Compounds useful for regulating KLHDC1 and KLHDC2 activity

Abstract

The present disclosure relates to compounds useful for the in vitro, in vitro, or in vivo modulation of KLHDC1 and KLHDC2 activity. The present disclosure also provides a pharmaceutically acceptable composition comprising said compounds, and a method of using the composition in the treatment of various diseases, conditions, and / or disorders.

Description

Technology Field

[0001] Cross-reference

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 602,189 filed on November 22, 2023, the contents of which are incorporated herein by reference in their entirety for all purposes.

[0003] Technology field

[0004] The present disclosure provides a novel compound for regulating KLHDC2 and a method for treating a disease affected by subsequent KLHDC2 activity. Background Technology

[0005] Kelch domain containing protein 2 (KLHDC2) was first identified in 2001 as a uniquely novel and ubiquitously expressed protein ligase associated with the cellular transcription cofactors HCF-1 and HCF-2. Zhou et al . J. Biol. Chem. 2001 , 276 , 28933. KLHDC2 represses LZIP-mediated transcription. Zhou et al LZIP is a cell transcription factor believed to be involved in cell proliferation. Zhou et al KLHDC2 reduces transcription by inhibiting LZIP through regulating or interfering with LZIP's DNA binding activity or ability. Zhou et al Since LZIP possesses tumor suppressor activity, KLHDC2 expression can affect cell proliferation through the inhibition of LZIP. Chin et al . Mol. Cell Biochem . 2007 , 296 , 109.

[0006] Kelch domain containing protein 1 (KLHDC1) was first identified in 2007 and is a close homolog of KLHDC2, sharing 47% identity and 65% similarity at the amino acid sequence level. Chin et al KLHDC1 degrades cleaved redox-inactive SELENOS associated with the generation of reactive oxygen species and ER stress-induced apoptosis. Okumura et al . iScience , 2020 , 23 , 100970.

[0007] Both KLHDC1 and KLHDC2 are widely expressed in all tissues and show increased expression in some cancers. In particular, KLHDC2 is localized to the nucleus, while KLHDC1 is localized to the cytoplasm. Consequently, if the interest is in the inhibition of primarily nuclear processes such as transcription, inhibition of KLHDC2 is desirable, whereas inhibition of KLHDC1 is desirable for the inhibition of primarily cytoplasmic processes. For example, it has been shown that inhibition of KLHDC2 can inhibit LZIP-mediated transcription.

[0008] The product described herein is a novel small molecule that is recognized by the activity of KLHDC1, KLHDC2, or both, and is useful for regulating them.

[0009] The present invention provides a compound capable of regulating KLHDC1 and KLHDC2 activity. The compound is useful, for example, for the treatment or prevention of inflammatory, autoimmune, and proliferative diseases and disorders in subjects requiring it.

[0010] In one aspect, the present invention has the following formula Compounds having

[0011] Or a pharmaceutically acceptable salt is provided, in the above formula, is selected from the group consisting of aryl, heteroaryl, bicyclic aryl, and bicyclic heteroaryl, wherein the aryl, heteroaryl, bicyclic aryl, and bicyclic heteroaryl are unsubstituted or substituted with alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, halo, or heteroaryl; R 1 silver , , , , , , , , , or or; or each R 1 is further substituted with alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, halo, or heteroaryl, wherein R 5 is independently hydrogen or alkyl; R 6 is a hydrogen or amino acid side chain; R 7 -O R 7a , -N R 7a R 7b , or and, here R 7a and R 7b is independently hydrogen or alkyl; aa is 1 to 5; R 8 is a heteroalkyl; R 9 is aryl, benzo[ d ][1,3]dioxol, heteroalkyl, or heteroaryl comprising at least one nitrogen, oxygen, or sulfur, wherein the aryl and heteroaryl are unsubstituted or substituted with alkyl, -OH, hydroxyalkyl, alkoxy, cyano, pyridazine, and pyrazol;R 10 is hydrogen, alkyl, or hydroxyalkyl; R 11 is a heteroaryl, where the heteroaryl is unsubstituted or alkyl, haloalkyl, alkoxy, -OH, -C(O)N R 11a R 11b , or It is replaced with, and here R 11a and R 11b is independently hydrogen or alkyl; X 6 It is oxygen or N R 5 And; t 1 is 1 to 5; t 2 is 0 or 1 and; R 3 Silver hydrogen, , aryl, or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted with an alkyl, heteroalkyl, heterocycloalkyl, and / or halo; X 5 is nitrogen or oxygen; R 3a is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, a 5- to 15-membered spiro dicyclic heterocycloalkyl containing at least one nitrogen, wherein at least one nitrogen is unsubstituted or substituted with alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl; -C(O)-(a 3- to -8-membered heterocycloalkyl containing at least one nitrogen, wherein at least one nitrogen is unsubstituted or substituted with alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl); 3- to -8-membered heterocycloalkyl containing at least one nitrogen, wherein at least one nitrogen is unsubstituted or substituted with an alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl; -alkylene-(3- to -8-membered heterocycloalkyl containing at least one nitrogen, wherein at least one nitrogen is unsubstituted or substituted with an alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl); -alkylene-N( R 3aa )C(O)alkyl, where R 3aa is hydrogen or alkyl; or X 5 If it is oxygen, it is absent; R 3b is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl; and R 3c represents 1, 2, or 3 hydrogens, alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, cyano, alkoxy, or halo.

[0012] In one aspect, the present invention has the following formula A compound having or a pharmaceutically acceptable salt thereof is provided, wherein Is ; ; ; ; ; or and; here X 1 is CH, C-OH, C-alkyl, C-alkoxy, C-haloalkoxy, or nitrogen; X 1a is CH, C-OH, C-alkyl, C-alkoxy, C-haloalkoxy, or nitrogen; X 2 is CH, C-OH, C-alkyl, C-alkoxy, C-haloalkoxy, or nitrogen; X 3 It is carbon or nitrogen; X 4 is nitrogen or oxygen; Y is CH or nitrogen; is a single bond or a double bond; R 1 silver , , , , , , , , , or or; or each R 1 is further substituted with alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, halo, or heteroaryl, wherein each R 1a is independently -CH2- or -C(O)-, andR 1b is independently -CH2- or -NH-; R 5 is independently a hydrogen alkyl or cycloalkyl; R 6 is a hydrogen or amino acid side chain; R 7 -O R 7a , -N R 7a R 7b , or and, here R 7a and R 7b is independently hydrogen or alkyl; aa is 1 to 5; R 8 is a heteroalkyl; R 9 Is , , or and, here is an aryl or heteroaryl, where the aryl or heteroaryl is unsubstituted or substituted with an alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, halo, or heteroaryl; and each R 9a is independently hydrogen or alkyl; R 9b is -C(O)O R 9c or and; each R 9c is hydrogen or C 1-5 It is alkyl; and bb is 1 or 2 and; cc is 0, 1, or 2; aryl, benzo[ d][1,3]dioxol, heteroalkyl, or heteroaryl comprising at least one nitrogen, oxygen, or sulfur, wherein the aryl and heteroaryl are unsubstituted or substituted with alkyl, -OH, hydroxyalkyl, alkoxy, cyano, pyridazine, and pyrazol; R 10 is hydrogen, alkyl, or hydroxyalkyl; R 11 is a heteroaryl, where the heteroaryl is unsubstituted or alkyl, haloalkyl, alkoxy, -OH, -C(O)N R 11a R 11b , or It is replaced with, and here R 11a and R 11b is independently hydrogen or alkyl; X 6 It is oxygen or N R 5 And; t 1 is 1 to 5; t 2 is 0 or 1 and; R 2 is independently hydrogen, -OH, -SH, -S-alkyl, -N R 7a R 7b , alkyl, alkoxy, or haloalkoxy, 1 to 3 of which are; R 3 In the case where it exists, hydrogen, , , aryl, or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted with an alkyl, heteroalkyl, heterocycloalkyl, and / or halo; X 5 is nitrogen or oxygen; R 3a is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, a 5- to 15-membered spiro dicyclic heterocycloalkyl comprising at least one nitrogen, wherein at least one nitrogen is unsubstituted or substituted with alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl; -C(O)-(a 3- to 8-membered heterocycloalkyl comprising at least one nitrogen, wherein at least one nitrogen is unsubstituted or substituted with alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, or -C(O)-alkylene-C(O) R 3aaa It is replaced with, and here R 3aaa is -O R 7a , -N R 7a R 7b or is alkyl); is a 3- to -8-membered heterocycloalkyl containing at least one nitrogen, wherein at least one nitrogen is unsubstituted or substituted with an alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl; -alkylene-(a 3- to -8-membered heterocycloalkyl containing at least one nitrogen, wherein at least one nitrogen is unsubstituted or substituted with an alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl); -alkylene-N( R 3aa )C(O)alkyl, where R 3aa is hydrogen or alkyl; -C(O)-alkylene-C(O) R 3aaa and, here R 3aaa is -O R 7a , -N R 7a R 7b or alkyl; or X 5 If it is oxygen, it is absent; R 3b is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl; R 3c represents 1, 2, or 3 hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, cyano, alkoxy, or halo; R 4 is hydrogen, alkyl, haloalkyl, arylalkyl, aryl, heteroaryl, or heterocycloalkyl where present, wherein aryl, heteroaryl, or heterocycloalkyl is unsubstituted or alkyl, alkenyl, alkynyl, heteroalkyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, -C(O)-alkylene-C(O) R 3aaa It is replaced with, and here R 3aaa is -O R 7a , -N R 7a R 7b or alkyl; or -C(O)N R 4a R 4b and, here R 4a and R 4b is independently hydrogen or alkyl; is a 5- to 15-one-spiro dicyclic heterocycloalkyl containing at least one nitrogen, wherein at least one nitrogen is unsubstituted or is an alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, or -C(O)-alkylene-C(O) R 3aaa It is replaced with, and here R 3aaa is -O R 7a , -NR7a R 7b or alkyl; -NR4a R 4b and, here R 4a and R 4b is independently hydrogen, alkyl, aryl, heteroaryl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, or arylalkyl; is a 3- to 8-membered heterocycloalkyl comprising at least one nitrogen, wherein at least one nitrogen is unsubstituted or acyl, -C(O)-heteroalkylene-N R 4a R 4b , alkyl, -C(O)-alkylene-COO R 5 , -C(O)-alkylene-C(O)N R 4a R 4b , -C(O)-alkylene-C(O)N( R 4a )-heteroalkylene-substituted with halo, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl, where R 4a and R 4b is independently hydrogen, alkyl, or acyl; -alkylene-N R 4a R 4b and, here R 4a and R 4b is independently hydrogen, alkyl, or acyl; or -N( R 5 )C(O)-alkylene-N R 4a R 4b and, here R 4a and R 4b is independently hydrogen, alkyl, or acyl.

[0013] In one aspect, the present invention has the following formula A compound having or a pharmaceutically acceptable salt thereof is provided, wherein Is ; ; ; ; or and; here X 1 is CH, C-OH, C-alkyl, C-alkoxy, C-haloalkoxy, or nitrogen; X 1a is CH, C-OH, C-alkyl, C-alkoxy, C-haloalkoxy, or nitrogen; X 2 is CH, C-OH, C-alkyl, C-alkoxy, C-haloalkoxy, or nitrogen; X 3 It is carbon or nitrogen; X 4 is nitrogen or oxygen; Y is CH or nitrogen; is a single bond or a double bond; R 1 silver , , , , , , , , , or or

[0014] each R 1 is further substituted with alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, halo, or heteroaryl, wherein each R 1a is independently -CH2- or -C(O)-, and R 1b is independently -CH2- or -NH-; R 5 is independently hydrogen or alkyl; R 6 is a hydrogen or amino acid side chain; R 7 -O R 7a , -N R 7a R 7b , or and, here R 7a and R 7b is independently hydrogen or alkyl; aa is 1 to 5; R 8 is a heteroalkyl; R 9 is aryl, benzo[ d ][1,3]dioxol, heteroalkyl, or heteroaryl comprising at least one nitrogen, oxygen, or sulfur, wherein the aryl and heteroaryl are unsubstituted or substituted with alkyl, -OH, hydroxyalkyl, alkoxy, cyano, pyridazine, and pyrazol; R 10 is hydrogen, alkyl, or hydroxyalkyl; R 11 is a heteroaryl, where the heteroaryl is unsubstituted or alkyl, haloalkyl, alkoxy, -OH,

[0015] -C(O)N R 11a R 11b , or It is replaced with, and here R 11a and R 11b is independently hydrogen or alkyl; X 6 It is oxygen or N R 5 And; t 1 is 1 to 5; t 2 is 0 or 1 and; R 2 is independently one to three of hydrogen, -OH, alkyl, alkoxy, or haloalkoxy; R 3 In the case where it exists, hydrogen, , aryl, or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted with an alkyl, heteroalkyl, heterocycloalkyl, and / or halo; X 5 is nitrogen or oxygen; R 3a is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, a 5- to 15-one-spiro dicyclic heterocycloalkyl comprising at least one nitrogen, wherein at least one nitrogen is unsubstituted or substituted with alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl;

[0016] -C(O)-(a 3- to -8-membered heterocycloalkyl containing at least one nitrogen, wherein at least one nitrogen is unsubstituted or substituted with an alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl); a 3- to -8-membered heterocycloalkyl containing at least one nitrogen, wherein at least one nitrogen is unsubstituted or substituted with an alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl; -alkylene-(a 3- to 8-membered heterocycloalkyl containing at least one nitrogen, wherein at least one nitrogen is unsubstituted or substituted with an alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl); -alkylene-N( R 3aa )C(O)alkyl, where R 3aa is hydrogen or alkyl; or X 5 If it is oxygen, it is absent; R 3b is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl; R 3c represents 1, 2, or 3 hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, cyano, alkoxy, or halo; R 4 is hydrogen, alkyl, haloalkyl, arylalkyl, aryl, heteroaryl, or heterocycloalkyl where present, wherein aryl, heteroaryl, or heterocycloalkyl is unsubstituted or alkyl, alkenyl, alkynyl, heteroalkyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, or -C(O)NR 4a R 4b It is replaced with, and here R 4a and R 4b is independently hydrogen or alkyl; is a 5- to 15-one-spiro dicyclic heterocycloalkyl comprising at least one nitrogen, wherein at least one nitrogen is unsubstituted or substituted with an alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl; -N R 4a R 4b and, here R 4a and R 4b is independently hydrogen, alkyl, aryl, heteroaryl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, or arylalkyl; is a 3- to 8-membered heterocycloalkyl containing at least one nitrogen, wherein at least one nitrogen is unsubstituted or acyl,

[0017] -C(O)-heteroalkylene-N R 4a R 4b , alkyl, -C(O)-alkylene-COO R 5 , -C(O)-alkylene-C(O)N R 4a R 4b , substituted with heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl, where R 4a and R 4b is independently hydrogen, alkyl, or acyl; -alkylene-N R 4a R 4b and, here R 4a and R 4b is independently hydrogen, alkyl, or acyl; or -N( R 5 )C(O)-alkylene-N R 4a R 4b and, here R 4a and R 4b is independently hydrogen, alkyl, or acyl.

[0018] In one aspect, the present invention has the following formula A compound having or a pharmaceutically acceptable salt thereof is provided, wherein Is ; ; or and; here X 1 It is CH or nitrogen; X 2 is CH or nitrogen; X 3 It is carbon or nitrogen; X 4 is nitrogen or oxygen; Y is CH or nitrogen; R 1 silver , , , , , , , , , or and, here R 5 is independently hydrogen or alkyl; R 6 is a hydrogen or amino acid side chain; R 7 -O R 7a , -N R 7a R 7b , or and, here R 7a and R 7b is independently hydrogen or alkyl; aa is 1 to 5; R 8 is a heteroalkyl; R 9 is aryl, benzo[ d ][1,3]dioxol, heteroalkyl, or heteroaryl comprising at least one nitrogen, oxygen, or sulfur, wherein the aryl and heteroaryl are unsubstituted or substituted with alkyl, -OH, hydroxyalkyl, alkoxy, cyano, pyridazine, and pyrazol; R 10 is hydrogen, alkyl, or hydroxyalkyl; R 11 is a heteroaryl, where the heteroaryl is unsubstituted or alkyl, haloalkyl, alkoxy, -OH,

[0019] -C(O)N R 11a R 11b , or It is replaced with, and here R 11a and R 11b is independently hydrogen or alkyl; X 6 It is oxygen or N R 5 And; t 1 is 1 to 5; t 2 is 0 or 1 and; R 2 is independently one to three of hydrogen, -OH, alkyl, alkoxy, or haloalkoxy; R 3 In the case where it exists, hydrogen, , aryl, or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted with an alkyl, heteroalkyl, heterocycloalkyl, and / or halo; X 5 is nitrogen or oxygen; R 3a is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, a 5- to 15-membered spiro dicyclic heterocycloalkyl containing at least one nitrogen, wherein at least one nitrogen is unsubstituted or substituted with alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl, and -C(O)-(a 3- to 8-membered heterocycloalkyl containing at least one nitrogen, wherein at least one nitrogen is unsubstituted or substituted with alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl), a 3- to 8-membered heterocycloalkyl containing at least one nitrogen It is a heterocycloalkyl, wherein at least one nitrogen is unsubstituted or substituted with an alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl, and -alkylene-(a 3- to 8-membered heterocycloalkyl containing at least one nitrogen, wherein at least one nitrogen is unsubstituted or substituted with an alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl), or X 5 If it is oxygen, it is absent; R 3b is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl; R 3c is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, cyano, or halo; R 4 is hydrogen, alkyl, haloalkyl, arylalkyl, aryl, heteroaryl, or heterocycloalkyl where present, wherein the aryl, heteroaryl, or heterocycloalkyl is unsubstituted or substituted with an alkyl, alkenyl, alkynyl, heteroalkyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl; is a 5- to 15-one-spiro dicyclic heterocycloalkyl comprising at least one nitrogen, wherein at least one nitrogen is unsubstituted or substituted with an alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl; -N R 4a R 4b and, here R 4a and R 4b is independently hydrogen, alkyl, aryl, heteroaryl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, or arylalkyl; is a 3- to 8-membered heterocycloalkyl comprising at least one nitrogen, wherein at least one nitrogen is unsubstituted or acyl, -C(O)-heteroalkylene-N R 4a R 4b , alkyl, -C(O)-alkylene-COO R 5 , -C(O)-alkylene-C(O)N R 4a R 4b , substituted with heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl, where R 4a and R 4b is independently hydrogen, alkyl, or acyl; -alkylene-N R 4a R 4b and, here R 4a and R 4b is independently hydrogen, alkyl, or acyl; or -N( R 5 )C(O)-alkylene-N R 4a R 4b and, here R 4a and R 4b is independently hydrogen, alkyl, or acyl.

[0020] In one aspect, the present invention has the following formula A compound having or a pharmaceutically acceptable salt thereof is provided, wherein each is independently an arylene or heteroarylene, where the arylene or heteroarylene is unsubstituted or one or more alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, halo, heteroaryl, or -C(O)N R 1 R 2 It is replaced with, and here R 1 and R 2 is independently hydrogen or alkyl; is a cycloalkylene or heterocycloalkylene, wherein the cycloalkylene or heterocycloalkylene is unsubstituted or one or more alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, halo, heteroaryl, or -C(O)N R 1 R 2 It is replaced with, and here R 1 and R 2 is independently hydrogen or alkyl; each X 1 -N( R 3 )-, oxygen, or sulfur, and here R 3 It is hydrogen or alkyl; X 2 is N( R 4 ), oxygen, or sulfur, and here R 4 is hydrogen or alkyl; and each n is an integer from 1 to 5.

[0021] In one aspect, the present invention has the following formula A compound having or a pharmaceutically acceptable salt thereof is provided, wherein is a cycloalkylene or heterocycloalkylene, wherein the cycloalkylene or heterocycloalkylene is unsubstituted or one or more alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, halo, heteroaryl, or -C(O)N R a R b It is replaced with, and here R a and R b is independently hydrogen or alkyl; is an arylene or heteroarylene, where the arylene or heteroarylene is unsubstituted or one or more alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, halo, heteroaryl, or -C(O)N R a R b It is replaced with, and here R a and R b is independently hydrogen or alkyl; each R 1 is independently hydrogen or alkyl; R 2 is hydrogen or alkyl; and each n is an independent integer from 1 to 8.

[0022] In one aspect, the following equation A compound having or a pharmaceutically acceptable salt thereof is provided, wherein and is independently an arylene or heteroarylene, where the arylene or heteroarylene is unsubstituted or one or more alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, halo, heteroaryl, or -C(O)N R a R b It is replaced with, and here R a and R b is independently hydrogen or alkyl; each R 1 is independently hydrogen or alkyl; R 2 is hydrogen or alkyl; and each n is an independent integer from 1 to 8.

[0023] In another aspect, the present invention provides a pharmaceutical composition. The pharmaceutical composition comprises one or more pharmaceutically acceptable carriers, diluents, and / or excipients together with the following formulas described herein. It includes compounds having

[0024] In another aspect, the present invention provides a method for treating a disease or disorder in a subject in need, the method being the following formula as described herein The method comprises the step of administering a therapeutically effective amount of a compound having or a pharmaceutical composition thereof to a subject. In certain embodiments, the present invention relates to the following formula described herein for use in therapy. Compounds and compositions having [the following] are provided. In certain embodiments, the present invention provides the following formulas described herein for use in the treatment or prevention of inflammatory, autoimmune, or proliferative diseases and disorders. Compounds and compositions having are provided. In certain embodiments, the present invention provides the following formula described herein for the manufacture of a medicine. Uses of compounds and compositions having are provided. In certain embodiments, the present invention provides the following formula described herein for the manufacture of medicines for the treatment or prevention of inflammatory, autoimmune, or proliferative diseases and disorders. Uses of compounds and compositions having are provided. In certain embodiments, the disease or disorder is an autoimmune disease or disorder. In certain embodiments, the disease or disorder is a proliferative disease or disorder, e.g., T-cell lymphoma. In certain embodiments, the disease or disorder is cancer.

[0025] In a specific embodiment, the following formula described herein A compound or composition having is intended for use in the treatment of cancer. Specific details for implementing the invention

[0026] definition

[0027] For the purposes of this invention, chemical elements are identified according to the Periodic Table of Elements, CAS version, Handbook of Chemistry and Physics, 75th edition. Additionally, general principles of organic chemistry are described in “Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry,” 5th edition, edited by Smith, MB and March, J., John Wiley & Sons, New York: 2001, the contents of which are incorporated herein by reference.

[0028] As described herein, a “protecting group” refers to a moiety or functionality introduced into a molecule by chemical modification of a functional group to obtain chemoselectivity in a subsequent chemical reaction. Standard protecting groups are provided in Wuts and Greene: “Greene’s Protective Groups in Organic Synthesis,” 4th edition, Wuts, PGM and Greene, TW, Wiley-Interscience, New York: 2006.

[0029] As described herein, the compounds of the present invention may be optionally substituted with one or more substituents such as those generally exemplified herein or exemplified by specific classes, subclasses, and / or species of the present description.

[0030] As used herein, the term “hydroxyl” or “hydroxy” refers to the -OH moiety.

[0031] As used herein, the term “aliphatic” encompasses the terms alkyl, alkenyl, and alkynyl, each of which is optionally substituted as shown below.

[0032] As used herein, “alkyl” or divalent “alkylene” groups refer to saturated aliphatic hydrocarbon groups comprising 1 to 12 (e.g., 1 to 8, 1 to 6, or 1 to 4) carbon atoms. Alkyl or alkylene groups may be straight-chain or branched. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec -butyl, tert -butyl, n -pentyl, n- Includes, but is not limited to, heptyl or 2-ethylhexyl. Examples of alkylene groups include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, or -CH2CH2CH2CH2CH2CH2CH2-. The alkyl or alkylene group is halo, phospho, cycloaliphatic (e.g., cycloalkyl or cycloalkenyl), heterocycloaliphatic (e.g., heterocycloalkyl or heterocycloalkenyl), aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl (e.g., (aliphatic) carbonyl, (cycloaliphatic) carbonyl, or (heterocycloaliphatic) carbonyl), nitro, cyano (i.e., -CN), amido (e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, It may be substituted (i.e., optionally substituted) with one or more substituents such as arylaminocarbonyl, or heteroarylaminocarbonyl), amino (e.g., aliphatic amino, cycloaliphatic amino, or heterocycloaliphatic amino), sulfonyl (e.g., aliphatic-SO2-, cycloaliphatic-SO2-, or aryl-SO2-), sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carboxy, carbamoyl, cycloaliphatic oxy, heterocycloaliphatic oxy, aryloxy, heteroaryloxy, aracleyloxy, heteroarylalkoxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxy).Without limitation, some examples of substituted alkyls include carboxyalkyls (e.g., HOOC-alkyl, alkoxycarbonylalkyl, and alkylcarbonyloxyalkyl), cyanoalkyl, hydroxyalkyl, alkoxyalkyl, acylalkyl, aralkyl, (alkoxyaryl)alkyl, (sulfonylamino)alkyl (e.g., (alkyl-SO2-amino)alkyl), aminoalkyl, amidoalkyl, (cycloaliphatic)alkyl, or haloalkyl.

[0033] As used herein, the “alkenyl” group refers to an aliphatic carbon group comprising 2 to 8 (e.g., 2 to 4 or 2 to 6) carbon atoms and at least one double bond. Like alkyl groups, the alkenyl group may be straight-chain or branched. Examples of alkenyl groups include, but are not limited to, allyl, 1- or 2-isopropenyl, 2-butenyl, and 2-hexenyl. The alkenyl group is halo, phospho, cycloaliphatic (e.g., cycloalkyl or cycloalkenyl), heterocycloaliphatic (e.g., heterocycloalkyl or heterocycloalkenyl), aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl (e.g., (aliphatic) carbonyl, (cycloaliphatic) carbonyl, or (heterocycloaliphatic) carbonyl), nitro, cyano, amido (e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, or It may be optionally substituted with one or more substituents such as heteroarylaminocarbonyl), amino (e.g., aliphatic amino, cycloaliphatic amino, heterocycloaliphatic amino, or aliphatic sulfonylamino), sulfonyl (e.g., alkyl-SO2-, cycloaliphatic-SO2-, or aryl-SO2-), sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carboxy, carbamoyl, cycloaliphatic oxy, heterocycloaliphatic oxy, aryloxy, heteroaryloxy, aracleyloxy, heteroaralcoxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxy).Some examples of substituted alkenyls, without limitation, include cyanoalkenyl, alkoxyalkenyl, acylalkenyl, hydroxyalkenyl, aralkenyl, (alkoxyaryl)alkenyl, (sulfonylamino)alkenyl (e.g., (alkyl-SO2-amino)alkenyl), aminoalkenyl, amidoalkenyl, (cycloaliphatic)alkenyl, or haloalkenyl.

[0034] As used herein, the “alkynyl” group refers to an aliphatic carbon group comprising 2 to 8 (e.g., 2 to 4 or 2 to 6) carbon atoms and having at least one triple bond. The alkynyl group may be straight or branched. Examples of alkynyl groups include, but are not limited to, propargyl and butynyl. The alkynyl group is aroyl, heteroaroyl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, nitro, carboxyl, cyano, halo, hydroxy, sulfo, mercapto, sulfanyl (e.g., aliphatic sulfanyl or cycloaliphatic sulfanyl), sulfinyl (e.g., aliphatic sulfinyl or cycloaliphatic sulfinyl), sulfonyl (e.g., aliphatic-SO2-, aliphatic amino-SO2-, or cycloaliphatic-SO2-), amido (e.g., aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, cycloalkylcarbonylamino, arylaminocarbonyl, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, It may be optionally substituted with one or more substituents such as (cycloalkylalkyl)carbonylamino, heteroarylkylcarbonylamino, heteroarylcarbonylamino, or heteroarylaminocarbonyl), urea, thiourea, sulfamoyl, sulfamide, alkoxycarbonyl, alkylcarbonyloxy, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, acyl (e.g., (cycloaliphatic)carbonyl or (heterocycloaliphatic)carbonyl), amino (e.g., aliphatic amino), sulfoxy, oxo, carboxy, carbamoyl, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, or (heteroaryl)alkoxy.

[0035] As used herein, “heteroalkyl” refers to an alkyl group in which one or more carbon atoms are replaced by heteroatoms. As used herein, “heteroalkenyl” refers to an alkenyl group in which one or more carbon atoms are replaced by heteroatoms. As used herein, “heteroalkynyl” refers to an alkynyl group in which one or more carbon atoms are replaced by heteroatoms. Suitable heteroatoms include, but are not limited to, halos, nitrogen, oxygen, and sulfur atoms. Heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted. Examples of heteroalkyl moiety include, but are not limited to, aminoalkyl, sulfonylalkyl, and sulfinylalkyl. Examples of heteroalkyl moiety also include, but are not limited to, methylamino, methylsulfonyl, and methylsulfinyl.

[0036] As used herein, the “amido” group includes both “aminocarbonyl” and “carbonylamino”. When these terms are used alone or in combination with other groups, or when used as a terminal, -N( R X )-C(O)- R Y or -C(O)-N( R X Refers to an amido group such as )2, and when used internally -C(O)-N( R X )- or -N( R X Refers to )-C(O)-, where R X and R Y It may be aliphatic, cycloaliphatic, aryl, araliphatic, heterocycloaliphatic, heteroaryl, or heteroaraliphatic. Examples of the amido group include alkylamido (e.g., alkylcarbonylamino or alkylaminocarbonyl), (heterocycloaliphatic)amido, (heteroaralkyl)amido, (heteroaryl)amido, (heterocycloalkyl)alkylamido, arylamido, aralkylamido, (cycloalkyl)alkylamido, or cycloalkylamido.

[0037] As used herein, the “amino” group is -N R X R Y Refers to, here R X and R Y Each is independently hydrogen (H or -H), aliphatic, cycloaliphatic, (cycloaliphatic)aliphatic, aryl, araliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, heteroaryl, carboxyl, sulfanyl, sulfinyl, sulfonyl, (aliphatic)carbonyl, (cycloaliphatic)carbonyl, ((cycloaliphatic)aliphatic)carbonyl, arylcarbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, (heteroaryl)carbonyl, or (heteroaraliphatic)carbonyl, each of which is defined elsewhere in this invention and is optionally substituted. Examples of amino groups include alkylamino, dialkylamino, or arylamino. Where the term “amino” is not a terminal group (e.g., alkylcarbonylamino), it is -N R X Indicated by -, here R X has the same meaning as defined above.

[0038] As used herein, the “aryl” group, used alone or as part of a larger moiety as in “araclel,” “aralcoxi,” or “aryloxyalkyl,” refers to a monocyclic (e.g., phenyl); a bicyclic (e.g., indenyl, naphthalenyl, tetrahydronaphthyl, or tetrahydroindenyl); and a tricyclic (e.g., fluorenyl tetrahydrofluorenyl, tetrahydroanthracenyl, or anthracenyl) ring system, wherein the monocyclic ring system is aromatic, or at least one of the rings in the bicyclic or tricyclic ring system is aromatic. The bicyclic and tricyclic groups comprise a benzofused (e.g., 2-membered or 3-membered, or bicyclic or tricyclic carbocyclic) ring. For example, the benzofused group comprises two or more C 4-8It includes a phenyl group fused to a carbocyclic moiety. The aryl is aliphatic (e.g., alkyl, alkenyl, or alkynyl); cycloaliphatic; (cycloaliphatic)aliphatic; heterocycloaliphatic; (heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy; (cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy; heteroaryloxy; (aralaliphatic)oxy; (heteroaralaliphatic)oxy; aroyl; heteroaroyl; amino; oxo (i.e., on a non-aromatic carbon within the carbocyclic ring of a benzofused bicyclic or tricyclic aryl); nitro; carboxy; amido; Acyl (e.g., (aliphatic) carbonyl; (cycloaliphatic) carbonyl; ((cycloaliphatic)aliphatic) carbonyl; (aralaliphatic) carbonyl; (heterocycloaliphatic) carbonyl; ((heterocycloaliphatic)aliphatic) carbonyl; or (heteroaralaliphatic) carbonyl); sulfonyl (e.g., aliphatic-SO2- or amino-SO2-); sulfinyl (e.g., aliphatic-S(O)- or cycloaliphatic-S(O)-); sulfanyl (e.g., aliphatic-S-); cyano; halo; hydroxy; mercapto; sulfoxy; urea; thiourea; sulfamoyl; sulfamide; or carbamoyl is optionally substituted with one or more substituents. Alternatively, the aryl may be unsubstituted.

[0039] Non-limiting examples of substituted aryls include haloaryls (e.g., mono-, di- (e.g. p,m-Dihaloaryl), and (tri-halo)aryl); (carboxy)aryl (e.g., (alkoxycarbonyl)aryl, ((aralkyl)carbonyloxy)aryl, and (alkoxycarbonyl)aryl); (amido)aryl (e.g., (aminocarbonyl)aryl, (((alkylamino)alkyl)aminocarbonyl)aryl, (alkylcarbonyl)aminoaryl, (arylaminocarbonyl)aryl, and (((heteroaryl)amino)carbonyl)aryl); aminoaryl (e.g., ((alkylsulfonyl)amino)aryl or ((dialkyl)amino)aryl); (cyanoalkyl)aryl; (alkoxy)aryl; (sulfamoyl)aryl (e.g., (aminosulfonyl)aryl); (alkylsulfonyl)aryl; (cyano)aryl; (hydroxyalkyl)aryl; ((alkoxy)alkyl)aryl; (hydroxy)aryl, ((carboxy)alkyl)aryl; (((dialkyl)amino)alkyl)aryl; (nitroalkyl)aryl; (((alkylsulfonyl)amino)alkyl)aryl; ((heterocycloaliphatic)carbonyl)aryl; ((alkylsulfonyl)alkyl)aryl; (cyanoalkyl)aryl; (hydroxyalkyl)aryl; (alkylcarbonyl)aryl; alkylaryl; (trihaloalkyl)aryl; p -amino- m - Alkoxycarbonylaryl; p -amino- m -Cyanoaryl; p -Hello- m -aminoaryl; or ( m -(Heterocycloaliphatic)- o - Contains (alkyl))aryl.

[0040] As used herein, “araliphatic,” such as an “aralkyl” group, refers to an aliphatic group substituted with an aryl group (e.g., C 1-4 It refers to an alkyl group. “Aliphatic,” “alkyl,” and “aryl” are defined elsewhere in this application. An example of an aryliphatic group, such as an arylkyl group, is benzyl.

[0041] As used herein, the “araclel” group is an alkyl group substituted with an aryl group (e.g., C 1-4It refers to an alkyl group. Both “alkyl” and “aryl” are defined above. An example of an aryl group is benzyl. Aralyl is aliphatic (e.g., including haloalkyl groups such as alkyl, alkenyl, or alkynyl, carboxyalkyl, hydroxyalkyl, or trifluoromethyl), cycloaliphatic (e.g., cycloalkyl or cycloalkenyl), (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, ararchyloxy, heteroararchyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, amido (e.g., aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, ararchylcarbonylamino, (heterocycloalkyl)carbonylamino, It is optionally substituted with one or more substituents such as (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, or heteroarylalkylcarbonylamino), cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.

[0042] As used herein, “bicyclic ring systems” comprise a 6- to 12-membered (e.g., 8- to 12-membered or 9-, 10-membered, or 11-membered) structure forming two rings, wherein the two rings have at least one atom in common (e.g., two atoms in common). Bicyclic ring systems include bicycloaliphatic (e.g., bicycloalkyl or bicycloalkenyl), bicycloheteroaliphatic, bicyclic aryls, and bicyclic heteroaryls.

[0043] As used herein, “cycloaliphatic” groups include “cycloalkyl” groups and “cycloalkenyl” groups, each of which is optionally substituted as shown below.

[0044] As used herein, the “cycloalkyl” group refers to a saturated carbocyclic monocyclic or bicyclic (fused, bridged, or spiro) ring of 3 to 10 (e.g., 5 to 10) carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, cubyl, octahydro-indenyl, decahydro-naphthyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decyl, bicyclo[2.2.2]octyl, adamantyl, spiro[3.3]heptanyl, or ((aminocarbonyl)cycloalkyl)cycloalkyl.

[0045] As used herein, the “cycloalkenyl” group refers to a non-aromatic carbocyclic ring of 3 to 10 (e.g., 4 to 8) carbon atoms having one or more double bonds. Examples of cycloalkenyl groups include cyclopentenyl, 1,4-cyclohexa-di-enyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl, bicyclo[2.2.2]octenyl, or bicyclo[3.3.1]nonenyl.

[0046] The “cycloalkyl” or “cycloalkenyl” group is phospho, aliphatic (e.g., alkyl, alkenyl, or alkynyl), cycloaliphatic, (cycloaliphatic)aliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy, heteroaryloxy, (aralaliphatic)oxy, (hetero-aralaliphatic)oxy, aroyl, hetero-arroyl, amino, amido (e.g., (aliphatic)carbonylamino, (cycloaliphatic)carbonylamino, ((cycloaliphatic)aliphatic)carbonylamino, (aryl)carbonylamino, (aralaliphatic)carbonylamino, (heterocycloaliphatic)carbonylamino, ((heterocycloaliphatic)aliphatic)carbonylamino, With one or more substituents such as (heteroaryl)carbonylamino, or (heteroaraliponic)carbonylamino), nitro, carboxyl (e.g., HOOC-, alkoxycarbonyl, or alkylcarbonyloxy), acyl (e.g., (cycloaliphatic)carbonyl, ((cycloaliphatic)aliphatic)carbonyl, (araliponic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, or (heteroaraliponic)carbonyl, cyano, halo, hydroxy, mercapto, sulfonyl (e.g., alkyl-SO2- and aryl-SO2-), sulfinyl (e.g., alkyl-S(O)-), sulfanyl (e.g., alkyl-S-), sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl) It can be selectively substituted.

[0047] As used herein, the term “heterocycloaliphatic” includes heterocycloalkyl groups and heterocycloalkenyl groups, each of which is optionally substituted as shown below.

[0048] As used herein, “heterocycloalkyl” or divalent “heterocycloalkylene” groups refer to a 3- to 15-membered monocyclic or dicyclic (e.g., 5- to 10-membered monocyclic or dicyclic) saturated ring structure (e.g., fused, cross-linked, or spiro), wherein one or more of the ring atoms are heteroatoms (e.g., nitrogen (N), oxygen (O), sulfur (S), or a combination thereof). Non-limiting examples of heterocycloalkyl (or divalent heterocycloalkylene) groups include piperidyl or piperidinyl, piperazyl or piperazinyl, tetrahydropyranil, tetrahydrofuryl or tetrahydrofuranil, 1,4-dioxolanil, 1,4-dithianil, 1,3-dioxolanil, oxazolidyl or oxazolidinyl, isoxazolidyl or isoxazolidinyl, morpholinyl, thiomorpholinyl, octahydrobenzofuryl or octahydrobenzofuranil, octahydrochromemenyl, octahydrothiochromemenyl, octahydroindolyl or octahydroindolinyl, octahydropyrindinyl or octahydro-1 H -Cyclopenta[ x ]Pyridin, here x Is b or c Igo, decahydroquinolinil, octahydrobenzo[ b ]Thiophenail, 2-oxa-bicyclo[2.2.2]octyl, 1-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, 3,8-diazabicyclo[3.2.1]octyl, decahydro-2,7-naphthiridine, 2,8-diazaspiro[4.5]decane, 2-azaspiro[3.3]heptane, 2-azaspiro[3.5]nonane, 3-azaspiro[5.5]undecane, 2,7-diazaspiro[3.5]nonane, octahydropyrrolo[3,4- c ]Pyrrol, Octahydro-1 H -pyrrolo[3,4- b ]pyridine, 2,5-diazabicyclo[2.2.1]heptane, 1-oxa-8-azaspiro[4.5]decane, and 2,6-dioxa-tricyclo[3.3.1.0 3,7] Includes nonyl. A monocyclic heterocycloalkyl group may be fused with a phenyl moiety to form, for example, tetrahydroisoquinoline, which may be classified as a heteroaryl as defined elsewhere in this invention.

[0049] As used herein, the “heterocycloalkenyl” group refers to a monocyclic or bicyclic (e.g., 5- to 10-membered monocyclic or bicyclic) non-aromatic ring structure having one or more double bonds, wherein one or more of the ring atoms are heteroatoms (e.g., nitrogen (N), oxygen (O), or sulfur (S)). Monocyclic and bicyclic heterocycloalkenyls are numbered according to standard chemical nomenclature.

