Inhibitors of MENIN-MLL interaction

Abstract

The invention relates to an inhibitor of MENIN-MLL interaction, in particular to an inhibitor of interaction of menin, MLL and MLL fusion protein, a pharmaceutical composition containing the inhibitor and application of the inhibitor to treatment of cancers and other diseases mediated by the menin-MLL interaction.

Description

Technical Field

[0001] This application is a divisional application of patent application No. 201780063763.2, filed on September 15, 2017, entitled "Inhibitor of MENIN-MLL Interaction".

[0002] This invention relates to inhibitors of the interaction between menin and MLL and MLL fusion proteins, pharmaceutical compositions containing such inhibitors, and their use in treating cancer and other diseases mediated by menin-MLL interaction. Background Technology

[0003] Mixed lineage leukemia (MLL) protein is a histone methyltransferase that is mutated in a clinically and biologically characteristic subset of acute leukemia. Rearranged mixed lineage leukemia (MLL-r) involves repeated translocations at the 11q23 chromosomal locus, resulting in an aggressive form of acute leukemia with limited therapeutic options. These translocations target the MLL gene, producing oncogenic fusion proteins containing N-terminal MLL fusions with more than 60 different fusion protein partners within the frame. Menin, a universally expressed nuclear protein encoded by the tumor suppressor gene for type 1 multiple endocrine tumors (MEN1), has a high-affinity binding interaction with MLL fusion proteins and is an essential cofactor for oncogenic MLL-r fusion proteins (Yokoyama et al., 2005, Cell, 123: 207-18; Cierpicki & Grembecka, 2014, Future Med. Chem., 6: 447-462). Disruption of this interaction leads to selective growth inhibition and apoptosis of MLL-r leukemia cells in both in vitro (Grembecka et al., 2012, Nat. Chem. Biol., 8: 277-284) and in vivo (Yokoyama et al., 2005, op. cit.; Borkin et al., 2015, Cancer Cell, 27: 589-602).

[0004] The menin-MLL complex plays a role in castration-resistant / advanced prostate cancer, and menin-MLL inhibitors have been shown to reduce tumor growth in vivo (Malik et al., 2015, Nat. Med., 21:344-352). Furthermore, menin-MLL inhibitors have been shown to enhance human β-cell proliferation (Chamberlain et al., 2014, J. Clin. Invest., 124:4093-4101), supporting the role of inhibitors of the menin-MLL interaction in the treatment of diabetes (Yang et al., 2010, Proc Natl Acad Sci US A., 107:20358-20363). The interaction between menin and MLL or MLL fusion proteins is an attractive target for therapeutic intervention, and there is a need for novel agents that inhibit the menin-MLL interaction for the treatment of various diseases and conditions, including leukemia, other cancers, and diabetes. Summary of the Invention

[0005] This invention provides inhibitors of menin-MLL interaction, such as compounds of formula I:

[0006]

[0007] I

[0008] Or a pharmaceutically acceptable salt thereof, wherein the compositional variables are as defined in this application.

[0009] The present invention further provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

[0010] The present invention further provides a method for inhibiting the interaction between menin and MLL, which includes contacting menin and MLL with any compound of formula I or a pharmaceutically acceptable salt thereof.

[0011] The present invention further provides a method for treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0012] The present invention further provides a method for treating a patient with insulin resistance, prediabetes, diabetes, diabetes risk, or hyperglycemia, comprising administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0013] The present invention further provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of an agent for inhibiting the interaction between menin and MLL.

[0014] The present invention further provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating cancer in patients.

[0015] The present invention further provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating patients with insulin resistance, prediabetes, diabetes, risk of diabetes, or hyperglycemia.

[0016] The present invention further provides a compound of formula I or a pharmaceutically acceptable salt thereof for inhibiting the interaction between menin and MLL.

[0017] The present invention further provides a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of cancer in patients.

[0018] The present invention further provides a compound of formula I or a pharmaceutically acceptable salt thereof for treating patients with insulin resistance, prediabetes, diabetes, diabetes risk, or hyperglycemia. Attached Figure Description

[0019] Figure 1 XRPD pattern features are shown for 5-fluoro-N-isopropyl-N-methyl-2-(3-(1-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide mono-(2R,3S,4R,5S)-2,3,4,5-tetrahydroxyhexanoate (mucilage). Detailed Implementation

[0020] This invention provides inhibitors of menin-MLL interaction, such as compounds of formula I:

[0021]

[0022] I

[0023] Or its pharmaceutically acceptable salt, wherein:

[0024] Ring A is C 6-10 Aryl, 5- to 14-membered heteroaryl, C 3-14 Cycloalkyl or 4- to 14-membered heterocyclic alkyl groups;

