrated HCl to pH 2. The mixture was extracted three times with DCM. The organic layer was dried over sodium sulfate and concentrated until a solid started to precipitate. The mixture is then cooled in a brine / ice bath for 20 minutes and filtered to collect the desired material in two lots that are used without further purification to give 2.1 g of the title compound. MS (m / z) 386.4 [M+H] + . Synthesis of (S)-tert-butyl 1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-ynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamate (19E):

[0442] To N-(4-chloro-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)methanesulfonamide (39 mg, 0.1 mmol) in dioxane (5 mL) and DMF (0.3 ml) was added 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 h. The reaction was cooled and diluted with EtOAc and brine. The mixture was extracted twice with EtOAc and the organic layer was dried over sodium sulfate, concentrated and purified by flash column chromatography to give 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-methylbut-1-ynyl)pyridin-3-yl)-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamide TFA salt (19F):

[0443] To (S)-tert-butyl 1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-ynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamate (30 mg, 0.04 mmol) in DCM (4 mL) was added TFA (2 ml). The reaction mixture was stirred at room temperature for 0.5 h. The reaction was concentrated and used without further purification to give the title compound. MS (m / z) 574.4 [M+H] + . (S)-N-(1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-ynyl)pyridin-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]pyrazol-1-yl)acetamide (19G):

[0444] The title compound (19G) was prepared according to the method presented for the synthesis of compound 4G in Example 4 utilizing 2-((3bS,4aR)-5,5-difluoro-3-(difluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid and (S)-N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-ynyl)pyridin-3-yl)-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamide to yield 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-(methylsulfonamido)-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-ynyl)pyridin-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]pyrazol-1-yl)acetamide (20):

[0446] The title compound was prepared following the method presented for the synthesis of compound 19G utilizing N-(1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)methanesulfonamide and compound 14B. [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] CH 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). 2 Cl 2 To the mixture in (100 mL) was added N,N-diisopropylethylamine (17.4 mL, 100 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 min and then CH 2 Cl 2 This was washed with water and half-brine. The organic layer was separated and diluted with MgSO 4 The mixture was dried at 40° C., filtered and concentrated. The crude product was purified by silica gel chromatography to give 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 min. 2 O (1.06 mL), 15% aqueous NaOH (1.06 mL), and H 2 O (3.18 mL) was then added very slowly to the mixture at 0° C. The resulting precipitate was filtered and washed with THF. The filtrate was concentrated in vacuo to give the crude title compound. MS (m / z): 233.14, [M+H] + . Synthesis of (S)-N-((5-bromo-2-(methylthio)pyrimidin-4-yl)methylene)-2-methylpropane-2-sulfinamide (21C):

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

[0451] To a solution of (S)-N-((5-bromo-2-(methylthio)pyrimidin-4-yl)methylene)-2-methylpropane-2-sulfinamide (21C, 2.97 g, 8.8 mmol) in THF (18 mL) cooled to -78°C, 3,5-difluorobenzylmagnesium bromide (53 mL, 0.25 M in ether, 13.3 mmol) was added dropwise. After stirring at -78°C for 10 min, NH 4 Cl (sat. aq.) (10 ml) was added to the reaction and allowed to warm to ambient temperature. Extracted with EtOAc and the organic layer was washed with Na 2 SO 4 (solid). The solvent was removed and the residue was purified by silica gel chromatography to give the title compound 21D (1.44 g). MS (m / z) 465.87 [M+H] + Synthesis of (S)-1-(5-bromo-2-(methylthio)pyrimidin-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. To this was added 4N HCl / 1,4-dioxane (10.7 mL). The reaction mixture was stirred for 20 minutes and to this was added diethyl ether. The resulting precipitate was collected by vacuum filtration and then dried to give the title product 21E. MS (m / z) 362.02 [ M+H] + . Synthesis of (S)-N-(1-(5-bromo-2-(methylthio)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide (21F):

[0453] A mixture of 2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-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. To this was added N,N-diisopropylethylamine (1.05 mL, 6 mmol) dropwise. The reaction mixture was stirred at 0° C. for 10 min and then slowly poured into ice water with stirring. The resulting precipitate was collected by vacuum filtration and then dried to give 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-indazol-1-yl)-N-(2-(3,5-difluorophenyl)-1-(2-(methylthio)-5-(3-oxoisoindolin-5-yl)pyrimidin-4-yl)ethyl)acetamide (21G):