[0050] The heterocycloalkyl or heterocycloalkenyl group is phospho, aliphatic (e.g., alkyl, alkenyl, or alkynyl), cycloaliphatic, (cycloaliphatic)aliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy, heteroaryloxy, (aralaliphatic)oxy, (hetero-aralaliphatic)oxy, aroyl, heteroaroyl, amino, amido (e.g., (aliphatic)carbonylamino, (cycloaliphatic)carbonylamino, ((cycloaliphatic)aliphatic)carbonylamino, (aryl)carbonylamino, (aralaliphatic)carbonylamino, (heterocycloaliphatic)carbonylamino, ((heterocycloaliphatic)aliphatic)carbonylamino, Optionally one or more substituents such as (heteroaryl)carbonylamino, or (heteroaraliponic)carbonylamino, nitro, carboxyl (e.g., HOOC-, alkoxycarbonyl, or alkylcarbonyloxy), acyl (e.g., (cycloaliphatic)carbonyl, ((cycloaliphatic)aliphatic)carbonyl, (araliponic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, or (heteroaraliponic)carbonyl), nitro, cyano, halo, hydroxy, mercapto, sulfonyl (e.g., alkylsulfonyl or arylsulfonyl), sulfinyl (e.g., alkylsulfinyl), sulfanyl (e.g., alkylsulfanyl), sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl It can be substituted.

[0051] As used herein, a “heteroaryl” group refers to a monocyclic, bicyclic, or tricyclic ring system having 4 to 15 ring atoms, wherein at least one of the ring atoms is a heteroatom (e.g., N, O, S, or a combination thereof), and the monocyclic ring system is aromatic, or at least one of the rings in the bicyclic or tricyclic ring system is aromatic. The heteroaryl group comprises a benzofused ring system having 2 to 3 rings. For example, the benzofused group comprises one or two 4- to 8-membered heterocycloaliphatic moietys (e.g., indolizinyl, indolyl, isoindolyl, isoindolinyl-1,3-dione, isoindolinyl-1-one, 3 H -Indolyl, Indolinyl, Benzo[ b ]furyl, benzo[ b Includes thiopenyl, quinolinyl, or isoquinolinyl). Some examples of heteroaryls are pyridyl, 1 H -Indazolyl, furyl or furanyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl or benzofuranyl, isoquinolinyl, 1-oxoisoquinoline-2(1 H )-yl, benzthiazolyl, xanthen, thioxanthen, phenothiazine, dihydroindole, benzo[1,3]dioxol, benzo[ b ]furyl, benzo[ b ]Thiophenail, Indazolyl, Benzimidazolyl, 3-methyl-2-oxo-2,3-dihydro-1 H -Benzo[ d ]Imidazole-1-yl, benzthiazolyl, furyl or furinyl, cinnolyl, quinolyl, quinazolyl, phthalazil, quinazolyl, quinoxalyl, isoquinolyl, 4 H -quinolidinyl, benzo-1,2,5-thiadiazolyl, or 1,8-naftiridyl. Other examples of heteroaryls are 1,2,3,4-tetrahydroisoquinoline and 4,5,6,7-tetrahydropyrazolo[1,5- a ] Contains pyrazine.

[0052] Without restriction, monocyclic heteroaryls are furyl, thiophene-yl, 2H - Includes pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isooxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyridazyl, pyrimidyl, pyrazolyl, pyrazyl, or 1,3,5-triazyl. Monocyclic heteroaryls are numbered according to standard chemical nomenclature.

[0053] Without restriction, bicyclic heteroaryls include indolizinyl, indolyl, isoindolyl, 3 H -Indolyl, Indolinyl, Benzo[ b ]furyl, benzo[ b ] Thiopeneal, Quinolinyl, Isoquinolinyl, Indazolyl, Benzimidazyl, Benzthiazolyl, Purinyl, 4 H - Includes quinoliginil, quinolyl, isoquinolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, 1,8-naphthiridyl, or pteridyl. Bicyclic heteroaryls are numbered according to standard chemical nomenclature.

[0054] Heteroaryl is aliphatic (e.g., alkyl, alkenyl, or alkynyl); cycloaliphatic; (cycloaliphatic)aliphatic; heterocycloaliphatic; (heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy; (cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy; heteroaryloxy; (aralaliphatic)oxy; (heteroararalaliphatic)oxy; aroyl; heteroaroyl; amino; oxo (on the non-aromatic carbocyclic or heterocyclic ring of a bicyclic or tricyclic heteroaryl); carboxyl; amido; It is optionally substituted with one or more substituents such as acyl (e.g., (aliphatic) carbonyl; (cycloaliphatic) carbonyl; ((cycloaliphatic)aliphatic) carbonyl; (aralaliphatic) carbonyl; (heterocycloaliphatic) carbonyl; ((heterocycloaliphatic)aliphatic) carbonyl; or (heteroaralaliphatic) carbonyl); sulfonyl (e.g., aliphatic sulfonyl or aminosulfonyl); sulfinyl (e.g., aliphatic sulfinyl); sulfanyl (e.g., aliphatic sulfanyl); nitro; cyano; halo; hydroxy; mercapto; sulfoxy; urea; thiourea; sulfamoyl; sulfamide; or carbamoyl. Alternatively, the heteroaryl may be unsubstituted.

[0055] Non-limiting examples of substituted heteroaryls include (halo)heteroaryls (e.g., mono- and di-(halo)heteroaryls); (carboxy)heteroaryls (e.g., (alkoxycarbonyl)heteroaryls); cyanoheteroaryls; aminoheteroaryls (e.g., (alkylsulfonyl)amino)heteroaryls and ((dialkyl)amino)heteroaryls); (amido)heteroaryls (e.g., aminocarbonylheteroaryls, (alkylcarbonyl)amino)heteroaryls, (((alkyl)amino)alkyl)aminocarbonyl)heteroaryls, (((heteroaryl)amino)carbonyl)heteroaryls, ((heterocycloaliphatic)carbonyl)heteroaryls, and ((alkylcarbonyl)amino)heteroaryls); (cyanoalkyl)heteroaryl; (alkoxy)heteroaryl; (sulfamoyl)heteroaryl (e.g., (aminosulfonyl)heteroaryl); (sulfonyl)heteroaryl (e.g., (alkylsulfonyl)heteroaryl); (hydroxyalkyl)heteroaryl; (alkoxyalkyl)heteroaryl; (hydroxy)heteroaryl; ((carboxy)alkyl)heteroaryl; (((dialkyl)amino)alkyl)heteroaryl; (heterocycloaliphatic)heteroaryl; (cycloaliphatic)heteroaryl; (nitroalkyl)heteroaryl; (((alkylsulfonyl)amino)alkyl)heteroaryl; ((alkylsulfonyl)alkyl)heteroaryl; (cyanoalkyl)heteroaryl; It includes (acyl)heteroaryl (e.g., (alkylcarbonyl)heteroaryl); (alkyl)heteroaryl; or (haloalkyl)heteroaryl (e.g., trihaloalkylheteroaryl).

[0056] As used herein, “heteroaraliphatic” (e.g., heteroaralkyl group) refers to an aliphatic group substituted with a heteroaryl group (e.g., C 1-4 It refers to an alkyl group. “Aliphatic,” “alkyl,” and “heteroaryl” are defined above.

[0057] As used herein, “arylalkyl” refers to a monovalent moiety that is a radical of an alkyl compound, wherein the alkyl compound is substituted with an aromatic substituent (i.e., the aromatic compound contains a single bond to the alkyl group, wherein the radical is localized on the alkyl group). The arylalkyl group is bonded to the chemical structure exemplified through the alkyl group. Arylalkyls are, for example, or It can be expressed in the structure of, and here B is an aromatic moiety, e.g., aryl or phenyl. The arylalkyl group is optionally substituted (i.e., the aryl group and / or alkyl group may be substituted as disclosed herein). Examples of arylalkyl groups include, but are not limited to, benzyl.

[0058] As used herein, the “heteroaralkyl” group is an alkyl group substituted with a heteroaryl group (e.g., C 1-4 It refers to an alkyl group. Both “alkyl” and “heteroaryl” are defined above. Hetero-aralkyl is alkyl (including haloalkyls such as carboxyalkyl, hydroxyalkyl, and trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, It is optionally substituted with one or more substituents such as heteroarylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.

[0059] As used herein, “cyclic moiety” and “cyclic group” refer to mono-, 2-, and 3-cyclic ring systems including cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl, each of which has been previously defined.

[0060] As used herein, “crosslinked bicyclic ring system” refers to a bicyclic heterocycloaliphatic (or heterocycloaliphatic) ring system or a bicyclic cycloaliphatic ring system in which the ring is crosslinked. Examples of crosslinked bicyclic ring systems are adamantanil, norbornanil, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decyl, 2-oxabicyclo[2.2.2]octyl, 1-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.0 3,7 Includes, but is not limited to, nonil. The crosslinking dicyclic ring system is alkyl (including haloalkyls such as carboxyalkyl, hydroxyalkyl, and trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, ararchyloxy, heteroararchyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, ararchylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, It can be optionally substituted with one or more substituents such as heteroarylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.

[0061] As used herein, “Asil” is R X Refers to -C(O)- (same as alkyl-C(O)-, also referred to as “alkyl carbonyl”), where R X and “alkyl” have been previously defined. Acetyl and pivaloyl are examples of acyl groups.

[0062] As used herein, “aroyl” or “heteroaroyl” refers to aryl-C(O)- or heteroaryl-C(O)-. The aryl and heteroaryl portions of an aroyl or heteroaroyl are optionally substituted as defined prior to this invention. For example, an aroyl includes a benzoyl.

[0063] As used herein, the “alkoxy” group refers to the “alkyl” group defined prior to this invention.

[0064] As used herein, “haloalkoxy” refers to an alkoxy as defined above, wherein the alkoxy comprises at least one substituent selected from halogens (e.g., F, Cl, Br, or I).

[0065] As used herein, the “carbamoyl” group is of the formula -O-CO-N R X R Y or -N R X -CO-O- R Z It refers to a substance that possesses, and here R X and R Y is defined above and R Z It can be an aliphatic, aryl, araglial, heterocycloaliphatic, heteroaryl, or heteroaraglial.

[0066] As used herein, the “carboxy” group refers to -COOH when used as a terminal group; or -OC(O)- or -C(O)O- when used as an internal group.

[0067] As used herein, “ester” is -COO when used as a terminal group. R X ; or when used as an internal unit -COO R X Referring to -, here R X is defined above.

[0068] As used herein, the term “alkoxycarbonyl” included by the term ester refers to a group such as alkyl-OC(O)- (i.e., carbonate ester) when used alone or in relation to other groups.

[0069] As used herein, “formate” refers to -OC(O)H.

[0070] As used herein, “acetate” is -OC(O) R X Refers to, and here R X is defined above. In one embodiment, the acetate is -OC(O)Me.

[0071] As used herein, “haloliphatic” or “haloalkyl” groups refer to aliphatic or alkyl groups substituted with one to three halogen atoms. For example, haloalkyls include -CF3.

[0072] As used herein, the “mercapto” or “sulfhydryl” group refers to -SH.

[0073] As used herein, the “sulfo” group, when used as a terminal, is -SO3H or -SO3 R X -S(O)3- is used to refer to or internally. In one embodiment, -SO3H is sulfonic acid. In one embodiment, R X SO3 - is a sulfonate.

[0074] As used herein, the “sulfamide” group is used as the terminal, formula -N R X -S(O)2-N R Y R Z and when used internally, expression -N R X -S(O)2-N R Y Referring to -, here R X , R Y , and R Z is defined above.

[0075] As used herein, the “sulfamoyl” group is formula -S(O)2-N R Y R Z Refers to, and here R Y and R Z is defined above. In one embodiment, -OS(O)2-N R Y R Z is sulfamate.

[0076] As used herein, when the “sulfonamide” group is used as a terminal, the formula R Z -S(O)2-N R X R Y or -N R X -S(O)2- R Z Referring to; when used internally -S(O)2-N R X -, or -N R X Refers to -S(O)2-, where R X , R Y , and R Z is defined above.

[0077] As used herein, the “sulfide” group is used as the -S- when used as a terminal. R X and refers to -S- when used internally, where R X ...is defined above. Examples of sulfanyl include aliphatic-S-, cycloaliphatic-S-, aryl-S-, etc.

[0078] As used herein, the “sulfinyl” group when used as a terminal -S(O)- R X and when used internally, it refers to -S(O)-, where R X ...is defined above. Examples of sulfinyl groups include aliphatic-S(O)-, aryl-S(O)-, (cycloaliphatic(aliphatic))-S(O)-, cycloalkyl-S(O)-, heterocycloaliphatic-S(O)-, heteroaryl-S(O)-, etc.

[0079] As used herein, the “sulfonyl” group when used as a terminal -S(O)2- R X and when used internally, it refers to -S(O)2-, where R X ...is defined above. Examples of sulfonyl groups include aliphatic-S(O)2-, aryl-S(O)2-, (cycloaliphatic(aliphatic))-S(O)2-, cycloaliphatic-S(O)2-, heterocycloaliphatic-S(O)2-, heteroaryl-S(O)2-, (cycloaliphatic(amido(aliphatic)))-S(O)2-, etc.

[0080] As used herein, the “sulfinate” group is used as -OS(O)- when used as a terminal. R X , or -S(O)-O- R X It refers to, and when used internally, refers to -OS(O)- or -S(O)-O-, where R X is defined above.

[0081] As used herein, the “halogen” or “halo” group refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0082] As used herein, “alkoxyalkyl” refers to an alkyl group modified with an alkoxy group such as an alkyl-O-alkyl- or ether, wherein alkyl is defined above.

[0083] As used herein, “carbonyl” or “oxo” refers to -C(O)- or =O.

[0084] As used herein, the term “phospho” refers to phosphinates, phosphonates, phosphine oxide, phosphoramidates, phosphinic amides, and phosphonamidates. Examples of phosphinates, phosphonates, phosphine oxide, phosphoramidates, phosphinic amides, and phosphonamidates are -P(O)( R P )2, ( R P )2P(O)O R P , and R P - PO(O R P Includes )2, where R P is an aliphatic, alkoxy, aryloxy, heteroaryloxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryl, heteroaryl, cycloaliphatic, or amino.

[0085] As used herein, “aminoalkyl” is of the formula ( R X )referring to 2N-alkyl-, where R X is defined above.

[0086] As used herein, “cyanoalkyl” refers to the formula (NC)-alkyl-.

[0087] As used herein, when the “urea” group is used as a terminal, formula -N R X -CO-N R Y R Z It refers to and when “thiourea” is used as a terminal, formula -N R X -CS-N R Y R Z Refers to, and when used internally, -N respectively R X -CO-N R Y - or -N R X -CS-N R Y Referring to -, here R X , R Y , and R Z is defined above.

[0088] As used herein, the “guanidine” group is represented by the formula -N=C(N( R X R Y ))(N( R X R Y )) or -N R X -C(=N R X )N R X R Y Refers to, and here R X and R Y is defined above.

[0089] As used herein, the term “amidino” refers to the formula -C(N R X )N R X R Y Refers to, and here R X and R Y is defined above.

[0090] As used herein, the term “vicinal” generally refers to an arrangement of substituents in a gas phase comprising two or more carbon atoms, wherein the substituents are attached to adjacent carbon atoms.

[0091] As used herein, the term “geminal” generally refers to the arrangement of substituents on the same carbon atom.

[0092] As used herein, “aliphatic chain” refers to a branched or straight-chain aliphatic group (e.g., alkyl group, alkenyl group, or alkynyl group). A straight-chain aliphatic chain has the structure -[CH2] v - having, here v is 1 to 12. A branched aliphatic chain is a straight aliphatic chain substituted with one or more aliphatic groups. A branched aliphatic chain is -[C QQ ] v - It has a structure, and here each Q is independently a hydrogen (H or -H) or an aliphatic group; however, Q It must be an aliphatic group in at least one case.

[0093] The term aliphatic chain includes alkyl chains, alkenyl chains, and alkynyl chains, wherein alkyl, alkenyl, and alkynyl are defined above.

[0094] The phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted” herein. As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, as generally exemplified above, or as exemplified by specific classes, subclasses, and species within this description. As described herein, variables included in any expression described herein R, X, L, Z, and other variables include specific groups, e.g., alkyl and aryl. Unless otherwise specified, variables R, X, L, and Z, Each specific group within and other variables included therein may be optionally substituted with one or more substituents described herein. Each substituent of a specific group is further optionally substituted with one to three halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, cycloaliphatic, heterocycloaliphatic, heteroaryl, haloalkyl, and / or alkyl. For example, the alkyl group may be substituted with alkylsulfanyl, and the alkylsulfanyl may be optionally substituted with one to three halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl. As a further example, the cycloalkyl portion of (cycloalkyl)carbonylamino may be optionally substituted with one to three halo, cyano, alkoxy, hydroxy, nitro, haloalkyl, and alkyl. When two alkoxy groups are bonded to the same or adjacent atoms, the two alkoxy groups can form a ring together with the atom(s) to which they are bonded.

[0095] As used herein, the term “substituted” generally refers to replacing one or more hydrogen atoms in a given chemical structure with radicals of specified substituents, whether or not the term “optional” precedes it. Specific substituents are defined above and are described below within the compounds and examples thereof. Unless otherwise specified, optionally substituted groups may have substituents at each substitutable position of the group, and when more than one position within any given structure may be substituted with more than one substituent selected from the specified group, the substituents may be the same or different at all positions. Ring substituents, such as heterocycloalkyls, may be bonded to other rings, such as cycloalkyls, to form spiro-dicyclic ring systems, for example, where the two rings share one common atom. Non-limiting examples of spiro heterocycloalkyls are ; and It includes. Spiro compounds depicted as nested rings indicate that spirocyclic rings can bond at any vertex. For example, spiro groups In this case, two rings can be bonded at any of the three available vertex atoms within one of the rings.

[0096] As recognized by those skilled in the art, the combination of substituents conceived by this description is a combination that results in the formation of a stable or chemically feasible compound.

[0097] As used herein, “amino acid side chain” refers to an additional chemical moiety on the same carbon that holds the primary or secondary amine and carboxylic acid of an amino acid. As understood by those skilled in the art, there are 21 “standard” amino acids. Exemplary “standard” amino acids include, without limitation, alanine, serine, proline, arginine, and aspartic acid. Other amino acids include cysteine, selenocysteine, and glycine (e.g., where the additional chemical moiety on the same carbon that holds the primary amine and carboxylic acid of glycine is hydrogen). Exemplary amino acid side chains include, without limitation, methyl (i.e., alanine), sec -Butyl (i.e., isoleucine), Iso -butyl (i.e., leucine), -CH2CH2SCH3 (i.e., methionine), -CH2Ph ​​(i.e., phenylalanine), (i.e., tryptophan), (i.e., tyrosine), Iso -propyl (i.e., valine), hydroxymethyl (i.e., serine), -CH(OH)CH3 (i.e., threonine), -CH2C(O)NH2 (i.e., asparagine), -CH2CH2C(O)NH2 (i.e., glutamine), -CH2SH (i.e., cysteine), -CH2SeH (i.e., selenocysteine), -CH2NH2 (i.e., glycine), propylene or -CH2CH2CH2- (i.e., proline), -CH2CH2CH2NHC(=NH)NH2 (i.e., arginine), It includes (i.e., histidine), -CH2CH2CH2CH2NH2 (i.e., lysine), -CH2COOH (i.e., aspartic acid), and -CH2CH2COOH (i.e., glutamic acid).

[0098] As used herein, the phrase “stable or chemically feasible” refers to a compound that does not substantially change when exposed to conditions that allow its production, detection, recovery, purification, and / or use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or a chemically feasible compound is a compound that does not substantially change when maintained at a temperature of 40°C or lower for at least one week in the absence of moisture or other chemically reactive conditions.

[0099] As used herein, the “effective dose” is defined as the amount required to impart a therapeutic effect to the treated subject or patient, and is typically determined based on the subject or patient’s age, surface area, body weight, and / or condition. The correlation between dosages for animals and humans (based on milligrams per square meter of body surface area) is Freireich et al This is described in ., Cancer Chemother. Rep., 50: 219 (1966). Body surface area may be roughly determined from the height and weight of the subject or patient. For example, see Scientific Tables, Geigy Pharmaceuticals, Ardsley, New York, 537 (1970). As used herein, “patient” refers to animals, alternatively mammals including humans.

[0100] The terms “pharmaceutical formulation” and “pharmaceutical composition” refer to a form that allows the biological activity of an active ingredient to be effective and does not contain any additional ingredients that are unacceptably toxic to the individual or subject to whom the formulation or composition is to be administered. Such formulation or composition may be sterile.

[0101] As used herein, the term “excipient” includes pharmaceutically acceptable excipients, carriers, vehicles, or stabilizers that are non-toxic to subjects, cells, or mammals exposed thereto at the doses and concentrations used. In certain embodiments, a physiologically acceptable excipient is an aqueous pH buffer solution.

[0102] The terms “treating” or “treatment” of a disease refer to performing a protocol that may include administering one or more therapeutic agents to a subject and / or individual (human or other) as an effort to obtain a beneficial or desired outcome, including clinical results, in a subject or individual. In certain embodiments, the beneficial or desired clinical outcome includes, but is not limited to, the alleviation or improvement of one or more symptoms, a reduction in the extent of the disease, a stabilized (i.e., not worsening) disease state, prevention of disease spread, delay or slowing of disease progression, improvement or alleviation of the disease state, and remission (partial or total). In certain embodiments, “treatment” may also mean extending the duration of survival compared to the expected survival of an individual not receiving treatment. In certain embodiments, “treating” and “treatment” may occur upon the administration of a single dose of the therapeutic agent or therapeutic agents, or upon the administration of a series of doses of the therapeutic agent or therapeutic agents. In certain embodiments, “treating” or “treatment” does not require complete alleviation of signs or symptoms, nor does it require a cure. In certain embodiments, “treatment” may also refer to a clinical intervention, such as administering one or more therapeutic agents to a subject and / or individual, which is designed to alter the natural course of the subject, individual, or cell being treated (i.e., to alter the course of the individual or cell that would occur in the absence of clinical intervention). In certain embodiments, the term “therapeutic agent” may refer to a compound or drug, or a composition thereof, that induces or modulates KLHDC1 or KLHDC2 activity.

[0103] The terms “individual,” “patient,” or “subject” refer to mammals. In certain embodiments, “mammals” for therapeutic purposes include humans; non-human primates; livestock and farm animals; and zoo, sports, or pet animals, e.g., dogs, horses, rabbits, cattle, pigs, hamsters, gerbils, mice, ferrets, rats, cats, etc. In some embodiments, the individual or subject is a human.

[0104] As used herein, the term “about” means within ±10% of the specified value. For example, a dose of about 100 mg / kg means that the dose may be between 90 mg / kg and 110 mg / kg. As a further example, an additional therapeutic amount in the range of about 50% to about 100% means that the additional therapeutic amount is in the range of 45-55% to 90-110%. Those skilled in the art will understand the range and application of the term “about” when used to describe other specified values ​​disclosed herein.

[0105] Unless otherwise specified, the structures described herein are also intended to include all isomer forms of the chemical structure (e.g., enantiomers, diastereomers, and geometric (or conformational) isomers); for example, for each asymmetric center ( R )- and ( S )- placement, ( Z )- and ( E)- double bond isomers, and syn- / cis- and anti- / trans- stereochemical isomers. Thus, not only the single stereochemical isomers of the compound, but also enantiomers, diastereomers, and geometric (or stereochemical) mixtures are within the scope of this description. Alternatively, as used herein, “enantiomeric excess (ee)” refers to a dimensionless molar ratio describing the purity of a chiral substance, for example, containing a single stereocenter. For example, an enantiomeric excess of 0 would indicate racemic (e.g., a 50:50 mixture of enantiomers, or one enantiomeric is not present in excess of the other). As an additional example, an enantiomeric excess of 99 would indicate a nearly stereopure enantiomeric compound (i.e., one enantiomeric is in excess of the other). Percentage enantiomer excess, % ee = ([( R )-compound]-[( S )-compound]) / ([( R )-compound]+[( S )-compound]) x 100, and here ( R )-compound > ( S )-compound and; or % ee = ([( S )-compound]-[( R )-compound]) / ([( S )-compound]+[( R )-compound]) x 100, and here ( S )-compound > ( RIt is a )-compound. Also, as used herein, “diastereomeric excess (de)” refers to a dimensionless molar ratio describing the purity of a chiral substance containing more than one stereocenter. For example, a diastereomeric excess of 0 would represent an equimolar mixture of diastereomerics. As an additional example, a diastereomeric excess of 99 would represent a nearly stereopure diastereomeric compound (i.e., an excess of one diastereomeric than the other). Diastereomeric excess can be calculated using a method similar to ee. As understood by those skilled in the art, de is generally reported as a percentage de (% de). % de can be calculated in a manner similar to % ee.

[0106] In certain embodiments, the compound or inhibitor described herein has more than 0 ee, de, % ee, or % de. For example, in certain embodiments, the compound or inhibitor described herein has 10 ee, de, % ee, or % de. In certain embodiments, the compound or inhibitor described herein has 25 ee, de, % ee, or % de. In certain embodiments, the compound or inhibitor described herein has 50 ee, de, % ee, or % de. In certain embodiments, the compound or inhibitor described herein has 75 ee, de, % ee, or % de. In certain embodiments, the compound or inhibitor described herein has 99 ee, de, % ee, or % de.

[0107] In certain embodiments, the compound or inhibitor described herein has ee, de, % ee, or % de in the range of 90 to 100. In certain embodiments, the compound or inhibitor described herein has ee, de, % ee, or % de in the range of 95 to 100. In certain embodiments, the compound or inhibitor described herein has ee, de, % ee, or % de in the range of 97 to 100. In certain embodiments, the compound or inhibitor described herein has ee, de, % ee, or % de in the range of 98 to 100. In certain embodiments, the compound or inhibitor described herein has ee, de, % ee, or % de in the range of 99 to 100.

[0108] In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 1. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 2. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 3. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 4. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 5. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 6. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 7. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 8. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 9. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 10. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 11. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 12. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 13. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 14. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 15. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 16. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 17.In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 18. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 19. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 20. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 21. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 22. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 23. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 24. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 25. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 26. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 27. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 28. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 29. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 30. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 31. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 32. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 33. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 34.In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 35. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 36. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 37. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 38. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 39. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 40. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 41. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 42. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 43. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 44. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 45. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 46. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 47. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 48. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 49. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 50. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 51.In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 52. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 53. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 54. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 55. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 56. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 57. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 58. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 59. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 60. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 61. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 62. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 63. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 64. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 65. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 66. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 67. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 68.In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 69. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 70. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 71. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 72. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 73. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 74. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 75. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 76. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 77. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 78. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 79. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 80. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 81. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 82. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 83. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 84. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 85.In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 86. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 87. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 88. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 89. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 90. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 91. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 92. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 93. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 94. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 95. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 96. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 97. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 98. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 99. In one embodiment of the compound or inhibitor described herein, ee, de, % ee, or % de is 100. In certain embodiments, the compound or inhibitor described in Table 1 of this Appendix has ee, de, % ee, or % de as described in this paragraph.In certain embodiments, the compounds or inhibitors described in the Examples and / or Biological Examples have ee, de, % ee, or % de as described in this paragraph. Unless otherwise specified, all tautomeric forms of the compounds described herein are within the scope of this description. Additionally, unless otherwise specified, the structures described herein are also intended to contain compounds that differ only in the presence of one or more isotopicly enriched atoms. For example, hydrogen is replaced by deuterium or tritium, or carbon. 13 C- or 14 Compounds having this structure, except for those replaced by C-enriched carbons, are within the scope of this description. Such compounds are useful, for example, as analytical tools or probes in biological assays, or as therapeutic agents.

[0109] As used herein, the term “&1” means that a compound containing the notation “&1” in a specific chemical element or atom (e.g., carbon) in the compound is prepared as a mixture of two stereoisomers (e.g., a mixture of diastereomers having de or % de as described above) in the mentioned chemical element or atom.

[0110] The chemical structure and nomenclature are derived from ChemDraw, version 23.1, Cambridge, MA.

[0111] Note that the use of descriptors such as “first,” “second,” “third,” etc., is used to distinguish distinct elements (e.g., solvent, reaction step, process, reagent, etc.) and may or may not refer to the relative order or relative chronology of the described elements.

[0112] compound

[0113] In a specific embodiment, the present invention includes the following formula A compound having is provided, where Is And;R 3 If it exists, And; R 4 is a 3- to 8-membered heterocycloalkyl containing at least one nitrogen, where present, and at least one nitrogen is unsubstituted or acyl, -C(O)-heteroalkylene-N R 4a R 4b , alkyl, -C(O)-alkylene-COO R 5 , -C(O)-alkylene-C(O)N R 4a R 4b , substituted with heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl, where R 4a and R 4b is independently hydrogen, alkyl, or acyl.

[0114] In one embodiment, R 3a is alkyl and; R 3b is hydrogen; R 3c is one or more alkoxy or halo. In one embodiment, R 3 silver , , , , or is. In one embodiment, R 3 silver is. In one embodiment, R 3 silver is. In one embodiment, R 3 silver is. In one embodiment, R 3 silver is. In one embodiment, R 3 silver is. In one embodiment, R 4 is a 3- to 8-membered heterocycloalkyl containing at least one nitrogen, where at least one nitrogen is unsubstituted or substituted with an acyl. In one embodiment, R 4 Is , , , , or is. In one embodiment, R 4 Is is. In one embodiment, R 4 Is is. In one embodiment, R 4 Is is. In one embodiment, R 4 Is is. In one embodiment, R 4 Is is. In one embodiment, R 1 silver is. In a specific embodiment, the compound is (2-(3-(1-acetylasetidine-3-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-binindazole]-1-yl)acetyl)glycylglycine ( 1 ), N -(2-((2 H -tetrazole-5-yl)amino)-2-oxoethyl)-2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-byindazole]-1-yl)acetamide ( 2 ), N -((2 H -tetrazole-5-yl)methyl)-2-(2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)acetamide (3 ), 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(2-((2-amino-2-oxoethyl)amino)-2-oxoethyl)acetamide ( 4 ), N -((2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycyl)- N -methylglycine ( 5 ), N -((2 H -tetrazole-5-yl)methyl)-2-(2-(2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)acetamido)acetamide ( 6 ), N -( N -(2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -Methylglycyl)- N -methylglycine ( 7 ), N -(2-((5 H -tetrazole-5-yl)amino)-2-oxoethyl)-2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -methylacetamide ( 8 ), (2-(5'-fluoro-1'-methyl-3-(piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 76 ), (2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1'H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 9 ), N -(2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycine ( 10 ), (2-(3-(1-acetylpiperidine-4-yl)-4-(5-fluoro-1-methyl-1 H -Indazole-6-il)-1 H -pyrazolo[3,4- b ]pyridine-1-yl)acetyl)glycylglycine ( 11 ), rac-( R )-( R )-(2-(3-(1-acetylasepan-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 12 ), N -(2-(3-(1-acetylasedidine-3-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycine ( 13 ), (2-(3-(4-acetylpiperazine-1-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 14 ), (2-(3-(1-acetylpiperidine-4-yl)-5'-methoxy-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 15 ), (2-(3-(1-acetylpiperidine-4-yl)-7'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 16 ), methyl (2-(5'-fluoro-1'-methyl-3-(piperidine-4-yl)-1H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 215 ), tert -butyl (2-(5'-fluoro-1'-methyl-3-(piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 216 ), methyl (2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 217 ), (2-(3-(1-acetylpiperidine-4-yl)-5',7'-difluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 218 ), and (2-(3-(1-acetylpiperidine-4-yl)-4'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 17 It is selected from the group consisting of ). In one embodiment, the compound is (2-(3-(1-acetylasetidine-3-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 1 ) is. In one embodiment, the compound is N -(2-((2 H -tetrazole-5-yl)amino)-2-oxoethyl)-2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-byindazole]-1-yl)acetamide ( 2 ) is. In one embodiment, the compound is N -((2 H -tetrazole-5-yl)methyl)-2-(2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H-[4,6'-Byindazole]-1-yl)acetamido)acetamide ( 3 ) In one embodiment, the compound is 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(2-((2-amino-2-oxoethyl)amino)-2-oxoethyl)acetamide ( 4 ) is. In one embodiment, the compound is N -((2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycyl)- N -methylglycine ( 5 ) is. In one embodiment, the compound is N -((2 H -tetrazole-5-yl)methyl)-2-(2-(2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)acetamido)acetamide ( 6 ) is. In one embodiment, the compound is N -( N -(2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -Methylglycyl)- N -methylglycine ( 7 ) is. In one embodiment, the compound is N -(2-((5 H -tetrazole-5-yl)amino)-2-oxoethyl)-2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -methylacetamide ( 8 ) is. In one embodiment, the compound is (2-(5'-fluoro-1'-methyl-3-(piperidine-4-yl)-1H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 76 ) In one embodiment, the compound is (2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 9 ) is. In one embodiment, the compound is N -(2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycine ( 10 ) In one embodiment, the compound is (2-(3-(1-acetylpiperidine-4-yl)-4-(5-fluoro-1-methyl-1 H -Indazole-6-il)-1 H -pyrazolo[3,4- b ]pyridine-1-yl)acetyl)glycylglycine ( 11 ) is. In one embodiment, the compound is rac-( R )-( R )-(2-(3-(1-acetylasepan-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 12 ) is. In one embodiment, the compound is N -(2-(3-(1-acetylasedidine-3-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycine ( 13 ) In one embodiment, the compound is (2-(3-(4-acetylpiperazine-1-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 14) In one embodiment, the compound is (2-(3-(1-acetylpiperidine-4-yl)-5'-methoxy-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 15 ) In one embodiment, the compound is (2-(3-(1-acetylpiperidine-4-yl)-7'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 16 ) In one embodiment, the compound is methyl (2-(5'-fluoro-1'-methyl-3-(piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 215 ) is. In one embodiment, the compound is tert -butyl (2-(5'-fluoro-1'-methyl-3-(piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 216 ) In one embodiment, the compound is methyl (2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 217 ) In one embodiment, the compound is (2-(3-(1-acetylpiperidine-4-yl)-5',7'-difluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 218 ) In one embodiment, the compound is (2-(3-(1-acetylpiperidine-4-yl)-4'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 17 )am.

[0115] In a specific implementation example, R 1 silver is. In a specific embodiment, the compound is 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(4-(hydroxymethyl)-2-methylthiophene-3-yl)acetamide ( 18 ), 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(1,6-naphthiridine-4-yl)acetamide ( 19 ), 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(isoquinoline-4-yl)acetamide ( 20 ), 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(3-methylisoxazole-4-yl)acetamide ( 21 ), 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(1,7-naphthiridine-4-yl)acetamide ( 22 ), 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(5-methylpyridine-3-yl)acetamide ( 23 ), 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(4-methylpyridine-3-yl)acetamide ( 24), 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(7-hydroxy-5-methyl-[1,2,4]triazolo[1,5- a ]pyrimidine-6-yl)acetamide ( 25 ), 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(pyrazolo[1,5-a]pyridin-4-yl)acetamide ( 26 ), 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(pyrazolo[1,5-b]pyridazine-3-yl)acetamide ( 27 ), 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(Benzo[ d ][1,3]dioxol-4-yl)acetamide ( 28 ), 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(2-(2-methoxyethoxy)ethyl)acetamide ( 29 ), 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(2-(methoxymethyl)-2 H -1,2,3-triazole-4-yl)acetamide ( 30 ), N -(4-(1 H-pyrazol-1-yl)pyrimidine-5-yl)-2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-byindazole]-1-yl)acetamide ( 31 ), 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(1-(Piridajin-3-il)-1 H -pyrazol-5-yl)acetamide ( 32 ), 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(Pirido[3,4- b ]Pyrazine-8-yl)acetamide ( 33 ), 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(2,7-naphthiridine-4-yl)acetamide ( 34 ), N -([1,2,4]triazolo[1,5- a ]pyridine-8-yl)-2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-byindazole]-1-yl)acetamide ( 35 ), and 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(3-cyano-2-methylphenyl)acetamide ( 36 It is selected from the group consisting of ). In one embodiment, the compound is 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N-(4-(hydroxymethyl)-2-methylthiophene-3-yl)acetamide ( 18 ) In one embodiment, the compound is 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(1,6-naphthiridine-4-yl)acetamide ( 19 ) In one embodiment, the compound is 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(isoquinoline-4-yl)acetamide ( 20 ) In one embodiment, the compound is 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(3-methylisoxazole-4-yl)acetamide ( 21 ) In one embodiment, the compound is 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(1,7-naphthiridine-4-yl)acetamide ( 22 ) In one embodiment, the compound is 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(5-methylpyridine-3-yl)acetamide ( 23 ) In one embodiment, the compound is 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(4-methylpyridine-3-yl)acetamide ( 24) In one embodiment, the compound is 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(7-hydroxy-5-methyl-[1,2,4]triazolo[1,5- a ]pyrimidine-6-yl)acetamide ( 25 ) In one embodiment, the compound is 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(pyrazolo[1,5-a]pyridin-4-yl)acetamide ( 26 ) In one embodiment, the compound is 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(pyrazolo[1,5-b]pyridazine-3-yl)acetamide ( 27 ) In one embodiment, the compound is 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(Benzo[ d ][1,3]dioxol-4-yl)acetamide ( 28 )am.

[0116] In one embodiment, the compound is 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(2-(2-methoxyethoxy)ethyl)acetamide ( 29 ) In one embodiment, the compound is 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(2-(methoxymethyl)-2 H-1,2,3-triazole-4-yl)acetamide ( 30 ) is. In one embodiment, the compound is N -(4-(1 H -pyrazol-1-yl)pyrimidine-5-yl)-2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-byindazole]-1-yl)acetamide ( 31 ) In one embodiment, the compound is 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(1-(Piridajin-3-il)-1 H -pyrazol-5-yl)acetamide ( 32 ) In one embodiment, the compound is 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(Pirido[3,4- b ]Pyrazine-8-yl)acetamide ( 33 ) In one embodiment, the compound is 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(2,7-naphthiridine-4-yl)acetamide ( 34 ) is. In one embodiment, the compound is N -([1,2,4]triazolo[1,5- a ]pyridine-8-yl)-2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-byindazole]-1-yl)acetamide ( 35 ) In one embodiment, the compound is 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N-(3-cyano-2-methylphenyl)acetamide ( 36 )am.

[0117] In a specific implementation example, R 1 silver is. In a specific embodiment, the compound is ( S )-2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(2-hydroxy-1-(5-methyl-1 H -1,2,4-triazole-3-yl)ethyl)acetamide ( 37 ), ( R )-2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -((3-(1-hydroxyethyl)-1 H -1,2,4-triazole-5-yl)methyl)acetamide ( 38 ), 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -((5-ethyloxazole-2-yl)methyl)acetamide ( 39 ), 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -((5-(difluoromethyl)-1,24-oxadiazole-3-yl)methyl)acetamide ( 40 ), 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -((2-methoxypyrimidine-4-yl)methyl)acetamide ( 41 ), 3-((2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1'H -[4,6'-Byindazole]-1-yl)acetamido)methyl)-1,2,4-oxadiazole-5-carboxamide ( 42 ), 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -((5-hydroxy-6-methoxypyridine-2-yl)methyl)acetamide ( 43 ), and 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -methyl- N -((5-methyl-1,2,4-oxadiazole-3-yl)methyl)acetamide ( 44 It is selected from the group consisting of ). In one embodiment, the compound is ( S )-2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(2-hydroxy-1-(5-methyl-1 H -1,2,4-triazole-3-yl)ethyl)acetamide ( 37 ) is. In one embodiment, the compound is ( R )-2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -((3-(1-hydroxyethyl)-1 H -1,2,4-triazole-5-yl)methyl)acetamide ( 38 ) In one embodiment, the compound is 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -((5-ethyloxazole-2-yl)methyl)acetamide ( 39) In one embodiment, the compound is 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -((5-(difluoromethyl)-1,24-oxadiazole-3-yl)methyl)acetamide ( 40 ) In one embodiment, the compound is 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -((2-methoxypyrimidine-4-yl)methyl)acetamide ( 41 ) In one embodiment, the compound is 3-((2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)methyl)-1,2,4-oxadiazole-5-carboxamide ( 42 ) In one embodiment, the compound is 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -((5-hydroxy-6-methoxypyridine-2-yl)methyl)acetamide ( 43 ) In one embodiment, the compound is 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -methyl- N -((5-methyl-1,2,4-oxadiazole-3-yl)methyl)acetamide ( 44 )am.