[0025] U is N or CR U , where R U H, halogen, CN, OH, C 1-4 Alkyl, C 1-4 Alkoxy, amino, C 1-4 Alkylamino or C 2-8 Dialkylamino;

[0026] Partially selected from:

[0027] , , , and , where R Y H, halogen, CN, OH, C 1-4 Alkyl, C 1-4 Alkoxy, amino, C 1-4 Alkylamino or C 2-8 Dialkylamino;

[0028] X is either F or Cl;

[0029] L is selected from -C 1-6 Alkylene- and -(C 1-4 Alkylene) a -Q-(C 1-4 Alkylene) b -, where C 1-6 Alkylene and -(C 1-4 Alkylene) a -Q-(C 1-4 Alkylene) b -Any C in the group 1-4 The alkylene group is optionally substituted by one, two, or three independent substituents selected from the following: halogen, CN, OH, C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, amino, C 1-3 Alkylamino and di(C) 1-3 alkyl)amino;

[0030] Q is -O-, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, -C(=O)NR q1 -、-C(=O)O-、-OC(=O)NR q1 -、-NR q1 -、-NR q1 C(=O)O-、-NR q1 C(=O)NR q1 -、-S(=O)2NR q1 -、-C(=NR q2 - or -C(=NR) q2 )-NR q1 -, where each R q1 Independently selected from H and C 1-6 Alkyl and C 1-3 hydroxyalkyl and wherein each R q2Independently selected from H and C 1-6 Alkyl groups and CN;

[0031] Cy represents connectivity C. 6-14 Aryl, Connecting C 3-18 Cycloalkyl, linked 5- to 16-membered heteroaryl, or linked 4- to 18-membered heterocycloalkyl, each optionally selected independently by one, two, three, or four from R Cy Substituents of the substituents;

[0032] Each R Cy Independently selected from halogens, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, CN, NO2, OR a1 SR a1 C(O)R b1 C(O)NR c1 R d1 C(O)OR a1 OC(O)R b1 OC(O)NR c1 R d1 C(=NR) e1 )NR c1 R d1 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 S(O)R b1 S(O)NR c1 R d1 S(O)2R b1 and S(O)2NR c1 Rd1 The C mentioned therein 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 The cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl groups are each optionally substituted by one, two, three, or four independent substituents selected from the following: CN, NO2, OR a1 SR a1 C(O)R b1 C(O)NR c1 R d1 C(O)OR a1 OC(O)R b1 OC(O)NR c1 R d1 C(=NR) e1 )NR c1 R d1 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 S(O)R b1 S(O)NR c1 R d1 S(O)2R b1 and S(O)2NR c1 R d1 ;

[0033] R 1 For H, Cy 1 Halogen, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl, C 2-6 alkenyl, C 2-6 Alkyne, CN, NO2, OR a2 SR a2C(O)R b2 C(O)NR c2 R d2 C(O)OR a2 OC(O)R b2 OC(O)NR c2 R d2 C(=NR) e2 )NR c2 R d2 NR c2 C(=NR e2 )NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 NR c2 S(O)2NR c2 R d2 S(O)R b2 S(O)NR c2 R d2 S(O)2R b2 and S(O)2NR c2 R d2 The C mentioned therein 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Each of the alkynyl groups may be optionally substituted by one, two, three, or four independent substituents selected from the following: halogen, CN, NO2, OR. a2 SR a2 C(O)R b2 C(O)NR c2 R d2 C(O)OR a2 OC(O)R b2 OC(O)NR c2 R d2 C(=NR) e2 )NR c2 R d2 NR c2 C(=NR e2 )NR c2 R d2 NR c2R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 NR c2 S(O)2NR c2 R d2 S(O)R b2 S(O)NR c2 R d2 S(O)2R b2 and S(O)2NR c2 R d2 ;

[0034] Z is Cy 2 Halogen, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl, C 2-6 alkenyl, C 2-6 Alkyne, CN, NO2, OR a3 SR a3 C(O)R b3 C(O)NR c3 R d3 C(S)NR c3 R d3 C(O)OR a3 OC(O)R b3 OC(O)NR c3 R d3 C(=NR) e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)OR a3 NR c3 C(O)NR c3 R d3 NR c3 S(O)R b3 NRc3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 S(O)R b3 S(O)NR c3 R d3 S(O)2R b3 S(O)2NR c3 R d3 and P(O)R c3 R d3 The C mentioned therein 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Each of the ynyl groups is optionally substituted by one, two, three, or four independent substituents selected from the following: Cy 2 Halogen, CN, NO2, CN, NO2, OR a3 SR a3 C(O)R b3 C(O)NR c3 R d3 C(O)OR a3 OC(O)R b3 OC(O)NR c3 R d3 C(=NR) e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)OR a3 NR c3 C(O)NR c3 R d3 NR c3 S(O)R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 S(O)R b3 S(O)NR c3 R d3 S(O)2R b3 and S(O)2NR c3 R d3 ;