[0454] In a microwave tube, compound 21F (300 mg, 0.47 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (181 mg, 0.7 mmol) and PdCl 2 [P(Cy) 3 ] 2 (17 mg, 0.023 mmol). To the mixture was added 10 mL of 1,4-dioxane and 1.4 mL of aqueous sodium bicarbonate (1M). The mixture was heated to 155 °C in a microwave synthesizer for 25 min. After cooling to room temperature, it was partitioned between EtOAc and water. The organic layer was separated and washed with brine and then MgSO 4 The residue was purified by silica gel chromatography to give 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-indazol-1-yl)-N-(2-(3,5-difluorophenyl)-1-(2-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-(3-oxoisoindolin-5-yl)pyrimidin-4-yl)ethyl)acetamide (21H):

[0455] Solid CuI (3.3 mg, 0.017 mmol), Pd(dppf)Cl 2 A mixture of 2-methylbut-3-yn-2-ol (7 mg, 0.009 mmol), 2-methylbut-3-yn-2-ol (22 mg, 0.26 mmol) and compound 21G (60 mg, 0.086 mmol) was added to THF (1 mL) and Et 3 N (0.06 mL, 0.4 mmol) was added. The reaction mixture was heated in a microwave at 160° C. for 20 min. After cooling to room temperature, it was diluted with EtOAc. To this was added Si-thiol (130 mg, 1.37 mmol / g) and the mixture was stirred at 40° C. for 1 h. It was then filtered and the filtrate was diluted with 10% NH 4 The organic layer was washed with aqueous OH, water and brine. 4 The mixture was dried at rt, filtered, concentrated, and purified by reverse phase HPLC to give the title compound (21H). [ka] MS(m / z):732.99[M+H] + . Example 22 [ka] Synthesis of N-((S)-1-(5-bromo-2-(methylthio)pyrimidin-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]pyrazol-1-yl)acetamide (22A):

[0456] The title compound (22A) was prepared according to the method presented for the synthesis of compound 21F in Example 21 utilizing 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid and compound 21E. 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]pyrazol-1-yl)-N-((S)-2-(3,5-difluorophenyl)-1-(2-(methylthio)-5-(3-oxoisoindolin-5-yl)pyrimidin-4-yl)ethyl)acetamide (22B):

[0457] The title compound (22B) was prepared by utilizing compound 22A and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one according to the method presented 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 Synthesis of ]pyrazol-1-yl)-N-((S)-2-(3,5-difluorophenyl)-1-(2-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-(3-oxoisoindolin-5-yl)pyrimidin-4-yl)ethyl)acetamide (22C):

[0458] The title compound (22C) was prepared utilizing compound 22B and 2-methylbut-3-yn-2-ol following the procedure provided 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]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-2-(methylthio)pyrimidin-5-yl)-2-fluorobenzamide (23A):

[0459] The title compound (23A) was prepared by utilizing compound 22A and 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide according to the method presented for the synthesis of compound 21G in Example 21. MS (m / z) 683.06 [M+H] + . 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]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-2-(3-hydroxy-3-methylbut-1-yn-1-yl)pyrimidin-5-yl)-2-fluorobenzamide (23B):

[0460] The title compound (23B) was prepared utilizing compound 23A and 2-methylbut-3-yn-2-ol following the procedure provided 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)isoquinolin-1(2H)-one (24A):

[0461] 5-Bromoisoquinolin-1(2H)-one (40 mg, 0.18 mmol) in dioxane (1 mL) was treated with bis(pinacolato)diboron (63 mg, 0.25 mmol) and PdCl 2 [P(Ph) 3 ] 2 (6 mg, 0.01 mmol) was added. The reaction mixture was sealed and heated to 100° C. for 1 h. The reaction 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]pyrazol-1-yl)-N-((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(1-oxo- Synthesis of 1,2-dihydroisoquinolin-5-yl)pyridin-2-yl)ethyl)acetamide (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 1M NaHCO 3 Aqueous solution (0.22 mL, 0.22 mmol) was added. The reaction mixture was sealed and heated to 160° C. in a microwave reactor for 20 min. Upon cooling, the reaction mixture was diluted with EtOAc and washed three times with brine. The organic layer was extracted with Na 2 SO 4 The mixture was dried at 40° C., filtered, concentrated in vacuo, and purified by reverse phase HPLC to give the title compound 24B as a mixture of atropisomers. MS (m / z) 724.2 [M+H] + HPLC retention times 6.95 and 7.09 min (2–98% acetonitrile:water with 0.1% trifluoroacetic acid, 8.5 min gradient on a Phenomonex Kinetex C18 column). (Example 25) [ka] Synthesis of N-((S)-1-(3-(3-amino-1-methyl-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-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]pyrazol-1-yl)acetamide (25):