[0118] In a specific implementation example, R 1 silver is. In a specific implementation, R 1 silver is. In a specific implementation, R 1 silver is. In a specific implementation, R 1 silver is. In a specific implementation, R 1 silver is. In one embodiment, the compound is rac-2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -((2 R ,3 R )-2-(1-methyl-1 H -Imidazole-2-yl)tetrahydrofuran-3-yl)acetamide ( 45 ) In one embodiment, the compound is rac-2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -methyl- N -(((2 R ,3 R )-3-(3-methyl-1 H -1,2,4-triazole-5-yl)tetrahydrofuran-2-yl)methyl)acetamide ( 46 ) In one embodiment, the compound is 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Beiindazole]-1-yl)-1-(3-(hydroxymethyl)-6,7-dihydro-[1,2,3]triazolo[1,5- a ]Pyrazine-5(4 H )-il)ethane-1-one ( 47 ) is. In one embodiment, the compound is N -([1,2,4]Triazolo[3,4- b ][1,3,4]thiadiazole-6-yl)-2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-byindazole]-1-yl)acetamide ( 48) In one embodiment, the compound is 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(1-methyl-4-oxo-1,4-dihydropyrimidine-2-yl)acetamide ( 49 ) is. In one embodiment, the compound is N -(2-(2 H -tetrazole-2-yl)ethyl)-2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-byindazole]-1-yl)acetamide ( 50 )am.

[0119] In a specific embodiment, the present invention includes the following formula A compound having is provided, where Is And; R 3a is alkyl and; R 3b is hydrogen; R 3c is cyano. In certain embodiments, R 3 silver is. In a specific implementation, R 4 is a 3- to 8-membered heterocycloalkyl containing at least one nitrogen, where present, and at least one nitrogen is unsubstituted or substituted with an acyl. In certain embodiments, R 4 Is is. In a specific implementation, R 1 silver is. In one embodiment, the compound is (2-(3-(1-acetylpiperidine-4-yl)-5'-cyano-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 51 )am.

[0120] In a specific embodiment, the present invention includes the following formula A compound having is provided, where Is And; R 3a is alkyl and; R 3b is hydrogen; R 3c is chloro. In certain embodiments, R 3 silver is. In a specific implementation, R 4 is a 3- to 8-membered heterocycloalkyl containing at least one nitrogen, where present, and at least one nitrogen is unsubstituted or substituted with an acyl. In certain embodiments, R 4 Is is. In a specific implementation, R 1 silver is. In one embodiment, the compound is (2-(3-(1-acetylpiperidine-4-yl)-5'-chloro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 52 )am.

[0121] In a specific embodiment, the present invention includes the following formula A compound having is provided, where Is And; R 3a is alkyl and; R 3b is hydrogen; R 3c is an alkyl. In certain embodiments, R 3 silver is. In a specific implementation, R 4 is a 3- to 8-membered heterocycloalkyl containing at least one nitrogen, where present, and at least one nitrogen is unsubstituted or substituted with an acyl. In certain embodiments, R 4 Is is. In a specific implementation, R 1 silver is. In one embodiment, the compound is (2-(3-(1-acetylpiperidine-4-yl)-1',5'-dimethyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 53 )am.

[0122] In a specific embodiment, the present invention includes the following formula A compound having is provided, where Is And; R 3 silver is. In a specific implementation, R 4 is a heterocycloalkyl where present, wherein the heterocycloalkyl is unsubstituted or substituted with an alkyl. In certain embodiments, R 4 Is or is. In a specific implementation, R 1 silver is. In one embodiment, the compound is (2-(5'-fluoro-1'-methyl-3-morpholino-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 54 ) or (2-(3-((2 R ,6 S )-2,6-dimethylmorpholino)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 55 ) In one embodiment, the compound is (2-(5'-fluoro-1'-methyl-3-morpholino-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 54 ) is. In one embodiment, the compound is (2-(3-((2 R ,6 S)-2,6-dimethylmorpholino)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 55 )am.

[0123] In a specific embodiment, the present invention includes the following formula A compound having is provided, where Is And; R 3 silver is. In a specific implementation, R 4 is hydrogen, alkyl, haloalkyl, aryl, heteroaryl, or arylalkyl, if present. In certain embodiments, R 4 is hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, phenyl, pyridyl, or benzyl. In certain embodiments, R 1 silver is. In a specific embodiment, the compound is (2-(5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 56 ), N -(2-((2 H -tetrazole-5-yl)amino)-2-oxoethyl)-2-(2-(5'-fluoro-1',3-dimethyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)acetamide ( 57 ), (2-(5'-fluoro-1',3-dimethyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 58 ), (2-(3-ethyl-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 59 ), N -(2-((2 H-tetrazole-5-yl)amino)-2-oxoethyl)-2-(2-(5'-fluoro-3-isopropyl-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)acetamide ( 60 ), (2-(5'-fluoro-3-isopropyl-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 61 ), (2-(5'-fluoro-1'-methyl-3-(trifluoromethyl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 62 ), N -(2-(5'-fluoro-1'-methyl-3-(trifluoromethyl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycine ( 63 ), N -(2-((2 H -tetrazole-5-yl)amino)-2-oxoethyl)-2-(2-(5'-fluoro-1'-methyl-3-(trifluoromethyl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)acetamide ( 64 ), (2-(5'-fluoro-1'-methyl-3-phenyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 65 ), (2-(5'-fluoro-1'-methyl-3-(pyridine-3-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 66 ), (2-(3-benzyl-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 67 ), (2-(4-(5-fluoro-1-methyl-1 H -Indazole-6-il)-1H -pyrazolo[4,3- c ]pyridine-1-yl)acetyl)glycylglycine ( 68 ), and (2-(4-(5-fluoro-1-methyl-1 H -Indazole-6-il)-1 H -pyrazolo[3,4- c ]pyridine-1-yl)acetyl)glycylglycine ( 69 It is selected from the group consisting of ). In one embodiment, the compound is (2-(5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 56 ) is. In one embodiment, the compound is N -(2-((2 H -tetrazole-5-yl)amino)-2-oxoethyl)-2-(2-(5'-fluoro-1',3-dimethyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)acetamide ( 57 ) is. In one embodiment, the compound is (2-(5'-fluoro-1',3-dimethyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 58 ) In one embodiment, the compound is (2-(3-ethyl-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 59 ) is. In one embodiment, the compound is N -(2-((2 H -tetrazole-5-yl)amino)-2-oxoethyl)-2-(2-(5'-fluoro-3-isopropyl-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)acetamide ( 60 ) is. In one embodiment, the compound is (2-(5'-fluoro-3-isopropyl-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine (61 ) is. In one embodiment, the compound is (2-(5'-fluoro-1'-methyl-3-(trifluoromethyl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 62 ) is. In one embodiment, the compound is N -(2-(5'-fluoro-1'-methyl-3-(trifluoromethyl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycine ( 63 ) is. In one embodiment, the compound is N -(2-((2 H -tetrazole-5-yl)amino)-2-oxoethyl)-2-(2-(5'-fluoro-1'-methyl-3-(trifluoromethyl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)acetamide ( 64 ) is. In one embodiment, the compound is (2-(5'-fluoro-1'-methyl-3-phenyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 65 ) is. In one embodiment, the compound is (2-(5'-fluoro-1'-methyl-3-(pyridine-3-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 66 ) In one embodiment, the compound is (2-(3-benzyl-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 67 ) In one embodiment, the compound is (2-(4-(5-fluoro-1-methyl-1 H -Indazole-6-il)-1 H -pyrazolo[4,3- c ]pyridine-1-yl)acetyl)glycylglycine ( 68 ) In one embodiment, the compound is (2-(4-(5-fluoro-1-methyl-1H -Indazole-6-il)-1 H -pyrazolo[3,4- c ]pyridine-1-yl)acetyl)glycylglycine ( 69 )am.

[0124] In a specific embodiment, the present invention includes the following formula A compound having is provided, where Is And; R 3 silver is. In a specific implementation, R 4 is a 3- to 8-membered heterocycloalkyl containing at least one nitrogen, where present, and at least one nitrogen is unsubstituted or -C(O)-heteroalkylene-N R 4a R 4b It is replaced with, and here R 4a and R 4b is independently hydrogen, alkyl, or acyl. In certain embodiments, R 4 Is is. In a specific implementation, R 1 silver is. In a specific embodiment, the compound is methyl (2-(3-(1-(3-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propanoyl)piperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 70 ) and (2-(3-(1-(3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propanoyl)piperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 71 It is selected from a group consisting of ). In one embodiment, the compound is methyl (2-(3-(1-(3-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propanoyl)piperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 70 ) In one embodiment, the compound is (2-(3-(1-(3-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propanoyl)piperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 71 )am.

[0125] In a specific embodiment, the present invention includes the following formula A compound having is provided, where Is And; R 3 silver is. In a specific implementation, R 4 is a 3- to 8-membered heterocycloalkyl containing at least one nitrogen, where present, and at least one nitrogen is unsubstituted or

[0126] -C(O)-alkylene-COO R 5 or -C(O)-alkylene-C(O)N R 4a R 4b It is replaced with, and here R 4a and R 4b is independently hydrogen, alkyl, or acyl. In certain embodiments, R 4 Is or is. In a specific implementation, R 1 silver is. In a specific embodiment, the compound is 4-(4-(1-(2-((2-((carboxymethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-4-(5-fluoro-1-methyl-1 H -Indazole-6-il)-1 H -pyrazolo[3,4- b ]pyridine-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 72 ), (2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-4-(5-fluoro-1-methyl-1 H -Indazole-6-il)-1 H -pyrazolo[3,4- b ]pyridine-1-yl)acetyl)glycylglycine ( 73 ), and methyl (2-(5'-fluoro-1'-methyl-3-(1-(4-(methylamino)-4-oxobutanoyl)piperidin-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 229 It is selected from the group consisting of ). In one embodiment, the compound is 4-(4-(1-(2-((2-((carboxymethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-4-(5-fluoro-1-methyl-1 H -Indazole-6-il)-1 H -pyrazolo[3,4- b ]pyridine-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 72 ) In one embodiment, the compound is (2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-4-(5-fluoro-1-methyl-1 H -Indazole-6-il)-1 H -pyrazolo[3,4- b ]pyridine-1-yl)acetyl)glycylglycine ( 73 ) In one embodiment, the compound is methyl (2-(5'-fluoro-1'-methyl-3-(1-(4-(methylamino)-4-oxobutanoyl)piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 229 )am.

[0127] In a specific embodiment, the present invention includes the following formula A compound having is provided, where Is And; R 3 silver is. In a specific implementation, R 4 If exists, -N( R 5 )C(O)-alkylene-N R 4a R 4b and, here R 4a and R 4b is independently hydrogen, alkyl, or acyl. In certain embodiments, R 4 Is is. In a specific implementation, R 1 silver is. In one embodiment, the compound is (2-(3-(3-acetamidopropaneamido)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 74 )am.

[0128] In a specific embodiment, the present invention includes the following formula A compound having is provided, where Is And; R 3 silver is. In a specific implementation, R 4 If present, -alkylene-N R 4a R 4b and, here R 4a and R 4b is independently hydrogen, alkyl, or acyl. In certain embodiments, R 4 Is is. In a specific implementation,R 1 silver is. In one embodiment, the compound is (2-(3-(3-acetamidopropyl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 75 )am.

[0129] In a specific embodiment, the present invention includes the following formula A compound having is provided, where Is And; R 3 silver is. In a specific implementation, R 4 is a 3- to 8-membered heterocycloalkyl containing at least one nitrogen, where present, and at least one nitrogen is unsubstituted or substituted with an alkyl. In certain embodiments, R 4 Is or is. In a specific implementation, R 1 silver is. In a specific embodiment, the compound is (2-(5'-fluoro-1'-methyl-3-(piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 76 ) and (2-(5'-fluoro-1'-methyl-3-(1-methylpiperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 77 It is selected from the group consisting of ). In one embodiment, the compound is (2-(5'-fluoro-1'-methyl-3-(piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 76 ) is. In one embodiment, the compound is (2-(5'-fluoro-1'-methyl-3-(1-methylpiperidine-4-yl)-1 H ,1'H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 77 )am.

[0130] In a specific embodiment, the present invention includes the following formula A compound having is provided, where Is And; R 3 silver is. In a specific implementation, R 4 is a 5- to 15-one-spiro bicyclic heterocycloalkyl containing at least one nitrogen, where present, the at least one nitrogen is unsubstituted or substituted with an alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl. In certain embodiments, the 5- to 15-one-spiro bicyclic heterocycloalkyl containing at least one nitrogen is And, additionally here n 1 It is 0 to 6, and n 2 is 0 to 3, and n 3 is 1 to 3. In a specific embodiment, R 4 Is is. In a specific implementation, R 1 silver is. In one embodiment, the compound is (2-(3-(2-acetyl-2-azaspiro[3.3]heptane-6-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 78 ) or N -(2-(3-(2-acetyl-2-azaspiro[3.3]heptane-6-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycine ( 79) In one embodiment, the compound is (2-(3-(2-acetyl-2-azaspiro[3.3]heptane-6-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 78 ) is. In one embodiment, the compound is N -(2-(3-(2-acetyl-2-azaspiro[3.3]heptane-6-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycine ( 79 )am.

[0131] In a specific embodiment, the present invention includes the following formula A compound having is provided, where Is And; R 3 silver is. In a specific implementation, R 4 If exists, -N R 4a R 4b and, here R 4a and R 4b is independently hydrogen, alkyl, aryl, heteroaryl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, or arylalkyl. In certain embodiments, R 4 Is is. In a specific implementation, R 1 silver is. In one embodiment, the compound is (2-(5'-fluoro-1'-methyl-3-(methyl(phenyl)amino)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 80 )am.

[0132] In a specific embodiment, the present invention includes the following formula A compound having is provided, where Is And; R 3a is alkyl and; R 3b is hydrogen; R 3c is an alkyl or hydrogen. In certain embodiments, R 3 silver is. In a specific implementation, R 4 is a 3- to 8-membered heterocycloalkyl containing at least one nitrogen, where present, and at least one nitrogen is unsubstituted or substituted with an acyl. In certain embodiments, R 4 Is is. In a specific implementation, R 1 silver is. In a specific embodiment, the compound is (2-(3-(1-acetylpiperidin-4-yl)-1'-methyl-1 H ,1' H -[4,5'-Byindazole]-1-yl)acetyl)glycylglycine ( 81 ) and (2-(3-(1-acetylpiperidine-4-yl)-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 82 It is selected from the group consisting of ). In one embodiment, the compound is (2-(3-(1-acetylpiperidine-4-yl)-1'-methyl-1 H ,1' H -[4,5'-Byindazole]-1-yl)acetyl)glycylglycine ( 81 ) is. In one embodiment, the compound is (2-(3-(1-acetylpiperidine-4-yl)-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 82 )am.

[0133] In a specific embodiment, the present invention includes the following formula A compound having is provided, where Is And;R 3a is a 5- to 15-one-spiro dicyclic heterocycloalkyl containing at least one nitrogen, wherein at least one nitrogen is unsubstituted or substituted with an alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl group;

[0134] -C(O)-(a 3- to -8-membered heterocycloalkyl containing at least one nitrogen, wherein at least one nitrogen is unsubstituted or substituted with an alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl group);

[0135] 3- to -8-membered heterocycloalkyl containing at least one nitrogen, wherein at least one nitrogen is unsubstituted or substituted with an alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl; -alkylene-(3- to -8-membered heterocycloalkyl containing at least one nitrogen, wherein at least one nitrogen is unsubstituted or substituted with an alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl); or -alkylene-N( R 3aa )C(O)alkyl, where R 3aa is hydrogen or alkyl; R 3b is hydrogen; R 3c is a fluoro. In certain embodiments, R 3 silver , , , , or is. In a specific implementation, R 4 is hydrogen or alkyl if present. In certain embodiments,R 4 is hydrogen or methyl. In certain embodiments, R 1 silver is. In a specific embodiment, the compound is (2-(1'-(2-acetyl-2-azaspiro[3.3]heptane-6-yl)-5'-fluoro-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 83 ), (2-(1'-(1-acetylpiperidine-4-carbonyl)-5'-fluoro-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 84 ), (2-(1'-(1-acetylpiperidine-4-yl)-5'-fluoro-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 85 ), (2-(5'-fluoro-3-methyl-1'-((1-methylpiperidine-4-yl)methyl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 86 ), and (2-(1'-(2-acetamidoethyl)-5'-fluoro-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 87 It is selected from the group consisting of ). In one embodiment, the compound is (2-(1'-(2-acetyl-2-azaspiro[3.3]heptane-6-yl)-5'-fluoro-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 83 ) In one embodiment, the compound is (2-(1'-(1-acetylpiperidine-4-carbonyl)-5'-fluoro-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 84 ) In one embodiment, the compound is (2-(1'-(1-acetylpiperidine-4-yl)-5'-fluoro-1 H ,1'H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 85 ) In one embodiment, the compound is (2-(5'-fluoro-3-methyl-1'-((1-methylpiperidine-4-yl)methyl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 86 ) is. In one embodiment, the compound is (2-(1'-(2-acetamidoethyl)-5'-fluoro-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 87 )am.

[0136] In a specific embodiment, the present invention includes the following formula A compound having is provided, where Is And; R 3 If present, it is hydrogen; R 4 is a 3- to 8-membered heterocycloalkyl containing at least one nitrogen, where present, and at least one nitrogen is unsubstituted or substituted with an acyl. In certain embodiments, R 4 is hydrogen or alkyl if present. In certain embodiments, R 4 Is or is. In a specific implementation, R 1 silver is. In a specific embodiment, the compound is (2-(3-(1-acetylasetidine-3-yl)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 88 ) and (2-(3-(1-acetylpiperidine-4-yl)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 89 It is selected from the group consisting of ). In one embodiment, the compound is (2-(3-(1-acetylasetidine-3-yl)-1 H -Indazole-1-yl)acetyl)glycylglycine (88 ) is. In one embodiment, the compound is (2-(3-(1-acetylpiperidine-4-yl)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 89 )am.

[0137] In a specific embodiment, the present invention includes the following formula A compound having is provided, where Is And; R 3 If present, it is hydrogen; R 4 If it exists, it is hydrogen; R 1 silver is. In a specific embodiment, the compound is (2-(1 H -Indazole-1-yl)acetyl)glycylglycine ( 90 ) and methyl (2-(1 H -indole-1-yl)acetyl)glycylglycinate ( 91 It is selected from the group consisting of ). In one embodiment, the compound is (2-(1 H -Indazole-1-yl)acetyl)glycylglycine ( 90 ) is. In one embodiment, the compound is methyl (2-(1 H -indole-1-yl)acetyl)glycylglycinate ( 91 )am.

[0138] In a specific embodiment, the present invention includes the following formula A compound having is provided, where Is And; R 3 is present, if present, an aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted with an alkyl, heteroalkyl, heterocycloalkyl, and / or halo; R 4 is a 3- to 8-membered heterocycloalkyl containing at least one nitrogen, where present, and at least one nitrogen is unsubstituted or acyl or -C(O)-heteroalkylene-N R 4a R 4b It is replaced with, and here R 4a and R 4b is independently hydrogen, alkyl, or acyl. In certain embodiments, R 3 silver , , , , , , , , , , , and It is selected from a group consisting of.

[0139] In one embodiment, R 3 silver is. In one embodiment, R 3 silver is. In one embodiment, R 3 silver is. In one embodiment, R 3 silver is. In one embodiment, R 3 silver is. In one embodiment, R 3 silver is. In one embodiment, R 3 silver is. In one embodiment, R 3 silver is. In one embodiment, R 3 silver is. In one embodiment, R 3 silver is. In one embodiment, R 3 silver is. In one embodiment, R 3 silver is. In a specific implementation,R 4 Is is. In a specific implementation, R 1 silver is. In a specific embodiment, the compound is (2-(3-(1-acetylpiperidine-4-yl)-4-(naphthalene-2-yl)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 92 ), (2-(3-(1-acetylpiperidine-4-yl)-4-(2-fluoro-4-methylphenyl)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 93 ), (2-(3-(1-acetylpiperidine-4-yl)-4-(2,6-difluoro-4-methylphenyl)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 94 ), (2-(3-(1-acetylpiperidine-4-yl)-4-(quinoline-3-yl)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 95 ), (2-(3-(1-acetylpiperidine-4-yl)-4-(quinoline-7-yl)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 96 ), (2-(3-(1-acetylpiperidine-4-yl)-4-(isoquinoline-6-yl)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 97 ), (2-(3-(1-acetylpiperidine-4-yl)-4-(3-methylbenzo[ d ]Speed ​​Soldier-6-Day)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 98 ), (2-(3-(1-acetylpiperidine-4-yl)-4-(benzofuran-2-yl)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 99 ), (2-(3-(1-acetylpiperidine-4-yl)-4-(benzofuran-6-yl)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 100 ), (2-(3-(1-acetylpiperidine-4-yl)-4-(benzo[ d ]isothiazol-6-yl)-1 H-Indazole-1-yl)acetyl)glycylglycine ( 101 ), (2-(3-(1-acetylpiperidine-4-yl)-4-(isoquinoline-7-yl)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 102 ), and (2-(3-(1-acetylpiperidine-4-yl)-4-(quinoline-6-yl)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 103 It is selected from the group consisting of ). In one embodiment, the compound is (2-(3-(1-acetylpiperidine-4-yl)-4-(naphthalene-2-yl)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 92 ) is. In one embodiment, the compound is (2-(3-(1-acetylpiperidine-4-yl)-4-(2-fluoro-4-methylphenyl)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 93 ) is. In one embodiment, the compound is (2-(3-(1-acetylpiperidine-4-yl)-4-(2,6-difluoro-4-methylphenyl)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 94 ) In one embodiment, the compound is (2-(3-(1-acetylpiperidine-4-yl)-4-(quinoline-3-yl)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 95 ) In one embodiment, the compound is (2-(3-(1-acetylpiperidine-4-yl)-4-(quinoline-7-yl)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 96 ) is. In one embodiment, the compound is (2-(3-(1-acetylpiperidine-4-yl)-4-(isoquinoline-6-yl)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 97 ) is. In one embodiment, the compound is (2-(3-(1-acetylpiperidine-4-yl)-4-(3-methylbenzo[ d ]Speed ​​Soldier-6-Day)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 98) is. In one embodiment, the compound is (2-(3-(1-acetylpiperidine-4-yl)-4-(benzofuran-2-yl)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 99 ) is. In one embodiment, the compound is (2-(3-(1-acetylpiperidine-4-yl)-4-(benzofuran-6-yl)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 100 ) is. In one embodiment, the compound is (2-(3-(1-acetylpiperidine-4-yl)-4-(benzo[ d ]isothiazol-6-yl)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 101 ) In one embodiment, the compound is (2-(3-(1-acetylpiperidine-4-yl)-4-(isoquinoline-7-yl)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 102 ) In one embodiment, the compound is (2-(3-(1-acetylpiperidine-4-yl)-4-(quinoline-6-yl)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 103 )am.

[0140] In a specific embodiment, the present invention includes the following formula A compound having is provided, where Is And; R 3 silver is. In a specific implementation, R 4 Is is. In a specific implementation, R 1 silver is. In one embodiment, the compound is methyl (2-(3-(1-(3-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propanoyl)piperidine-4-yl)-4-(5-methyl-6-morpholinopyridine-3-yl)-1 H -Indazole-1-yl)acetyl)glycylglycinate ( 104 )am.

[0141] In a specific embodiment, the present invention includes the following formula A compound having is provided, where Is And; R 3 If it exists, And; R 4 is hydrogen if present. In certain embodiments, R 3a is alkyl and; R 3b is hydrogen; R 3c is a halo. In a specific embodiment, R 3 silver is. In a specific implementation, R 1 silver is. In one embodiment, the compound is (2-(4-(5-fluoro-1-methyl-1 H -Indazole-6-il)-1 H -indole-1-yl)acetyl)glycylglycine ( 105 )am.

[0142] In a specific embodiment, the present invention includes the following formula A compound having is provided, where Is Igo R 3 If it exists, is. In a specific implementation, X 3 It is nitrogen. X 4 is nitrogen. In a specific embodiment, R 3a is alkyl and; R 3b is hydrogen; R 3c is a halo. In a specific embodiment, R 3 silver is. In a specific implementation, R 1 silver is. In one embodiment, the compound is (2-(4-(5-fluoro-1-methyl-1 H -Indazole-6-il)-1 H -Benzo[d ]Imidazole-1-yl)acetyl)glycylglycine ( 106 )am.

[0143] In a specific embodiment, the present invention includes the following formula A compound having is provided, where Is And, X 3 Silver is carbon, and X 4 is oxygen. In a specific embodiment, R 3a is alkyl and; R 3b is hydrogen; R 3c is a halo. In a specific embodiment, R 3 silver is. In a specific implementation, R 1 silver is. In one embodiment, the compound is (2-(7-(5-fluoro-1-methyl-1 H -Indazole-6-yl)benzofuran-3-yl)acetyl)glycylglycine ( 107 )am.

[0144] In a specific embodiment, the present invention includes the following formula A compound having is provided, where Is or Igo R 3 If it exists, is. In a specific implementation, R 3a is alkyl and; R 3b is hydrogen; R 3c is a halo. In a specific embodiment, R 3 silver is. In a specific implementation, R 1 silver is. In one embodiment, the compound is (2-(5-(5-fluoro-1-methyl-1 H -Indazole-6-yl)Naphthalene-1-yl)Acetyl)Glycylglycine (108 ), (2-(8-(5-fluoro-1-methyl-1 H -Indazole-6-yl)quinoline-4-yl)acetyl)glycylglycine ( 219 ), and (2-(4-(5-fluoro-1-methyl-1 H -Indazole-6-yl)quinoline-8-yl)acetyl)glycylglycine ( 109 It is selected from the group consisting of ). In one embodiment, the compound is (2-(5-(5-fluoro-1-methyl-1 H -Indazole-6-yl)Naphthalene-1-yl)Acetyl)Glycylglycine ( 108 ) In one embodiment, the compound is (2-(8-(5-fluoro-1-methyl-1 H -Indazole-6-yl)quinoline-4-yl)acetyl)glycylglycine ( 219 ) In one embodiment, the compound is (2-(4-(5-fluoro-1-methyl-1 H -Indazole-6-yl)quinoline-8-yl)acetyl)glycylglycine ( 109 )am.

[0145] In a specific embodiment, the present invention includes the following formula A compound having is provided, where Is And; R 3 If it exists, And; R 4 is a heterocycloalkyl where present, wherein the heterocycloalkyl is unsubstituted or alkyl, alkenyl, alkynyl, heteroalkyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, or -C(O)N R 4a R 4b It is replaced with, and here R 4a and R 4b is independently hydrogen or alkyl. In certain embodiments, R 3a is alkyl and; R 3b is hydrogen; R 3c is a halo. In a specific embodiment, R 3 silver is. In a specific implementation, R 4 If present, it is a heterocycloalkyl, where the heterocycloalkyl is unsubstituted or -C(O)N R 4a R 4b It is replaced with, and here R 4a and R 4b is independently hydrogen or alkyl. In certain embodiments, R 4 Is is. In a specific implementation, R 1 silver is. In one embodiment, the compound is (2-(5'-fluoro-1'-methyl-3-(4-(methylcarbamoyl)piperidine-1-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 110 )am.

[0146] In a specific embodiment, the present invention includes the following formula A compound having is provided, where Is And; R 3 If it exists, And; R 4 is a 3- to 8-membered heterocycloalkyl containing at least one nitrogen, where present, and at least one nitrogen is unsubstituted or acyl, -C(O)-heteroalkylene-N R 4a R 4b , alkyl, -C(O)-alkylene-COO R 5 , -C(O)-alkylene-C(O)N R 4a R 4b , substituted with heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl, where R 4a and R 4b is independently hydrogen, alkyl, or acyl.

[0147] In a specific implementation example, R 3a is alkyl and; R 3b is hydrogen; R 3c is a halo. In a specific embodiment, R 3 silver is. In a specific implementation, R 4 is a 3- to 8-membered heterocycloalkyl containing at least one nitrogen, where present, and at least one nitrogen is unsubstituted or substituted with an acyl. In certain embodiments, R 4 Is is. In a specific implementation, R 1 silver is. In one embodiment, the compound is (2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)ethyl)glycylglycine ( 111 ), (2-(2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)ethyl)glycine ( 112 ), and (5-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)pentanoyl)glycine ( 113 It is selected from the group consisting of ). In one embodiment, the compound is (2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H,1' H -[4,6'-Byindazole]-1-yl)ethyl)glycylglycine ( 111 ) In one embodiment, the compound is (2-(2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)ethyl)glycine ( 112 ) In one embodiment, the compound is (5-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)pentanoyl)glycine ( 113 )am.

[0148] In a specific embodiment, the present invention includes the following formula A compound having is provided, where Is And; R 3 If present, it is a heteroaryl, where the heteroaryl is unsubstituted or substituted with an alkyl, heteroalkyl, heterocycloalkyl, and / or halo; R 4 If it exists, it is hydrogen; R 1 silver is. In one embodiment, the compound is (2-(4-(4-fluoro-1-methyl-1 H -Pyrazole-5-il)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 114 ) or (2-(4-(1-methyl-1 H -Pyrazole-5-il)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 115 ) In one embodiment, the compound is (2-(4-(4-fluoro-1-methyl-1 H -Pyrazole-5-il)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 114 ) In one embodiment, the compound is (2-(4-(1-methyl-1 H -Pyrazole-5-il)-1 H-Indazole-1-yl)acetyl)glycylglycine ( 115 )am.

[0149] In a specific embodiment, the present invention includes the following formula A compound having is provided, where Is And; R 3 If it exists, And; R 4 is hydrogen if present. In certain embodiments, R 3a is alkyl and; R 3b is hydrogen; R 3c is a halo. In a specific embodiment, R 3 silver is. In a specific implementation, R 1 silver is. In one embodiment, the compound is (2-(5'-fluoro-7-hydroxy-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 116 ), (2-(5'-fluoro-1'-methyl-7-(trifluoromethoxy)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 117 ), (2-(5'-fluoro-1',7-dimethyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 118 ), (2-(5'-fluoro-7-methoxy-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 119 ), (2-(5'-fluoro-1',6-dimethyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 120 ), and (2-(5'-fluoro-1',5-dimethyl-1H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 121 It is selected from the group consisting of ). In one embodiment, the compound is (2-(5'-fluoro-7-hydroxy-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 116 ) In one embodiment, the compound is (2-(5'-fluoro-1'-methyl-7-(trifluoromethoxy)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 117 ) is. In one embodiment, the compound is (2-(5'-fluoro-1',7-dimethyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 118 ) In one embodiment, the compound is (2-(5'-fluoro-7-methoxy-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 119 ) is. In one embodiment, the compound is (2-(5'-fluoro-1',6-dimethyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 120 ) is. In one embodiment, the compound is (2-(5'-fluoro-1',5-dimethyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 121 )am.

[0150] In a specific implementation example, the following expression Compounds having or a pharmaceutically acceptable salt thereof is provided, wherein R 3a One of them is hydrogen or C 1-5 It is alkyl; R 5 is hydrogen or C 1-5It is alkyl; R 9 Is and; each R 9a is independently hydrogen or alkyl; R 9b is -C(O)O R 9c or and; each R 9c is hydrogen or C 1-5 It is alkyl; bb is 1 or 2 and; R 3c is hydrogen, halogen, or CN. In certain embodiments, each R 9a is hydrogen. In a specific embodiment, R 9c is hydrogen or methyl. In certain embodiments, bb is 1. In a specific implementation, bb is 2.

[0151] In a specific embodiment, the following formula as described elsewhere in this invention A compound having or a pharmaceutically acceptable salt thereof is provided, wherein R 3a is -C(O)-alkylene-C(O) R 3aaa and, here R 3aaa is -O R 7a , -N R 7a R 7b or is alkyl; R 3b is hydrogen; R 3c is a fluoro. In a specific embodiment, the following formula A compound having is provided. In a specific embodiment, R 3 silver , , or is. In a specific implementation, R 4 is hydrogen or alkyl if present. In certain embodiments, R 4 is hydrogen, methyl, or isopropyl. In certain embodiments, R 1 silver is. In a specific embodiment, the compound is 4-(1-(2-((2-((carboxymethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-5'-fluoro-3-methyl-1 H ,1' H -[4,6'-baindazole]-1'-yl)-4-oxobutanoic acid ( 122 ), 4-(5'-fluoro-1-(2-((2-((2-methoxy-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-3-methyl-1 H ,1' H -[4,6'-baindazole]-1'-yl)-4-oxobutanoic acid ( 123 ), 4-(1-(2-((2-((2-( tert -butoxy)-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-5'-fluoro-3-methyl-1 H ,1' H -[4,6'-baindazole]-1'-yl)-4-oxobutanoic acid ( 124 ), (2-(1'-(4-amino-4-oxobutanoyl)-5'-fluoro-3-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 125 ), methyl (2-(1'-(4-amino-4-oxobutanoyl)-5'-fluoro-3-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 126 ), tert -butyl (2-(1'-(4-amino-4-oxobutanoyl)-5'-fluoro-3-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 127 ), (2-(5'-fluoro-3-methyl-1'-(4-oxopentanoyl)-1 H ,1' H-[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 128 ), methyl (2-(5'-fluoro-3-methyl-1'-(4-oxopentanoyl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 129 ), tert -butyl (2-(5'-fluoro-3-methyl-1'-(4-oxopentanoyl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 130 ), 4-(1-(2-((2-((carboxymethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-5'-fluoro-3-isopropyl-1 H ,1' H -[4,6'-baindazole]-1'-yl)-4-oxobutanoic acid ( 131 ), 4-(5'-fluoro-3-isopropyl-1-(2-((2-((2-methoxy-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1 H ,1' H -[4,6'-baindazole]-1'-yl)-4-oxobutanoic acid ( 132 ), 4-(1-(2-((2-((2-( tert -butoxy)-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-5'-fluoro-3-isopropyl-1 H ,1' H -[4,6'-baindazole]-1'-yl)-4-oxobutanoic acid ( 133 ), (2-(1'-(4-amino-4-oxobutanoyl)-5'-fluoro-3-isopropyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 134 ), methyl (2-(1'-(4-amino-4-oxobutanoyl)-5'-fluoro-3-isopropyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 135 ), tert-butyl (2-(1'-(4-amino-4-oxobutanoyl)-5'-fluoro-3-isopropyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 136 ), (2-(5'-fluoro-3-isopropyl-1'-(4-oxopentanoyl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 137 ), methyl (2-(5'-fluoro-3-isopropyl-1'-(4-oxopentanoyl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 138 ), and tert -butyl (2-(5'-fluoro-3-isopropyl-1'-(4-oxopentanoyl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 139 It is selected from a group consisting of ).

[0152] In one embodiment, the compound is 4-(1-(2-((2-((carboxymethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-5'-fluoro-3-methyl-1 H ,1' H -[4,6'-baindazole]-1'-yl)-4-oxobutanoic acid ( 122 ) In one embodiment, the compound is 4-(5'-fluoro-1-(2-((2-((2-methoxy-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-3-methyl-1 H ,1' H -[4,6'-baindazole]-1'-yl)-4-oxobutanoic acid ( 123 ) is. In one embodiment, the compound is 4-(1-(2-((2-((2-( tert -butoxy)-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-5'-fluoro-3-methyl-1 H ,1' H -[4,6'-baindazole]-1'-yl)-4-oxobutanoic acid ( 124) In one embodiment, the compound is (2-(1'-(4-amino-4-oxobutanoyl)-5'-fluoro-3-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 125 ) In one embodiment, the compound is methyl (2-(1'-(4-amino-4-oxobutanoyl)-5'-fluoro-3-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 126 ) is. In one embodiment, the compound is tert -butyl (2-(1'-(4-amino-4-oxobutanoyl)-5'-fluoro-3-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 127 ) is. In one embodiment, the compound is (2-(5'-fluoro-3-methyl-1'-(4-oxopentanoyl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 128 ) In one embodiment, the compound is methyl (2-(5'-fluoro-3-methyl-1'-(4-oxopentanoyl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 129 ) is. In one embodiment, the compound is tert -butyl (2-(5'-fluoro-3-methyl-1'-(4-oxopentanoyl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 130 ) In one embodiment, the compound is 4-(1-(2-((2-((carboxymethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-5'-fluoro-3-isopropyl-1 H ,1' H -[4,6'-baindazole]-1'-yl)-4-oxobutanoic acid ( 131) is. In one embodiment, the compound is 4-(5'-fluoro-3-isopropyl-1-(2-((2-((2-methoxy-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1 H ,1' H -[4,6'-baindazole]-1'-yl)-4-oxobutanoic acid ( 132 ) is. In one embodiment, the compound is 4-(1-(2-((2-((2-( tert -butoxy)-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-5'-fluoro-3-isopropyl-1 H ,1' H -[4,6'-baindazole]-1'-yl)-4-oxobutanoic acid ( 133 ) In one embodiment, the compound is (2-(1'-(4-amino-4-oxobutanoyl)-5'-fluoro-3-isopropyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 134 ) In one embodiment, the compound is methyl (2-(1'-(4-amino-4-oxobutanoyl)-5'-fluoro-3-isopropyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 135 ) is. In one embodiment, the compound is tert -butyl (2-(1'-(4-amino-4-oxobutanoyl)-5'-fluoro-3-isopropyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 136 ) is. In one embodiment, the compound is (2-(5'-fluoro-3-isopropyl-1'-(4-oxopentanoyl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 137 ) In one embodiment, the compound is methyl (2-(5'-fluoro-3-isopropyl-1'-(4-oxopentanoyl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate (138 ) is. In one embodiment, the compound is tert -butyl (2-(5'-fluoro-3-isopropyl-1'-(4-oxopentanoyl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 139 )am.

[0153] In a specific embodiment, the following formula as described elsewhere in this invention A compound having or a pharmaceutically acceptable salt thereof is provided, wherein R 3 silver , , , or is. In a specific implementation, R 4 is a 3- to 8-membered heterocycloalkyl containing at least one nitrogen, where at least one nitrogen is -C(O)-alkylene-C(O) R 3aaa It is replaced with, and here R 3aaa is -O R 7a , -N R 7a R 7b or is alkyl; or is alkyl.

[0154] In a specific implementation example, the following expression A compound having is provided, where R 4aa is -C(O)-alkylene-C(O) R 3aaa and, here R 3aaa is -O R 7a , -N R 7a R 7b or is alkyl; or is alkyl. In certain embodiments, R 4aa is methyl, , , or is. In a specific embodiment, the compound is 2-(4-((2-(5'-fluoro-1'-methyl-3-(1-methylpiperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)methyl)-1 H -1,2,3-triazole-1-yl)acetic acid ( 140 ), methyl 2-(4-((2-(5'-fluoro-1'-methyl-3-(1-methylpiperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)methyl)-1 H -1,2,3-triazole-1-yl)acetate ( 141 ), tert -butyl 2-(4-((2-(5'-fluoro-1'-methyl-3-(1-methylpiperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)methyl)-1 H -1,2,3-triazole-1-yl)acetate ( 142 ), 4-(4-(1-(2-(((1-(carboxymethyl)-1 H -1,2,3-triazole-4-yl)methyl)amino)-2-oxoethyl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 143 ), 4-(4-(5'-fluoro-1-(2-(((1-(2-methoxy-2-oxoethyl)-1 H -1,2,3-triazole-4-yl)methyl)amino)-2-oxoethyl)-1'-methyl-1 H ,1' H -[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 144 ), 4-(4-(1-(2-(((1-(2-( tert -butoxy-2-oxoethyl-1 H -1,2,3-triazole-4-yl)methyl)amino)-2-oxoethyl)-5'-fluoro-1'-methyl-1 H ,1' H-[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 145 ), 2-(4-((2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)methyl)-1 H -1,2,3-triazole-1-yl)acetic acid ( 146 ), methyl 2-(4-((2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)methyl)-1 H -1,2,3-triazole-1-yl)acetate ( 147 ), tert -butyl 2-(4-((2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)methyl)-1 H -1,2,3-triazole-1-yl)acetate ( 148 ), 2-(4-((2-(5'-fluoro-1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)methyl)-1 H -1,2,3-triazole-1-yl)acetic acid ( 149 ), methyl 2-(4-((2-(5'-fluoro-1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)methyl)-1 H -1,2,3-triazole-1-yl)acetate ( 150 ), and tert -butyl 2-(4-((2-(5'-fluoro-1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1 H ,1' H-[4,6'-Byindazole]-1-yl)acetamido)methyl)-1H-1,2,3-triazole-1-yl)acetate ( 151 It is selected from a group consisting of ).