[0035] Each R 2 R 3 R 4 and R 5 Independently selected from H, halogen, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl, C 2-6 alkenyl, C 2-6 Alkyne, CN, NO2, OR a4 SR a4 C(O)R b4 C(O)NR c4 R d4 C(O)OR a4 OC(O)R b4 OC(O)NR c4 R d4 C(=NR) e4 )NR c4 R d4 NR c4 C(=NR e4 )NR c4 R d4 NR c4 R d4 NR c4 C(O)R b4 NR c4 C(O)OR a4 NR c4 C(O)NR c4 R d4 NR c4 S(O)R b4 NR c4 S(O)2R b4 NR c4 S(O)2NR c4 R d4 S(O)R b4 S(O)NR c4 R d4 S(O)2R b4 and S(O)2NR c4 R d4 The C mentioned therein 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Each of the alkynyl groups may be optionally substituted by one, two, three, or four independent substituents selected from the following: halogen, CN, NO2, OR. a4 SR a4 C(O)R b4 C(O)NR c4 Rd4 C(O)OR a4 OC(O)R b4 OC(O)NR c4 R d4 C(=NR) e4 )NR c4 R d4 NR c4 C(=NR e4 )NR c4 R d4 NR c4 R d4 NR c4 C(O)R b4 NR c4 C(O)OR a4 NR c4 C(O)NR c4 R d4 NR c4 S(O)R b4 NR c4 S(O)2R b4 NR c4 S(O)2NR c4 R d4 S(O)R b4 S(O)NR c4 R d4 S(O)2R b4 and S(O)2NR c4 R d4 ;

[0036] Each Cy 1 Selected independently from C 6-14 Aryl, C 3-18 Cycloalkyl, 5- to 16-membered heteroaryl, and 4- to 18-membered heterocycloalkyl, each optionally selected independently by one, two, three, or four from R Cy1 Substituents of the substituents;

[0037] Each Cy 2 Selected independently from C 6-14 Aryl, C 3-18 Cycloalkyl, 5- to 16-membered heteroaryl, and 4- to 18-membered heterocycloalkyl, each optionally selected independently by one, two, three, or four from R Cy2 Substituents of the substituents;

[0038] Each R Cy1 and R Cy2 Independently selected from halogens, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl, C 2-6alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl, CN, NO2, OR a5 SR a5 C(O)R b5 C(O)NR c5 R d5 C(O)OR a5 OC(O)R b5 OC(O)NR c5 R d5 C(=NR) e5 )NR c5 R d5 NR c5 C(=NR e5 )NR c5 R d5 NR c5 R d5 NR c5 C(O)R b5 NR c5 C(O)OR a5 NR c5 C(O)NR c5 R d5 NR c5 S(O)R b5 NR c5 S(O)2R b5 NR c5 S(O)2NR c5 R d5 S(O)R b5 S(O)NR c5 R d5 S(O)2R b5 and S(O)2NR c5 R d5 The C mentioned therein 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 The cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl groups are each optionally substituted by one, two, three, or four independent substituents selected from the following: CN, NO2, OR a5 SR a5 C(O)R b5 C(O)NR c5 R d5 C(O)OR a5 OC(O)R b5 OC(O)NR c5 R d5C(=NR) e5 )NR c5 R d5 NR c5 C(=NR e5 )NR c5 R d5 NR c5 R d5 NR c5 C(O)R b5 NR c5 C(O)OR a5 NR c5 C(O)NR c5 R d5 NR c5 S(O)R b5 NR c5 S(O)2R b5 NR c5 S(O)2NR c5 R d5 S(O)R b5 S(O)NR c5 R d5 S(O)2R b5 and S(O)2NR c5 R d5 ;

[0039] Each R a1 R b1 R c1 R d1 R a2 R b2 R c2 R d2 R a3 R b3 R c3 R d3 R a4 R b4 R c4 R d4 R a5 R b5 R c5 and R d5 Independently selected from H and C 1-6 Alkyl, C 1-4 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl, C 3-10 cycloalkyl-C1-6 Alkyl, (5 to 10-membered heteroaryl)-C 1-6 Alkyl and (4 to 10-membered heterocyclic alkyl)-C 1-6 Alkyl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl, C 3-10 cycloalkyl-C 1-6 Alkyl, (5 to 10-membered heteroaryl)-C 1-6 Alkyl and (4 to 10-membered heterocyclic alkyl)-C 1-6 Each alkyl group is optionally selected independently from R by one, two, three, four, or five alkyl groups. g Substituents of the substituents;

[0040] Each R e1 R e2 R e3 R e4 and R e5 Independently selected from H and C 1-4 Alkyl groups and CN;

[0041] Each R g Choose independently the following groups: OH, NO2, CN, halogens, C 1-20 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-4 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, cyano-C 1-3 Alkyl, HO-C 1-3 Alkyl, amino, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, mercapto, C 1-6 Alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carboxyl, C 1-6 alkyl carbonyl and C 1-6 alkoxycarbonyl;

[0042] n is 0 or 1;

[0043] m is 0 or 1;

[0044] p is 0, 1, 2 or 3;

[0045] r is 0, 1, or 2;

[0046] a is 0 or 1; and

[0047] b is 0 or 1.