[0463] The title compound (25) was prepared as a mixture of atropisomers utilizing 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid and 37A 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]pyrazol-1-yl)-N-((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)pyridin-2-yl)ethyl)acetamide (26):

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

[0465] To 3-bromo-6-chloro-2-methylpyridine (1.53 g, 7.41 mmol) in dioxane (4.5 ml) was added hydrazine hydrate (1.8 ml, 37 mmol). The reaction was heated in a microwave reactor at 160° C. for 55 min. After cooling to ambient temperature, the reaction mixture was partitioned between EtOAc and saturated aqueous NaCl. The organics were separated and evaporated in vacuo. The product was used directly in the following step. MS (m / z) 202.0 [M+H] + . Synthesis of 6-bromo-5-methyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (27C):

[0466] 3-Bromo-6-hydrazinyl-2-methylpyridine (4.55 g, 22.52 mmol) was dissolved in DCE (35 ml) and to this was added trichloromethyl chloroformate (2.72 ml, 22.52 mmol). The reaction was stirred at ambient temperature for 1 hour. Hexane (15 ml) was added and the solid was filtered to give the desired product. The volume of the eluent 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]pyridin-3(2H)-one (27D):

[0467] 6-Bromo-5-methyl-[1,2,4]triazolo[4,3-a]pyridine-3(2 The H)-one (3.62 g, 15.87 mmol) was dissolved in bis(pinacolato)diboron (6.05 g, 23.81 mmol), KOAc (3.12 g, 31.75 mmol) and PdCl in dioxane (80 ml). 2 (PCy 3 ) 2 (0.23 g, 0.32 mmol). Argon was bubbled through the reaction solution for 15 min. The reaction was then heated to 85° C. for 15 h. Additional PdCl 2 (PCy 3 ) 2(250 mg) was added and the temperature was raised to 125° C. and heated for 15 h. After cooling to ambient temperature the reaction was partitioned between EtOAc and water. The organics were separated, dried and removed in vacuo. The residue was suspended in EtOAc (50 ml) and the resulting solid was filtered to give the title compound. MS (m / z) 276.2 [M+H] + . Synthesis of (S)-tert-butyl(2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(5-methyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)pyridin-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]pyridin-3(2H)-one (55 mg, 0.2 mmol) were dissolved in dioxane (2 mL) and 1 M NaHCO 3 aqueous solution (0.4 mL) and PdCl 2 (PCy 3 ) 2 (10 mg). The mixture was heated to 150° C. for 20 min. After cooling to ambient temperature, the reaction was partitioned between EtOAc and water. The organics were separated, dried and removed in vacuo and the residue purified by column chromatography on silica to give 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-methylbut-1-yn-1-yl)pyridin-3-yl)-5-methyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (27F):

[0469] The title compound (27F) was prepared as a mixture of atropisomers utilizing 27E following the method presented 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]pyrazol-1-yl)-N-((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(5-methyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)pyridin-2-yl)ethyl)acetamide (27G):

[0470] The title compound (27G) was prepared as a mixture of atropisomers following the procedure presented for the synthesis of 37E in Example 37 utilizing 27F and 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid. [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-indazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-2-fluorobenzamide (28):

[0471] The title compound (28) was prepared according to the method provided for the synthesis of compound 33F in Example 33 utilizing (3-carbamoyl-4-fluorophenyl)boronic acid and 2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid. [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-indazol-3-amine (29A):

[0472] 7-Bromo-1H-indazol-3-amine (75 mg, 0.35 mmol) in dioxane (3 mL) was treated with bis(pinacolato)diboron (126 mg, 0.5 mmol) and PdCl 2 [P(Ph) 3 ] 2 (12 mg, 0.01 mmol) was added. The reaction mixture was sealed and heated to 100° C. for 16 h. The reaction 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-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-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]pyrazol-1-yl)acetamide (29B):