[0155] In one embodiment, the compound is 2-(4-((2-(5'-fluoro-1'-methyl-3-(1-methylpiperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)methyl)-1 H -1,2,3-triazole-1-yl)acetic acid ( 140 ) In one embodiment, the compound is methyl 2-(4-((2-(5'-fluoro-1'-methyl-3-(1-methylpiperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)methyl)-1 H -1,2,3-triazole-1-yl)acetate ( 141 ) is. In one embodiment, the compound is tert -butyl 2-(4-((2-(5'-fluoro-1'-methyl-3-(1-methylpiperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)methyl)-1 H -1,2,3-triazole-1-yl)acetate ( 142 ) In one embodiment, the compound is 4-(4-(1-(2-(((1-(carboxymethyl)-1 H -1,2,3-triazole-4-yl)methyl)amino)-2-oxoethyl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 143 ) In one embodiment, the compound is 4-(4-(5'-fluoro-1-(2-(((1-(2-methoxy-2-oxoethyl)-1 H -1,2,3-triazole-4-yl)methyl)amino)-2-oxoethyl)-1'-methyl-1 H ,1' H -[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid (144 ) is. In one embodiment, the compound is 4-(4-(1-(2-(((1-(2-( tert -butoxy-2-oxoethyl-1 H -1,2,3-triazole-4-yl)methyl)amino)-2-oxoethyl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 145 ) In one embodiment, the compound is 2-(4-((2-(3-(1-(4-amino-4-oxobutanoyl)piperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)methyl)-1 H -1,2,3-triazole-1-yl)acetic acid ( 146 ) In one embodiment, the compound is methyl 2-(4-((2-(3-(1-(4-amino-4-oxobutanoyl)piperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)methyl)-1 H -1,2,3-triazole-1-yl)acetate ( 147 ) is. In one embodiment, the compound is tert -butyl 2-(4-((2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)methyl)-1 H -1,2,3-triazole-1-yl)acetate ( 148 ) In one embodiment, the compound is 2-(4-((2-(5'-fluoro-1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)methyl)-1 H -1,2,3-triazole-1-yl)acetic acid ( 149) In one embodiment, the compound is methyl 2-(4-((2-(5'-fluoro-1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)methyl)-1 H -1,2,3-triazole-1-yl)acetate ( 150 ) is. In one embodiment, the compound is tert -butyl 2-(4-((2-(5'-fluoro-1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)methyl)-1H-1,2,3-triazole-1-yl)acetate ( 151 )am.

[0156] In a specific embodiment, the following formula as described elsewhere in this invention A compound having or a pharmaceutically acceptable salt thereof is provided, wherein R 4 is a 5- to 15-one-spiro dicyclic heterocycloalkyl containing at least one nitrogen, where present, and the at least one nitrogen is unsubstituted or alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, or -C(O)-alkylene-C(O) R 3aaa It is replaced with, and here R 3aaa is -O R 7a , -N R 7a R 7b or is an alkyl. In certain embodiments, the following formula A compound having is provided, where R 3b is alkyl and R 3c is a halo. In a specific embodiment, the compound is 4-(6-(1-(2-((2-((carboxymethyl)amino)-2-oxoethyl)(methyl)amino)-2-oxoethyl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Baindazole]-3-yl)-2-Azaspiro[3,3]heptane-2-yl)-4-oxobutanoic acid ( 152 ), 4-(6-(5'-fluoro-1-(2-((2-((2-methoxy-2-oxoethyl)amino)-2-oxoethyl)(methyl)amino)-2-oxoethyl)-1'-methyl-1 H ,1' H -[4,6'-Baindazole]-3-yl)-2-Azaspiro[3,3]heptane-2-yl)-4-oxobutanoic acid ( 153 ), 4-(6-(1-(2-((2-((2-( tert -butoxy)-2-oxoethyl)amino)-2-oxoethyl)(methyl)amino)-2-oxoethyl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Baindazole]-3-yl)-2-Azaspiro[3,3]heptane-2-yl)-4-oxobutanoic acid ( 154 ), N -(2-(3-(2-(4-amino-4-oxobutanoyl)-2-azaspiro[3.3]heptane-6-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycine ( 155 ), methyl N -(2-(3-(2-(4-amino-4-oxobutanoyl)-2-azaspiro[3.3]heptane-6-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycinate ( 156 ), tert -butyl N -(2-(3-(2-(4-amino-4-oxobutanoyl)-2-azaspiro[3.3]heptane-6-yl)-5'-fluoro-1'-methyl-1 H ,1' H-[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycinate ( 157 ), N -(2-(5'-fluoro-1'-methyl-3-(2-(4-oxopentanoyl)-2-azspiro[3.3]heptane-6-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycine ( 158 ), methyl N -(2-(5'-fluoro-1'-methyl-3-(2-(4-oxopentanoyl)-2-azspiro[3.3]heptane-6-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycinate ( 159 ), and tert -butyl N -(2-(5'-fluoro-1'-methyl-3-(2-(4-oxopentanoyl)-2-azspiro[3.3]heptane-6-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycinate ( 160 It is selected from a group consisting of ).

[0157] In one embodiment, the compound is 4-(6-(1-(2-((2-((carboxymethyl)amino)-2-oxoethyl)(methyl)amino)-2-oxoethyl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Baindazole]-3-yl)-2-Azaspiro[3,3]heptane-2-yl)-4-oxobutanoic acid ( 152 ) In one embodiment, the compound is 4-(6-(5'-fluoro-1-(2-((2-((2-methoxy-2-oxoethyl)amino)-2-oxoethyl)(methyl)amino)-2-oxoethyl)-1'-methyl-1 H ,1' H -[4,6'-Baindazole]-3-yl)-2-Azaspiro[3,3]heptane-2-yl)-4-oxobutanoic acid ( 153) is. In one embodiment, the compound is 4-(6-(1-(2-((2-((2-( tert -butoxy)-2-oxoethyl)amino)-2-oxoethyl)(methyl)amino)-2-oxoethyl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Baindazole]-3-yl)-2-Azaspiro[3,3]heptane-2-yl)-4-oxobutanoic acid ( 154 ) is. In one embodiment, the compound is N -(2-(3-(2-(4-amino-4-oxobutanoyl)-2-azaspiro[3.3]heptane-6-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycine ( 155 ) is. In one embodiment, the compound is methyl N -(2-(3-(2-(4-amino-4-oxobutanoyl)-2-azaspiro[3.3]heptane-6-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycinate ( 156 ) is. In one embodiment, the compound is tert -butyl N -(2-(3-(2-(4-amino-4-oxobutanoyl)-2-azaspiro[3.3]heptane-6-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycinate ( 157 ) is. In one embodiment, the compound is N -(2-(5'-fluoro-1'-methyl-3-(2-(4-oxopentanoyl)-2-azspiro[3.3]heptane-6-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycine ( 158 ) is. In one embodiment, the compound is methyl N-(2-(5'-fluoro-1'-methyl-3-(2-(4-oxopentanoyl)-2-azspiro[3.3]heptane-6-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycinate ( 159 ) is. In one embodiment, the compound is tert -butyl N -(2-(5'-fluoro-1'-methyl-3-(2-(4-oxopentanoyl)-2-azspiro[3.3]heptane-6-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycinate ( 160 )am.

[0158] In a specific embodiment, the following formula as described elsewhere in this invention A compound having or a pharmaceutically acceptable salt thereof is provided, wherein R 3 silver , , , , or is. In a specific implementation, R 4 is a 3- to 8-membered heterocycloalkyl containing at least one nitrogen, where present, and at least one nitrogen is unsubstituted or -C(O)-alkylene-C(O) R 3aaa It is replaced with, and here R 3aaa is -O R 7a , -N R 7a R 7b or is alkyl. In certain embodiments, R 1 silver is. In a specific embodiment, the formula of the compound is , , , , and It is selected from the group consisting of. In one embodiment, the formula of the compound is is. In one embodiment, the formula of the compound is is. In one embodiment, the formula of the compound is is. In one embodiment, the formula of the compound is is. In one embodiment, the formula of the compound is is. In a specific embodiment, the compound is 4-(4-(1-(2-((2-((carboxymethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 161 ), 4-(4-(5'-fluoro-1-(2-((2-((2-methoxy-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1'-methyl-1 H ,1' H -[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 162 ), 4-(4-(1-(2-((2-((2-( tert -butoxy)-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 163 ), (2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 164 ), methyl (2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 165 ), tert -butyl (2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 166 ), (2-(5'-fluoro-1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 167 ), methyl (2-(5'-fluoro-1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 168 ), tert -butyl (2-(5'-fluoro-1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 169 ), 4-(4-(1-(2-((2-((carboxymethyl)amino)-2-oxoethyl)(methyl)amino)-2-oxoethyl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 170 ), 4-(4-(5'-fluoro-1-(2-((2-((2-methoxy-2-oxoethyl)amino)-2-oxoethyl)(methyl)amino)-2-oxoethyl)-1'-methyl-1 H ,1' H -[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 171 ), 4-(4-(1-(2-((2-((2-( tert -butoxy)-2-oxoethyl)amino)-2-oxoethyl)(methyl)amino)-2-oxoethyl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 172 ), N -(2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycine ( 173 ), methyl N -(2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycinate ( 174 ), tert -butyl N -(2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycinate ( 175 ), N -(2-(5'-fluoro-1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycine ( 176 ), methyl N -(2-(5'-fluoro-1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycinate ( 177 ), tert -butyl N -(2-(5'-fluoro-1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycinate ( 178 ), 4-(4-(1-(2-((2-((carboxymethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1'-methyl-1 H ,1' H-[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 179 ), 4-(4-(1-(2-((2-((2-methoxy-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1'-methyl-1 H ,1' H -[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 180 ), 4-(4-(1-(2-((2-((2-( tert -butoxy)-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1'-methyl-1 H ,1' H -[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 181 ), (2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 182 ), methyl (2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 183 ), tert -butyl (2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 184 ), (2-(1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 185 ), methyl (2-(1'-methyl-3-(1-(4-oxopentanoyl)piperidin-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 186 ), tert-butyl (2-(1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 187 ), 4-(4-(1-(2-((2-((carboxymethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-4-(5-fluoro-1-methyl-1 H -Indazole-6-il)-1 H -pyrazolo[3,4- b ]pyridine-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 188 ), 4-(4-(4-(5-fluoro-1-methyl-1 H -Indazole-6-yl)-1-(2-((2-((2-methoxy-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1 H -pyrazolo[3,4- b ]pyridine-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 189 ), 4-(4-(1-(2-((2-((2-( tert -butoxy)-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-4-(5-fluoro-1-methyl-1 H -Indazole-6-il)-1 H -pyrazolo[3,4- b ]pyridine-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 190 ), (2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-4-(5-fluoro-1-methyl-1 H -Indazole-6-il)-1 H -pyrazolo[3,4- b ]pyridine-1-yl)acetyl)glycylglycine ( 191 ), methyl (2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-4-(5-fluoro-1-methyl-1 H -Indazole-6-il)-1 H -pyrazolo[3,4- b ]pyridine-1-yl)acetyl)glycylglycinate ( 192 ), tert-butyl (2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-4-(5-fluoro-1-methyl-1 H -Indazole-6-il)-1 H -pyrazolo[3,4- b ]pyridine-1-yl)acetyl)glycylglycinate ( 193 ), (2-(4-(5-fluoro-1-methyl-1 H -Indazole-6-yl)-3-(1-(4-oxopentanoyyl)piperidine-4-yl)-1 H -pyrazolo[3,4- b ]pyridine-1-yl)acetyl)glycylglycine ( 194 ), methyl (2-(4-(5-fluoro-1-methyl-1 H -Indazole-6-yl)-3-(1-(4-oxopentanoyyl)piperidine-4-yl)-1 H -pyrazolo[3,4- b ]pyridine-1-yl)acetyl)glycylglycinate ( 195 ), tert -butyl (2-(4-(5-fluoro-1-methyl-1) H -Indazole-6-yl)-3-(1-(4-oxopentanoyyl)piperidine-4-yl)-1 H -pyrazolo[3,4- b ]pyridine-1-yl)acetyl)glycylglycinate ( 196 ), 4-(4-(1-(2-((2-((carboxymethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-7'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 197 ), 4-(4-(7'-fluoro-1-(2-((2-((2-methoxy-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1'-methyl-1 H ,1' H -[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 198 ), 4-(4-(1-(2-((2-((2-( tert -butoxy)-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-7'-fluoro-1'-methyl-1 H,1' H -[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 199 ), (2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-7'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 200 ), methyl (2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-7'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 201 ), tert -butyl (2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-7'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 202 ), (2-(7'-fluoro-1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 203 ), methyl (2-(7'-fluoro-1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 204 ), and tert -butyl (2-(7'-fluoro-1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 205 It is selected from a group consisting of ).

[0159] In one embodiment, the compound is 4-(4-(1-(2-((2-((carboxymethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-5'-fluoro-1'-methyl-1 H ,1' H-[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 161 ) In one embodiment, the compound is 4-(4-(5'-fluoro-1-(2-((2-((2-methoxy-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1'-methyl-1 H ,1' H -[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 162 ) is. In one embodiment, the compound is 4-(4-(1-(2-((2-((2-( tert -butoxy)-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 163 ) In one embodiment, the compound is (2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 164 ) In one embodiment, the compound is methyl (2-(3-(1-(4-amino-4-oxobutanoyl)piperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 165 ) is. In one embodiment, the compound is tert -butyl (2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 166 ) In one embodiment, the compound is (2-(5'-fluoro-1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 167) In one embodiment, the compound is methyl (2-(5'-fluoro-1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 168 ) is. In one embodiment, the compound is tert -butyl (2-(5'-fluoro-1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 169 ) In one embodiment, the compound is 4-(4-(1-(2-((2-((carboxymethyl)amino)-2-oxoethyl)(methyl)amino)-2-oxoethyl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 170 ) In one embodiment, the compound is 4-(4-(5'-fluoro-1-(2-((2-((2-methoxy-2-oxoethyl)amino)-2-oxoethyl)(methyl)amino)-2-oxoethyl)-1'-methyl-1 H ,1' H -[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 171 ) is. In one embodiment, the compound is 4-(4-(1-(2-((2-((2-( tert -butoxy)-2-oxoethyl)amino)-2-oxoethyl)(methyl)amino)-2-oxoethyl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 172 ) is. In one embodiment, the compound is N -(2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycine ( 173) is. In one embodiment, the compound is methyl N -(2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycinate ( 174 ) is. In one embodiment, the compound is tert -butyl N -(2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycinate ( 175 ) is. In one embodiment, the compound is N -(2-(5'-fluoro-1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycine ( 176 ) is. In one embodiment, the compound is methyl N -(2-(5'-fluoro-1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycinate ( 177 ) is. In one embodiment, the compound is tert -butyl N -(2-(5'-fluoro-1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycinate ( 178 ) In one embodiment, the compound is 4-(4-(1-(2-((2-((carboxymethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1'-methyl-1 H ,1' H-[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 179 ) In one embodiment, the compound is 4-(4-(1-(2-((2-((2-methoxy-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1'-methyl-1 H ,1' H -[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 180 ) is. In one embodiment, the compound is 4-(4-(1-(2-((2-((2-( tert -butoxy)-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1'-methyl-1 H ,1' H -[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 181 ) is. In one embodiment, the compound is (2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 182 ) In one embodiment, the compound is methyl (2-(3-(1-(4-amino-4-oxobutanoyl)piperidine-4-yl)-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 183 ) is. In one embodiment, the compound is tert -butyl (2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 184 ) In one embodiment, the compound is (2-(1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 185 ) In one embodiment, the compound is methyl (2-(1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 186 ) is. In one embodiment, the compound is tert -butyl (2-(1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 187 ) In one embodiment, the compound is 4-(4-(1-(2-((2-((carboxymethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-4-(5-fluoro-1-methyl-1 H -Indazole-6-il)-1 H -pyrazolo[3,4- b ]pyridine-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 188 ) In one embodiment, the compound is 4-(4-(4-(5-fluoro-1-methyl-1 H -Indazole-6-yl)-1-(2-((2-((2-methoxy-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1 H -pyrazolo[3,4- b ]pyridine-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 189 ) is. In one embodiment, the compound is 4-(4-(1-(2-((2-((2-( tert -butoxy)-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-4-(5-fluoro-1-methyl-1 H -Indazole-6-il)-1 H -pyrazolo[3,4- b ]pyridine-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 190 ) In one embodiment, the compound is (2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-4-(5-fluoro-1-methyl-1 H -Indazole-6-il)-1 H -pyrazolo[3,4- b ]pyridine-1-yl)acetyl)glycylglycine ( 191) In one embodiment, the compound is methyl (2-(3-(1-(4-amino-4-oxobutanoyl)piperidine-4-yl)-4-(5-fluoro-1-methyl-1 H -Indazole-6-il)-1 H -pyrazolo[3,4- b ]pyridine-1-yl)acetyl)glycylglycinate ( 192 ) is. In one embodiment, the compound is tert -butyl (2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-4-(5-fluoro-1-methyl-1 H -Indazole-6-il)-1 H -pyrazolo[3,4- b ]pyridine-1-yl)acetyl)glycylglycinate ( 193 ) In one embodiment, the compound is (2-(4-(5-fluoro-1-methyl-1 H -Indazole-6-yl)-3-(1-(4-oxopentanoyyl)piperidine-4-yl)-1 H -pyrazolo[3,4- b ]pyridine-1-yl)acetyl)glycylglycine ( 194 ) In one embodiment, the compound is methyl (2-(4-(5-fluoro-1-methyl-1 H -Indazole-6-yl)-3-(1-(4-oxopentanoyyl)piperidine-4-yl)-1 H -pyrazolo[3,4- b ]pyridine-1-yl)acetyl)glycylglycinate ( 195 ) is. In one embodiment, the compound is tert -butyl (2-(4-(5-fluoro-1-methyl-1) H -Indazole-6-yl)-3-(1-(4-oxopentanoyyl)piperidine-4-yl)-1 H -pyrazolo[3,4- b ]pyridine-1-yl)acetyl)glycylglycinate ( 196 ) In one embodiment, the compound is 4-(4-(1-(2-((2-((carboxymethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-7'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid (197 ) In one embodiment, the compound is 4-(4-(7'-fluoro-1-(2-((2-((2-methoxy-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1'-methyl-1 H ,1' H -[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 198 ) is. In one embodiment, the compound is 4-(4-(1-(2-((2-((2-( tert -butoxy)-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-7'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 199 ) In one embodiment, the compound is (2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-7'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 200 ) In one embodiment, the compound is methyl (2-(3-(1-(4-amino-4-oxobutanoyl)piperidine-4-yl)-7'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 201 ) is. In one embodiment, the compound is tert -butyl (2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-7'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 202 ) In one embodiment, the compound is (2-(7'-fluoro-1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 203) In one embodiment, the compound is methyl (2-(7'-fluoro-1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 204 ) is. In one embodiment, the compound is tert -butyl (2-(7'-fluoro-1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 205 )am.

[0160] In a specific embodiment, the following formula as described elsewhere in this invention A compound having or a pharmaceutically acceptable salt thereof is provided, wherein R 3a -C(O)-(3- to 8-membered heterocycloalkyl containing at least one nitrogen, wherein at least one nitrogen is unsubstituted or alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, or -C(O)-alkylene-C(O) R 3aaa It is replaced with, and here R 3aaa is -O R 7a , -N R 7a R 7b or is an alkyl); R 3b is hydrogen; R 3c is a fluoro. In certain embodiments, R 4 is hydrogen or alkyl if present. In certain embodiments, R 1 silver is. In a specific implementation, the following expression A compound having is provided. In a specific embodiment, the compound is 4-(4-(1-(2-((2-((carboxymethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-5'-fluoro-1 H ,1' H -[4,6'-Beiindazole]-1'-carbonyl)piperidine-1-yl)-4-oxobutanoic acid ( 206 ), 4-(4-(5'-fluoro-1-(2-((2-((2-methoxy-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1 H ,1' H -[4,6'-Beiindazole]-1'-carbonyl)piperidine-1-yl)-4-oxobutanoic acid ( 207 ), 4-(4-(1-(2-((2-((2-( tert -butoxy)-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-5'-fluoro-1 H ,1' H -[4,6'-Beiindazole]-1'-carbonyl)piperidine-1-yl)-4-oxobutanoic acid ( 208 ), (2-(1'-(1-(4-amino-4-oxobutanoyl)piperidine-4-carbonyl)-5'-fluoro-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 209 ), methyl (2-(1'-(1-(4-amino-4-oxobutanoyl)piperidine-4-carbonyl)-5'-fluoro-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 210 ), tert -butyl (2-(1'-(1-(4-amino-4-oxobutanoyl)piperidine-4-carbonyl)-5'-fluoro-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 211 ), (2-(5'-fluoro-1'-(1-(4-oxopentanoyl)piperidine-4-carbonyl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 212), methyl (2-(5'-fluoro-1'-(1-(4-oxopentanoyl)piperidine-4-carbonyl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 213 ), and tert -butyl (2-(5'-fluoro-1'-(1-(4-oxopentanoyl)piperidine-4-carbonyl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 214 It is selected from a group consisting of ).

[0161] In one embodiment, the compound is 4-(4-(1-(2-((2-((carboxymethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-5'-fluoro-1 H ,1' H -[4,6'-Beiindazole]-1'-carbonyl)piperidine-1-yl)-4-oxobutanoic acid ( 206 ) In one embodiment, the compound is 4-(4-(5'-fluoro-1-(2-((2-((2-methoxy-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1 H ,1' H -[4,6'-Beiindazole]-1'-carbonyl)piperidine-1-yl)-4-oxobutanoic acid ( 207 ) is. In one embodiment, the compound is 4-(4-(1-(2-((2-((2-( tert -butoxy)-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-5'-fluoro-1 H ,1' H -[4,6'-Beiindazole]-1'-carbonyl)piperidine-1-yl)-4-oxobutanoic acid ( 208 ) In one embodiment, the compound is (2-(1'-(1-(4-amino-4-oxobutanoyl)piperidine-4-carbonyl)-5'-fluoro-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 209) In one embodiment, the compound is methyl (2-(1'-(1-(4-amino-4-oxobutanoyl)piperidine-4-carbonyl)-5'-fluoro-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 210 ) is. In one embodiment, the compound is tert -butyl (2-(1'-(1-(4-amino-4-oxobutanoyl)piperidine-4-carbonyl)-5'-fluoro-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 211 ) In one embodiment, the compound is (2-(5'-fluoro-1'-(1-(4-oxopentanoyl)piperidine-4-carbonyl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 212 ) In one embodiment, the compound is methyl (2-(5'-fluoro-1'-(1-(4-oxopentanoyl)piperidine-4-carbonyl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 213 ) is. In one embodiment, the compound is tert -butyl (2-(5'-fluoro-1'-(1-(4-oxopentanoyl)piperidine-4-carbonyl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 214 )am.

[0162] In a specific embodiment, the following formula as described elsewhere in this invention A compound having or a pharmaceutically acceptable salt thereof is provided, wherein Is And; R 3 If it exists, And; R 4 is a 3- to 8-membered heterocycloalkyl containing at least one nitrogen, where present, and at least one nitrogen is unsubstituted or acyl, -C(O)-heteroalkylene-N R 4a R 4b , alkyl, -C(O)-alkylene-COO R 5 , -C(O)-alkylene-C(O)N R 4a R 4b , substituted with heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl, where R 4a and R 4b is independently hydrogen, alkyl, or acyl.

[0163] In a specific implementation example, R 3a is alkyl and; R 3b is hydrogen; R 3c is one or more alkoxy or halo. In certain embodiments, R 3 silver , , , , or is. In a specific implementation, R 4 is a 3- to 8-membered heterocycloalkyl containing at least one nitrogen, where present, and at least one nitrogen is unsubstituted or substituted with an acyl. In certain embodiments, R 4 Is , , , , or is. In a specific implementation, R 1 silver Igo R 9 Is , or is. In a specific implementation, R 9 Is , , or is. In a specific embodiment, the compound is 3-((2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)methyl)-4-fluorobenzoic acid ( 220 ), 2-(2-((2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)methyl)thiazole-4-yl)acetic acid ( 221 ), 2-(4-((2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)methyl)-1 H -1,2,3-triazole-1-yl)acetic acid ( 222 ), and 2-(4-((2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -methylacetamido)methyl)-1 H -1,2,3-triazole-1-yl)acetic acid ( 226 It is selected from a group consisting of ).

[0164] In one embodiment, the compound is 3-((2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)methyl)-4-fluorobenzoic acid ( 220 ) In one embodiment, the compound is 2-(2-((2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H-[4,6'-Byindazole]-1-yl)acetamido)methyl)thiazole-4-yl)acetic acid ( 221 ) In one embodiment, the compound is 2-(4-((2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)methyl)-1 H -1,2,3-triazole-1-yl)acetic acid ( 222 ) In one embodiment, the compound is 2-(4-((2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -methylacetamido)methyl)-1 H -1,2,3-triazole-1-yl)acetic acid ( 226 )am.

[0165] In a specific embodiment, the following formula as described elsewhere in this invention A compound having or a pharmaceutically acceptable salt thereof is provided, wherein Is And; R 3 If it exists, And; R 4 is a 3- to 8-membered heterocycloalkyl containing hydrogen or at least one nitrogen, where present, and at least one nitrogen is unsubstituted or acyl, -C(O)-heteroalkylene-N R 4a R 4b , alkyl, -C(O)-alkylene-COO R 5 , -C(O)-alkylene-C(O)N R 4a R 4b , substituted with heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl, where R 4a andR 4b is independently hydrogen, alkyl, or acyl. In certain embodiments, R 3a is alkyl and; R 3b is hydrogen; R 3c is one or more alkoxy or halo. In certain embodiments, R 3 silver , , , , or is. In a specific implementation, R 4 is a 3- to 8-membered heterocycloalkyl comprising hydrogen or at least one nitrogen, where present, wherein at least one nitrogen is unsubstituted or substituted with an acyl. In certain embodiments, R 4 is hydrogen, , , , , or is. In a specific implementation, R 1 silver is. In a specific embodiment, the compound is (2-(3-(1-acetylpiperidine-4-yl)-7-amino-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 223 ) and (2-(5'-fluoro-1'-methyl-7-(methylthio)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 224 It is selected from the group consisting of ). In one embodiment, the compound is (2-(3-(1-acetylpiperidine-4-yl)-7-amino-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 223) is. In one embodiment, the compound is (2-(5'-fluoro-1'-methyl-7-(methylthio)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 224 )am.

[0166] In a specific embodiment, the following formula as described elsewhere in this invention A compound having or a pharmaceutically acceptable salt thereof is provided, wherein Is And; R 3 If it exists, or And; R 4 is a 3- to 8-membered heterocycloalkyl containing at least one nitrogen, where present, and at least one nitrogen is unsubstituted or acyl, -C(O)-heteroalkylene-N R 4a R 4b , alkyl, -C(O)-alkylene-COO R 5 , -C(O)-alkylene-C(O)N R 4a R 4b , substituted with heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl, where R 4a and R 4b is independently hydrogen, alkyl, or acyl; or is a 5- to 15-one-spiro dicyclic heterocycloalkyl comprising at least one nitrogen, wherein at least one nitrogen is unsubstituted or is an alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, or -C(O)-alkylene-C(O) R 3aaa It is replaced with, and here R 3aaa is -OR 7a , -N R 7a R 7b or is alkyl. In certain embodiments, R 3a is alkyl and; R 3b is hydrogen; R 3c is one or more alkoxy, cyano, or halo. In certain embodiments, R 3 silver , , , , , or is. In a specific implementation, R 4 is, where present, a 3- to 8-membered heterocycloalkyl containing at least one nitrogen; or a 5- to 15-membered spiro dicyclic heterocycloalkyl containing at least one nitrogen, wherein at least one nitrogen is unsubstituted or substituted with an acyl. In certain embodiments, R 4 Is , , , , , or is. In a specific implementation, R 1 silver is. In a specific embodiment, the compound is N -(2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -Cyclopropylglycylglycine ( 225 ), N -(2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-2'-methyl-1 H ,2' H -[4,6'-Byindazole]-1-yl)acetyl)- N -Cyclopropylglycylglycine ( 227), and N -(2-(3-(2-acetyl-2-azaspiro[3.3]heptane-6-yl)-5'-cyano-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycine ( 228 It is selected from the group consisting of ). In one embodiment, the compound is N -(2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -Cyclopropylglycylglycine ( 225 ) is. In one embodiment, the compound is N -(2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-2'-methyl-1 H ,2' H -[4,6'-Byindazole]-1-yl)acetyl)- N -Cyclopropylglycylglycine ( 227 ) is. In one embodiment, the compound is N -(2-(3-(2-acetyl-2-azaspiro[3.3]heptane-6-yl)-5'-cyano-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycine ( 228 )am.

[0167] In a specific embodiment, the following formula as described elsewhere in this invention A compound having or a pharmaceutically acceptable salt thereof is provided, wherein Is And; R 3 is present, if present, an aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted with an alkyl, heteroalkyl, heterocycloalkyl, and / or halo; R 4 is a 3- to 8-membered heterocycloalkyl containing at least one nitrogen, where present, and at least one nitrogen is unsubstituted or acyl, -C(O)-heteroalkylene-N R 4a R 4b , alkyl, -C(O)-alkylene-COO R 5 , -C(O)-alkylene-C(O)N R 4a R 4b , substituted with heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl, where R 4a and R 4b is independently hydrogen, alkyl, or acyl. In certain embodiments, R 3 silver or is. In a specific implementation, R 4 is a 3- to 8-membered heterocycloalkyl containing at least one nitrogen, where present, and at least one nitrogen is unsubstituted or substituted with an acyl. In certain embodiments, R 4 Is , , , , or is. In a specific implementation, R 1 silver is. In a specific embodiment, the compound is (2-(3-(1-acetylpiperidine-4-yl)-4-(isoquinoline-3-yl)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 230 ) and (2-(3-(1-acetylpiperidine-4-yl)-4-(1-methyl-1 H -Dolmen-6-day)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 231It is selected from the group consisting of ). In one embodiment, the compound is (2-(3-(1-acetylpiperidine-4-yl)-4-(isoquinoline-3-yl)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 230 ) In one embodiment, the compound is (2-(3-(1-acetylpiperidin-4-yl)-4-(1-methyl-1 H -Dolmen-6-day)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 231 )am.

[0168] In a specific embodiment, the following formula as described elsewhere in this invention A compound having or a pharmaceutically acceptable salt thereof is provided, wherein Is And; R 3 If it exists, And; R 4 is a 3- to 8-membered heterocycloalkyl containing at least one nitrogen, where present, and at least one nitrogen is unsubstituted or acyl, -C(O)-heteroalkylene-N R 4a R 4b , alkyl, -C(O)-alkylene-COO R 5 , -C(O)-alkylene-C(O)N R 4a R 4b , -C(O)-alkylene-C(O)N( R 4a )-heteroalkylene-substituted with halo, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl, where R 4a and R 4b is independently hydrogen, alkyl, or acyl. In certain embodiments, R 3a is alkyl and; R 3b is hydrogen; R 3c is one or more alkoxy or halo. In certain embodiments, R 3 silver , , , , or is. In a specific implementation, R 4 is a 3- to 8-membered heterocycloalkyl containing at least one nitrogen, where present, and at least one nitrogen is unsubstituted or -C(O)-alkylene-C(O)N( R 4a )-Substituted with a heteroalkylene-halo, where R 4a is hydrogen, alkyl, or acyl. In certain embodiments, R 4 Is , , , and It is selected from a group consisting of. In a specific embodiment, R 1 silver is. In a specific embodiment, the compound is (2-(3-(1-(20-chloro-4-oxo-8,11,14-trioxa-5-azycosanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 232 ), methyl (2-(3-(1-(20-chloro-4-oxo-8,11,14-trioxa-5-azycosanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 233 ), (2-(3-(1-(23-chloro-4-oxo-8,11,14,17-tetraoxa-5-azatricosanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine (234 ), methyl (2-(3-(1-(23-chloro-4-oxo-8,11,14,17-tetraoxa-5-azatricosanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 235 ), (2-(3-(1-(26-chloro-4-oxo-8,11,14,17,20-pentaoxa-5-azahexacosanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 236 ), methyl (2-(3-(1-(26-chloro-4-oxo-8,11,14,17,20-pentaoxa-5-azahexacosanoyl)piperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 237 ), (2-(3-(1-(29-chloro-4-oxo-8,11,14,17,20,23-hexaoxa-5-azanocosanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 238 ), and methyl (2-(3-(1-(29-chloro-4-oxo-8,11,14,17,20,23-hexaoxa-5-azanocosanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 239 It is selected from a group consisting of ).

[0169] In one embodiment, the compound is (2-(3-(1-(20-chloro-4-oxo-8,11,14-trioxa-5-azycosanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 232) In one embodiment, the compound is methyl (2-(3-(1-(20-chloro-4-oxo-8,11,14-trioxa-5-azycosanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 233 ) In one embodiment, the compound is (2-(3-(1-(23-chloro-4-oxo-8,11,14,17-tetraoxa-5-azatricosanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 234 ) In one embodiment, the compound is methyl (2-(3-(1-(23-chloro-4-oxo-8,11,14,17-tetraoxa-5-azatricosanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 235 ) In one embodiment, the compound is (2-(3-(1-(26-chloro-4-oxo-8,11,14,17,20-pentaoxa-5-azahexacosanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 236 ) In one embodiment, the compound is methyl (2-(3-(1-(26-chloro-4-oxo-8,11,14,17,20-pentaoxa-5-azahexacosanoyl)piperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 237 ) In one embodiment, the compound is (2-(3-(1-(29-chloro-4-oxo-8,11,14,17,20,23-hexaoxa-5-azanocosanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H-[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 238 ) In one embodiment, the compound is methyl (2-(3-(1-(29-chloro-4-oxo-8,11,14,17,20,23-hexaoxa-5-azanocosanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 239 )am.

[0170] In a specific embodiment, the following formula as described elsewhere in this invention A compound having or a pharmaceutically acceptable salt thereof is provided, wherein the compound is ( S )-5-(2-fluoro-6-hydroxypyridine-3-yl)- N -methyl-2-((1-(3-((1-methyl-1 H -tetrazole-5-yl)methoxy)benzoyl)piperidin-3-yl)methoxy)benzamide ( 240 ), ( R )-5-(2-fluoro-6-hydroxypyridine-3-yl)- N -methyl-2-((1-(3-((1-methyl-1 H -tetrazole-5-yl)methoxy)benzoyl)piperidin-3-yl)methoxy)benzamide ( 241 ), ( S )-5-(2-fluoro-6-hydroxypyridine-3-yl)- N -methyl-2-((4-(3-((1-methyl-1 H -tetrazole-5-yl)methoxy)benzoyl)morpholine-2-yl)methoxy)benzamide ( 242 ), and ( R )-5-(2-fluoro-6-hydroxypyridine-3-yl)- N -methyl-2-((4-(3-((1-methyl-1 H -tetrazole-5-yl)methoxy)benzoyl)morpholine-2-yl)methoxy)benzamide ( 243 It is selected from the group consisting of ). In one embodiment, the compound is ( S )-5-(2-fluoro-6-hydroxypyridine-3-yl)- N-methyl-2-((1-(3-((1-methyl-1 H -tetrazole-5-yl)methoxy)benzoyl)piperidin-3-yl)methoxy)benzamide ( 240 ) is. In one embodiment, the compound is ( R )-5-(2-fluoro-6-hydroxypyridine-3-yl)- N -methyl-2-((1-(3-((1-methyl-1 H -tetrazole-5-yl)methoxy)benzoyl)piperidin-3-yl)methoxy)benzamide ( 241 ) is. In one embodiment, the compound is ( S )-5-(2-fluoro-6-hydroxypyridine-3-yl)- N -methyl-2-((4-(3-((1-methyl-1 H -tetrazole-5-yl)methoxy)benzoyl)morpholine-2-yl)methoxy)benzamide ( 242 ) is. In one embodiment, the compound is ( R )-5-(2-fluoro-6-hydroxypyridine-3-yl)- N -methyl-2-((4-(3-((1-methyl-1 H -tetrazole-5-yl)methoxy)benzoyl)morpholine-2-yl)methoxy)benzamide ( 243 )am.

[0171] In a specific embodiment, the following formula as described elsewhere in this invention A compound having or a pharmaceutically acceptable salt thereof is provided, wherein the compound is N -(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-6-(4-(2-(1-(2-(3,5-dioxomorpholino)acetamido)cyclobutyl)acetamido)piperidin-1-yl)nicotinamide ( 244 )am.

[0172] In a specific embodiment, the following formula as described elsewhere in this invention A compound having or a pharmaceutically acceptable salt thereof is provided, wherein the compound is N -(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-5-((2-(3,5-dioxomorpholino)-N -(Imidajo[2,1- b ]thiazole-3-ylmethyl)acetamido)methyl)-2,4-dimethylbenzamide ( 245 )am.

[0173] Pharmaceutical composition

[0174] The compounds described herein may be formulated into pharmaceutical compositions further comprising pharmaceutically acceptable carriers, diluents, adjuvants, or carriers. In one embodiment, the present disclosure provides a pharmaceutical composition comprising one or more of the compounds described herein and a pharmaceutically acceptable carrier, diluent, adjuvant, or carrier. In one embodiment, the present disclosure provides a pharmaceutical composition comprising an effective amount of one or more of the compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, adjuvant, or carrier. The pharmaceutically acceptable carrier comprises a pharmaceutical diluent, excipient, or carrier that is appropriately selected, for example, in relation to the intended dosage form and is consistent with ordinary pharmaceutical practice.

[0175] According to another embodiment, the present description provides a composition comprising one or more compounds of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or transporter. The pharmaceutical composition of the present description is a formula It comprises a therapeutically effective amount of one or more compounds, wherein the “therapeutically effective amount” is (a) an amount effective to modulate KLHDC1 and / or KLHDC2 activity in a biological sample or patient; or (b) an amount effective to treat and / or improve a disease or disorder mediated by KLHDC1 and / or KLHDC2.

[0176] Additionally, it will be understood that certain compounds of the present disclosure may be present in a free form (e.g., neutral compounds) for therapeutic purposes, or, where appropriate, as pharmaceutically acceptable derivatives (e.g., salts). According to the present disclosure, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any other adducts / starting materials (educts) or derivatives that, when administered to a patient in need, may directly or indirectly provide one or more compounds, metabolites, or residues otherwise described herein.

[0177] As used herein, the term “pharmaceuticalally acceptable salt” refers to a salt suitable for use in contact with cells, tissues, and / or tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., within the scope of sound medical practice or judgment.

[0178] Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. J. Pharmaceutical Sciences 1977 , 66Pharmaceutically acceptable salts are described in detail in , 1-19, which are incorporated herein by reference. Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts include inorganic acids such as hydrochloric acid, hydrobromide, phosphoric acid, sulfuric acid, and perchloric acid; or salts of amino groups formed with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid; or salts of amino groups formed by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, maleate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, Pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p - Includes toluenesulfonate, undecanoate, and valerate salts, etc. Salts derived from suitable bases are alkali metals, alkaline earth metals, ammonium (NH4 + ), and N + (C 1-4It includes alkyl)tetrasalts. This description also envisions the quaternization of any basic nitrogen-containing group of the compounds disclosed herein. By such quaternization, water-soluble, oil-soluble, or dispersible products may be obtained. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Additional pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfons, and aryl sulfons.

[0179] A pharmaceutically acceptable carrier may include an inactive component that does not excessively inhibit the biological activity of the compound described herein. The pharmaceutically acceptable carrier must be biocompatible, for example, when administered to a subject, and must be non-toxic, non-inflammatory, non-immunogenic, and / or biocompatible without other unwanted reactions or side effects. Standard pharmaceutical formulation techniques may be used.

[0180] As used herein, pharmaceutically acceptable carriers, adjuvants, or carriers include any and all solvents, diluents, or other liquid carriers, dispersants, or suspension aids, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc. suitable for a specific desired dosage form. Remington's Pharmaceutical Sciences, Sixteenth Edition, EW Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used to formulate pharmaceutically acceptable compositions and known techniques for their manufacture. The use of any conventional carrier medium is considered to be within the scope of this description, except where such conventional carrier medium is incompatible with the compounds described herein, such as by producing any undesirable biological effect or otherwise interacting in a harmful manner with any other component(s) of the pharmaceutically acceptable composition. As used herein, the term “adverse effect” encompasses unwanted and harmful effects of a therapy (e.g., prophylactic or therapeutic agents). While adverse effects are typically unwanted, unwanted effects are not necessarily harmful or unbeneficial. Harmful effects from a therapy (e.g., prophylactic or therapeutic agents) may be harmful, uncomfortable, or dangerous.Adverse effects include, but are not limited to, fever, chills, lethargy, gastrointestinal toxicity (including gastric and intestinal ulcers and erosions), nausea, vomiting, neurotoxicity, nephrotoxicity or nephrotoxicity (including conditions such as papillary necrosis and chronic interstitial nephritis), hepatotoxicity (including elevated serum liver enzyme levels), myelotoxicity (including leukopenia, bone marrow suppression, thrombocytopenia, and anemia), dry mouth, metallic taste, prolonged pregnancy, weakness, drowsiness, pain (including muscle pain, bone pain, and headache), hair loss, asthenia, dizziness, extrapyramidal symptoms, akathisia, cardiovascular disorders, and sexual dysfunction.