[0048] Any of the cycloalkyl or heteroalkyl groups may optionally be further substituted with one or two oxo groups.

[0049] And the compound in question is not:

[0050] , , or

[0051] .

[0052] In some implementation schemes:

[0053] Ring A is C 6-10 Aryl, 5- to 14-membered heteroaryl, C 3-14 Cycloalkyl or 4- to 14-membered heterocyclic alkyl groups;

[0054] U is N or CR U , where R U H, halogen, CN, OH, C 1-4 Alkyl, C 1-4 Alkoxy, amino, C 1-4 Alkylamino or C 2-8 Dialkylamino;

[0055] Partially selected from:

[0056] , , , and , where R Y H, halogen, CN, OH, C 1-4 Alkyl, C 1-4 Alkoxy, amino, C 1-4 Alkylamino or C 2-8 Dialkylamino;

[0057] X is either F or Cl;

[0058] L is selected from -C 1-6 Alkylene- and -(C 1-4 Alkylene) a -Q-(C 1-4 Alkylene) b -, where C 1-6 Alkylene and -(C 1-4 Alkylene) a -Q-(C 1-4 Alkylene) b-Any C in the group 1-4 The alkylene group is optionally substituted by one, two, or three independent substituents selected from the following: halogen, CN, OH, C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, amino, C 1-3 Alkylamino and di(C) 1-3 alkyl)amino;

[0059] Q is -O-, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, -C(=O)NR q1 -、-C(=O)O-、-OC(=O)NR q1 -、-NR q1 -、-NR q1 C(=O)O-、-NR q1 C(=O)NR q1 -、-S(=O)2NR q1 -、-C(=NR q2 - or -C(=NR) q2 )-NR q1 -, where each R q1 Independently selected from H and C 1-6 Alkyl groups, wherein each R q2 Independently selected from H and C 1-6 Alkyl groups and CN;

[0060] Cy represents connectivity C. 6-14 Aryl, Connecting C 3-18 Cycloalkyl, linked 5- to 16-membered heteroaryl, or linked 4- to 18-membered heterocycloalkyl, each optionally selected independently by one, two, three, or four from R Cy Substituents of the substituents;

[0061] Each R Cy Independently selected from halogens, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, CN, NO2, OR a1 SR a1 C(O)R b1 C(O)NR c1 R d1 C(O)OR a1 OC(O)Rb1 OC(O)NR c1 R d1 C(=NR) e1 )NR c1 R d1 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 S(O)R b1 S(O)NR c1 R d1 S(O)2R b1 and S(O)2NR c1 R d1 The C mentioned therein 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 The cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl groups are each optionally substituted by one, two, three, or four independent substituents selected from the following: CN, NO2, OR a1 SR a1 C(O)R b1 C(O)NR c1 R d1 C(O)OR a1 OC(O)R b1 OC(O)NR c1 R d1 C(=NR) e1 )NR c1 R d1 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 S(O)R b1 S(O)NR c1 R d1 S(O)2R b1 and S(O)2NR c1 R d1 ;

[0062] R 1 For H, Cy 1 Halogen, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl, C 2-6 alkenyl, C 2-6 Alkyne, CN, NO2, OR a2 SR a2 C(O)R b2 C(O)NR c2 R d2 C(O)OR a2 OC(O)R b2 OC(O)NR c2 R d2 C(=NR) e2 )NR c2 R d2 NR c2 C(=NR e2 )NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 NR c2 S(O)2NRc2 R d2 S(O)R b2 S(O)NR c2 R d2 S(O)2R b2 and S(O)2NR c2 R d2 The C mentioned therein 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Each of the alkynyl groups may be optionally substituted by one, two, three, or four independent substituents selected from the following: halogen, CN, NO2, OR. a2 SR a2 C(O)R b2 C(O)NR c2 R d2 C(O)OR a2 OC(O)R b2 OC(O)NR c2 R d2 C(=NR) e2 )NR c2 R d2 NR c2 C(=NR e2 )NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 NR c2 S(O)2NR c2 R d2 S(O)R b2 S(O)NR c2 R d2 S(O)2R b2 and S(O)2NR c2 R d2 ;