[0473] The title compound (29) was prepared using 29A according to the method presented for the synthesis of compound 24B in Example 24. MS (m / z) 712.4 [M+H] + PLC retention time 6.02 min (2–98% acetonitrile:water with 0.1% trifluoroacetic acid, 8.5 min gradient on a Phenomonex Kinetex C18 column). (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]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-2,3-difluorobenzamide (30):

[0474] The title compound (30) was prepared according to the method presented for the synthesis of compound 33F in Example 33 utilizing 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]pyrazol-1-yl)acetic acid. [ka] MS(m / z)736.1[M+H] + . (Example 31) [ka] Synthesis of (S)-N-(1-(3-(3-amino-1-methyl-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide (31):

[0475] The title compound (31) was prepared as a mixture of atropisomers following the procedure presented for the synthesis of compound 33F in Example 33 utilizing 37A and 2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid. [ka] MS(m / z)746.2[M+H] + . Example 32 [ka] Synthesis of N-((S)-1-(3-(3-amino-1-methyl-1H-indazol-7-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-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]pyrazol-1-yl)acetamide (32):

[0476] Utilizing 37A and following the method presented for the synthesis of compound 33F in Example 33, the title compound (32) was prepared as a mixture of atropisomers. [ka] MS(m / z)708.2[M+H] + . (Example 33) [ka] Synthesis of 7-bromo-1-methyl-1H-indazol-3-amine (33A):

[0477] A solution of 3-bromo-2-fluorobenzonitrile (2 g, 10 mmol) in ethanol (10 mL) in a microwave vial was treated with methylhydrazine (2.1 mL, 40 mmol), sealed and heated to 120° C. in a microwave reactor for 35 min. The reaction was concentrated in vacuo and the crude product was dissolved in EtOAc (30 mL) and washed with water (30 mL) followed by 2M NaCl (aq, 30 mL). The organics were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. The product was purified by silica chromatography to give the title compound. MS (m / z) 227.1 [M+H] + . Synthesis of N-(7-bromo-1-methyl-1H-indazol-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) was added methanesulfonyl chloride (532.0 mg, 4.64 mmol) dropwise at 0° C. The reaction was allowed to warm to room temperature and stirred for 2 h. The reaction was washed with water and diluted with Na 2 SO 4 The mixture was dried over 500 ml, 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 h. The ethanol was removed in vacuo and the pH was adjusted to approximately 2 with 1.0 HCl, then extracted with EtOAc. The organics were washed with Na 2SO 4 The mixture was dried at 40° C., filtered and concentrated. The product was purified by silica chromatography to give 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-indazol-3-yl)methanesulfonamide (33C):

[0479] To 33B (1.2 g, 3.9 mmol) in dioxane (15 mL), bis(pinacolato)diboron (1.9 mg, 5.5 mmol) and PdCl 2 [P(Ph) 3 ] 2 (138 mg, 0.19 mmol) was added. The reaction mixture was sealed and heated to 100° C. for 1 h. The reaction was cooled to room temperature and filtered through Celite using ethyl acetate to rinse the pad. The combined organic phase was concentrated in vacuo and purified by silica gel chromatography to give the title compound. MS (m / z) 352.1 [M+H] + . Synthesis of (S)-tert-butyl (2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-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-indazol-3-yl)methanesulfonamide (33C, 253 mg, 0.72 mmol), PdCl 2 [P(Ph) 3 ] 2 (35 mg, 0.05 mmol) and 1M NaHCO 3Aqueous solution (1.5 mL, 1.5 mmol) was added. The reaction mixture was sealed and heated to 150° C. in a microwave reactor for 20 min. Upon cooling, the reaction mixture was diluted with EtOAc and washed three times with brine. The organic layer was extracted with Na 2 SO 4 The mixture was dried at 40° C., filtered, concentrated in vacuo, and purified by silica gel column chromatography eluting with 0-100% EtOAc in hexanes to give 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-methylbut-1-yn-1-yl)pyridin-3-yl)-1-methyl-1H-indazol-3-yl)methanesulfonamide (33E):

[0481] To a solution of 33D (47 mg, 0.07 mmol) in DCM was added 4M HCl in dioxane (0.7 mL, 2.9 mmol). The reaction mixture was stirred at room temperature for 0.5 h. Upon complete removal of the Boc protecting group, the reaction was concentrated in vacuo to give the title compound 33E as a mixture of atropisomers. Synthesis of 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N-((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)ethyl)acetamide (33F):

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

[0483] 37A and 2-(3-(difluoromethyl)-5,5a,6,6a-...

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