[0181] Some examples of substances that can serve as pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffering substances (e.g., Tween 80, phosphate, glycine, sorbic acid, or potassium sorbate), mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, or zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, methylcellulose, hydroxypropyl methylcellulose, wool, lactose, glucose, and sugars such as sucrose; starches such as corn starch and potato starch; Cellulose and derivatives thereof such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanths; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solution, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweeteners, flavoring agents, and perfumes. Preservatives and antioxidants may also be present in the composition at the discretion of the formulation developer (formulator).

[0182] administration

[0183] The compositions of the present disclosure may be administered orally, parenterally, via inhaled spray, topically, rectally, nasally, buccally, vaginally, or through an implanted reservoir. As used herein, the term “parenterally” includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intravertebral, intraocular, intrahepatic, intralesional, and intracranial injection or infusion techniques. The compositions may be administered orally, intraperitoneally, or intravenously. The sterile injectable form of the compositions of the present disclosure may be an aqueous or oily suspension. Such suspensions may be formulated according to techniques known in the art using suitable dispersants or wetting agents and suspending agents. The sterile injectable formulation may also be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Acceptable carriers and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile fixative oil is commonly used as a solvent or suspension medium.

[0184] For this purpose, any mild fixed oil, including synthetic mono- or di-glycerides, may be used. Fatty acids, such as oleic acid and its glyceride derivatives, are useful for the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, particularly in their polyoxyethylated versions. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tween, Span, and other emulsifiers or bioavailability enhancers commonly used in the preparation of pharmaceutically acceptable solid, liquid, or other dosage forms, may also be used for the purpose of formulation.

[0185] The pharmaceutically acceptable compositions of the present disclosure may be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions. For tablets for oral use, carriers commonly used include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. If an aqueous suspension is required for oral use, the active ingredient is combined with an emulsifier and a suspending agent. If desired, certain sweeteners, flavorings, or colorings may also be added.

[0186] Alternatively, the pharmaceutically acceptable composition of the present disclosure may be administered in the form of a suppository for rectal or vaginal administration. This may be prepared by mixing the formulation with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal or vaginal temperature and thus melts in the rectal or vaginal cavity to release the drug. Such materials include cocoa butter, polyethylene glycol, or suppository wax that is solid at ambient temperature but liquid at body temperature and thus melts in the rectal or vaginal cavity to release the active compound.

[0187] The pharmaceutically acceptable compositions of the present disclosure may also be administered topically, particularly where the therapeutic target involves a site or organ easily accessible by topical application, including diseases of the eye, skin, or lower gastrointestinal tract. Suitable topical formulations are readily prepared for each of these sites or organs.

[0188] Topical application to the lower intestine may be performed via rectal suppository formulations (see above) or suitable enema formulations. Topical transdermal patches may also be used.

[0189] For topical application, a pharmaceutically acceptable composition may be formulated into a suitable ointment comprising an active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying waxes, and water. Alternatively, a pharmaceutically acceptable composition may be formulated into a suitable lotion or cream comprising an active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0190] For ophthalmic use, pharmaceutically acceptable compositions may be formulated as a finely divided suspension, for example, in isotonic, pH-adjusted sterile saline or other aqueous solutions, or as a solution in isotonic, pH-adjusted sterile saline or other aqueous solutions, in the presence or absence of a preservative such as benzyl alcoholnium chloride. Alternatively, for ophthalmic use, pharmaceutically acceptable compositions may be formulated as an ointment such as petroleum jelly. Pharmaceutically acceptable compositions of the present disclosure may also be administered by nasal aerosol or inhalation. Such compositions may be prepared according to techniques well known in the field of pharmaceutical formulation and may be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption promoters to improve bioavailability, fluorocarbons, and / or other conventional solubilizers or dispersants.

[0191] In certain embodiments, the composition of the present disclosure is administered orally. The pharmaceutically acceptable composition of the present description may be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions. For tablets for oral use, carriers commonly used include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. If an aqueous suspension is required for oral use, the active ingredient is combined with an emulsifier and a suspending agent. If desired, certain sweeteners, flavorings, or colorings may also be added.

[0192] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the biologically active compounds of the present invention, liquid dosage forms may include inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, fatty acid esters of tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions may also include auxiliary agents such as humectants, emulsifiers and suspending agents, sweeteners, flavoring agents, and flavoring agents.

[0193] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the biologically active compound(s) described herein shall comprise at least one inert pharmaceutically acceptable excipient or carrier, such as sodium citrate or calcium hydrogen phosphate, and / or a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants, such as glycerol; d) disintegrants, such as agar—agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retardants, such as paraffin; f) absorption promoters, such as quaternary ammonium compounds; g) a wetting agent such as, for example, cetyl alcohol and glycerol monostearate; h) an adsorbent such as kaolin and bentonite clay; and i) a lubricant such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also include a buffer.

[0194] Similar types of solid compositions can also be used as fillers in soft and hard-filled gelatin capsules using excipients such as high molecular weight polyethylene glycol, as well as lactose. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be manufactured with coatings and shells, such as enteric coatings and other coatings well known in the field of pharmaceutical formulation. Solid dosage forms may optionally contain opacifying agents. These solid dosage forms may also be compositions that allow the active ingredient(s) to be released selectively in a delayed manner, for example, only in specific parts of the intestinal tract. Examples of embedded compositions that can be used include polymeric materials and waxes. Similar types of solid compositions can also be used as fillers in soft and hard-filled gelatin capsules using excipients such as high molecular weight polyethylene glycol, as well as lactose.

[0195] The active compound of the present invention may also be in a micro-encapsulated form with one or more of the excipients mentioned above. Solid dosage forms such as tablets, coated tablets, capsules, pills, and granules may be manufactured with coatings and shells, such as enteric coatings, controlled-release coatings, and other coatings well known in the field of pharmaceutical formulation. In these solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. These dosage forms may also, in accordance with common practice, include additional materials other than the inert diluent, such as tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also include a buffer. They may optionally include an opacifying agent and may also be compositions that allow the active ingredient(s) to be released selectively in a delayed manner, for example, only in specific parts of the intestinal tract. Examples of embedding compositions that may be used include polymeric materials and waxes.

[0196] The compounds described herein are formulated in dose units for ease of administration and uniformity of dosage. As used herein, the phrase “dose unit form” refers to physically distinct units of the formulation appropriate for the subject, cell, tissue, or patient to be treated. However, it will be understood that the total daily use of the compounds and compositions of this disclosure will be determined by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular subject, cell, tissue, patient, or organism will depend on various factors including the disorder being treated and the severity of the disorder; the activity of the specific compound(s) used; the specific composition(s) used; the age, weight, overall health status, gender, and diet of the subject, cell, tissue, and / or patient; the time of administration, route of administration, and elimination rate of the specific compound(s) used; the duration of treatment; drugs used in combination or simultaneously with the specific compound(s) used; and similar factors well known in the medical field.

[0197] The amount of the compound of the present disclosure that may be combined with a carrier material to produce a composition in a single-dose form will vary depending on the subject, cell, tissue, and / or host being treated, the specific mode of administration, and other factors. The composition should be formulated so that a dose between 0.01 and 100 mg / kg body weight / day of the compound(s) or inhibitor(s) can be administered to the subject, cell, tissue, and / or patient receiving such composition.

[0198] Depending on the specific condition or disease to be treated or prevented, additional therapeutic agents typically administered to treat or prevent such condition may also be present in the composition of the present disclosure. As used herein, additional therapeutic agents typically administered to treat or prevent a specific disease or condition are known to be “appropriate to the disease or condition being treated.”

[0199] A compound or composition may be administered simultaneously, prior to, or after one or more additional therapeutically active agents. Generally, each agent will be administered according to a dosage and / or time schedule determined for that agent. It will be further understood that additional therapeutically active agents used in the combination may be administered together in a single composition or separately in different compositions. The specific combination to be used in the regimen will take into account the compatibility of the compound and additional therapeutically active agents described herein and / or the desired therapeutic effect to be achieved. Generally, additional therapeutically active agents used in combination are expected to be used at a level that does not exceed the level at which they are used individually. In some embodiments, the level used in combination will be lower than the level used individually. Additional therapeutic active agents include, but are not limited to, small organic molecules such as drug compounds (e.g., compounds approved by the Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional therapeutic active agent is an anticancer agent (e.g., a biotherapeutic agent or a chemotherapy anticancer agent). In other embodiments, the additional therapeutic active agent is an anti-inflammatory agent.

[0200] The amount of additional therapeutic agent present in the composition of the present disclosure will be less than or equal to the amount ordinarily administered in a composition comprising that therapeutic agent as the sole active agent. The amount of additional therapeutic agent in the composition disclosed herein will be in the range of about 50% to 100% of the amount ordinarily present in a composition comprising that agent as the sole therapeutically active agent.

[0201] How to use

[0202] The compounds described herein are useful for inhibiting or regulating KLHDC1 or KLHDC2 in biological samples or patients. Accordingly, one embodiment of the present disclosure provides a method for treating a disease or disorder by regulating KLHDC1 or KLHDC2 activity. As used herein, the term “KLHDC1- or KLHDC2-mediated disease or disorder” means any disease, disorder, or other harmful condition known to involve KLHDC1 or KLHDC2. In some cases, a KLHDC1- or KLHDC2-mediated disease or disorder is a proliferative disorder or an autoimmune disorder. Examples of proliferative disorders include cancer.

[0203] In one aspect, the present invention provides a method for treating or preventing cancer in a subject in need. In a specific embodiment, the method comprises the step of orally administering to a subject an amount of the compound(s) described herein capable of modulating KLHDC1 or KLHDC2 activity. In a specific embodiment, the amount is effective for treating or preventing cancer.

[0204] In a specific embodiment, the cancer is any of the cancers described below. In a specific embodiment, the cancer includes a solid tumor. In a specific embodiment, the cancer is a B-cell malignancy. In a specific embodiment, the cancer is selected from the group consisting of chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), transformed CLL or Richter's transformation, small cell lymphoma, follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), non-Hodgkin lymphoma, mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), Waldenstrom macroglobulinemia (WM), and central nervous system (CNS) lymphoma. In a specific embodiment, the cancer is chronic lymphocytic leukemia. In a specific embodiment, the cancer is small cell lymphoma. In a specific embodiment, the cancer is follicular lymphoma. In a specific embodiment, the cancer is diffuse large B-cell lymphoma. In a specific embodiment, the cancer is non-Hodgkin lymphoma. In a specific embodiment, the cancer is mantle cell lymphoma. In a specific embodiment, the cancer is marginal zone lymphoma. In a specific embodiment, the cancer is Waldenström macroglobulinemia. In a specific embodiment, the cancer is small lymphocytic lymphoma (SLL). In a specific embodiment, the cancer is CNS lymphoma. In a specific embodiment, the cancer is converted CLL or converted Richter. In a specific embodiment, the cancer is chronic lymphocytic leukemia (CLL).

[0205] In another aspect, the present invention provides a method for inhibiting or regulating KLHDC1 or KLHDC2 in a subject requiring it. The method comprises the step of orally administering to a subject an amount of compound(s) described herein capable of regulating KLHDC1 or KLHDC2. In certain embodiments, the amount is effective for inhibiting KLHDC1 or KLHDC2 in the subject. In certain embodiments, the amount is effective for regulating KLHDC1 or KLHDC2 in the subject. KLHDC1 or KLHDC2 may be expressed in any cell or tissue of the subject.

[0206] The compound(s) described herein may be administered at any dose deemed appropriate by a skilled practitioner. In certain embodiments, the dose is 0.1-1000 mg / kg. In certain embodiments, the dose is 0.1-900 mg / kg. In certain embodiments, the dose is 0.1-800 mg / kg. In certain embodiments, the dose is 0.1-700 mg / kg. In certain embodiments, the dose is 0.1-600 mg / kg. In certain embodiments, the dose is 0.1-500 mg / kg. In certain embodiments, the dose is 0.1-400 mg / kg. In certain embodiments, the dose is 0.1-300 mg / kg. In certain embodiments, the dose is 0.1-200 mg / kg. In certain embodiments, the dose is 0.1-100 mg / kg. In a specific embodiment, the dose is selected from the group consisting of 100 mg / kg, 200 mg / kg, 300 mg / kg, 450 mg / kg, 600 mg / kg, 800 mg / kg, and 1000 mg / kg. In a specific embodiment, the dose is about 25 mg / kg. In a specific embodiment, the dose is about 50 mg / kg. In a specific embodiment, the dose is about 75 mg / kg. In a specific embodiment, the dose is about 100 mg / kg. In a specific embodiment, the dose is about 150 mg / kg. In a specific embodiment, the dose is about 200 mg / kg. In a specific embodiment, the dose is about 250 mg / kg. In a specific embodiment, the dose is about 300 mg / kg. In a specific embodiment, the dose is about 400 mg / kg. In a specific embodiment, the dose is about 450 mg / kg. In a specific embodiment, the dose is about 500 mg / kg. In a specific embodiment, the dose is about 600 mg / kg. In a specific embodiment, the dose is about 700 mg / kg. In a specific embodiment, the dose is about 750 mg / kg. In a specific embodiment, the dose is about 800 mg / kg. In a specific embodiment, the dose is about 900 mg / kg. In a specific embodiment, the dose is about 1000 mg / kg.

[0207] The dose may be administered according to a schedule deemed appropriate by a person skilled in the art. In a specific embodiment, the dose is administered once a day. In a specific embodiment, the dose is administered twice a day. In a specific embodiment, the dose is administered three times a day. In a specific embodiment, the dose is administered four times a day. In a specific embodiment, the dose is administered as a divided dose. In a specific embodiment, the dose is administered as a divided dose twice a day. In a specific embodiment, the dose is administered as a divided dose three times a day. In a specific embodiment, the dose is administered as a divided dose four times a day.

[0208] Administration may continue for any period deemed appropriate by a person skilled in the art. In a specific embodiment, the dose is administered daily for 14 days. In a specific embodiment, the dose is administered daily for 13 days. In a specific embodiment, the dose is administered daily for 12 days. In a specific embodiment, the dose is administered daily for 11 days. In a specific embodiment, the dose is administered daily for 10 days. In a specific embodiment, the dose is administered daily for 9 days. In a specific embodiment, the dose is administered daily for 8 days. In a specific embodiment, the dose is administered daily for 7 days. In a specific embodiment, the dose is administered daily for 6 days. In a specific embodiment, the dose is administered daily for 5 days. In a specific embodiment, the dose is administered daily for 4 days. In a specific embodiment, the dose is administered daily for 3 days. In a specific embodiment, the dose is administered daily for 2 days. In a specific embodiment, the dose is administered for 1 day.

[0209] In the administration schedule, the dose may be administered on consecutive days or periodically at the judgment of a skilled practitioner. In a specific embodiment, the dose is administered on consecutive days. In a specific embodiment, the dose is administered at intervals between doses. In a specific embodiment, the interval is 1 day. In a specific embodiment, the interval is 2 days. In a specific embodiment, the interval is 3 days. In a specific embodiment, the interval is 4 days. In a specific embodiment, the interval is 5 days. In a specific embodiment, the interval is 6 days.

[0210] In a specific embodiment, the dose is administered once a week. In a specific embodiment, the dose is administered twice a week. In a specific embodiment, the dose is administered three times a week.

[0211] In a specific embodiment, dose(s) are administered for a period of time with a first interval between dose(s), and then dose(s) are re-administered for a period of time after the first interval between dose(s), wherein this administration regimen may be repeated at the judgment of a skilled practitioner (i.e., periodically or cyclically, for example, after a second, third, etc. interval between subsequent administrations of dose(s). For example, in one embodiment, a first dose is administered for one week, followed by a first interval of one week without administration of the first dose; then, a second dose is re-administered for another week, followed by a second interval of one week without administration of the first or second dose, and proceeds cyclically in this manner. Other perturbations to the first, second, and third dose(s), subsequent perturbations to the first, second, and third interval(s), and combinations thereof are conceived herein as understood by a skilled practitioner and by the needs of the subject, cell, tissue, and / or patient. For example, in one embodiment, the first dose is administered daily for one week, followed by a first interval of three weeks without the first daily dose; subsequently, the second dose is re-administered every other week for another week, followed by a second interval of four weeks without the first daily or second every-other-week dose, and proceeds cyclically in this manner.

[0212] The compound may be administered by any route of administration that a skilled practitioner deems appropriate. In certain embodiments, the dose is administered orally. Formulations and techniques for administration are described elsewhere in this invention.

[0213] In certain embodiments, the term “cancer” includes, but is not limited to, the following cancers: epidermoid oral: buccal cavity, lip, tongue, mouth, pharynx, squamous cell carcinoma of the head and neck (HNSCC); cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; Lung: Bronchogenic carcinoma (squamous cell or epidermoid, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, non-small cell lung cancer (NSCLC);Gastrointestinal: gastric cancer, esophagus (squamous cell carcinoma, larynx, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small bowel or small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, Hemangioma, lipoma, neurofibroma, fibroma), large bowel or large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colon, colon-rectum, colorectal, microsatellite stable colorectal cancer (MSS CRC), rectum;Genitourinary tract: Kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor), Lipoma), metastatic castrate-resistant prostate cancer (mCRPC), muscle-invasive urothelial cancer; Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, biliary passage;Bone: Osteogenic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma (MM), malignant giant cell tumor chordoma, osteochondroma (osteocartilaginous exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor;Nervous system: Skull (osteoma, hemangioma, granuloma, xanthoma, osteoitis deformans), Meninges (meningioma, meningiosarcoma, gliomatosis), Brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal cord neurofibroma, meningioma, glioma, Breeding);Gynecological: Uterus (endometrial carcinoma), Cervix (cervical cancer, cervical carcinoma, pre-tumor cervical dysplasia), Ovary (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), Vulva (squamous cells Carcinoma (squamous cell carcinoma), intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma)), fallopian tube (carcinoma), breast, triple-negative breast cancer (TNBC), platinum-resistant epithelial ovarian cancer (EOC);Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disease, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma), hairy cell; lymphoid disorder (e.g., mantle cell lymphoma, Waldenström macroglobulinemia, marginal zone lymphoma, and follicular lymphoma); Skin: Malilymphgnant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, keratoacanthoma, mole or dysplastic nevus, lipoma, angioma, dermatofibroma, keloid, psoriasis; Thyroid gland: Papillary thyroid carcinoma, follicular thyroid carcinoma;Medullary thyroid carcinoma, undifferentiated thyroid cancer, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid cancer, pheochromocytoma, paraganglioma; adrenal gland: neuroblastoma; and metastatic melanoma.;

[0214] In certain embodiments, the term “autoimmune disease” includes, but is not limited to, the following autoimmune diseases: uticaria, graft-versus-host disease (GVHD), acute graft-versus-host disease, pemphigus vulgaris, achalasia, Addison's disease, Adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune Autoimmune dysautonomia, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, axonal and neuronal neuropathy (AMAN), Balo's disease (Bal disease), Behcet's disease, benign mucosal pemphigoid, bullous pemphigoid, Castleman disease (CD), celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss Syndrome (CSS) or eosinophilic granulomatosis (EGPA), cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, congenital heart block, Coxsackie Coxsackie myocarditis, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis;EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schönlein Henoch-Schonlein purpura (HSP), herpes gestationis or pemphigoid gestationis (PG), hidradenitis suppurativa (HS) (Acne Inversa), hypogammalglobulinemia, IgA nephropathy, IgG4-related sclerosing disease, immune thrombocytopenic purpura (ITP), inclusion body myositis (IBM), interstitial cystitis;IC), juvenile arthritis, juvenile diabetes (Type 1 diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, ligneous conjunctivitis, linear IgA disease (LAD), lupus, chronic Lyme disease, Meniere's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease disease), Multifocal Motor Neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, palindromic rheumatism (PR), PANDAS, paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria;PNH), Parry Romberg syndrome, pars planitis (peripheral uveitis), Parsonnage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia (PA), POEMS syndrome, polyarteritis nodosa, polyglandular syndrome type I, II, or III, polymyalgia rheumatica, polymyositis, postmyocardial infarction syndrome, postpericardiotomy syndrome, primary biliary Primary biliary cirrhosis, primary sclerosing cholangitis, progesterone dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia (PRCA), pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome;RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjögren's syndrome (Sj; Gren's syndrome), sperm and testicular autoimmunity, stiff person syndrome (SPS), subacute bacterial endocarditis (SBE), Susac's syndrome, sympathetic ophthalmia (SO), Takayasu's arteritis, temporal arteritis (giant cell arteritis), thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), transverse myelitis, Type 1 diabetes, ulcerative colitis (UC), undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vitiligo, Vogt-Koyanagi-Harada disease, and Wegener's granulomatosis (or granulomatosis with polyangiitis (GPA)).

[0215] In certain embodiments, the term “inflammatory disease” includes, but is not limited to, the following inflammatory diseases: encephalitis, myelitis, meningitis, arachnoiditis, neuritis, dacryoadenitis, scleritis, episcleritis, keratitis, retinitis, chorioretinitis, blepharitis, conjunctivitis, uveitis, otitis externa, otitis media, labyrinthitis, mastoiditis, endocarditis, myocarditis, pericarditis, vasculitis, arteritis, phlebitis, Capillaritis, sinusitis, rhinitis, pharyngitis, laryngitis, tracheitis, bronchitis, bronchiolitis, pneumonitis, pleuritis, mediastinitis, stomatitis, gingivitis, gingivostomatitis, glossitis, tonsillitis, sialadenitis / parotitis, cheilitis, pulpitis, gnathitis, esophagitis, gastritis, gastroenteritis, enteritis, colitis, enterocolitis,Duodenitis, ileitis, caecitis, appendicitis, proctitis, hepatitis, ascending cholangitis, cholecystitis, pancreatitis, peritonitis, dermatitis, folliculitis, cellulitis, hidradenitis, arthritis, dermatomyositis, myositis, synovitis / tenosynovitis, bursitis, enthesitis, fasciitis, capsulitis, epicondylitis, tendinitis, panniculitis, Osteochondritis / osteitis / osteomyelitis, spondylitis, perioostitis, chondritis, nephritis, glomerulonephritis, pyelonephritis, ureteritis, cystitis, urethritis, oophoritis, salpingitis, endometritis, parametritis, cervicitis, vaginitis, vulvitis, mastitis, orchitis, epididymitis, prostatitis, seminal vesiculitis, balanitis, posthitis, balanoposthitis, chorioamnionitis,Funisitis, omphalitis, insulitis, hypophysitis, thyroiditis, parathyroiditis, adrenalitis, lymphangitis, and lymphadenitis.

[0216] Manufactured items and kits

[0217] Manufactured articles comprising any of the compounds or pharmaceutical compositions described herein are also provided. Manufactured articles comprise suitable containers or packaging materials for the compounds or pharmaceutical compositions. Examples of suitable containers include, but are not limited to, bottles, vials, syringes, intravenous bags, or tubes.

[0218] A kit comprising any compound or pharmaceutical composition described herein is also provided. The kit may contain the compound or pharmaceutical composition within a suitable container or packaging material, comprising but not limited to a bottle, vial, syringe, intravenous bag, or tube. The kit may contain the compound or pharmaceutical composition for administration to a subject, cell, tissue, and / or individual in a single-dose form or a multiple-dose form. The kit may further comprise instructions or a label for administering the compound or pharmaceutical composition to a subject, cell, tissue, and / or individual according to any method disclosed herein. The kit may further comprise equipment for administering the compound or pharmaceutical composition to a subject, cell, tissue, and / or individual, comprising but not limited to a needle, syringe, tubing, or intravenous bag. The kit may further comprise instructions for producing any compound or pharmaceutical composition disclosed herein.

[0219] Manufactured articles comprising any of the compounds or pharmaceutical compositions described herein are also provided. Manufactured articles comprise suitable containers or packaging materials for the compounds or pharmaceutical compositions. Manufactured articles comprise suitable containers or packaging materials for the compounds or pharmaceutical compositions. Examples of suitable containers include, but are not limited to, bottles, vials, syringes, intravenous bags, or tubes.

[0220] The present disclosure will be more fully understood by referring to the following examples. However, these should not be construed as limiting the scope of the present disclosure. The examples and embodiments described herein are for illustrative purposes only, and it is understood that various modifications or changes will be suggested to those skilled in the art in light of this and should be included within the spirit and scope of the present application and the scope of the appended claims.

[0221] Examples

[0222] Additional embodiments are disclosed in further detail in the following embodiments, which are not intended to limit the scope of the claims in any way.

[0223] Analysis methods and instruments

[0224] The proton nuclear magnetic resonance (NMR) spectrum is Bruker Ascend TM It was obtained using a 500 MHz spectrometer. The NMR spectrum was reported as follows: chemical shift δ (ppm), multiplicity, and coupling constant. J(Hz), and (relative) integral. Abbreviations s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and br = broad were used throughout. Mass spectrum data were measured using the following system: a Waters Acquity i-class ultra-high performance liquid chromatography (UPLC) system equipped with an Acquity Photodiode Array Detector, an Acquity Evaporative Light Scattering Detector (ELSD), and a Waters ZQ Mass Spectrometer. Data were acquired using Waters MassLynx 4.1 software, and purity was characterized by UV wavelength 220 nm, Evaporative Light Scattering Detector (ELSD), and Electrospray Cation I (ESI) (Column: Acquity UPLC BEH C18 1.7 μL 2.1 x 50 mm). Solvent used: Acetonitrile / water containing 0.1% formic acid; flow rate 0.7 mL / min. Preparatory HPLC purification was performed at a flow rate of 15 mL / min and UV wavelength detection at 214 nm and 254 nm (Column: Jupiterⓒ 10 μM Proteo 90 Å, 250 x 21.2 mm A, Solvent: Acetonitrile / water containing a modifier such as 0.1% trifluoroacetic acid).

[0225] The abbreviations used in the examples include the following:

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

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[0248]

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[0250]

[0251]

[0252]

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[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

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[0269]

[0270]

[0271]

[0272]

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[0280]

[0281]

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[0289]

[0290]

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[0297]

[0298]

[0299]

[0300]

[0301]

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[0310]

[0311]

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[0315]

[0316]

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[0318]

[0319]

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[0321]

[0322]

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[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

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[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

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[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365] Common Intermediate tert -butyl 4-(4-bromo-1-(2-ethoxy-2-oxoethyl)-1 H Synthesis of -indazole-3-yl)piperidine-1-carboxylate (5)

[0366]

[0367] Step-1: tert -butyl 4-((2-bromo-6-fluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate ( 2 Synthesis of )

[0368] LDA (2 M, 44 mL, 88.0 mmol, 1.1 equivalents) was added dropwise to a stirred solution of 1-bromo-3-fluoro-2-iodobenzene (14 g, 80.460 mmol, 1 equivalent) in THF (150 mL) at -78 °C under a nitrogen atmosphere. The resulting mixture was stirred at -78 °C under a nitrogen atmosphere for 1 hour. Then, in THF (50 mL) tert β-butyl 4-formylpiperidin-1-carboxylate (34.32 g, 160.920 mmol, 2 equivalents) was added to the above mixture. The resulting mixture was stirred at -78 °C for 1 hour under a nitrogen atmosphere. The mixture was quenched with water. The resulting solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with petroleum ether (PE):EtOAc = 1:1. tert -Butyl 4-((2-bromo-6-fluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (25.86 g, 82.78% yield, 90.0% purity) was obtained as a yellow oil. m / z = 388.1 (M+H) + .

[0369] Step-2: tert -Butyl 4-(2-bromo-6-fluorobenzoyl)piperidine-1-carboxylate ( 3 Synthesis of )

[0370] In DCM (100 mL) tert PCC (27.76 g, 128.774 mmol, 2 equivalents) was added to a stirred solution of β-butyl 4-((2-bromo-6-fluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (25 g, 64.387 mmol, 90.0% purity, 1 equivalent). The resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted at PE:EtOAc = 3:1, tert -Butyl 4-(2-bromo-6-fluorobenzoyl)piperidine-1-carboxylate (18.85 g, 75.79% yield, 85.0% purity) was obtained as a yellow solid. m / z = 386.1 (M+H) + .

[0371] Step-3: tert -butyl 4-(4-bromo-1 H -Indazole-3-yl)piperidine-1-carboxylate ( 4 Synthesis of )

[0372] in dioxane (50 mL) tert N2H4·H2O (10.92 g, 218.115 mmol, 5 equivalents) was added to a stirred solution of β-butyl 4-(2-bromo-6-fluorobenzoyl)piperidine-1-carboxylate (16.85 g, 43.623 mmol, 85.0% purity, 1 equivalent). The resulting mixture was stirred at 110 °C for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted at PE:EtOAc = 1:1, tert -butyl 4-(4-bromo-1 H-indazole-3-yl)piperidine-1-carboxylate (11 g, 66.31% yield, 88.0% purity) was obtained as a yellow solid. m / z = 380.1 (M+H) + .

[0373] Step-4: tert -butyl 4-(4-bromo-1-(2-ethoxy-2-oxoethyl)-1 H -Indazole-3-yl)piperidine-1-carboxylate ( 5 Synthesis of )

[0374] In DMF (10 mL) tert -butyl 4-(4-bromo-1 H K2CO3 (0.73 g, 5.260 mmol, 2 equivalents) and ethyl bromoacetate (0.44 g, 2.630 mmol, 1 equivalent) were added to a stirred solution of indazole-3-yl)piperidine-1-carboxylate (1 g, 2.630 mmol, 88.0% purity, 1 equivalent). The resulting mixture was stirred at 80 °C for 4 hours under a nitrogen atmosphere. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE:EtOAc = 2:1, tert -butyl 4-(4-bromo-1-(2-ethoxy-2-oxoethyl)-1 H -Indazole-3-yl)piperidine-1-carboxylate (800 mg, 65.57% yield, 90.0% purity) was obtained as a white solid. m / z = 466.1 (M+H) + .

[0375] Commonly used pinacol ester of boronic acid (3 ) Synthesis of.

[0376]

[0377] Step-1: 6-Bromo-5-fluoro-1-methylindazole ( 2 Synthesis of )

[0378] 6-bromo-5-fluoro-1 in MeCN (30 mL) HCs2CO3 (30.31 g, 93.012 mmol, 2 equivalents) and MeI (7.92 g, 55.807 mmol, 1.2 equivalents) were added to a stirred solution of methylindazole (10 g, 46.506 mmol, 1 equivalent). The resulting mixture was stirred at 70 °C for 3 hours under a nitrogen atmosphere. Subsequently, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with petroleum ether:ethyl acetate = 2:1 to obtain 6-bromo-5-fluoro-1-methylindazole (8 g, 75.10% yield, 90.0% purity) as a pale yellow solid. m / z = 229.0 (M+H) + .

[0379] Step-2: 5-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole ( 3 Synthesis of )

[0380] Pd(dppf)Cl2 (2.62 g, 3.580 mmol, 0.2 equivalents), bis(pinacolato)diborone (11.36 g, 44.750 mmol, 2.5 equivalents), and KOAc (8.78 g, 89.500 mmol, 5 equivalents) were added to a stirred solution of 6-bromo-5-fluoro-1-methylindazole (4.1 g, 17.900 mmol, 90% purity, 1.0 equivalent) in 1,4-dioxane (100 mL). The resulting mixture was stirred at 90 °C for 2 hours under a nitrogen atmosphere. Subsequently, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with petroleum ether:ethyl acetate = 3:1 to obtain 5-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (4.2176 g, 84.91% yield, 99.5% purity) as a light orange solid. LCMS: R t = 1.478 min, m / z = 277.0 (M+H) + . 1 H NMR (300 MHz, DMSO- d6) δ 8.02 (d, J = 1.2 Hz, 1H), 7.90 - 7.85 (m, 1H), 7.47 (d, J = 9.6 Hz, 1H), 4.09 (s, 3H), 1.34 (s, 12H).

[0381] General pathway for substituent installation to explore the SAR of di-glycine

[0382]

[0383] Step-1: tert -butyl 4-[1-(2-ethoxy-2-oxoethyl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-3-yl]piperidine-1-carboxylate ( 6 Synthesis of )

[0384] Dioxane (5 mL):H2O (1 mL) tert To a stirred solution of butyl 4-[4-bromo-1-(2-ethoxy-2-oxoethyl)indazole-3-yl]piperidine-1-carboxylate (300 mg, 0.643 mmol, 90.0% purity, 1 equivalent), K2CO3 (240.03 g, 1.736 mmol, 2 equivalents), 5-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (335.6 mg, 1.215 mmol, 1.89 equivalents), and Pd(dppf)Cl2·CH2Cl2 (57.6 mg, 0.071 mmol, 0.10 equivalents) were added. The resulting mixture was stirred at 75 °C for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted at PE:EtOAc = 5:1. tert -Butyl 4-[1-(2-ethoxy-2-oxoethyl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-3-yl]piperidine-1-carboxylate (370 mg, 93.19% yield, 90.0% purity) was obtained as a pale yellow solid. m / z = 536.2 (M+H) + .

[0385] Step-2: Ethyl 2-[5'-fluoro-1'-methyl-3-(piperidine-4-yl)-[4,6'-baindazole]-1-yl]acetate ( 7 Synthesis of )

[0386] In DCM (5 mL) tert HCl (gas) (4 M, 5 mL) in 1,4-dioxane was added to a stirred solution of butyl 4-[1-(2-ethoxy-2-oxoethyl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-3-yl]piperidine-1-carboxylate (370 mg, 0.691 mmol, 90.0% purity, 1 equivalent). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure to obtain ethyl 2-[5'-fluoro-1'-methyl-3-(piperidine-4-yl)-[4,6'-baindazole]-1-yl]acetate (250 mg, 83.00% yield, 90.0% purity) as a pale yellow solid. m / z = 436.2 (M+H) + .

[0387] Step-3: Ethyl 2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]acetate ( 8 Synthesis of )

[0388] TEA (186.9 mg, 1.848 mmol, 2.98 equivalents) and acetyl chloride (72.3 mg, 0.918 mmol, 1.48 equivalents) were added to a stirred solution of ethyl 2-[5'-fluoro-1'-methyl-3-(piperidin-4-yl)-[4,6'-baindazole]-1-yl]acetate (250 mg, 0.620 mmol, 90.0% purity, 1 equivalent) in DCM (5 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1.5 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted at PE:EtOAc = 5:1 to obtain ethyl 2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]acetate (280 mg, 91.33% yield, 88.0% purity) as a pale yellow solid. m / z = 478.2 (M+H) + .

[0389] Step-4: [3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-byindazole]-1-yl]acetic acid ( 9 Synthesis of )

[0390] LiOH·H2O (63.8 mg, 1.522 mmol, 2.85 equivalents) was added to a stirred solution of ethyl 2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]acetate (255 mg, 0.534 mmol, 88.0% purity, 1 equivalent) in THF (2 mL):H2O (2 mL):MeOH (2 mL). The resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was acidified with HCl (aq. 1 M) to pH 5. The precipitated solid was collected by filtration, washed with water, and dried, and volatile substances were removed under reduced pressure to obtain [3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]acetic acid (120 mg, 50.00% yield, 90.0% purity) as a pale yellow solid. m / z = 450.2 (M+H) + .

[0391] Step-5: Methyl 2-{2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]- N -methylacetamido}acetate ( 10 Synthesis of )

[0392] Methyl 2-(methylamino)acetate hydrochloride (37.1 mg, 0.267 mmol, 1 equivalent), HATU (152.2 mg, 0.401 mmol, 1.5 equivalents), and DIEA (172.5 mg, 1.335 mmol, 5 equivalents) were added to a stirred solution of [3-(1-acetylpiperidin-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]acetic acid (120 mg, 0.267 mmol, 90.0% purity, 1.00 equivalents) in DMF (5 mL). The resulting mixture was stirred at room temperature for 1.5 hours. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were combined and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography using acetonitrile (ACN):H2O (1:3) to methyl 2- {2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]- N methylacetamido acetate (140 mg, 95.10% yield, 85.0% purity) was obtained as a white solid. m / z = 535.2 (M+H) + .

[0393] Step-6: {2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]- N -methylacetamido}acetic acid ( 11 Synthesis of )

[0394] Methyl 2- in THF (2 mL):H2O (2 mL):MeOH (2 mL) { 2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]- N LiOH·H2O (13.4 mg, 0.562 mmol, 2 equivalents) was added to a stirred solution of methylacetamido acetate (150 mg, 0.281 mmol, 85.0% purity, 1 equivalent). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was acidified with HCl (aq. 1 M) to pH 5. The precipitated solid was collected by filtration, washed with water, dried, and volatile substances removed under reduced pressure { 2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]- N methylacetamidoacetic acid (100 mg, 68.46%, 92.0% purity) was obtained as a white solid. m / z = 521.2 (M+H) + .

[0395] Step-7: Ethyl 2-(2-{2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]- N -methylacetamido}acetamido)acetate ( 12 Synthesis of )

[0396] In ACN (5 mL) {2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]- N NMI (157.7 mg, 1.920 mmol, 10 equivalents), glycine ethyl ester hydrochloride (40 mg, 0.288 mmol, 1.5 equivalents), and TCFH (80.8 mg, 0.288 mmol, 1.5 equivalents) were added to a stirred solution of methylacetamidoacetic acid (100 mg, 0.192 mmol, 92.0% purity, 1 equivalent). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted at PE:EtOAc = 1:1 to obtain ethyl 2-(2- { 2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]- N methylacetamido}acetamido)acetate (80 mg, 68.76% yield, 90.0% purity) was obtained as a yellow solid. m / z = 606.3 (M+H) + .

[0397] Step-8: (2-{2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]- N -methylacetamido}acetamido)acetic acid ( 13 Synthesis of )

[0398] Ethyl 2-(2- in THF (1 mL):H2O (1 mL):MeOH (1 mL) { 2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]- NLiOH·H2O (4.7 mg, 0.198 mmol, 2 equivalents) was added to a stirred solution of methylacetamido}acetamido)acetate (60 mg, 0.099 mmol, 90.0% purity, 1 equivalent). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was acidified with HCl (aq. 1 M) to pH 5. The resulting solution was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography using ACN:H2O (1:3) to obtain (2- { 2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]- N methylacetamido}acetamido)acetic acid (29.7 mg, 51.39% yield, 99.0% purity) was obtained as a white solid. LCMS: R t = 1.504 min, m / z = 578.25 (M+H) + . 1 1H NMR (400 MHz, methanol- d 4) δ 8.24 - 7.99 (m, 1H), 7.73 - 7.59 (m, 3H), 7.55 - 7.46 (m, 1H), 7.15 - 7.07 (m, 1H), 5.49 (d, J = 1.6 Hz, 1H), 5.41 (s, 1H), 4.43 (d, J = 6.4 Hz, 1H), 4.35 (s, 1H), 4.24 (d, J = 9.6 Hz, 1H), 4.17 (d, J = 1.6 Hz, 1H), 4.12 (s, 3H), 3.95 - 3.81 (m, 2H), 3.69 (d, J = 8.0 Hz, 1H), 3.29 (s, 1H), 3.01 (s, 1H), 2.74 - 2.60 (m, 1H), 2.49 - 2.15 (m, 1H), 2.01 (d, J = 8.4 Hz, 3H), 1.96 - 1.78 (m, 2H), 1.69 (d, J= 12.4 Hz, 1H), 1.63 - 1.41 (m, 2H).

[0399] General pathway for substituent introduction to explore SAR of Biaryl

[0400]

[0401] Step-1: Ethyl 2-[4-bromo-3-(piperidin-4-yl)indazole-1-yl]acetate ( 2 Synthesis of )

[0402] tert 15 mL of HCl (gas) in 1,4-dioxane was added to a stirred solution of butyl 4-[4-bromo-1-(2-ethoxy-2-oxoethyl)indazole-3-yl]piperidine-1-carboxylate (6.5 g, 13.978 mmol, 1 equivalent). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure to obtain ethyl 2-[4-bromo-3-(piperidine-4-yl)indazole-1-yl]acetate (5 g, 88.20% yield, 90.0% purity) as a yellow solid. m / z = 366.2 (M+H) + .