[0063] Z is Cy 2 C 2-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl, C 2-6 alkenyl, C2-6 Alkyne, CN, NO2, OR a3 SR a3 C(O)R b3 C(O)NR c3 R d3 C(S)NR c3 R d3 C(O)OR a3 OC(O)R b3 OC(O)NR c3 R d3 C(=NR) e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)OR a3 NR c3 C(O)NR c3 R d3 NR c3 S(O)R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 S(O)R b3 S(O)NR c3 R d3 S(O)2R b3 S(O)2NR c3 R d3 and P(O)R c3 R d3 The C mentioned therein 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Each of the ynyl groups is optionally substituted by one, two, three, or four independent substituents selected from the following: Cy 2 Halogen, CN, NO2, CN, NO2, OR a3 SR a3 C(O)R b3 C(O)NR c3 R d3 C(O)OR a3 OC(O)R b3 OC(O)NR c3 Rd3 C(=NR) e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)OR a3 NR c3 C(O)NR c3 R d3 NR c3 S(O)R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 S(O)R b3 S(O)NR c3 R d3 S(O)2R b3 and S(O)2NR c3 R d3 ;

[0064] Each R 2 R 3 R 4 and R 5 Independently selected from H, halogen, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl, C 2-6 alkenyl, C 2-6 Alkyne, CN, NO2, OR a4 SR a4 C(O)R b4 C(O)NR c4 R d4 C(O)OR a4 OC(O)R b4 OC(O)NR c4 R d4 C(=NR) e4 )NR c4 R d4 NR c4 C(=NR e4 )NR c4 R d4 NR c4 R d4 NRc4 C(O)R b4 NR c4 C(O)OR a4 NR c4 C(O)NR c4 R d4 NR c4 S(O)R b4 NR c4 S(O)2R b4 NR c4 S(O)2NR c4 R d4 S(O)R b4 S(O)NR c4 R d4 S(O)2R b4 and S(O)2NR c4 R d4 The C mentioned therein 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Each of the alkynyl groups may be optionally substituted by one, two, three, or four independent substituents selected from the following: halogen, CN, NO2, OR. a4 SR a4 C(O)R b4 C(O)NR c4 R d4 C(O)OR a4 OC(O)R b4 OC(O)NR c4 R d4 C(=NR) e4 )NR c4 R d4 NR c4 C(=NR e4 )NR c4 R d4 NR c4 R d4 NR c4 C(O)R b4 NR c4 C(O)OR a4 NR c4 C(O)NR c4 R d4 NR c4 S(O)R b4 NR c4 S(O)2R b4 NR c4 S(O)2NR c4 R d4 S(O)R b4S(O)NR c4 R d4 S(O)2R b4 and S(O)2NR c4 R d4 ;

[0065] Each Cy 1 Selected independently from C 6-14 Aryl, C 3-18 Cycloalkyl, 5- to 16-membered heteroaryl, and 4- to 18-membered heterocycloalkyl, each optionally selected independently by one, two, three, or four from R Cy1 Substituents of the substituents;

[0066] Each Cy 2 Selected independently from C 6-14 Aryl, C 3-18 Cycloalkyl, 5- to 16-membered heteroaryl, and 4- to 18-membered heterocycloalkyl, each optionally selected independently by one, two, three, or four from R Cy2 Substituents of the substituents;

[0067] Each R Cy1 and R Cy2 Independently selected from halogens, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl, CN, NO2, OR a5 SR a5 C(O)R b5 C(O)NR c5 R d5 C(O)OR a5 OC(O)R b5 OC(O)NR c5 R d5 C(=NR) e5 )NR c5 R d5 NR c5 C(=NR e5 )NR c5 R d5 NR c5 R d5 NR c5 C(O)R b5 NR c5 C(O)OR a5 NR c5 C(O)NR c5 R d5NR c5 S(O)R b5 NR c5 S(O)2R b5 NR c5 S(O)2NR c5 R d5 S(O)R b5 S(O)NR c5 R d5 S(O)2R b5 and S(O)2NR c5 R d5 The C mentioned therein 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 The cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl groups are each optionally substituted by one, two, three, or four independent substituents selected from the following: CN, NO2, OR a5 SR a5 C(O)R b5 C(O)NR c5 R d5 C(O)OR a5 OC(O)R b5 OC(O)NR c5 R d5 C(=NR) e5 )NR c5 R d5 NR c5 C(=NR e5 )NR c5 R d5 NR c5 R d5 NR c5 C(O)R b5 NR c5 C(O)OR a5 NR c5 C(O)NR c5 R d5 NR c5 S(O)R b5 NR c5 S(O)2R b5 NR c5 S(O)2NR c5 R d5 S(O)R b5 S(O)NR c5 R d5 S(O)2R b5 and S(O)2NR c5 Rd5 ;