[0403] Step-2: Ethyl 2-[3-(1-acetylpiperidine-4-yl)-4-bromoindazole-1-yl]acetate ( 3 Synthesis of )

[0404] Acetyl chloride (1.29 g, 16.382 mmol, 1.2 equivalents) and TEA (4.14 g, 40.956 mmol, 3 equivalents) were added to a stirred solution of ethyl 2-[4-bromo-3-(piperidin-4-yl)indazole-1-yl]acetate (5 g, 13.652 mmol, 90% purity, 1.0 equivalent) in DCM (15 mL). The resulting mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with petroleum ether:ethyl acetate = 3:1 to obtain ethyl 2-[3-(1-acetylpiperidine-4-yl)-4-bromoindazole-1-yl]acetate (5 g, 89.70% yield, 90.0% purity) as a yellow solid. m / z = 408.2 (M+H) + .

[0405] Step-3: [3-(1-acetylpiperidine-4-yl)-4-bromoindazole-1-yl]acetic acid ( 4 Synthesis of )

[0406] LiOH (0.59 g, 24.492 mmol, 2 equivalents) was added to a stirred solution of ethyl 2-[3-(1-acetylpiperidin-4-yl)-4-bromoindazole-1-yl]acetate (5 g, 12.246 mmol, 90% purity, 1.0 equivalent) in THF (10 mL):H2O (10 mL):MeOH (10 mL). The resulting mixture was stirred at room temperature for 2 hours. The solution was then concentrated under reduced pressure and acidified to pH 4 with HCl (1 M). The mixture was then extracted with EtOAc. The organic layers were combined and evaporated to obtain [3-(1-acetylpiperidin-4-yl)-4-bromoindazole-1-yl]acetic acid (4 g, 85.90% yield, 90.0% purity) as a white solid. m / z = 380.2 (M+H) + .

[0407] Step-4: Methyl 2-(2-{2-[3-(1-acetylpiperidine-4-yl)-4-bromoindazole-1-yl]acetamido}acetamido)acetate ( 5 Synthesis of )

[0408] NMI (8.64 g, 105.200 mmol, 10 equivalents), TCFH (4.43 g, 15.780 mmol, 1.5 equivalents), and methyl 2-(2-aminoacetamido)acetate hydrochloride (2.31 g, 12.624 mmol, 1.2 equivalents) were added to a stirred solution of [3-(1-acetylpiperidine-4-yl)-4-bromoindazole-1-yl]acetic acid (4 g, 10.520 mmol, 90% purity, 1.0 equivalent) in ACN (20 mL). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with petroleum ether:ethyl acetate = 1:1 to obtain methyl 2-(2- {2-[3-(1-acetylpiperidine-4-yl)-4-bromoindazole-1-yl]acetamido}acetamido)acetamido)acetate (4 g, 74.80% yield, 90.0% purity) was obtained as a white solid. m / z = 507.1 (M+H) + .

[0409] Step-5: (2-{2-[3-(1-acetylpiperidine-4-yl)-1'-methyl-[4,6'-byindazole]-1-yl]acetamido}acetamido)acetic acid ( 6 Synthesis of )

[0410] Methyl 2-(2- in dioxane (10 mL):H2O (2 mL) { To a stirred solution of 2-[3-(1-acetylpiperidine-4-yl)-4-bromoindazole-1-yl]acetamido}acetamido)acetate (100 mg, 0.197 mmol, 90% purity, 1.0 equivalent), 1-methylindazole-6-ylboronic acid (34.62 mg, 0.197 mmol, 1 equivalent), K2CO3 (54.37 mg, 0.394 mmol, 2 equivalents), and Pd(dppf)Cl2 (28.79 mg, 0.039 mmol, 0.2 equivalents) were added. The resulting mixture was stirred at 75 °C for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was subjected to the following conditions: column, C18; (2-{2-[3-(1-acetylpiperidine-4-yl)-1'-methyl-[4,6'-baindazole]-1-yl]acetamido}acetamido)acetic acid (10.5 mg, 9.76% yield, 99.8% purity) was obtained as a white solid by reverse-phase flash chromatography using a mobile phase of acetonitrile (NH4HCO3) in water with a 20% to 25% gradient for 10 minutes and a detector of UV 254 nm. LCMS: R t = 1.268 min, m / z = 546.2 (M+H) + . 1 H NMR (300 MHz, methanol- d 4) δ 8.13 (s, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.67 (s, 1H), 7.59 (d, J= 8.4 Hz, 1H), 7.54 - 7.44 (m, 1H), 7.37 - 7.24 (m, 1H), 7.15 (d, J = 6.9 Hz, 1H), 5.21 (s, 2H), 4.42 - 4.21 (m, 1H), 4.13 (s, 3H), 3.96 (d, J = 8.7 Hz, 4H), 3.82 - 3.63 (m, 1H), 2.92 - 2.71 (m, 1H), 2.52 (s, 1H), 2.00 (s, 4H), 1.70 (s, 4H).

[0411] Example 1

[0412] Synthesis of 2-{2-[2-(1H-indole-1-yl)acetamido]acetamido}acetic acid

[0413]

[0414] Step 1: Synthesis of Indole-1-Acetic Acid

[0415] Indole (1.54 g, 13.1454 mmol), potassium carbonate (4.54 g, 32.8636 mmol), and DMF (20 mL) were placed in a 100 mL round-bottom flask. Ethyl bromoacetate (1.04 mL, 1.57 g, 9.3896 mmol) was added while stirring. A reflux condenser was fitted to the flask, and the mixture was stirred overnight at 70°C. Subsequently, the mixture was cooled to room temperature. Incomplete conversion was confirmed by LCMS. The mixture was filtered, and the filtrate was concentrated. The crude product was dissolved in methanol (15 mL), and lithium hydroxide monohydrate (15.00 mL, 2.52 g, 60.0000 mmol) was added. The desired product was confirmed by LCMS. The pH was adjusted to 4 with saturated aqueous citric acid. The aqueous phase was extracted with ethyl acetate (3 x 20 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated. The crude product was chromatographed on a 24 g silica gel column (0-10% MeOH:DCM) to obtain indole-1-acetic acid (0.432 g, 18.76%). LCMS m / z : 176.2.

[0416] Step-2: (2-(1 H Synthesis of -indole-1-yl)acetyl)glycylglycine

[0417] Indole-1-acetic acid (20.00 mg, 0.1142 mmol), [(dimethylamino)([1,2,3]triazolo[4,5-b]pyridine-3-yloxy)methylidene]dimethylazanium; hexafluoro-lambda5-phosphanoid (43.41 mg, 0.1142 mmol), and DMF (0.3 mL) were added to a 1-dram vial. N , N-Diisopropylethylamine (79.76 μL, 59.02 mg, 0.4567 mmol) was added, and the mixture was stirred at room temperature. 150 μL of the mixture was taken, and the intermediate methyl ester was purified by HPLC. The remaining mixture was treated with lithium hydroxide monohydrate (0.30 mL, 0.05 g, 1.2000 mmol) at room temperature. After stirring for 1 hour, the desired product was identified by LCMS. The pH was adjusted to 4 with saturated aqueous citric acid. The crude product was applied to HPLC purification (2-(1 H -Indole-1-yl)acetyl)glycylglycin (0.0042 g, 12.72%) was obtained. C 14 H 15 LCMS theoretical value for N3O4: 289.29, measured value m / z : 289.9 [M+H] + . 1 ¹H NMR (500 MHz, DMSO- d 6 ) δ 8.40 (t, J = 5.8 Hz, 1H), 8.22 (t, J = 5.8 Hz, 1H), 7.54 (dt, J = 7.9, 1.0 Hz, 1H), 7.39 (dt, J = 8.2, 0.9 Hz, 1H), 7.33 (d, J = 3.1 Hz, 1H), 7.11 (ddd, J = 8.2, 7.1, 1.2 Hz, 1H), 7.02 (ddd, J = 7.9, 7.0, 0.9 Hz, 1H), 6.43 (dd, J = 3.1, 0.9 Hz, 1H), 4.89 (s, 2H), 3.77 (dd, J = 13.5, 5.7 Hz, 4H).

[0418] Example 2

[0419] Synthesis of 2-[2-(2-{5'-fluoro-1'-methyl-1H,1'H-[4,6'-baindazole]-1-yl}acetamido)acetamido]acetamido]acetic acid

[0420]

[0421] Step-1: Ethyl 2-(4-bromoindazole-1-yl) acetate ( 2 Synthesis of )

[0422] 4-bromo-1 in DMF (30 mL) H Ethyl 2-bromoacetate (8.47 g, 50.752 mmol, 1.0 equivalent) and K2CO3 (14.02 g, 101.504 mmol, 2 equivalents) were added to a stirred solution of β-indazole (10 g, 50.752 mmol, 1.0 equivalent). The resulting mixture was stirred overnight at 80°C under a nitrogen atmosphere. The resulting mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted at PE:EtOAc = 5:1 to obtain ethyl 2-(4-bromoindazole-1-yl)acetate (8 g, 55.67% yield, 90.0% purity) as a white solid. m / z = 283.0 (M+H) + .

[0423] Step-2: Ethyl 2- { 5'-fluoro-1'-methyl-[4,6'-byindazole]-1-yl}acetate ( 3 Synthesis of )

[0424] To a stirred solution of ethyl 2-(4-bromoindazole-1-yl) acetate (500 mg, 1.766 mmol, 90% purity, 1.0 equivalent) in 1,4-dioxane (5 mL) and H2O (1 mL), 5-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (731.4 mg, 2.649 mmol, 1.5 equivalents), Pd(dppf)Cl2 (143.8 mg, 0.177 mmol, 0.1 equivalents), and K2CO3 (536.9 mg, 3.885 mmol, 2.0 equivalents) were added. The resulting mixture was stirred at 75 °C for 2 hours under a nitrogen atmosphere. Subsequently, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted at PE:EtOAc = 1:1 to obtain ethyl 2-{5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl}acetate (380 mg, 61.07% yield, 90.0% purity) as a white solid. m / z = 353.1 (M+H) + .

[0425] Step-3: {5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl} Acetic acid ( 4 Synthesis of )

[0426] LiOH (47.5 mg, 1.986 mmol, 2.0 equivalents) was added to a stirred solution of ethyl 2-{5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl}acetate (350 mg, 0.993 mmol, 90% purity, 1.0 equivalent) in THF (3 mL):H2O (3 mL):MeOH (3 mL). The resulting mixture was stirred at room temperature for 2 hours. Subsequently, the resulting mixture was concentrated under reduced pressure. The residue was acidified to pH 5 with HCl (aq. 1 M) and concentrated under vacuum. The residue was subjected to the following conditions: column, C18; mobile phase, ACN (0.1% NH4HCO3) in water, 30% to 40% gradient for 10 minutes; {5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl}acetic acid (260 mg, 80.71% yield, 90.0% purity) was obtained as a white solid by purification using reverse-phase flash chromatography with a UV 254 nm detector. m / z = 325.1 (M+H) + .

[0427] Step-4: Methyl 2-[2-(2-{5'-fluoro-1'-methyl-[4,6'-baindazole]-1 day} Acetamido) Acetamido]acetate ( 5 Synthesis of )

[0428] Methyl 2-(2-aminoacetamido)acetate hydrochloride (78.6 mg, 0.432 mmol, 1.0 equivalent), NMI (354.4 mg, 4.320 mmol, 10 equivalents), and TCFH (181.6 mg, 0.648 mmol, 1.5 equivalents) were added to a stirred solution of {5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl}acetic acid (140 mg, 0.432 mmol, 90% purity, 1.0 equivalent) in DMF (5 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. Subsequently, the resulting mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with DCM:MeOH = 20:1 to obtain methyl 2-[2-(2-{5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl} acetamido) acetamido] acetate (100 mg, 51.20% yield, 90.0% purity) as a white solid. m / z = 453.2 (M+H) + .

[0429] Step-5: [2-(2-{5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl} acetamido) acetamido] acetic acid ( 6 Synthesis of )

[0430] LiOH (9.5 mg, 0.398 mmol, 2.0 equivalents) was added to a stirred solution of methyl 2-[2-(2-{5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl} acetamido) acetamido] acetate (90 mg, 0.199 mmol, 90% purity, 1.0 equivalent) in H2O (2 mL):THF (2 mL):MeOH (2 mL). The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was then concentrated under reduced pressure. The residue was acidified to pH 5 with HCl (aq. 1 M) and concentrated under vacuum. The residue was subjected to the following conditions: column, C18; mobile phase, ACN (0.1% NH4HCO3) in water, 20% to 30% gradient for 10 minutes; It was purified by reverse-phase flash chromatography using a UV 254 nm detector. By this, [2-(2-{5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl} acetamido) acetamido]acetic acid (39.6 mg, 45.36% yield, 99.9% purity) was obtained as a white solid. C 21 H 19 Theoretical value for FN6O4: 438.42, measured value R t = 1.094 min, m / z : 439.1 [M+H] + . 1 1H NMR (400 MHz, methanol- d 4) δ 8.11 (s, 1H), 7.99 (s, 1H), 7.87 (d, J = 5.9 Hz, 1H), 7.77 - 7.69 (m, 1H), 7.56 - 7.47 (m, 2H), 7.29 (d, J = 7.0 Hz, 1H), 5.24 (s, 2H), 4.11 (s, 3H), 3.78 (d, J = 5.6 Hz, 2H), 3.48 (d, J = 4.9 Hz, 2H).

[0431] Example 3

[0432] 2-(2-{2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H Synthesis of acetic acid ([4,6'-baindazole]-1-yl]acetamido}-N-methylacetamido)acetic acid

[0433]

[0434] Step-1: Methyl 2-(2-{2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]acetamido}- N -methylacetamido)acetate ( 2 Synthesis of )

[0435] NMI (162.1 mg, 1.970 mmol, 10 equivalents), methyl 2-(methylamino)acetate hydrochloride (54.8 mg, 0.394 mmol, 2 equivalents), and TCFH (110.8 mg, 0.394 mmol, 2 equivalents) were added to a stirred solution of {2-[3-(1-acetylpiperidin-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]acetamido}acetic acid (100 mg, 0.197 mmol, 1 equivalent) in ACN (4 mL). The resulting mixture was stirred at room temperature for 2 hours. Subsequently, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted at PE:EtOAc = 1:1 to methyl 2-(2-{2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]acetamido}- N -methylacetamido)acetate (80 mg, 42.81% yield, 90.0% purity) was obtained as a white solid. m / z = 592.3 (M+H) + .

[0436] Step-2: (2-{2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]acetamido}-N-methylacetamido)acetic acid ( 3 Synthesis of )

[0437] Methyl 2-(2- in THF (1 mL):H2O (1 mL):MeOH (1 mL) { 2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]acetamido}-N LiOH (6.5 mg, 0.270 mmol, 2 equivalents) was added to a stirred solution of methylacetamido)acetate (80 mg, 0.135 mmol, 90.0% purity, 1 equivalent). The resulting mixture was stirred at room temperature for 2 hours. Subsequently, the resulting mixture was concentrated under reduced pressure. The residue was acidified with HCl (aq. 1 M) to pH 5. The resulting mixture was concentrated under vacuum. The residue was purified by reverse-phase column chromatography using ACN:H2O (1:3) to obtain (2- { 2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]acetamido}- N -methylacetamido)acetic acid (22.8 mg, 28.84% yield, 98.8% purity) was obtained as a white solid. C 29 H 32 LCMS theoretical value for FN7O5: 577.2, measured value R t = 1.522 minutes, m / z : 578.2 [M+H] + . 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.28 - 8.05 (m, 2H), 7.89 - 7.79 (m, 1H), 7.77 - 7.61 (m, 2H), 7.53 - 7.39 (m, 1H), 7.10 (d, J = 6.4 Hz, 1H), 5.29 - 5.07 (m, 2H), 4.34 - 3.99 (m, 5H), 3.94 - 3.82 (m, 2H), 3.76 - 3.53 (m, 3H), 2.95 (s, 1H), 2.80 (s, 2H), 2.37 - 2.16 (m, 1H), 1.89 (d, J = 12.8 Hz, 3H), 1.79 - 1.59 (m, 2H), 1.55 - 1.41 (m, 2H), 1.34 - 1.20 (m, 1H).

[0438] Example 4

[0439] 2- { 2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl]acetamido}- N Synthesis of (carbamoylmethyl)acetamide

[0440]

[0441] Step-1: Ethyl 2-{2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]acetamido} Acetate ( 2 Synthesis of )

[0442] NMI (365.3 mg, 4.450 mmol, 10 equivalents), glycine ethyl ester hydrochloride (61.9 mg, 0.445 mmol, 1 equivalent), and TCFH (249.7 mg, 0.890 mmol, 2 equivalents) were added to a stirred solution of [3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]acetic acid (200 mg, 0.445 mmol, 1 equivalent) in ACN (5 mL). The resulting mixture was stirred at room temperature for 2 hours. Subsequently, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with DCM:MeOH = 20:1 to obtain ethyl 2- { 2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]acetamido}acetate (160 mg, 67.26% yield, 90.0% purity) was obtained as a white solid. m / z = 535.2 (M+H) + .

[0443] Step-2: {2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]acetamido} Acetic acid ( 3 Synthesis of )

[0444] Ethyl 2- in THF (2 mL):H2O (2 mL):MeOH (2 mL) {LiOH (13.5 mg, 0.565 mmol, 2.01 equivalents) was added to a stirred solution of 2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]acetamido}acetate (150 mg, 0.281 mmol, 90.0% purity, 1 equivalent). The resulting mixture was stirred at room temperature for 2 hours. Subsequently, the resulting mixture was concentrated under reduced pressure. The residue was acidified with HCl (aq. 1 M) to pH 5. The precipitated solid was collected by filtration, washed with water, and dried under vacuum. { 2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]acetamido}acetic acid (110 mg, 77.39% yield, 90.0% purity) was obtained as a white solid. m / z = 507.2 (M+H) + .

[0445] Step-3: Ethyl 2-(2-{2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]acetamido} Acetamido)acetate ( 4 Synthesis of )

[0446] In ACN (5 mL) { NMI (162.1 mg, 1.970 mmol, 10 equivalents), glycine ethyl ester hydrochloride (27.4 mg, 0.197 mmol, 1 equivalent), and TCFH (110.8 mg, 0.394 mmol, 2 equivalents) were added to a stirred solution of 2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]acetamido}acetic acid (100 mg, 0.197 mmol, 90.0% purity, 1 equivalent). The resulting mixture was stirred at room temperature for 2 hours. Subsequently, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with DCM:MeOH = 20:1 to obtain ethyl 2-(2- {2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]acetamido}acetamido)acetamido)acetate (70 mg, 59.93% yield, 85.0% purity) was obtained as a white solid. m / z = 592.3 (M+H) + .

[0447] Step-4: (2-{2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]acetamido} Acetamido)acetic acid ( 5 Synthesis of )

[0448] LiOH (5.7 mg, 0.236 mmol, 2 equivalents) was added to a stirred solution of ethyl 2-(2-{2-[3-(1-acetylpiperidin-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]acetamido}acetamido)acetate (70 mg, 0.118 mmol, 85.0% purity, 1 equivalent) in THF (1 mL):H2O (1 mL):MeOH (1 mL). The resulting mixture was stirred at room temperature for 2 hours. Subsequently, the resulting mixture was concentrated under reduced pressure. The residue was acidified with HCl (aq. 1 M) to pH 5. The precipitated solid was collected by filtration, washed with water, and dried under vacuum to obtain (2-{2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]acetamido}acetamido)acetic acid (60 mg, 89.98% yield, 92.0% purity) as a white solid. m / z = 564.2 (M+H) + .

[0449] Step 5: 2-{2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl]acetamido}- N -(carbamoylmethyl)acetamide ( 6 Synthesis of )

[0450] In ACN (5 mL) (2- {NMI (102.0 mg, 1.240 mmol, 10 equivalents), NH4Cl (6.6 mg, 0.124 mmol, 1 equivalent), and TCFH (69.7 mg, 0.248 mmol, 2 equivalents) were added to a stirred solution of 2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]acetamido}acetamido)acetic acid (70 mg, 0.124 mmol, 92.0% purity, 1 equivalent). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography using ACN:H2O (1:3) to 2- { 2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl]acetamido- N -(Carbamoylmethyl)acetamide (58.0 mg, 79.68% yield, 96.0% purity) was obtained as a white solid. C 28 H 31 LCMS theoretical value for FN8O4: 562.2, measured value R t = 1.329 min, m / z : 563.2 [M+H] + . 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.49 - 8.37 (m, 1H), 8.15 (d, J = 12.4 Hz, 2H), 7.83 (d, J = 5.6 Hz, 1H), 7.77 - 7.68 (m, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.53 - 7.45 (m, 1H), 7.26 (s, 1H), 7.17 - 7.04 (m, 2H), 5.17 (s, 2H), 4.26 (d, J = 12.4 Hz, 1H), 4.09 (d, J = 1.6 Hz, 4H), 3.82 (d, J= 5.6 Hz, 2H), 3.79 - 3.64 (m, 3H), 2.37 - 1.96 (m, 1H), 1.89 (d, J = 12.8 Hz, 3H), 1.78 - 1.56 (m, 2H), 1.45 (d, J = 4.2 Hz, 2H), 1.34 - 1.16 (m, 1H).

[0451] Example 5

[0452] 2-(2-{2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl]- N Synthesis of acetic acid (methylacetamido / acetamido)

[0453]

[0454] Step-1: tert -butyl 4-((2-bromo-6-fluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate ( 2 Synthesis of )

[0455] LDA (2 M, 44 mL, 88.0 mmol, 1.1 equivalents) was added dropwise to a stirred solution of 1-bromo-3-fluoro-2-iodobenzene (14 g, 80.460 mmol, 1 equivalent) in THF (150 mL) at -78 °C under a nitrogen atmosphere. The resulting mixture was stirred at -78 °C under a nitrogen atmosphere for 1 hour. Then, in THF (50 mL) tert β-butyl 4-formylpiperidin-1-carboxylate (34.32 g, 160.920 mmol, 2 equivalents) was added to the above mixture. The resulting mixture was stirred at -78 °C for 1 hour under a nitrogen atmosphere. Subsequently, the mixture was quenched with water. The resulting solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting PE:EtOAc = 1:1, tert-Butyl 4-((2-bromo-6-fluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (25.86 g, 82.78% yield, 90.0% purity) was obtained as a yellow oil. m / z = 388.1 (M+H) + .

[0456] Step-2: tert -Butyl 4-(2-bromo-6-fluorobenzoyl)piperidine-1-carboxylate ( 3 Synthesis of )

[0457] In DCM (100 mL) tert PCC (27.76 g, 128.774 mmol, 2 equivalents) was added to a stirred solution of β-butyl 4-((2-bromo-6-fluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (25 g, 64.387 mmol, 90.0% purity, 1 equivalent). The resulting mixture was stirred overnight at room temperature. Subsequently, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted at PE:EtOAc = 3:1, tert -Butyl 4-(2-bromo-6-fluorobenzoyl)piperidine-1-carboxylate (18.85 g, 75.79% yield, 85.0% purity) was obtained as a yellow solid. m / z = 386.1 (M+H) + .

[0458] Step-3: tert -butyl 4-(4-bromo-1 H -Indazole-3-yl)piperidine-1-carboxylate ( 4 Synthesis of )

[0459] in dioxane (50 mL) tertN2H4·H2O (10.92 g, 218.115 mmol, 5 equivalents) was added to a stirred solution of β-butyl 4-(2-bromo-6-fluorobenzoyl)piperidine-1-carboxylate (16.85 g, 43.623 mmol, 85.0% purity, 1 equivalent). The resulting mixture was stirred at 110 °C for 2 hours. Subsequently, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted at PE:EtOAc = 1:1, tert -butyl 4-(4-bromo-1 H -indazole-3-yl)piperidine-1-carboxylate (11 g, 66.31% yield, 88.0% purity) was obtained as a yellow solid. m / z = 380.1 (M+H) + .

[0460] Step-4: tert -butyl 4-(4-bromo-1-(2-ethoxy-2-oxoethyl)-1 H -Indazole-3-yl)piperidine-1-carboxylate ( 5 Synthesis of )

[0461] In DMF (10 mL) tert -butyl 4-(4-bromo-1 H K2CO3 (0.73 g, 5.260 mmol, 2 equivalents) and ethyl bromoacetate (0.44 g, 2.630 mmol, 1 equivalent) were added to a stirred solution of indazole-3-yl)piperidine-1-carboxylate (1 g, 2.630 mmol, 88.0% purity, 1 equivalent). The resulting mixture was stirred at 80 °C for 4 hours under a nitrogen atmosphere. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE:EtOAc = 2:1, tert -butyl 4-(4-bromo-1-(2-ethoxy-2-oxoethyl)-1 H-Indazole-3-yl)piperidine-1-carboxylate (800 mg, 65.57% yield, 90.0% purity) was obtained as a white solid. m / z = 466.1 (M+H) + .

[0462] Step-5: tert -butyl 4-[1-(2-ethoxy-2-oxoethyl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-3-yl]piperidine-1-carboxylate ( 6 Synthesis of )

[0463] Dioxane (5 mL):H2O (1 mL) tert -butyl 4-(4-bromo-1-(2-ethoxy-2-oxoethyl)-1 H K2CO3 (240.03 g, 1.736 mmol, 2 equivalents), 5-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (335.6 mg, 1.215 mmol, 1.89 equivalents), and Pd(dppf)Cl2·CH2Cl2 (57.6 mg, 0.071 mmol, 0.10 equivalents) were added to a stirred solution of -indazole-3-yl)piperidine-1-carboxylate (300 mg, 0.643 mmol, 90.0% purity, 1 equivalent). The resulting mixture was stirred at 75 °C for 2 hours under a nitrogen atmosphere. Subsequently, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted at PE:EtOAc = 5:1, tert -Butyl 4-[1-(2-ethoxy-2-oxoethyl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-3-yl]piperidine-1-carboxylate (370 mg, 93.19% yield, 90.0% purity) was obtained as a pale yellow solid. m / z = 536.2 (M+H) + .

[0464] Step-6: 2-[5'-fluoro-1'-methyl-3-(piperidine-4-yl)-[4,6'-baindazole]-1-yl]acetate ( 7 Synthesis of )

[0465] HCl (gas) (4 M, 5 mL) in 1,4-dioxane was added to a stirred solution of tert-butyl 4-[1-(2-ethoxy-2-oxoethyl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-3-yl]piperidine-1-carboxylate (370 mg, 0.691 mmol, 90.0% purity, 1 equivalent) in DCM (5 mL). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was then concentrated under reduced pressure to obtain ethyl 2-[5'-fluoro-1'-methyl-3-(piperidine-4-yl)-[4,6'-baindazole]-1-yl]acetate (250 mg, 83.00% yield, 90.0% purity) as a pale yellow solid. m / z = 436.2 (M+H) + .

[0466] Step-7: Ethyl 2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]acetate ( 8 Synthesis of )

[0467] TEA (186.9 mg, 1.848 mmol, 2.98 equivalents) and acetyl chloride (72.3 mg, 0.918 mmol, 1.48 equivalents) were added to a stirred solution of ethyl 2-[5'-fluoro-1'-methyl-3-(piperidin-4-yl)-[4,6'-baindazole]-1-yl]acetate (250 mg, 0.620 mmol, 90.0% purity, 1 equivalent) in DCM (5 mL) at 0°C. The resulting mixture was then stirred at room temperature under a nitrogen atmosphere for 1.5 hours. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted at PE:EtOAc = 5:1 to obtain ethyl 2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]acetate (280 mg, 91.33% yield, 88.0% purity) as a pale yellow solid. m / z = 478.2 (M+H) + .

[0468] Step-8: [3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-byindazole]-1-yl]acetic acid ( 9 Synthesis of )

[0469] LiOH·H2O (63.8 mg, 1.522 mmol, 2.85 equivalents) was added to a stirred solution of ethyl 2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]acetate (255 mg, 0.534 mmol, 88.0% purity, 1 equivalent) in THF (2 mL):H2O (2 mL):MeOH (2 mL) at 0°C. The resulting mixture was stirred overnight at room temperature. The resulting mixture was then concentrated under reduced pressure. The residue was acidified with HCl (aq. 1 M) to pH 5. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to obtain [3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]acetic acid (120 mg, 50.00% yield, 90.0% purity) as a pale yellow solid. m / z = 450.2 (M+H) + .

[0470] Step-9: Methyl 2-{2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]- N -methylacetamido}acetate ( 10 Synthesis of )

[0471] Methyl 2-(methylamino)acetate hydrochloride (37.1 mg, 0.267 mmol, 1 equivalent), HATU (152.2 mg, 0.401 mmol, 1.5 equivalents), and DIEA (172.5 mg, 1.335 mmol, 5 equivalents) were added to a stirred solution of [3-(1-acetylpiperidin-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]acetic acid (120 mg, 0.267 mmol, 90.0% purity, 1.00 equivalents) in DMF (5 mL). The resulting mixture was stirred at room temperature for 1.5 hours. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were combined and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography using ACN:H2O (1:3) to methyl 2- {2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]- N methylacetamido acetate (140 mg, 95.10% yield, 85.0% purity) was obtained as a white solid. m / z = 535.2 (M+H) + .

[0472] Step-10: {2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-byindazole]-1-yl]- N -methylacetamido}acetic acid ( 11 Synthesis of )

[0473] Methyl 2-{2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]- in THF (2 mL):H2O (2 mL):MeOH (2 mL) at 0℃ N LiOH·H2O (13.4 mg, 0.562 mmol, 2 equivalents) was added to a stirred solution of methylacetamido}acetate (150 mg, 0.281 mmol, 85.0% purity, 1 equivalent). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was acidified with HCl (aq. 1 M) to pH 5. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to form {2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]- N methylacetamidoacetic acid (100 mg, 68.46%, 92.0% purity) was obtained as a white solid. m / z = 521.2 (M+H) + .

[0474] Step-11: Ethyl 2-(2-{2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]- N -methylacetamido}acetamido)acetate ( 12 Synthesis of )

[0475] In ACN (5 mL) { 2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]- NNMI (157.7 mg, 1.920 mmol, 10 equivalents), glycine ethyl ester hydrochloride (40 mg, 0.288 mmol, 1.5 equivalents), and TCFH (80.8 mg, 0.288 mmol, 1.5 equivalents) were added to a stirred solution of methylacetamido}acetic acid (100 mg, 0.192 mmol, 92.0% purity, 1 equivalent). The resulting mixture was stirred at room temperature for 1 hour. Subsequently, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting PE:EtOAc = 1:1 to obtain ethyl 2-(2-{2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]- N methylacetamido}acetamido)acetate (80 mg, 68.76% yield, 90.0% purity) was obtained as a yellow solid. m / z = 606.3 (M+H) + .

[0476] Step-12: 2-(2-{2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl]- N -methylacetamido}acetamido)acetic acid ( 13 Synthesis of )

[0477] Ethyl 2-(2-{2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]- in THF (1 mL):H2O (1 mL):MeOH (1 mL) at 0℃ NLiOH·H2O (4.7 mg, 0.198 mmol, 2 equivalents) was added to a stirred solution of 2-(2-{2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1)-acetamido)acetate (60 mg, 0.099 mmol, 90.0% purity, 1 equivalent). The resulting mixture was stirred at room temperature for 2 hours. Subsequently, the resulting mixture was concentrated under reduced pressure. The residue was acidified with HCl (aq. 1 M) to pH 5. The resulting solution was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography using ACN:H2O (1:3) to obtain 2-(2-{2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl]- N methylacetamido}acetamido)acetic acid (29.7 mg, 51.39% yield, 99.0% purity) was obtained as a white solid. C 29 H 32 LCMS theoretical value for FN7O5: 577.2, measured value R t = 1.504 min, m / z : 578.3 [M+H] + . 1 1H NMR (400 MHz, methanol- d 4) δ 8.24 - 7.99 (m, 1H), 7.73 - 7.59 (m, 3H), 7.55 - 7.46 (m, 1H), 7.15 - 7.07 (m, 1H), 5.49 (d, J = 1.6 Hz, 1H), 5.41 (s, 1H), 4.43 (d, J = 6.4 Hz, 1H), 4.35 (s, 1H), 4.24 (d, J = 9.6 Hz, 1H), 4.17 (d, J = 1.6 Hz, 1H), 4.12 (s, 3H), 3.95 - 3.81 (m, 2H), 3.69 (d, J= 8.0 Hz, 1H), 3.29 (s, 1H), 3.01 (s, 1H), 2.74 - 2.60 (m, 1H), 2.49 - 2.15 (m, 1H), 2.01 (d, J = 8.4 Hz, 3H), 1.96 - 1.78 (m, 2H), 1.69 (d, J = 12.4 Hz, 1H), 1.63 - 1.41 (m, 2H).

[0478] Example 6

[0479] 2-(2-{2-[1'-(1-acetylpiperidine-4-carbonyl)-5'-fluoro-1 H ,1' H Synthesis of acetic acid [4,6'-baindazole]-1-yl]acetamido}acetamido)

[0480]

[0481] Step-1: Methyl 2-[2-(2-{5'-fluoro-1' H -[4,6'-baindazole]-1-yl} Acetamido]Acetamido]Acetate ( 2 Synthesis of )

[0482] {5'-fluoro-1' in DMF (5 mL) HMethyl 2-(2-aminoacetamido)acetate hydrochloride (158.9 mg, 0.870 mmol, 1.5 equivalents), HATU (330.9 mg, 0.870 mmol, 1.5 equivalents), and DIEA (374.9 mg, 2.900 mmol, 5 equivalents) were added to a stirred solution of -[4,6'-baindazole]-1-yl}acetic acid (180 mg, 0.580 mmol, 90.0% purity, 1 equivalent). The resulting mixture was stirred at room temperature for 2 hours. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were combined and concentrated under reduced pressure. The residue was subjected to the following conditions: column, C18; mobile phase, MeCN (10 mmol / L NH4HCO3) in water, 20% to 40% gradient for 20 minutes; Purified by reverse-phase flash chromatography using a UV 220 nm detector, methyl 2-[2-(2-{5'-fluoro-1' H -[4,6'-Baindazole]-1-yl}acetamido]acetamido]acetamido]acetate (140 mg, 55.05% yield, 90.0% purity) was obtained as a yellow solid. m / z = 439.1 (M+H) + .

[0483] Step-2: [2-(2-{5'-fluoro-1' H -[4,6'-baindazole]-1-yl} Acetamido)Acetamido]Acetic acid ( 3 Synthesis of )

[0484] Methyl 2-[2-(2-{5'-fluoro-1') in THF (2 mL):H2O (2 mL):MeOH (2 mL) at 0 ℃ HLiOH (14.2 mg, 0.594 mmol, 2 equivalents) was added to a stirred solution of -[4,6'-baindazole]-1-yl}acetamido)acetamido]acetate (130 mg, 0.297 mmol, 90.0% purity, 1 equivalent). The resulting mixture was stirred at room temperature for 2 hours. Subsequently, the resulting mixture was concentrated under reduced pressure. The residue was acidified with HCl (aq., 1 M) to pH 5. The precipitated solid was collected by filtration, washed with water, and dried under vacuum to [2-(2-{5'-fluoro-1' H -[4,6'-Baindazole]-1-yl}acetamido]acetamido]acetic acid (100 mg, 79.47% yield, 90.0% purity) was obtained as a yellow solid. m / z = 425.1 (M+H) + .

[0485] Step 3: 2-(2-{2-[1'-(1-acetylpiperidine-4-carbonyl)-5'-fluoro-1 H ,1' H -[4,6'-Baindazole]-1-yl]acetamido}acetamido)acetic acid ( 4 Synthesis of )

[0486] [2-(2-{5'-fluoro-1' in DMF (5 mL) H[1-acetylpiperidine-4-carboxylic acid (40.34 mg, 0.236 mmol, 1 equivalent), HOBT (47.8 mg, 0.354 mmol, 1.5 equivalents), EDCI (67.8 mg, 0.354 mmol, 1.5 equivalents), and DIEA (152.27 mg, 1.180 mmol, 5 equivalents) were added to a stirred solution of -[4,6'-baindazole]-1-yl}acetamido]acetamido]acetic acid (100 mg, 0.236 mmol, 90.0% purity, 1 equivalent). The resulting mixture was stirred at room temperature for 2 hours. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were combined and concentrated under reduced pressure. The residues were subjected to the following conditions: column, Xselect CSH OBD; Mobile phase, ACN (formic acid (FA) 0.1%) in water, 23% to 33% gradient for 10 minutes; detector, purified by reverse-phase flash chromatography using UV 254 nm to 2-(2-{2-[1'-(1-acetylpiperidine-4-carbonyl)-5'-fluoro-1 H ,1' H -[4,6'-Baindazole]-1-yl]acetamido}acetamido)acetic acid (12.2 mg, 8.92% yield, 99.5% purity) was obtained as a white solid. C 28 H 28 LCMS theoretical value for FN7O6: 577.2, measured value R t = 1.391 min, m / z : 578.2 [M+H] + . 1 ¹H NMR (400 MHz, DMSO- d 6) δ 12.61 (s, 1H), 8.62 (s, 1H), 8.58 - 8.48 (m, 2H), 8.36 - 8.22 (m, 1H), 8.07 - 7.92 (m, 2H), 7.74 (d, J = 8.4 Hz, 1H), 7.58 - 7.50 (m, 1H), 7.31 (d, J = 7.2 Hz, 1H), 5.25 (s, 2H), 4.44 (d,J = 13.2 Hz, 1H), 4.04 - 3.89 (m, 2H), 3.86 - 3.71 (m, 4H), 3.30 - 3.08 (m, 1H), 2.83 - 2.68 (m, 1H), 2.03 (s, 5H), 1.81 - 1.68 (m, 1H), 1.60 - 1.50 (m, 1H).

[0487] Example 7

[0488] Synthesis of 2-{2-[2-(1H-indazole-1-yl)acetamido]acetamido}acetic acid

[0489]

[0490] Step-1: Ethyl 2-(1 H -Indazole-1-yl)acetate

[0491] Indazole (1.55 g, 13.1201 mmol) and potassium carbonate (3.63 g, 26.2403 mmol) were added to a 100 mL round-bottom flask. DMF (25.00 mL) was added, followed by the addition of ethyl bromoacetate (1.60 mL, 2.41 g, 14.4322 mmol). A reflux condenser was fitted to the flask, and the mixture was stirred in a mantle heated to 70°C. The mixture was stirred for 1 hour. In LCMS, a portion of the starting material and two products representing the desired mass were identified. Subsequently, the mixture was cooled to room temperature, filtered, and concentrated. The crude product was purified on a 24 g silica gel column (gradient 0-50% EtOAc:hexane). The fraction containing the first peak (least polar) with the desired mass was concentrated to obtain ethyl 2-(indazole-1-yl)acetate (1.216 g, 44.47%). LCMS (ESI) m / z: 205.3 [M+H] + . 1 H NMR (500 MHz, CDCl3) δ 8.06 (d, J = 1.0 Hz, 1H), 7.75 (dt, J= 8.1, 1.0 Hz, 1H), 7.41 (ddd, J = 8.4, 6.8, 1.1 Hz, 1H), 7.34 (dq, J = 8.5, 0.9 Hz, 1H), 7.18 (ddd, J = 7.9, 6.8, 0.9 Hz, 1H), 5.16 (s, 2H), 4.22 (q, J = 7.1 Hz, 2H), 1.25 (td, J = 7.2, 4.9 Hz, 4H).

[0492] Step-2: Indazole-1-monoacetic acid

[0493] Lithium hydroxide monohydrate (6.55 mL, 1.10 g, 26.2154 mmol) and THF (6.00 mL) were added to a 100 mL round-bottom flask containing ethyl 2-(indazole-1-yl)acetate (1.15 g, 5.6309 mmol). The mixture was stirred overnight at room temperature. A significant white precipitate was observed. The pH was adjusted to 4 with saturated aqueous citric acid solution and ethyl acetate (30 mL) while stirring rapidly. The precipitate became a finely dispersed suspension. The mixture was filtered and washed with water (40 mL). The precipitate was dried on a vacuum filter for 30 minutes to obtain the title compound (0.678 g, 68.34%). LCMS (ESI) m / z: 177.3 [M+H] + .

[0494] Step-3: {2-[2-(indazole-1-yl)acetamido]acetamido}acetic acid

[0495] Indazole-1-monoacetate (20.00 mg, 0.1135 mmol), [(dimethylamino)([1,2,3]triazolo[4,5- b ]pyridine-3-yloxy)methylidene]dimethylazanium; hexafluoro-lambda5-phosphanude (43.17 mg, 0.1135 mmol), and DMF (0.3 mL) were added to a 1-dram vial. N , NDiisopropylethylamine (79.31 μL, 58.69 mg, 0.4541 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. Methyl 2-(2-aminoacetamido)acetate hydrochloride (16.59 mg, 0.1135 mmol) was added, and the mixture was stirred at room temperature. After 20 minutes, the formation of the desired product was confirmed by LCMS. 150 μL of the mixture was used for HPLC purification to obtain the intermediate methyl ester (0.0068 g, 19.68%). The remaining solution was treated with lithium hydroxide monohydrate (0.30 mL, 0.05 g, 1.2000 mmol) at room temperature for 1 hour. The desired product was confirmed by LCMS. The pH was adjusted to 4 with saturated aqueous citric acid. The crude product was subjected to HPLC purification and {2-[2-(indazole-1-yl)acetamido]acetamido}acetic acid (0.0123 g, 37.10%) was obtained. C 13 H 14 LCMS theoretical value for N4O4: 290.1, measured value m / z : 291.0 [M+H] + . 1 ¹H NMR (500 MHz, DMSO- d 6 ) δ 12.21 (s, 1H), 8.44 (t, J = 5.7 Hz, 1H), 8.28 (t, J = 5.8 Hz, 1H), 8.07 (s, 1H), 7.79 - 7.73 (m, 1H), 7.59 (dt, J = 8.5, 1.0 Hz, 1H), 7.37 (ddd, J = 8.2, 6.9, 1.1 Hz, 1H), 7.14 (dd, J = 8.0, 6.9 Hz, 1H), 5.16 (s, 2H), 3.79 (t, J = 5.9 Hz, 4H).

[0496] Example 8

[0497] 2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl]- N -{[(2 H Synthesis of -1,2,3,4-tetrazole-5-yl)carbamoyl]methyl}acetamide

[0498]

[0499] Step-1: 2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl]- N -{[(2 H -1,2,3,4-tetrazole-5-yl)carbamoyl]methyl} Acetamide ( 2 Synthesis of )

[0500] PyBOP (231.2 mg, 0.444 mmol, 1.5 equivalents), 2 in a stirred solution of 2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-[4,6'-baindazole]-1-yl]acetamido}acetic acid (150 mg, 0.296 mmol, 90.0% purity, 1 equivalent) in DMF (5 mL) H Tetrazole-5-amine (50.4 mg, 0.591 mmol, 3 equivalents) and DIEA (51.0 mg, 0.394 mmol, 2 equivalents) were added. The resulting mixture was stirred at room temperature for 2 hours. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were combined and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, Xcelect CSH F-pheny OBD; mobile phase, ACN (FA 0.1%) in water, 30% to 40% gradient for 10 minutes; detector, UV 254 nm to obtain 2-[3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl]- N -{[(2 H-1,2,3,4-tetrazole-5-yl)carbamoyl]methyl}acetamide (16.6 mg, 9.70% yield, 96.9% purity) was obtained as a white solid. C 27 H 28 FN 11 LCMS theoretical value for O3: 573.2, measured value R t = 1.508 min, m / z : 574.3. 1 1H NMR (300 MHz, DMSO- d 6) δ 12.06 (s, 1H), 8.73 - 8.49 (m, 1H), 8.14 (s, 1H), 7.82 (d, J = 5.7 Hz, 1H), 7.76 - 7.69 (m, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.55 - 7.43 (m, 1H), 7.10 (d, J = 6.9 Hz, 1H), 5.20 (s, 2H), 4.27 (d, J = 13.2 Hz, 1H), 4.09 (d, J = 5.7 Hz, 5H), 3.81 - 3.49 (m, 1H), 3.31 (s, 1H), 2.35 - 2.20 (m, 1H), 2.11 - 1.84 (m, 3H), 1.78 - 1.59 (m, 2H), 1.52 - 1.38 (m, 2H), 1.35 - 1.11 (m, 1H).

[0501] Example 9

[0502] 2-(2-{2-[3-(1-acetylasetidine-3-yl)-5'-fluoro-1'-methyl-1 H ,1' H Synthesis of acetic acid [4,6'-baindazole]-1-yl]acetamido}acetamido)

[0503]

[0504] Step-1: tert -butyl 3-((2-bromo-6-fluorophenyl)(hydroxy)methyl)azetidine-1-carboxylate ( 2 Synthesis of )

[0505] In THF (30 mL) m LDA (2 M, 6.5 mL, 13.0 mmol, 1.13 equivalents) was added dropwise to a stirred solution of β-bromofluorobenzene (2 g, 11.429 mmol, 1 equivalent) at -78 °C under a nitrogen atmosphere. The resulting mixture was stirred at -78 °C under a nitrogen atmosphere for 1 hour. Then, in THF (5 mL) tert β-butyl 3-formylazetidin-1-carboxylate (4.23 g, 22.858 mmol, 2 equivalents) was added dropwise to the resulting solution. The resulting mixture was stirred at -78 °C for 1 hour under a nitrogen atmosphere. Subsequently, the mixture was quenched with water. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE:EtOAc = 1:1, tert -Butyl 3-((2-bromo-6-fluorophenyl)(hydroxy)methyl)azetidine-1-carboxylate (2.3 g, 55.87% yield, 90.0% purity) was obtained as a yellow oil. m / z = 360.0 (M+H) + .

[0506] Step-2: tert -butyl 3-(2-bromo-6-fluorobenzoyl)azetidine-1-carboxylate ( 3 Synthesis of )

[0507] In DCM (20 mL) tertPCC (1.54 g, 7.162 mmol, 2 equivalents) was added to a stirred solution of tert-butyl 3-((2-bromo-6-fluorophenyl)(hydroxy)methyl)azetidine-1-carboxylate (1.29 g, 3.581 mmol, 90.0% purity, 1 equivalent). The resulting mixture was stirred overnight at room temperature. Subsequently, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted to PE:EtOAc = 3:1 to obtain tert-butyl 3-(2-bromo-6-fluorobenzoyl)azetidine-1-carboxylate (1.1 g, 85.75% yield, 90.0% purity) as a yellow solid. m / z = 358.0 (M+H) + .

[0508] Step-3: tert -butyl 3-(4-bromo-1 H -Indazole-3-yl)Azetidine-1-carboxylate ( 4 Synthesis of )

[0509] in dioxane (10 mL) tert N2H4·H2O (0.77 g, 15.355 mmol, 5 equivalents) was added to a stirred solution of β-butyl 3-(2-bromo-6-fluorobenzoyl)azetidine-1-carboxylate (1.1 g, 3.071 mmol, 90.0% purity, 1 equivalent). The resulting mixture was stirred at 110 °C for 2 hours. Subsequently, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted at PE:EtOAc = 1:1, tert -butyl 3-(4-bromo-1 H -Indazole-3-yl)azetidine-1-carboxylate (900 mg, 83.21% yield, 85.0% purity) was obtained as a yellow solid. m / z = 352.0 (M+H) + .

[0510] Step-4: tert -butyl 3-[4-bromo-1-(2-ethoxy-2-oxoethyl)indazole-3-yl]azetidine-1-carboxylate ( 5 Synthesis of )

[0511] In DMF (10 mL) tert -butyl 3-(4-bromo-1 H K2CO3 (690.6 mg, 4.996 mmol, 2 equivalents) and ethyl bromoacetate (417.2 mg, 2.498 mmol, 1 equivalent) were added to a stirred solution of -indazole-3-yl)azetidine-1-carboxylate (880 mg, 2.498 mmol, 85.0% purity, 1 equivalent). The resulting mixture was stirred at 80 °C for 2 hours under a nitrogen atmosphere. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted at PE:EtOAc = 2:1, tert -Butyl 3-[4-bromo-1-(2-ethoxy-2-oxoethyl)indazole-3-yl]azetidine-1-carboxylate (900 mg, 82.19% yield, 90.0% purity) was obtained as a yellow oil. m / z = 438.1 (M+H) + .

[0512] Step-5: Ethyl 2-[3-(azetidine-3-yl)-4-bromoindazole-1-yl]acetate ( 6 Synthesis of )

[0513] In DCM (8 mL) at 0℃ tert HCl (gas) in 1,4-dioxane (8 mL, 4 M) was added to a stirred solution of butyl 3-[4-bromo-1-(2-ethoxy-2-oxoethyl)indazole-3-yl]azetidine-1-carboxylate (900 mg, 2.053 mmol, 90.0% purity, 1 equivalent). The resulting mixture was then stirred at room temperature for 2 hours. The resulting mixture was subsequently concentrated under reduced pressure to obtain ethyl 2-[3-(azetidine-3-yl)-4-bromoindazole-1-yl]acetate (610 mg, 90.00% yield, 90.0% purity) as a pale yellow solid. m / z = 338.0 (M+H) + .

[0514] Step-6: Ethyl 2-[3-(1-acetylasetidine-3-yl)-4-bromoindazole-1-yl]acetate ( 7 Synthesis of )

[0515] TEA (478.73 mg, 4.730 mmol, 2 equivalents) and acetyl chloride (278.53 mg, 3.548 mmol, 1.5 equivalents) were added to a stirred solution of ethyl 2-[3-(azetidine-3-yl)-4-bromoindazole-1-yl]acetate (800 mg, 2.365 mmol, 90.0% purity, 1 equivalent) in DCM (5 mL) at 0°C. The resulting mixture was stirred at room temperature for 1.5 hours. Subsequently, the resulting mixture was concentrated under reduced pressure. The residue w...