[0068] Each R a1 R b1 R c1 R d1 R a2 R b2 R c2 R d2 R a3 R b3 R c3 R d3 R a4 R b4 R c4 R d4 R a5 R b5 R c5 and R d5 Independently selected from H and C 1-6 Alkyl, C 1-4 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl, C 3-10 cycloalkyl-C 1-6 Alkyl, (5 to 10-membered heteroaryl)-C 1-6 Alkyl and (4 to 10-membered heterocyclic alkyl)-C 1-6 Alkyl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl, C 3-10 cycloalkyl-C 1-6 Alkyl, (5 to 10-membered heteroaryl)-C 1-6 Alkyl and (4 to 10-membered heterocyclic alkyl)-C 1-6 Each alkyl group is optionally selected independently from R by one, two, three, four, or five alkyl groups. g Substituents of the substituents;

[0069] Each R e1 R e2 R e3 R e4 and R e5 Independently selected from H and C 1-4Alkyl groups and CN;

[0070] Each R g Choose independently the following groups: OH, NO2, CN, halogens, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-4 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, cyano-C 1-3 Alkyl, HO-C 1-3 Alkyl, amino, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, mercapto, C 1-6 Alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carboxyl, C 1-6 alkyl carbonyl and C 1-6 alkoxycarbonyl, where C 1-6 alkyl groups further via C 1-6 Alkyl substitution;

[0071] n is 0 or 1;

[0072] m is 0 or 1;

[0073] p is 0, 1, 2 or 3;

[0074] r is 0, 1, or 2;

[0075] a is 0 or 1; and

[0076] b is 0 or 1.

[0077] Any of the cycloalkyl or heterocycloalkyl groups may optionally be further substituted with one or two oxo groups.

[0078] In some implementations, U is N.

[0079] In some implementations, U is CR U .

[0080] In some implementations, X is F.

[0081] In some implementations, X is Cl.

[0082] In some implementation schemes, part for .

[0083] In some implementation schemes, part for .

[0084] In some implementation schemes, part for .

[0085] In some implementation schemes, part for .

[0086] In some implementation schemes, part for .

[0087] In some implementation schemes, part for .

[0088] In some implementation schemes, part for .

[0089] In some implementations, ring A is a 5- to 10-membered heteroaryl group, and C... 3-10 Cycloalkyl or 4- to 10-membered heterocyclic alkyl. In some embodiments, ring A is C. 3-6 Cycloalkyl or 4- to 10-membered heterocyclic alkyl groups. In some embodiments, ring A is a monocyclic group. In some embodiments, ring A is a polycyclic group (e.g., bicyclic, fused, or spirocyclic group).

[0090] In some embodiments, ring A is a group having the following formula:

[0091] , , , , , , , , or , where e and f show the connection points with the remaining part of the molecule.

[0092] In some embodiments, ring A is a group having the following formula:

[0093] , , or , where e and f show the connection points with the remaining part of the molecule.

[0094] In some implementations, L is selected from -C 1-6 Alkylene- and -(C 1-4 Alkylene) a -Q-(C 1-4 Alkylene) b -, where C 1-6 Alkylene and -(C1-4 Alkylene) a -Q-(C 1-4 Alkylene) b -Any C in the group 1-4 The alkylene group is optionally substituted by one, two, or three independent substituents selected from the following: halogen, CN, OH, C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, amino, C 1-3 Alkylamino and di(C) 1-3 alkyl)amino;

[0095] In some embodiments, L is -C optionally substituted by one, two, or three substituents independently selected from the following. 1-6 Alkylene: Halogen, CN, OH, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, amino, C 1-3 Alkylamino and di(C) 1-3 Alkyl)amino.

[0096] In some implementations, L is -C 1-6 Alkylene-.

[0097] In some implementations, L is selected from methylene, ethylene, and butylene.

[0098] In some implementations, L is -(C 1-4 Alkylene) a -Q-(C 1-4 Alkylene) b -, where -(C 1-4 Alkylene) a -Q-(C 1-4 Alkylene) b -Any C in the group 1-4 The alkylene group is optionally substituted by one, two, or three independent substituents selected from the following: halogen, CN, OH, C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, amino, C 1-3 Alkylamino and di(C) 1-3 Alkyl)amino.