Claims

Claim 1 A compound having the following formula or a pharmaceutically acceptable salt thereof, In the above formula, is selected from the group consisting of aryl, heteroaryl, bicyclic aryl, and bicyclic heteroaryl, wherein the aryl, heteroaryl, bicyclic aryl, and bicyclic heteroaryl are unsubstituted or substituted with alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, halo, or heteroaryl; R 1 silver , , , , , , , , , or or; or each R 1 is further substituted with alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, halo, or heteroaryl, wherein R 5 is independently hydrogen or alkyl; R 6 is a hydrogen or amino acid side chain; R 7 -O R 7a , -N R 7a R 7b , or and, here R 7a and R 7b is independently hydrogen or alkyl; aa is 1 to 5; R 8 is a heteroalkyl; R 9 is aryl, benzo[ d ][1,3]dioxol, heteroalkyl, or heteroaryl comprising at least one nitrogen, oxygen, or sulfur, wherein the aryl and heteroaryl are unsubstituted or substituted with alkyl, -OH, hydroxyalkyl, alkoxy, cyano, pyridazine, and pyrazol; R 10 is hydrogen, alkyl, or hydroxyalkyl; R 11 is a heteroaryl, where the heteroaryl is unsubstituted or alkyl, haloalkyl, alkoxy, -OH, -C(O)N R 11a R 11b , or It is replaced with, and here R 11a and R 11b is independently hydrogen or alkyl; X 6 It is oxygen or N R 5 And; t 1 is 1 to 5; t 2 is 0 or 1 and; R 3 Silver hydrogen, , aryl, or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted with an alkyl, heteroalkyl, heterocycloalkyl, and / or halo; X 5 is nitrogen or oxygen; R 3a is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, a 5- to 15-membered spiro dicyclic heterocycloalkyl containing at least one nitrogen, wherein at least one nitrogen is unsubstituted or substituted with alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl; -C(O)-(a 3- to 8-membered heterocycloalkyl containing at least one nitrogen, wherein at least one nitrogen is unsubstituted or substituted with alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl); a 3- to -8-membered containing at least one nitrogen It is heterocycloalkyl, wherein at least one nitrogen is unsubstituted or substituted with an alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl; -alkylene-(a 3- to 8-membered heterocycloalkyl containing at least one nitrogen, wherein at least one nitrogen is unsubstituted or substituted with an alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl); -alkylene-N( R 3aa )C(O)alkyl, where R 3aa is hydrogen or alkyl; or X 5 If it is oxygen, it is absent; R 3b is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl; and R 3c represents 1, 2, or 3 hydrogens, alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, cyano, alkoxy, or halo. Claim 2 A compound having the following formula or a pharmaceutically acceptable salt thereof, In the above formula, Is ; ; ; ; ; or and; here X 1 is CH, C-OH, C-alkyl, C-alkoxy, C-haloalkoxy, or nitrogen; X 1a is CH, C-OH, C-alkyl, C-alkoxy, C-haloalkoxy, or nitrogen; X 2 is CH, C-OH, C-alkyl, C-alkoxy, C-haloalkoxy, or nitrogen; X 3 It is carbon or nitrogen; X 4 is nitrogen or oxygen; Y is CH or nitrogen; is a single bond or a double bond; R 1 silver , , , , , , , , , or or; or each R 1 is further substituted with alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, halo, or heteroaryl, wherein each R 1a is independently -CH2- or -C(O)-, and R 1b is independently -CH2- or -NH-; R 5 is independently a hydrogen alkyl or cycloalkyl; R 6 is a hydrogen or amino acid side chain; R 7 -O R 7a , -N R 7a R 7b , or , here R 7a and R 7b is independently hydrogen or alkyl; aa is 1 to 5; R 8 is a heteroalkyl; R 9 Is , , or and, here is an aryl or heteroaryl, where the aryl or heteroaryl is unsubstituted or substituted with an alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, halo, or heteroaryl; each R 9a is independently hydrogen or alkyl; R 9b is -C(O)O R 9c or and; each R 9c is hydrogen or C 1-5 It is alkyl; and bb is 1 or 2 and; cc is 0, 1, or 2; aryl, benzo[ d ][1,3]dioxol, heteroalkyl, or heteroaryl comprising at least one nitrogen, oxygen, or sulfur, wherein the aryl and heteroaryl are unsubstituted or substituted with alkyl, -OH, hydroxyalkyl, alkoxy, cyano, pyridazine, and pyrazol; R 10 is hydrogen, alkyl, or hydroxyalkyl; R 11 is a heteroaryl, where the heteroaryl is unsubstituted or alkyl, haloalkyl, alkoxy, -OH, -C(O)N R 11a R 11b , or It is replaced with, and here R 11a and R 11b is independently hydrogen or alkyl; X 6 It is oxygen or N R 5 And; t 1 is 1 to 5; t 2 is 0 or 1 and; R 2 is independently hydrogen, -OH, -SH, -S-alkyl, -N R 7a R 7b , alkyl, alkoxy, or haloalkoxy, 1 to 3 of which are; R 3 , if present, hydrogen, , , aryl, or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted with an alkyl, heteroalkyl, heterocycloalkyl, and / or halo; X 5 is nitrogen or oxygen; R 3a is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, a 5- to 15-membered spiro dicyclic heterocycloalkyl comprising at least one nitrogen, wherein at least one nitrogen is unsubstituted or substituted with alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl; -C(O)-(a 3- to 8-membered heterocycloalkyl comprising at least one nitrogen, wherein at least one nitrogen is unsubstituted or substituted with alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, or -C(O)-alkylene-C(O) R 3aaa It is replaced with, and here R 3aaa is -O R 7a , -N R 7a R 7b or is alkyl) or; is a 3- to -8-membered heterocycloalkyl containing at least one nitrogen, wherein at least one nitrogen is unsubstituted or substituted with an alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl; -alkylene-(a 3- to -8-membered heterocycloalkyl containing at least one nitrogen, wherein at least one nitrogen is unsubstituted or substituted with an alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl); -alkylene-N( R 3aa )C(O)alkyl, where R 3aa is hydrogen or alkyl; -C(O)-alkylene-C(O) R 3aaa and, here R 3aaa is -O R 7a , -N R 7a R 7b or alkyl; or X 5 If it is oxygen, it is absent; R 3b is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl; R 3c represents 1, 2, or 3 hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, cyano, alkoxy, or halo; R 4 is hydrogen, alkyl, haloalkyl, arylalkyl, aryl, heteroaryl, or heterocycloalkyl where present, wherein aryl, heteroaryl, or heterocycloalkyl is unsubstituted or alkyl, alkenyl, alkynyl, heteroalkyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, -C(O)-alkylene-C(O) R 3aaa It is replaced with, and here R 3aaa is -O R 7a , -N R 7a R 7b or alkyl; or -C(O)N R 4a R 4b and, here R 4a and R 4b is independently hydrogen or alkyl; is a 5- to 15-one-spiro dicyclic heterocycloalkyl containing at least one nitrogen, wherein at least one nitrogen is unsubstituted or alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, or -C(O)-alkylene-C(O) R 3aaa It is replaced with, and here R 3aaa is -O R 7a , -N R 7a R 7b or alkyl or;-N R 4a R 4b and, here R 4a and R 4b is independently hydrogen, alkyl, aryl, heteroaryl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, or arylalkyl; is a 3- to 8-membered heterocycloalkyl comprising at least one nitrogen, wherein at least one nitrogen is acyl, -C(O)-heteroalkylene-N R 4a R 4b , alkyl, -C(O)-alkylene-COO R 5 , -C(O)-alkylene-C(O)N R 4a R 4b , -C(O)-alkylene-C(O)N( R 4a )-heteroalkylene-substituted with halo, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl, where R 4a and R 4b is independently hydrogen, alkyl, or acyl; -alkylene-N R 4a R 4b and, here R 4a and R 4b is independently hydrogen, alkyl, or acyl; or -N( R 5 )C(O)-alkylene-N R 4a R 4b and, here R 4a and R 4b is independently hydrogen, alkyl, or acyl. Claim 3 A compound having the following formula or a pharmaceutically acceptable salt thereof, In the above formula, Is ; ; ; ; or and; here X 1 is CH, C-OH, C-alkyl, C-alkoxy, C-haloalkoxy, or nitrogen; X 1a is CH, C-OH, C-alkyl, C-alkoxy, C-haloalkoxy, or nitrogen; X 2 is CH, C-OH, C-alkyl, C-alkoxy, C-haloalkoxy, or nitrogen; X 3 It is carbon or nitrogen; X 4 is nitrogen or oxygen; Y is CH or nitrogen; is a single bond or a double bond; R 1 silver , , , , , , , , , or ; or each R 1 is further substituted with alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, halo, or heteroaryl, wherein each R 1a is independently -CH2- or -C(O)- and, R 1b is independently -CH2- or -NH-; R 5 is independently hydrogen or alkyl; R 6 is a hydrogen or amino acid side chain; R 7 -O R 7a , -N R 7a R 7b , or and, here R 7a and R 7b is independently hydrogen or alkyl; aa is 1 to 5; R 8 is a heteroalkyl; R 9 is aryl, benzo[ d ][1,3]dioxol, heteroalkyl, or heteroaryl comprising at least one nitrogen, oxygen, or sulfur, wherein the aryl and heteroaryl are unsubstituted or substituted with alkyl, -OH, hydroxyalkyl, alkoxy, cyano, pyridazine, and pyrazol; R 10 is hydrogen, alkyl, or hydroxyalkyl; R 11 is a heteroaryl, where the heteroaryl is unsubstituted or alkyl, haloalkyl, alkoxy, -OH, -C(O)N R 11a R 11b , or It is replaced with, and here R 11a and R 11b is independently hydrogen or alkyl; X 6 It is oxygen or N R 5 And; t 1 is 1 to 5; t 2 is 0 or 1 and; R 2 is independently one to three of hydrogen, -OH, alkyl, alkoxy, or haloalkoxy; R 3 In the case where it exists, hydrogen, , aryl, or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted with an alkyl, heteroalkyl, heterocycloalkyl, and / or halo; X 5 is nitrogen or oxygen; R 3a is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, a 5- to 15-membered spiro dicyclic heterocycloalkyl containing at least one nitrogen, wherein at least one nitrogen is unsubstituted or substituted with alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl; -C(O)-(a 3- to 8-membered heterocycloalkyl containing at least one nitrogen, wherein at least one nitrogen is unsubstituted or substituted with alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl); or a 3- to -8-membered heterocycloalkyl containing at least one nitrogen It is heterocycloalkyl, wherein at least one nitrogen is unsubstituted or substituted with an alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl; or -alkylene-(a 3- to 8-membered heterocycloalkyl containing at least one nitrogen, wherein at least one nitrogen is unsubstituted or substituted with an alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl) or -alkylene-N( R 3aa )C(O)alkyl, where R 3aa is hydrogen or alkyl; or X 5 If it is oxygen, it is absent; R 3b is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl; R 3c represents 1, 2, or 3 hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, cyano, alkoxy, or halo; R 4 is hydrogen, alkyl, haloalkyl, arylalkyl, aryl, heteroaryl, or heterocycloalkyl where present, wherein aryl, heteroaryl, or heterocycloalkyl is unsubstituted or alkyl, alkenyl, alkynyl, heteroalkyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, or -C(O)N R 4a R 4b It is replaced with, and here R 4a and R 4b is independently hydrogen or alkyl; is a 5- to 15-one-spiro dicyclic heterocycloalkyl containing at least one nitrogen, wherein at least one nitrogen is unsubstituted or substituted with an alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl; -N R 4a R 4b and, here R 4a and R 4b is independently hydrogen, alkyl, aryl, heteroaryl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, or arylalkyl; or a 3- to 8-membered heterocycloalkyl comprising at least one nitrogen, wherein at least one nitrogen is an acyl, -C(O)-heteroalkylene-N R 4a R 4b , alkyl, -C(O)-alkylene-COO R 5 , -C(O)-alkylene-C(O)N R 4a R 4b , substituted with heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl, where R 4a and R 4b is independently hydrogen, alkyl, or acyl; -alkylene-N R 4a R 4b and, here R 4a and R 4b is independently hydrogen, alkyl, or acyl; or -N( R 5 )C(O)-alkylene-N R 4a R 4b and, here R 4a and R 4b is independently hydrogen, alkyl, or acyl. Claim 4 In paragraph 3, Is And; R 3 is in the case where it exists And; R 4 is a 3- to 8-membered heterocycloalkyl containing at least one nitrogen where present, wherein at least one nitrogen is unsubstituted or acyl, -C(O)-heteroalkylene-N R 4a R 4b , alkyl, -C(O)-alkylene-COO R 5 , -C(O)-alkylene-C(O)N R 4a R 4b , substituted with heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl, wherein R4a and R4b are independently hydrogen, alkyl, or acyl, compounds. Claim 5 In paragraph 4, R 3a is alkyl and; R 3b is hydrogen; and R 3c is a compound of one or more alkoxy or haloin. Claim 6 In paragraph 5, R 3 silver , , , , or Phosphorus, compound. Claim 7 In paragraph 6, R 4 A compound comprising a 3- to 8-membered heterocycloalkyl containing at least one nitrogen when present, wherein at least one nitrogen is unsubstituted or substituted with an acyl. Claim 8 In Paragraph 7, R 4 Is , , , , or Phosphorus, compound. Claim 9 In paragraph 8, R 1 silver Phosphorus, compound. Claim 10 In paragraph 9, the compound is (2-(3-(1-acetylasedidine-3-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 1 ), N -(2-((2 H -tetrazole-5-yl)amino)-2-oxoethyl)-2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-byindazole]-1-yl)acetamide ( 2 ), N -((2 H -tetrazole-5-yl)methyl)-2-(2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)acetamide ( 3 ), 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(2-((2-amino-2-oxoethyl)amino)-2-oxoethyl)acetamide ( 4 ), N -((2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycyl)- N -methylglycine ( 5 ), N -((2 H -tetrazole-5-yl)methyl)-2-(2-(2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)acetamido)acetamide ( 6 ), N -( N -(2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -Methylglycyl)- N -methylglycine ( 7 ), N -(2-((5 H -tetrazole-5-yl)amino)-2-oxoethyl)-2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -methylacetamide ( 8 ), (2-(5'-fluoro-1'-methyl-3-(piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 76 ), (2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 9 ), N -(2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycine ( 10 ), (2-(3-(1-acetylpiperidine-4-yl)-4-(5-fluoro-1-methyl-1 H -Indazole-6-il)-1 H -pyrazolo[3,4- b ]pyridine-1-yl)acetyl)glycylglycine (11) , rac-(R)-(R)-(2-(3-(1-acetylasepan-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 12 ), N -(2-(3-(1-acetylasedidine-3-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycine ( 13 ), (2-(3-(4-acetylpiperazine-1-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 14 ), (2-(3-(1-acetylpiperidine-4-yl)-5'-methoxy-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 15 ), (2-(3-(1-acetylpiperidine-4-yl)-7'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 16 ), methyl (2-(5'-fluoro-1'-methyl-3-(piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 215 ), tert -butyl (2-(5'-fluoro-1'-methyl-3-(piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 216 ), methyl (2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 217 ), (2-(3-(1-acetylpiperidine-4-yl)-5',7'-difluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 218 ), and (2-(3-(1-acetylpiperidine-4-yl)-4'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 17 A compound selected from the group consisting of ). Claim 11 In paragraph 8, R 1 silver Phosphorus, compound. Claim 12 In paragraph 11, the compound is 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(4-(hydroxymethyl)-2-methylthiophene-3-yl)acetamide ( 18 ), 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(1,6-naphthiridine-4-yl)acetamide ( 19 ), 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(isoquinoline-4-yl)acetamide ( 20 ), 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(3-methylisoxazole-4-yl)acetamide ( 21 ), 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(1,7-naphthiridine-4-yl)acetamide ( 22 ), 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(5-methylpyridine-3-yl)acetamide ( 23 ), 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(4-methylpyridine-3-yl)acetamide ( 24 ), 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(7-hydroxy-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)acetamide ( 25 ), 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(pyrazolo[1,5-a]pyridin-4-yl)acetamide ( 26 ), 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(pyrazolo[1,5-b]pyridazine-3-yl)acetamide ( 27 ), 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(Benzo[ d ][1,3]dioxol-4-yl)acetamide ( 28 ), 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(2-(2-methoxyethoxy)ethyl)acetamide ( 29 ), 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(2-(methoxymethyl)-2 H -1,2,3-triazole-4-yl)acetamide ( 30 ), N -(4-(1 H -pyrazol-1-yl)pyrimidine-5-yl)-2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-byindazole]-1-yl)acetamide ( 31 ), 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(1-(Piridajin-3-il)-1 H -pyrazol-5-yl)acetamide ( 32 ), 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(Pirido[3,4- b ]Pyrazine-8-yl)acetamide ( 33 ), 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(2,7-naphthiridine-4-yl)acetamide ( 34 ), N -([1,2,4]triazolo[1,5- a ]pyridine-8-yl)-2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-byindazole]-1-yl)acetamide ( 35 ), and 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(3-cyano-2-methylphenyl)acetamide ( 36 A compound selected from the group consisting of ). Claim 13 In paragraph 8, R 1 silver Phosphorus, compound.. Claim 14 In paragraph 13, the compound is ( S )-2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(2-hydroxy-1-(5-methyl-1 H -1,2,4-triazole-3-yl)ethyl)acetamide ( 37 ), ( R )-2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -((3-(1-hydroxyethyl)-1 H -1,2,4-triazole-5-yl)methyl)acetamide ( 38 ), 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -((5-ethyloxazole-2-yl)methyl)acetamide ( 39 ), 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -((5-(difluoromethyl)-1,24-oxadiazole-3-yl)methyl)acetamide ( 40 ), 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -((2-methoxypyrimidine-4-yl)methyl)acetamide ( 41 ), 3-((2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)methyl)-1,2,4-oxadiazole-5-carboxamide ( 42 ), 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -((5-hydroxy-6-methoxypyridine-2-yl)methyl)acetamide ( 43 ), and 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -methyl- N -((5-methyl-1,2,4-oxadiazole-3-yl)methyl)acetamide ( 44 A compound selected from the group consisting of ). Claim 15 In paragraph 8, R 1 silver Phosphorus, compound. Claim 16 In paragraph 15, the compound is rac-2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -((2 R ,3 R )-2-(1-methyl-1 H -Imidazole-2-yl)tetrahydrofuran-3-yl)acetamide ( 45 )Pheno, compound. Claim 17 In paragraph 8, R 1 silver Phosphorus, compound. Claim 18 In paragraph 17, the compound is rac-2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -methyl- N -(((2 R ,3 R )-3-(3-methyl-1 H -1,2,4-triazole-5-yl)tetrahydrofuran-2-yl)methyl)acetamide ( 46 )Pheno, compound. Claim 19 In paragraph 8, the compound is 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)-1-(3-(hydroxymethyl)-6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazine-5(4 H )-il)ethane-1-one ( 47 )Pheno, compound. Claim 20 In paragraph 8, R 1 silver Phosphorus, compound. Claim 21 In paragraph 20, the compound is N -([1,2,4]Triazolo[3,4- b ][1,3,4]thiadiazole-6-yl)-2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-byindazole]-1-yl)acetamide ( 48 )Pheno, compound. Claim 22 In paragraph 8, R 1 silver Phosphorus, compound. Claim 23 In paragraph 22, the compound is 2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -(1-methyl-4-oxo-1,4-dihydropyrimidine-2-yl)acetamide ( 49 )Pheno, compound. Claim 24 In paragraph 8, R 1 silver Phosphorus, compound. Claim 25 In paragraph 24, the compound is N -(2-(2 H -tetrazole-2-yl)ethyl)-2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-byindazole]-1-yl)acetamide ( 50 )Pheno, compound. Claim 26 In paragraph 4, R 3a is alkyl and; R 3b is hydrogen; R 3c is cyanoin, a compound. Claim 27 In Paragraph 26, R 3 silver Phosphorus, compound. Claim 28 In paragraph 27, R 4 A compound comprising a 3- to 8-membered heterocycloalkyl containing at least one nitrogen when present, wherein at least one nitrogen is unsubstituted or substituted with an acyl. Claim 29 In paragraph 28, R 4 Is Phosphorus, compound. Claim 30 In Paragraph 29, R 1 silver Phosphorus, compound. Claim 31 In paragraph 30, the compound is (2-(3-(1-acetylpiperidine-4-yl)-5'-cyano-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 51 )Pheno, compound. Claim 32 In paragraph 4, R 3a is alkyl and; R 3b is hydrogen; R 3c is chloroin, a compound. Claim 33 In Paragraph 32, R 3 silver Phosphorus, compound. Claim 34 In Paragraph 33, R 4 A compound comprising a 3- to 8-membered heterocycloalkyl containing at least one nitrogen when present, wherein at least one nitrogen is unsubstituted or substituted with an acyl. Claim 35 In Paragraph 34, R 4 Is Phosphorus, compound. Claim 36 In paragraph 35, R 1 silver Phosphorus, compound. Claim 37 In paragraph 36, the compound is (2-(3-(1-acetylpiperidine-4-yl)-5'-chloro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 52 )Pheno, compound. Claim 38 In paragraph 3, R 3a is alkyl and; R 3b is hydrogen; R 3c is an alkyl compound. Claim 39 In Paragraph 38, R 3 silver Phosphorus, compound. Claim 40 In Paragraph 39, R 4 A compound comprising a 3- to 8-membered heterocycloalkyl containing at least one nitrogen when present, wherein at least one nitrogen is unsubstituted or substituted with an acyl. Claim 41 In Paragraph 40, R 4 Is Phosphorus, compound. Claim 42 In Paragraph 41, R 1 silver Phosphorus, compound. Claim 43 In paragraph 42, the compound is (2-(3-(1-acetylpiperidine-4-yl)-1',5'-dimethyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 53 ) Phosphorus, compound. Claim 44 In paragraph 6, R 4 A compound in which is heterocycloalkyl where present, wherein the heterocycloalkyl is unsubstituted or substituted with an alkyl. Claim 45 In Paragraph 44, R 4 Is or Phosphorus, compound. Claim 46 In paragraph 45, R 1 silver Phosphorus, compound. Claim 47 In paragraph 46, the compound is (2-(5'-fluoro-1'-methyl-3-morpholino-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 54 ) or (2-(3-((2 R ,6 S )-2,6-dimethylmorpholino)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 55 ) Phosphorus, compound. Claim 48 In paragraph 6, R 4 A compound that is hydrogen, alkyl, haloalkyl, aryl, heteroaryl, or arylalkyl in the presence of Claim 49 In Paragraph 48, R 4 is a compound of hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, phenyl, pyridyl, or benzyl. Claim 50 In Paragraph 49, R 1 silver Phosphorus, compound. Claim 51 In paragraph 50, the compound is (2-(5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 56 ), N -(2-((2 H -tetrazole-5-yl)amino)-2-oxoethyl)-2-(2-(5'-fluoro-1',3-dimethyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)acetamide ( 57 ), (2-(5'-fluoro-1',3-dimethyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 58 ), (2-(3-ethyl-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 59 ), N -(2-((2 H -tetrazole-5-yl)amino)-2-oxoethyl)-2-(2-(5'-fluoro-3-isopropyl-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)acetamide ( 60 ), (2-(5'-fluoro-3-isopropyl-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 61 ), (2-(5'-fluoro-1'-methyl-3-(trifluoromethyl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 62 ), N -(2-(5'-fluoro-1'-methyl-3-(trifluoromethyl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycine ( 63 ), N -(2-((2 H -tetrazole-5-yl)amino)-2-oxoethyl)-2-(2-(5'-fluoro-1'-methyl-3-(trifluoromethyl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)acetamide ( 64 ), (2-(5'-fluoro-1'-methyl-3-phenyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 65 ), (2-(5'-fluoro-1'-methyl-3-(pyridine-3-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 66 ), (2-(3-benzyl-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 67 ), (2-(4-(5-fluoro-1-methyl-1 H -Indazole-6-il)-1 H -pyrazolo[4,3-c]pyridin-1-yl)acetyl)glycylglycine ( 68 ), and (2-(4-(5-fluoro-1-methyl-1 H -Indazole-6-il)-1 H -pyrazolo[3,4-c]pyridin-1-yl)acetyl)glycylglycine ( 69 A compound selected from the group consisting of ). Claim 52 In paragraph 6, R 4 is a 3- to 8-membered heterocycloalkyl containing at least one nitrogen where present, wherein at least one nitrogen is unsubstituted or -C(O)-heteroalkylene-N R 4a R 4b It is replaced with, and here R 4a and R 4b is independently hydrogen, alkyl, or acyl, a compound. Claim 53 In Paragraph 52, R 4 Is Phosphorus, compound. Claim 54 In Paragraph 53, R 1 silver Phosphorus, compound. Claim 55 In paragraph 54, the compound is methyl (2-(3-(1-(3-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propanoyl)piperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 70 ) and (2-(3-(1-(3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propanoyl)piperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 71 A compound selected from the group consisting of ). Claim 56 In paragraph 6, R 4 is a 3- to 8-membered heterocycloalkyl containing at least one nitrogen where present, wherein at least one nitrogen is unsubstituted or -C(O)-alkylene-COO R 5 or -C(O)-alkylene-C(O)N R 4a R 4b It is replaced with, and here R 4a and R 4b is independently hydrogen, alkyl, or acyl, a compound. Claim 57 In Paragraph 56, R 4 Is or Phosphorus, compound. Claim 58 In paragraph 57, R 1 silver Phosphorus, compound. Claim 59 In paragraph 58, the compound is 4-(4-(1-(2-((2-((carboxymethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-4-(5-fluoro-1-methyl-1 H -Indazole-6-il)-1 H -pyrazolo[3,4- b ]pyridine-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 72 ), (2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-4-(5-fluoro-1-methyl-1 H -Indazole-6-il)-1 H -pyrazolo[3,4- b ]pyridine-1-yl)acetyl)glycylglycine ( 73 ), and methyl (2-(5'-fluoro-1'-methyl-3-(1-(4-(methylamino)-4-oxobutanoyl)piperidin-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 229 A compound selected from the group consisting of ). Claim 60 In paragraph 6, R 4 -N(if it exists R 5 )C(O)-alkylene-N R 4a R 4b and, here R 4a and R 4b is independently hydrogen, alkyl, or acyl, a compound. Claim 61 In Article 60, R 4 Is Phosphorus, compound. Claim 62 In Paragraph 61, R 1 silver Phosphorus, compound. Claim 63 In paragraph 62, the compound is (2-(3-(3-acetamidopropaneamido)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 74 ) Phosphorus, compound. Claim 64 In paragraph 6, R 4 -alkylene-N in the presence R 4a R 4b and, here R 4a and R 4b is independently hydrogen, alkyl, or acyl, a compound. Claim 65 In Paragraph 64, R 4 Is Phosphorus, compound. Claim 66 In paragraph 65, R 1 silver Phosphorus, compound. Claim 67 In paragraph 66, the compound is (2-(3-(3-acetamidopropyl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 75 ) Phosphorus, compound. Claim 68 In paragraph 6, R 4 A compound comprising a 3- to 8-membered heterocycloalkyl containing at least one nitrogen where present, wherein at least one nitrogen is unsubstituted or substituted with an alkyl group. Claim 69 In paragraph 68, R 4 Is or Phosphorus, compound. Claim 70 In paragraph 69, R 1 silver Phosphorus, compound. Claim 71 In paragraph 70, the compound is (2-(5'-fluoro-1'-methyl-3-(piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 76 ) and (2-(5'-fluoro-1'-methyl-3-(1-methylpiperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 77 A compound selected from the group consisting of ). Claim 72 In paragraph 6, R 4 A compound comprising a 5- to 15-one-spiro dicyclic heterocycloalkyl containing at least one nitrogen where present, wherein at least one nitrogen is unsubstituted or substituted with an alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl. Claim 73 In claim 72, the 5- to 15-one-spiro dicyclic heterocycloalkyl containing at least one nitrogen is and, additionally, here n 1 It is 0 to 6, and n 2 is 0 to 3, and n 3 A compound having 1 to 3 components. Claim 74 In Paragraph 73, R 4 Is Phosphorus, compound. Claim 75 In Paragraph 74, R 1 silver Phosphorus, compound. Claim 76 In paragraph 75, the compound is (2-(3-(2-acetyl-2-azaspiro[3.3]heptane-6-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 78 ) or N -(2-(3-(2-acetyl-2-azaspiro[3.3]heptane-6-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycine ( 79 )Pheno, compound. Claim 77 In paragraph 6, R 4 -N if it exists R 4a R 4b and, here R 4a and R 4b A compound that is independently hydrogen, alkyl, aryl, heteroaryl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, or arylalkyl. Claim 78 In Paragraph 77, R 4 Is Phosphorus, compound. Claim 79 In Paragraph 78, R 1 silver Phosphorus, compound. Claim 80 In paragraph 79, the compound is (2-(5'-fluoro-1'-methyl-3-(methyl(phenyl)amino)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 80 )Pheno, compound. Claim 81 In paragraph 3, R 3a is alkyl and; R 3b is hydrogen; R 3c is a compound that is hydrogen. Claim 82 In paragraph 81, R 3 silver Phosphorus, compound. Claim 83 In Article 82, R 4 A compound comprising a 3- to 8-membered heterocycloalkyl containing at least one nitrogen when present, wherein at least one nitrogen is unsubstituted or substituted with an acyl. Claim 84 In Paragraph 83, R 4 Is Phosphorus, compound. Claim 85 In Paragraph 84, R 1 silver Phosphorus, compound. Claim 86 In paragraph 85, the compound is (2-(3-(1-acetylpiperidine-4-yl)-1'-methyl-1 H ,1' H -[4,5'-Byindazole]-1-yl)acetyl)glycylglycine ( 81 ) and (2-(3-(1-acetylpiperidine-4-yl)-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 82 A compound selected from the group consisting of ). Claim 87 In paragraph 4, R 3a is a 5- to 15-membered spiro dicyclic heterocycloalkyl containing at least one nitrogen, wherein at least one nitrogen is unsubstituted or substituted with an alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl; -C(O)-(a 3- to -8-membered heterocycloalkyl containing at least one nitrogen, wherein at least one nitrogen is unsubstituted or substituted with an alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl); a 3- to -8-membered heterocycloalkyl containing at least one nitrogen, wherein at least one nitrogen is unsubstituted or substituted with an alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, Substituted with an arylalkyl or heteroaryl; -alkylene-(a 3- to 8-membered heterocycloalkyl containing at least one nitrogen, wherein at least one nitrogen is unsubstituted or substituted with an alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, arylalkyl, or heteroaryl); or -alkylene-N( R 3aa )C(O)alkyl, where R 3aa is hydrogen or alkyl; R 3b is hydrogen; and R 3c is a fluorophosphate, a compound. Claim 88 In Paragraph 87, R 3 silver , , , or Phosphorus, compound. Claim 89 In paragraph 88, R 4 A compound that is hydrogen or alkyl when present. Claim 90 In Paragraph 89, R 4 is a compound that is hydrogen or methyl. Claim 91 In Article 90, R 1 silver Phosphorus, compound. Claim 92 In paragraph 91, the compound is (2-(1'-(2-acetyl-2-azaspiro[3.3]heptane-6-yl)-5'-fluoro-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 83 ), (2-(1'-(1-acetylpiperidine-4-carbonyl)-5'-fluoro-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 84 ), (2-(1'-(1-acetylpiperidine-4-yl)-5'-fluoro-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 85 ), (2-(5'-fluoro-3-methyl-1'-((1-methylpiperidine-4-yl)methyl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 86 ), and (2-(1'-(2-acetamidoethyl)-5'-fluoro-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 87 A compound selected from the group consisting of ). Claim 93 In paragraph 4, R 3 is hydrogen if present; R 4 A compound comprising a 3- to 8-membered heterocycloalkyl containing at least one nitrogen when present, wherein at least one nitrogen is unsubstituted or substituted with an acyl. Claim 94 In Paragraph 93, R 4 A compound that is hydrogen or alkyl when present. Claim 95 In Paragraph 94, R 4 Is or Phosphorus, compound. Claim 96 In paragraph 95, R 1 silver Phosphorus, compound. Claim 97 In paragraph 96, the compound is (2-(3-(1-acetylasedidine-3-yl)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 88 ) and (2-(3-(1-acetylpiperidine-4-yl)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 89 A compound selected from the group consisting of ). Claim 98 In paragraph 4, silver And; R 3 is hydrogen if present; R 4 is hydrogen if present; R 1 silver Phosphorus, compound. Claim 99 In paragraph 98, the compound is (2-(1 H -Indazole-1-yl)acetyl)glycylglycine ( 90 ) and methyl (2-(1 H -indole-1-yl)acetyl)glycylglycinate ( 91 A compound selected from the group consisting of ). Claim 100 In paragraph 4, silver And; R 3 ...is an aryl or heteroaryl where present, wherein the aryl or heteroaryl is unsubstituted or substituted with an alkyl, heteroalkyl, heterocycloalkyl, and / or halo; R 4 is a 3- to 8-membered heterocycloalkyl containing at least one nitrogen where present, wherein at least one nitrogen is unsubstituted or acyl or -C(O)-heteroalkylene-N R 4a R 4b It is replaced with, and here R 4a and R 4b is independently hydrogen, alkyl, or acyl, a compound. Claim 101 In Article 100, R 3 silver , , , , , , , , , , and A compound selected from the group consisting of Claim 102 In Article 101, R 4 Is Phosphorus, compound. Claim 103 In Article 102, R 1 silver Phosphorus, compound. Claim 104 In paragraph 103, the compound is (2-(3-(1-acetylpiperidine-4-yl)-4-(naphthalene-2-yl)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 92 ), (2-(3-(1-acetylpiperidine-4-yl)-4-(2-fluoro-4-methylphenyl)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 93 ), (2-(3-(1-acetylpiperidine-4-yl)-4-(2,6-difluoro-4-methylphenyl)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 94 ), (2-(3-(1-acetylpiperidine-4-yl)-4-(quinoline-3-yl)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 95 ), (2-(3-(1-acetylpiperidine-4-yl)-4-(quinoline-7-yl)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 96 ), (2-(3-(1-acetylpiperidine-4-yl)-4-(isoquinoline-6-yl)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 97 ), (2-(3-(1-acetylpiperidine-4-yl)-4-(3-methylbenzo[d]isoxazole-6-yl)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 98 ), (2-(3-(1-acetylpiperidine-4-yl)-4-(benzofuran-2-yl)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 99 ), (2-(3-(1-acetylpiperidine-4-yl)-4-(benzofuran-6-yl)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 100 ), (2-(3-(1-acetylpiperidine-4-yl)-4-(benzo[d]isothiazol-6-yl)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 101 ), (2-(3-(1-acetylpiperidine-4-yl)-4-(isoquinoline-7-yl)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 102 ), and (2-(3-(1-acetylpiperidine-4-yl)-4-(quinoline-6-yl)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 103 A compound selected from the group consisting of ). Claim 105 In Article 100, R 3 silver Phosphorus, compound. Claim 106 In Article 105, R 4 Is Phosphorus, compound. Claim 107 In Paragraph 106, R 1 silver Phosphorus, compound. Claim 108 In paragraph 107, the compound is methyl (2-(3-(1-(3-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propanoyl)piperidine-4-yl)-4-(5-methyl-6-morpholinopyridine-3-yl)-1 H -Indazole-1-yl)acetyl)glycylglycinate ( 104 )Pheno, compound. Claim 109 In paragraph 4, silver And; R 3 is in the case where it exists And; R 4 A compound that is hydrogen when present. Claim 110 In Article 109, R 3a is alkyl and; R 3b is hydrogen; R 3c is a haloin, a compound. Claim 111 In Article 110, R 3 silver Phosphorus, compound. Claim 112 In Article 111, R 1 silver Phosphorus, compound. Claim 113 In paragraph 112, the compound is (2-(4-(5-fluoro-1-methyl-1 H -Indazole-6-il)-1 H -indole-1-yl)acetyl)glycylglycine ( 105 )Pheno, compound. Claim 114 In paragraph 3, silver Igo R 3 is in the case where it exists Phosphorus, compound. Claim 115 In Paragraph 114, X 3 It is nitrogen. X 4 is a compound containing nitrogen. Claim 116 In paragraph 115, R 3a is alkyl and; R 3b is hydrogen; R 3c is a haloin, a compound. Claim 117 In Paragraph 116, R 3 silver Phosphorus, compound. Claim 118 In Paragraph 117, R 1 silver Phosphorus, compound. Claim 119 In paragraph 118, the compound is (2-(4-(5-fluoro-1-methyl-1 H -Indazole-6-il)-1 H -Benzo[d]imidazole-1-yl)acetyl)glycylglycine ( 106 )Pheno, compound. Claim 120 In Paragraph 114, X 3 It is carbon. X 4 is a compound that is oxygen. Claim 121 In Article 120, R 3a is alkyl and; R 3b is hydrogen; R 3c is a haloin, a compound. Claim 122 In Article 121, R 3 silver Phosphorus, compound. Claim 123 In Article 122, R 1 silver Phosphorus, compound. Claim 124 In paragraph 123, the compound is (2-(7-(5-fluoro-1-methyl-1 H -Indazole-6-yl)benzofuran-3-yl)acetyl)glycylglycine ( 107 )Pheno, compound. Claim 125 In paragraph 2, silver or Igo R 3 is in the case where it exists Phosphorus, compound. Claim 126 In paragraph 125, R 3a is alkyl and; R 3b is hydrogen; R 3c is a haloin, a compound. Claim 127 In Paragraph 126, R 3 silver Phosphorus, compound. Claim 128 In Paragraph 127, R 1 silver Phosphorus, compound. Claim 129 In paragraph 128, the compound is (2-(5-(5-fluoro-1-methyl-1 H -Indazole-6-yl)Naphthalene-1-yl)Acetyl)Glycylglycine ( 108 ), (2-(8-(5-fluoro-1-methyl-1 H -Indazole-6-yl)quinoline-4-yl)acetyl)glycylglycine ( 219 ), and (2-(4-(5-fluoro-1-methyl-1 H -Indazole-6-yl)quinoline-8-yl)acetyl)glycylglycine ( 109 A compound selected from the group consisting of ). Claim 130 In paragraph 3, silver And; R 3 is in the case where it exists And; R 4 is a heterocycloalkyl if present, where heterocycloalkyl is unsubstituted or alkyl, alkenyl, alkynyl, heteroalkyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, or -C(O)N R 4a R 4b It is replaced with, and here R 4a and R 4b A compound that is independently hydrogen or alkyl. Claim 131 In Paragraph 130, R 3a is alkyl and; R 3b is hydrogen; R 3c is a haloin, a compound. Claim 132 In Paragraph 131, R 3 silver Phosphorus, compound. Claim 133 In Paragraph 132, R 4 is a heterocycloalkyl if present, where the heterocycloalkyl is unsubstituted or -C(O)N R 4a R 4b It is replaced with, and here R 4a and R 4b A compound that is independently hydrogen or alkyl. Claim 134 In Paragraph 133, R 4 Is Phosphorus, compound. Claim 135 In Paragraph 134, R 1 silver Phosphorus, compound. Claim 136 In paragraph 135, the compound is (2-(5'-fluoro-1'-methyl-3-(4-(methylcarbamoyl)piperidine-1-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 110 ) Phosphorus, compound. Claim 137 In paragraph 3, silver And; R 3 is in the case where it exists And; R 4 is a 3- to 8-membered heterocycloalkyl containing at least one nitrogen where present, wherein at least one nitrogen is unsubstituted or acyl, -C(O)-heteroalkylene-N R 4a R 4b , alkyl, -C(O)-alkylene-COO R 5 , -C(O)-alkylene-C(O)N R 4a R 4b , substituted with heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl, where R 4a and R 4b is independently hydrogen, alkyl, or acyl, a compound. Claim 138 In Paragraph 137, R 3a is alkyl and; R 3b is hydrogen; R 3c is a haloin, a compound. Claim 139 In Paragraph 138, R 3 silver Phosphorus, compound. Claim 140 In Paragraph 139, R 4 A compound comprising a 3- to 8-membered heterocycloalkyl containing at least one nitrogen when present, wherein at least one nitrogen is unsubstituted or substituted with an acyl. Claim 141 In Article 140, R 4 Is Phosphorus, compound. Claim 142 In Article 141, R 1 silver Phosphorus, compound. Claim 143 In paragraph 142, the compound is (2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)ethyl)glycylglycine ( 111 ), (2-(2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)ethyl)glycine ( 112 ), and (5-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)pentanoyl)glycine ( 113 A compound selected from the group consisting of ). Claim 144 In paragraph 3, silver And; R 3 is a heteroaryl where present, wherein the heteroaryl is unsubstituted or substituted with an alkyl, heteroalkyl, heterocycloalkyl, and / or halo; R 4 is hydrogen if present; R 1 silver Phosphorus, compound. Claim 145 In paragraph 144, the compound is (2-(4-(4-fluoro-1-methyl-1 H -Pyrazole-5-il)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 114 ) or (2-(4-(1-methyl-1 H -Pyrazole-5-il)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 115 ) Phosphorus, compound. Claim 146 In paragraph 3, silver And; R 3 is in the case where it exists And; R 4 A compound that is hydrogen when present. Claim 147 In Paragraph 146, R 3a is alkyl and; R 3b is hydrogen; R 3c is a haloin, a compound. Claim 148 In Paragraph 147, R 3 silver Phosphorus, compound. Claim 149 In Paragraph 148, R 1 silver Phosphorus, compound. Claim 150 In paragraph 149, the compound is (2-(5'-fluoro-7-hydroxy-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 116 ), (2-(5'-fluoro-1'-methyl-7-(trifluoromethoxy)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 117 ), (2-(5'-fluoro-1',7-dimethyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 118 ), (2-(5'-fluoro-7-methoxy-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 119 ), (2-(5'-fluoro-1',6-dimethyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 120 ), and (2-(5'-fluoro-1',5-dimethyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 121 A compound selected from the group consisting of ). Claim 151 In paragraph 2, a compound having the following formula or as a pharmaceutically acceptable salt thereof, R 3a One of them is hydrogen or C 1-5 It is alkyl; R 5 is hydrogen or C 1-5 It is alkyl; R 9 Is and; each R 9a is independently hydrogen or alkyl; R 9b is -C(O)O R 9c or and; each R 9c is hydrogen or C 1-5 It is alkyl; bb is 1 or 2; and R 3c is hydrogen, halogen, or CN. Claim 152 In Paragraph 151, each R 9a is a compound that is hydrogen. Claim 153 In Article 151 or Article 152, R 9c is a compound that is hydrogen or methyl. Claim 154 In any one of paragraphs 151 through 153, bb is a compound. Claim 155 In any one of paragraphs 151 through 153, bb is a compound of two. Claim 156 In paragraph 2, R 3a is -C(O)-alkylene-C(O) R 3aaa and, here R 3aaa is -O R 7a , -N R 7a R 7b or is alkyl; R 3b is hydrogen; and R 3c is a fluorophosphate, a compound. Claim 157 In paragraph 156, a compound having the following formula . Claim 158 In Paragraph 156, R 3 silver , , or Phosphorus, compound. Claim 159 In any one of paragraphs 156 through 158, R 4 A compound that is hydrogen or alkyl when present. Claim 160 In any one of paragraphs 156 through 159, R 4 A compound that is hydrogen, methyl, or isopropyl. Claim 161 In any one of paragraphs 156 through 160, R 1 silver Phosphorus, compound. Claim 162 In any one of claims 156 to 161, the compound is 4-(1-(2-((2-((carboxymethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-5'-fluoro-3-methyl-1 H ,1' H -[4,6'-baindazole]-1'-yl)-4-oxobutanoic acid ( 122 ), 4-(5'-fluoro-1-(2-((2-((2-methoxy-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-3-methyl-1 H ,1' H -[4,6'-baindazole]-1'-yl)-4-oxobutanoic acid ( 123 ), 4-(1-(2-((2-((2-( tert -butoxy)-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-5'-fluoro-3-methyl-1 H ,1' H -[4,6'-baindazole]-1'-yl)-4-oxobutanoic acid ( 124 ), (2-(1'-(4-amino-4-oxobutanoyl)-5'-fluoro-3-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 125 ), methyl (2-(1'-(4-amino-4-oxobutanoyl)-5'-fluoro-3-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 126 ), tert -butyl (2-(1'-(4-amino-4-oxobutanoyl)-5'-fluoro-3-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 127 ), (2-(5'-fluoro-3-methyl-1'-(4-oxopentanoyl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 128 ), methyl (2-(5'-fluoro-3-methyl-1'-(4-oxopentanoyl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 129 ), tert -butyl (2-(5'-fluoro-3-methyl-1'-(4-oxopentanoyl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 130 ), 4-(1-(2-((2-((carboxymethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-5'-fluoro-3-isopropyl-1 H ,1' H -[4,6'-baindazole]-1'-yl)-4-oxobutanoic acid ( 131 ), 4-(5'-fluoro-3-isopropyl-1-(2-((2-((2-methoxy-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1 H ,1' H -[4,6'-baindazole]-1'-yl)-4-oxobutanoic acid ( 132 ), 4-(1-(2-((2-((2-( tert -butoxy)-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-5'-fluoro-3-isopropyl-1 H ,1' H -[4,6'-baindazole]-1'-yl)-4-oxobutanoic acid ( 133 ), (2-(1'-(4-amino-4-oxobutanoyl)-5'-fluoro-3-isopropyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 134 ), methyl (2-(1'-(4-amino-4-oxobutanoyl)-5'-fluoro-3-isopropyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 135 ), tert -butyl (2-(1'-(4-amino-4-oxobutanoyl)-5'-fluoro-3-isopropyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 136 ), (2-(5'-fluoro-3-isopropyl-1'-(4-oxopentanoyl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 137 ), methyl (2-(5'-fluoro-3-isopropyl-1'-(4-oxopentanoyl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 138 ), and tert -butyl (2-(5'-fluoro-3-isopropyl-1'-(4-oxopentanoyl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 139 A compound selected from the group consisting of ). Claim 163 In paragraph 2, R 3 silver , , , or Phosphorus, compound. Claim 164 In Paragraph 163, R 4 is a 3- to 8-membered heterocycloalkyl containing at least one nitrogen where present, wherein at least one nitrogen is -C(O)-alkylene-C(O) R 3aaa It is replaced with, where R 3aaa is -O R 7a , -N R 7a R 7b or alkyl; or alkyl, a compound. Claim 165 In paragraph 163 or 164, having the following formula Here R 4aa is -C(O)-alkylene-C(O) R 3aaa and, here R 3aaa is -O R 7a , -N R 7a R 7b or alkyl; or alkyl, a compound. Claim 166 In any one of paragraphs 163 through 165, R 4aa is methyl, , , or Phosphorus, compound. Claim 167 In any one of claims 163 to 165, 2-(4-((2-(5'-fluoro-1'-methyl-3-(1-methylpiperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)methyl)-1 H -1,2,3-triazole-1-yl)acetic acid ( 140 ), methyl 2-(4-((2-(5'-fluoro-1'-methyl-3-(1-methylpiperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)methyl)-1 H -1,2,3-triazole-1-yl)acetate ( 141 ), tert -butyl 2-(4-((2-(5'-fluoro-1'-methyl-3-(1-methylpiperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)methyl)-1 H -1,2,3-triazole-1-yl)acetate ( 142 ), 4-(4-(1-(2-(((1-(carboxymethyl)-1 H -1,2,3-triazole-4-yl)methyl)amino)-2-oxoethyl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 143 ), 4-(4-(5'-fluoro-1-(2-(((1-(2-methoxy-2-oxoethyl)-1 H -1,2,3-triazole-4-yl)methyl)amino)-2-oxoethyl)-1'-methyl-1 H ,1' H -[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 144 ), 4-(4-(1-(2-(((1-(2-( tert -butoxy-2-oxoethyl-1 H -1,2,3-triazole-4-yl)methyl)amino)-2-oxoethyl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 145 ), 2-(4-((2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)methyl)-1 H -1,2,3-triazole-1-yl)acetic acid ( 146 ), methyl 2-(4-((2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)methyl)-1 H -1,2,3-triazole-1-yl)acetate ( 147 ), tert -butyl 2-(4-((2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)methyl)-1 H -1,2,3-triazole-1-yl)acetate ( 148 ), 2-(4-((2-(5'-fluoro-1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)methyl)-1 H -1,2,3-triazole-1-yl)acetic acid ( 149 ), methyl 2-(4-((2-(5'-fluoro-1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)methyl)-1 H -1,2,3-triazole-1-yl)acetate ( 150 ), and tert -butyl 2-(4-((2-(5'-fluoro-1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)methyl)-1 H -1,2,3-triazole-1-yl)acetate ( 151 A compound selected from the group consisting of ). Claim 168 In paragraph 2, R 4 is a 5- to 15-one-spiro dicyclic heterocycloalkyl containing at least one nitrogen where present, wherein at least one nitrogen is unsubstituted or alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, or -C(O)-alkylene-C(O) R 3aaa It is replaced with, and here R 3aaa is -O R 7a , -N R 7a R 7b or an alkyl compound. Claim 169 In Paragraph 168, having the following formula Here R 3b is alkyl and R 3c is a haloin, a compound. Claim 170 In paragraph 168 or 169, 4-(6-(1-(2-((2-((carboxymethyl)amino)-2-oxoethyl)(methyl)amino)-2-oxoethyl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Baindazole]-3-yl)-2-Azaspiro[3,3]heptane-2-yl)-4-oxobutanoic acid ( 152 ), 4-(6-(5'-fluoro-1-(2-((2-((2-methoxy-2-oxoethyl)amino)-2-oxoethyl)(methyl)amino)-2-oxoethyl)-1'-methyl-1 H ,1' H -[4,6'-Baindazole]-3-yl)-2-Azaspiro[3,3]heptane-2-yl)-4-oxobutanoic acid ( 153 ), 4-(6-(1-(2-((2-((2-( tert -butoxy)-2-oxoethyl)amino)-2-oxoethyl)(methyl)amino)-2-oxoethyl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Baindazole]-3-yl)-2-Azaspiro[3,3]heptane-2-yl)-4-oxobutanoic acid ( 154 ), N -(2-(3-(2-(4-amino-4-oxobutanoyl)-2-azaspiro[3.3]heptane-6-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycine ( 155 ), methyl N -(2-(3-(2-(4-amino-4-oxobutanoyl)-2-azaspiro[3.3]heptane-6-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycinate ( 156 ), tert -butyl N -(2-(3-(2-(4-amino-4-oxobutanoyl)-2-azaspiro[3.3]heptane-6-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycinate ( 157 ), N -(2-(5'-fluoro-1'-methyl-3-(2-(4-oxopentanoyl)-2-azspiro[3.3]heptane-6-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycine ( 158 ), methyl N -(2-(5'-fluoro-1'-methyl-3-(2-(4-oxopentanoyl)-2-azspiro[3.3]heptane-6-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycinate ( 159 ), and tert -butyl N -(2-(5'-fluoro-1'-methyl-3-(2-(4-oxopentanoyl)-2-azspiro[3.3]heptane-6-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycinate ( 160 A compound selected from the group consisting of ). Claim 171 In paragraph 2, R 3 silver , , , , or Phosphorus, compound. Claim 172 In Article 171, R 4 is a 3- to 8-membered heterocycloalkyl containing at least one nitrogen where present, wherein at least one nitrogen is unsubstituted or -C(O)-alkylene-C(O) R 3aaa It is replaced with, and here R 3aaa is -O R 7a , -N R 7a R 7b or an alkyl compound. Claim 173 In Article 171 or Article 172, R 1 silver Phosphorus, compound. Claim 174 In any one of paragraphs 171 to 173, the formula of the compound , , , , and A compound selected from the group consisting of Claim 175 In any one of claims 171 to 174, 4-(4-(1-(2-((2-((carboxymethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 161 ), 4-(4-(5'-fluoro-1-(2-((2-((2-methoxy-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1'-methyl-1 H ,1' H -[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 162 ), 4-(4-(1-(2-((2-((2-( tert -butoxy)-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 163 ), (2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 164 ), methyl (2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 165 ), tert -butyl (2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 166 ), (2-(5'-fluoro-1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 167 ), methyl (2-(5'-fluoro-1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 168 ), tert -butyl (2-(5'-fluoro-1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 169 ), 4-(4-(1-(2-((2-((carboxymethyl)amino)-2-oxoethyl)(methyl)amino)-2-oxoethyl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 170 ), 4-(4-(5'-fluoro-1-(2-((2-((2-methoxy-2-oxoethyl)amino)-2-oxoethyl)(methyl)amino)-2-oxoethyl)-1'-methyl-1 H ,1' H -[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 171 ), 4-(4-(1-(2-((2-((2-( tert -butoxy)-2-oxoethyl)amino)-2-oxoethyl)(methyl)amino)-2-oxoethyl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 172 ), N -(2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycine ( 173 ), methyl N -(2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycinate ( 174 ), tert -butyl N -(2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycinate ( 175 ), N -(2-(5'-fluoro-1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycine ( 176 ), methyl N -(2-(5'-fluoro-1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycinate ( 177 ), tert -butyl N -(2-(5'-fluoro-1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycinate ( 178 ), 4-(4-(1-(2-((2-((carboxymethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1'-methyl-1 H ,1' H -[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 179 ), 4-(4-(1-(2-((2-((2-methoxy-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1'-methyl-1 H ,1' H -[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 180 ), 4-(4-(1-(2-((2-((2-( tert -butoxy)-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1'-methyl-1 H ,1' H -[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 181 ), (2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 182 ), methyl (2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 183 ), tert -butyl (2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 184 ), (2-(1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 185 ), methyl (2-(1'-methyl-3-(1-(4-oxopentanoyl)piperidin-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 186 ), tert -butyl (2-(1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 187 ), 4-(4-(1-(2-((2-((carboxymethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-4-(5-fluoro-1-methyl-1 H -Indazole-6-il)-1 H -pyrazolo[3,4- b ]pyridine-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 188 ), 4-(4-(4-(5-fluoro-1-methyl-1 H -Indazole-6-yl)-1-(2-((2-((2-methoxy-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1 H -pyrazolo[3,4- b ]pyridine-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 189 ), 4-(4-(1-(2-((2-((2-( tert -butoxy)-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-4-(5-fluoro-1-methyl-1 H -Indazole-6-il)-1 H -pyrazolo[3,4- b ]pyridine-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 190 ), (2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-4-(5-fluoro-1-methyl-1 H -Indazole-6-il)-1 H -pyrazolo[3,4- b ]pyridine-1-yl)acetyl)glycylglycine ( 191 ), methyl (2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-4-(5-fluoro-1-methyl-1 H -Indazole-6-il)-1 H -pyrazolo[3,4- b ]pyridine-1-yl)acetyl)glycylglycinate ( 192 ), tert -butyl (2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-4-(5-fluoro-1-methyl-1 H -Indazole-6-il)-1 H -pyrazolo[3,4- b ]pyridine-1-yl)acetyl)glycylglycinate ( 193 ), (2-(4-(5-fluoro-1-methyl-1 H -Indazole-6-yl)-3-(1-(4-oxopentanoyyl)piperidine-4-yl)-1 H -pyrazolo[3,4- b ]pyridine-1-yl)acetyl)glycylglycine ( 194 ), methyl (2-(4-(5-fluoro-1-methyl-1 H -Indazole-6-yl)-3-(1-(4-oxopentanoyyl)piperidine-4-yl)-1 H -pyrazolo[3,4- b ]pyridine-1-yl)acetyl)glycylglycinate ( 195 ), tert -butyl (2-(4-(5-fluoro-1-methyl-1) H -Indazole-6-yl)-3-(1-(4-oxopentanoyyl)piperidine-4-yl)-1 H -pyrazolo[3,4- b ]pyridine-1-yl)acetyl)glycylglycinate ( 196 ), 4-(4-(1-(2-((2-((carboxymethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-7'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 197 ), 4-(4-(7'-fluoro-1-(2-((2-((2-methoxy-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1'-methyl-1 H ,1' H -[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 198 ), 4-(4-(1-(2-((2-((2-( tert -butoxy)-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-7'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Beiindazole]-3-yl)piperidine-1-yl)-4-oxobutanoic acid ( 199 ), (2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-7'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 200 ), methyl (2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-7'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 201 ), tert -butyl (2-(3-(1-(4-amino-4-oxobutanoyl)piperidin-4-yl)-7'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 202 ), (2-(7'-fluoro-1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 203 ), methyl (2-(7'-fluoro-1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 204 ), and tert -butyl (2-(7'-fluoro-1'-methyl-3-(1-(4-oxopentanoyl)piperidine-4-yl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 205 A compound selected from the group consisting of ). Claim 176 In paragraph 2, R 3a -C(O)-(3- to 8-membered heterocycloalkyl containing at least one nitrogen, wherein at least one nitrogen is unsubstituted or alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, or -C(O)-alkylene-C(O) R 3aaa It is replaced with, and here R 3aaa is -O R 7a , -N R 7a R 7b or is an alkyl) and; R 3b is hydrogen; and R 3c is a fluorophosphate, a compound. Claim 177 In Paragraph 176, R 4 A compound that is hydrogen or alkyl when present. Claim 178 In Article 176 or Article 177, R 1 silver Phosphorus, compound. Claim 179 In any one of paragraphs 176 to 178, a compound having the following formula: . Claim 180 In any one of claims 176 to 179, 4-(4-(1-(2-((2-((carboxymethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-5'-fluoro-1 H ,1' H -[4,6'-Beiindazole]-1'-carbonyl)piperidine-1-yl)-4-oxobutanoic acid ( 206 ), 4-(4-(5'-fluoro-1-(2-((2-((2-methoxy-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1 H ,1' H -[4,6'-Beiindazole]-1'-carbonyl)piperidine-1-yl)-4-oxobutanoic acid ( 207 ), 4-(4-(1-(2-((2-((2-( tert -butoxy)-2-oxoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-5'-fluoro-1 H ,1' H -[4,6'-Beiindazole]-1'-carbonyl)piperidine-1-yl)-4-oxobutanoic acid ( 208 ), (2-(1'-(1-(4-amino-4-oxobutanoyl)piperidine-4-carbonyl)-5'-fluoro-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 209 ), methyl (2-(1'-(1-(4-amino-4-oxobutanoyl)piperidine-4-carbonyl)-5'-fluoro-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 210 ), tert -butyl (2-(1'-(1-(4-amino-4-oxobutanoyl)piperidine-4-carbonyl)-5'-fluoro-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 211 ), (2-(5'-fluoro-1'-(1-(4-oxopentanoyl)piperidine-4-carbonyl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 212 ), methyl (2-(5'-fluoro-1'-(1-(4-oxopentanoyl)piperidine-4-carbonyl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 213 ), and tert -butyl (2-(5'-fluoro-1'-(1-(4-oxopentanoyl)piperidine-4-carbonyl)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 214 A compound selected from the group consisting of ). Claim 181 In paragraph 2, silver And; R 3 is in the case where it exists And; R 4 is a 3- to 8-membered heterocycloalkyl containing at least one nitrogen where present, wherein at least one nitrogen is unsubstituted or acyl, -C(O)-heteroalkylene-N R 4a R 4b , alkyl, -C(O)-alkylene-COO R 5 , -C(O)-alkylene-C(O)N R 4a R 4b , substituted with heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl, where R 4a and R 4b is independently hydrogen, alkyl, or acyl, a compound. Claim 182 In Article 181, R 3a is alkyl and; R 3b is hydrogen; R 3c is a compound of one or more alkoxy or haloin. Claim 183 In Paragraph 182, R 3 silver , , , , or Phosphorus, compound. Claim 184 In Paragraph 183, R 4 A compound comprising a 3- to 8-membered heterocycloalkyl containing at least one nitrogen when present, wherein at least one nitrogen is unsubstituted or substituted with an acyl. Claim 185 In Article 184, R 4 Is , , , , or Phosphorus, compound. Claim 186 In paragraph 185, R 1 silver Igo R 9 Is , or Phosphorus, compound. Claim 187 In Paragraph 186, R 9 Is , , or Phosphorus, compound. Claim 188 In paragraph 187, the compound is 3-((2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)methyl)-4-fluorobenzoic acid ( 220 ), 2-(2-((2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)methyl)thiazole-4-yl)acetic acid ( 221 ), 2-(4-((2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetamido)methyl)-1 H -1,2,3-triazole-1-yl)acetic acid ( 222 ), and 2-(4-((2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)- N -methylacetamido)methyl)-1 H -1,2,3-triazole-1-yl)acetic acid ( 226 A compound selected from the group consisting of ). Claim 189 In paragraph 2, silver And; R 3 is in the case where it exists And; R 4 is a 3- to 8-membered heterocycloalkyl comprising hydrogen or at least one nitrogen where present, wherein at least one nitrogen is unsubstituted or acyl, -C(O)-heteroalkylene-N R 4a R 4b , alkyl, -C(O)-alkylene-COO R 5 , -C(O)-alkylene-C(O)N R 4a R 4b , substituted with heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl, where R 4a and R 4b is independently hydrogen, alkyl, or acyl, a compound. Claim 190 In Paragraph 189, R 3a is alkyl and; R 3b is hydrogen; R 3c is a compound of one or more alkoxy or haloin. Claim 191 In Article 190, R 3 silver , , , , or Phosphorus, compound. Claim 192 In Article 191, R 4 A compound comprising a 3- to 8-membered heterocycloalkyl containing hydrogen or at least one nitrogen when present, wherein at least one nitrogen is unsubstituted or substituted with an acyl. Claim 193 In Article 192, R 4 is hydrogen, , , , , or Phosphorus, compound. Claim 194 In Paragraph 193, R 1 silver Phosphorus, compound. Claim 195 In paragraph 194, the compound is (2-(3-(1-acetylpiperidine-4-yl)-7-amino-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 223 ) and (2-(5'-fluoro-1'-methyl-7-(methylthio)-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 224 A compound selected from the group consisting of ). Claim 196 In paragraph 2, Is And; R 3 is in the case where it exists or and R 4 is a 3- to 8-membered heterocycloalkyl containing at least one nitrogen where present, wherein at least one nitrogen is unsubstituted or acyl, -C(O)-heteroalkylene-N R 4a R 4b , alkyl, -C(O)-alkylene-COO R 5 , -C(O)-alkylene-C(O)N R 4a R 4b , substituted with heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl, where R 4a and R 4b is independently hydrogen, alkyl, or acyl; or is a 5- to 15-one-spiro dicyclic heterocycloalkyl comprising at least one nitrogen, wherein at least one nitrogen is unsubstituted or is an alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, or -C(O)-alkylene-C(O) R 3aaa It is replaced with, and here R 3aaa is -O R 7a , -N R 7a R 7b or an alkyl compound. Claim 197 In Paragraph 196, R 3a is alkyl and; R 3b is hydrogen; R 3c is one or more alkoxy, cyano, or haloin compounds. Claim 198 In Paragraph 197, R 3 silver , , , , , or Phosphorus, compound. Claim 199 In Paragraph 198, R 4 A compound comprising: a 3- to 8-membered heterocycloalkyl containing at least one nitrogen where present; or a 5- to 15-membered spiro dicyclic heterocycloalkyl containing at least one nitrogen, wherein at least one nitrogen is unsubstituted or substituted with an acyl. Claim 200 In Paragraph 199, R 4 Is , , , , , or Phosphorus, compound. Claim 201 In Article 200, R 1 silver Phosphorus, compound. Claim 202 In paragraph 201, the compound is N -(2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -Cyclopropylglycylglycine ( 225 ), N -(2-(3-(1-acetylpiperidine-4-yl)-5'-fluoro-2'-methyl-1 H ,2' H -[4,6'-Byindazole]-1-yl)acetyl)- N -Cyclopropylglycylglycine ( 227 ), and N -(2-(3-(2-acetyl-2-azaspiro[3.3]heptane-6-yl)-5'-cyano-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)- N -methylglycylglycine ( 228 A compound selected from the group consisting of ). Claim 203 In paragraph 3, silver And; R 3 ...is an aryl or heteroaryl where present, wherein the aryl or heteroaryl is unsubstituted or substituted with an alkyl, heteroalkyl, heterocycloalkyl, and / or halo; R 4 is a 3- to 8-membered heterocycloalkyl containing at least one nitrogen where present, wherein at least one nitrogen is unsubstituted or acyl, -C(O)-heteroalkylene-N R 4a R 4b , alkyl, -C(O)-alkylene-COO R 5 , -C(O)-alkylene-C(O)N R 4a R 4b , substituted with heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl, where R 4a and R 4b is independently hydrogen, alkyl, or acyl, a compound. Claim 204 In Paragraph 203, R 3 silver or Phosphorus, compound. Claim 205 In Article 204, R 4 A compound comprising a 3- to 8-membered heterocycloalkyl containing at least one nitrogen when present, wherein at least one nitrogen is unsubstituted or substituted with an acyl. Claim 206 In Article 205, R 4 Is , , , , or Phosphorus, compound. Claim 207 In Article 206, R 1 silver Phosphorus, compound. Claim 208 In paragraph 207, the compound is (2-(3-(1-acetylpiperidine-4-yl)-4-(isoquinoline-3-yl)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 230 ) and (2-(3-(1-acetylpiperidine-4-yl)-4-(1-methyl-1 H -Dolmen-6-day)-1 H -Indazole-1-yl)acetyl)glycylglycine ( 231 A compound selected from the group consisting of ). Claim 209 In paragraph 2, Is And; R 3 is in the case where it exists And; R 4 is a 3- to 8-membered heterocycloalkyl containing at least one nitrogen where present, wherein at least one nitrogen is unsubstituted or acyl, -C(O)-heteroalkylene-N R 4a R 4b , alkyl, -C(O)-alkylene-COO R 5 , -C(O)-alkylene-C(O)N R 4a R 4b , -C(O)-alkylene-C(O)N( R 4a )-heteroalkylene-substituted with halo, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, or heteroaryl, where R 4a and R 4b is independently hydrogen, alkyl, or acyl, a compound. Claim 210 In Article 209, R 3a is alkyl and; R 3b is hydrogen; R 3c is a compound of one or more alkoxy or haloin. Claim 211 In Article 210, R 3 silver , , , , or Phosphorus, compound. Claim 212 In Article 211, R 4 is a 3- to 8-membered heterocycloalkyl containing at least one nitrogen where present, wherein at least one nitrogen is unsubstituted or -C(O)-alkylene-C(O)N( R 4a )-Substituted with a heteroalkylene-halo, where R 4a is hydrogen, alkyl, or acyl compound. Claim 213 In Article 212, R 4 Is , and A compound selected from the group consisting of Claim 214 In Paragraph 213, R 1 silver Phosphorus, compound. Claim 215 In paragraph 214, the compound is (2-(3-(1-(20-chloro-4-oxo-8,11,14-trioxa-5-azaicosanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 232 ), methyl (2-(3-(1-(20-chloro-4-oxo-8,11,14-trioxa-5-azaicosanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 233 ), (2-(3-(1-(23-chloro-4-oxo-8,11,14,17-tetraoxa-5-azatricosanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 234 ), methyl (2-(3-(1-(23-chloro-4-oxo-8,11,14,17-tetraoxa-5-azatricosanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 235 ), (2-(3-(1-(26-chloro-4-oxo-8,11,14,17,20-pentaoxa-5-azahexacosanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 236 ), methyl (2-(3-(1-(26-chloro-4-oxo-8,11,14,17,20-pentaoxa-5-azahexacosanoyl)piperidine-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 237 ), (2-(3-(1-(29-chloro-4-oxo-8,11,14,17,20,23-hexaoxa-5-azanocosanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycine ( 238 ), and methyl (2-(3-(1-(29-chloro-4-oxo-8,11,14,17,20,23-hexaoxa-5-azanocosanoyl)piperidin-4-yl)-5'-fluoro-1'-methyl-1 H ,1' H -[4,6'-Byindazole]-1-yl)acetyl)glycylglycinate ( 239 A compound selected from the group consisting of ). Claim 216 A compound having the following formula or a pharmaceutically acceptable salt thereof, In the above formula, each is independently an arylene or heteroarylene, where the arylene or heteroarylene is unsubstituted or one or more alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, halo, heteroaryl, or -C(O)N R 1 R 2 It is replaced with, and here R 1 and R 2 is independently hydrogen or alkyl; is a cycloalkylene or heterocycloalkylene, wherein the cycloalkylene or heterocycloalkylene is unsubstituted or one or more alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, halo, heteroaryl, or -C(O)N R 1 R 2 It is replaced with, and here R 1 and R 2 is independently hydrogen or alkyl; each X 1 -N( R 3 )-, oxygen, or sulfur, and here R 3 It is hydrogen or alkyl; X 2 is N( R 4 ), oxygen, or sulfur, and here R 4 is hydrogen or alkyl; and each n It is an integer from 1 to 5. Claim 217 In paragraph 216, ( S )-5-(2-fluoro-6-hydroxypyridine-3-yl)- N -methyl-2-((1-(3-((1-methyl-1 H -tetrazole-5-yl)methoxy)benzoyl)piperidin-3-yl)methoxy)benzamide ( 240 ), ( R )-5-(2-fluoro-6-hydroxypyridine-3-yl)- N -methyl-2-((1-(3-((1-methyl-1 H -tetrazole-5-yl)methoxy)benzoyl)piperidin-3-yl)methoxy)benzamide ( 241 ), ( S )-5-(2-fluoro-6-hydroxypyridine-3-yl)- N -methyl-2-((4-(3-((1-methyl-1 H -tetrazole-5-yl)methoxy)benzoyl)morpholine-2-yl)methoxy)benzamide ( 242 ), and ( R )-5-(2-fluoro-6-hydroxypyridine-3-yl)- N -methyl-2-((4-(3-((1-methyl-1 H -tetrazole-5-yl)methoxy)benzoyl)morpholine-2-yl)methoxy)benzamide ( 243 A compound selected from the group consisting of ). Claim 218 A compound having the following formula or a pharmaceutically acceptable salt thereof, In the above formula, is a cycloalkylene or heterocycloalkylene, wherein the cycloalkylene or heterocycloalkylene is unsubstituted or one or more alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, halo, heteroaryl, or -C(O)N R a R b It is replaced with, and here R a and R b is independently hydrogen or alkyl; is an arylene or heteroarylene, where the arylene or heteroarylene is unsubstituted or one or more alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, halo, heteroaryl, or -C(O)N R a R b It is replaced with, and here R a and R b is independently hydrogen or alkyl; each R 1 is independently hydrogen or alkyl; R 2 is hydrogen or alkyl; and each n is an independent integer from 1 to 8. Claim 219 In paragraph 218, the compound is N -(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-6-(4-(2-(1-(2-(3,5-dioxomorpholino)acetamido)cyclobutyl)acetamido)piperidin-1-yl)nicotinamide ( 244 ) Phosphorus, compound. Claim 220 A compound having the following formula or a pharmaceutically acceptable salt thereof, In the above formula, and is independently an arylene or heteroarylene, where the arylene or heteroarylene is unsubstituted or one or more alkyl, heteroalkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, haloalkyl, aryl, arylalkyl, halo, heteroaryl, or -C(O)N R a R b It is replaced with, and here R a and R b is independently hydrogen or alkyl; each R 1 is independently hydrogen or alkyl; R 2 is hydrogen or alkyl; and each n is an independent integer from 1 to 8. Claim 221 In paragraph 220, the compound is N -(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-5-((2-(3,5-dioxomorpholino)- N -(Imidajo[2,1- b ]thiazole-3-ylmethyl)acetamido)methyl)-2,4-dimethylbenzamide ( 245 ) Phosphorus, compound. Claim 222 A pharmaceutical composition comprising a compound of any one of claims 1 to 221 and a pharmaceutically acceptable carrier, excipient, and / or diluent. Claim 223 A method for treating a disease or disorder in a subject in need, comprising the step of administering a therapeutically effective amount of a compound or composition of any one of claims 1 to 222 to the subject. Claim 224 In paragraph 222, the disease or disability is cancer, method. Claim 225 A compound or composition of any one of claims 1 to 224 for use in treatment. Claim 226 A compound or composition of any one of claims 1 to 225 for use in the treatment of cancer.

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