[0099] In some implementations, Q is -O-, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, -C(=O)NR q1 -、-C(=O)O-、-OC(=O)NR q1 -、-NR q1 -、-NR q1 C(=O)O-、-NR q1 C(=O)NR q1 -、-S(=O)2NR q1 -、-C(=NR q2 - or -C(=NR) q2 )-NR q1 -, where each R q1 Independently selected from H and C 1-6 Alkyl groups, wherein each R q2 Independently selected from H and C 1-6 Alkyl groups and CN;

[0100] In some implementations, Q is -O-, -C(=O)-, or -C(=O)NR. q1 -、-C(=O)O-、-OC(=O)NR q1 -、-NR q1 -、-NR q1 C(=O)O-、-NR q1 C(=O)NR q1 - or -C(=NR) q2 )-NR q1 -

[0101] In some implementations, Q is -O-, -C(=O)-, or -NR. q1 - or -NR q1 C(=O)O-.

[0102] In some implementations, L is selected from -NH2CH2-, -N(CH3)CH 2- -NHC(O)-, -O-, -C(O)- and -C(O)CH2-.

[0103] In some implementations, Cy is the connectivity C 6-10 Aryl, Connecting C 3-10 Cycloalkyl, linked 5- to 10-membered heteroaryl, or linked 4- to 10-membered heterocycloalkyl, each optionally selected independently by one, two, three, or four from R Cy Substituents are substituted.

[0104] In some implementations, Cy is the connectivity C 6-10 Aryl, Connecting C 6-10Cycloalkyl, linked 5- to 10-membered heteroaryl, or linked 4- to 10-membered heterocycloalkyl, each optionally composed of one or two independently selected from R Cy Substituents are substituted.

[0105] In some implementations, Cy is a linked phenyl group, a linked C group, or a linked C group. 3-10 Cycloalkyl, linked 5- to 10-membered heteroaryl, or linked 4- to 10-membered heterocycloalkyl, each optionally selected independently by one, two, three, or four from R Cy Substituents are substituted.

[0106] In some implementations, Cy is a linked phenyl group, a linked C group, or a linked C group. 3-10 Cycloalkyl, linked 5- to 10-membered heteroaryl, or linked 4- to 10-membered heterocycloalkyl, each optionally composed of one or two independently selected from R Cy Substituents are substituted.

[0107] In some implementations, Cy is a linking group having the following formula:

[0108] , , , , , , , , , , , , , , , , or Each of them is optionally selected independently from R by one, two, three or four. Cy Substituents are substituted.

[0109] In some implementations, Cy is a linking group having the following formula:

[0110] , , or Each of them is optionally selected independently from R by one, two, three or four. Cy Substituents are substituted.

[0111] In some implementation schemes, each R Cy Independently selected from halogens, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4Cyanoalkyl, CN, OR a1 C(O)R b1 C(O)NR c1 R d1 C(O)OR a1 OC(O)R b1 OC(O)NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 S(O)R b1 S(O)NR c1 R d1 S(O)2R b1 and S(O)2NR c1 R d1 The C mentioned therein 1-6 The alkyl group is optionally substituted by one, two, three, or four independent substituents selected from the following: CN, NO2, OR a1 SR a1 C(O)R b1 C(O)NR c1 R d1 C(O)OR a1 OC(O)R b1 OC(O)NR c1 R d1 C(=NR) e1 )NR c1 R d1 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 Rd1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 S(O)R b1 S(O)NR c1 R d1 S(O)2R b1 and S(O)2NR c1 R d1 .

[0112] In some implementation schemes, each R Cy Independently selected from halogens, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl, CN, OR a1 C(O)R b1 C(O)NR c1 R d1 C(O)OR a1 OC(O)R b1 OC(O)NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 S(O)R b1 S(O)NR c1 R d1 S(O)2R b1 and S(O)2NR c1 R d1 The C mentioned therein 1-6 Alkyl groups are optionally selected from one or two independently selected from OR a1 and OC(O)R b1 Substituents are substituted.

[0113] In some implementation schemes, each R CyIndependently selected from halogens, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl, CN, OR a1 C(O)OR a1 C(O)NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 S(O)2R b1 and S(O)2R b1 The C mentioned therein 1-6 Alkyl groups are optionally selected from one or two independently selected from OR a1 and OC(O)R b1 Substituents are substituted.

[0114] In some implementations, Z is Cy 2 C 1-6 Alkyl, OR a3 C(O)R b3 C(O)NR c3 R d3 、or C(O)OR a3 Cy 2 Optionally selected from one or two independent choices of R Cy2 Substituents are substituted.

[0115] In some implementations, Z is Cy 2 C 1-6 Alkyl, OR a3 、or C(O)NR c3 R d3 Cy 2 Optionally selected from one or two independent choices of R Cy2 Substituents are substituted.

[0116] In some implementations, Z is Cy 2 OR a3 or C(O)NR c3 R d3 Cy 2 Optionally selected from one or two independent choices of R Cy2 Substituents are substituted.

[0117] In some implementations, Z is C(O)NR c3 R d3 .

[0118] In some implementations, Z is C(O)NR c3 Rd3 And R c3 and R d3 Independently selected from H and C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally selected from one or two independently selected from R g Substituents are substituted.

[0119] In some implementations, Z is C(O)NR c3 R d3 And R c3 and R d3 Independently selected from H and C 1-6 alkyl.

[0120] In some implementations, Z is C(O)NR c3 R d3 And R c3 and R d3 All are C 1-6 alkyl.

[0121] In some implementations, Z is C(O)NR c3 R d3 And R c3 and R d3 It is independently selected from methyl and isopropyl.

[0122] In some implementation schemes, R 3 For H.

[0123] In some implementation schemes, R 4 For H.

[0124] In some implementation schemes, R 5 For H.

[0125] In some implementations, n is 0.

[0126] In some implementations, n is 1.

[0127] In some implementations, m is 0.

[0128] In some implementations, m is 1.

[0129] In some implementations, p is 0.

[0130] In some implementations, p is 1.

[0131] In some implementations, r is 0.

[0132] In some implementations, r is 1.

[0133] In some implementations, a is 0.

[0134] In some implementations, a is 1.

[0135] In some implementations, b is 0.

[0136] In some implementations, b is 1.

[0137] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is a compound having formula IIa, IIb, IIc, IId, IIe, IIIa, IIIb, IIIc, or IIId:

[0138]

[0139]

[0140] Or its pharmaceutically acceptable salt.

[0141] In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, is a compound having formula IVa, IVb, IVc, IVd, Va, Vb, or Vc:

[0142]

[0143]

[0144] Or its pharmaceutically acceptable salt.

[0145] In some embodiments, the Formula I compound provided in this application, or a pharmaceutically acceptable salt of said compound, is crystalline. As used herein, “crystal” or “crystal form” means a particular crystal lattice configuration of a crystalline substance. Different crystal forms of the same substance typically have different crystal lattices (e.g., unit cells), which are the cause of different physical properties characteristic of each crystal form. In some cases, different crystal lattice configurations have different water or solvent contents.

[0146] Different crystal forms of the same compound or salt can have different overall properties regarding, for example, hygroscopicity, solubility, stability, and so on. Forms with high melting points generally exhibit good thermodynamic stability, which is beneficial for extending the shelf life of pharmaceutical preparations containing solid forms. Forms with lower melting points are generally less thermodynamically stable, but have the advantage of increased water solubility, which translates into increased bioavailability. Forms with weak hygroscopicity are desirable for their stability to heat and humidity and for resistance to degradation during long-term storage.

[0147] Different crystal forms can be identified using solid-state characterization methods, such as X-ray powder diffraction (XRPD). Other characterization methods, such as differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor adsorption (DVS), and the like, further aid in identifying the forms and in determining stability and solvent / water content.

[0148] The XRPD pattern of reflections (peaks) is generally regarded as a fingerprint of a specific crystal form. It is well known that the relative intensity of XRPD peaks can vary widely depending on, in particular, sample preparation techniques, crystal size distribution, the various filters used, sample setup procedures, and the specific instrument used. In some cases, new peaks may be observed, or existing peaks may disappear, depending on the instrument type or setup. The term "peak" as used herein refers to a reflection with a relative height / intensity of at least about 5% of the maximum peak height / intensity. Furthermore, instrument variations and other factors can affect the 2θ value. Therefore, peak assignments (such as those reported in this application) can vary by about 0.2° (2θ), and the terms "substantially" and "about" as used in the context of XRPD in this application are intended to cover the variations mentioned above.

[0149] This invention provides crystal forms of certain Formula I compounds or salts thereof. In some embodiments, the invention relates to pharmaceutically acceptable salts of 5-fluoro-N-isopropyl-N-methyl-2-(3-(1-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide.

[0150] In some embodiments, the pharmaceutically acceptable salt is 5-fluoro-N-isopropyl-N-methyl-2-(3-(1-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide mono-(2R,3S,4R,5S)-2,3,4,5-tetrahydroxyhexadiate (mucilage). In other embodiments, the mucilage is crystalline.

[0151] In some embodiments, the crystal form of 5-fluoro-N-isopropyl-N-methyl-2-(3-(1-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide mono-(2R,3S,4R,5S)-2,3,4,5-tetrahydroxyhexanoate (mucilage) is characterized by having at least one, at least two, or at least three Or at least four XRPD patterns selected from the following peaks (in terms of 2θ): approximately 7.2°, approximately 11.4°, approximately 12.4°, approximately 14.5°, approximately 15.7°, approximately 16.2°, approximately 17.6°, approximately 18.4°, approximately 18.8°, approximately 20.9°, approximately 21.6°, approximately 21.8°, approximately 23.9°, approximately 24.6°, approximately 24.8°, approximately 29.9°, approximately 28.0°, approximately 35.0°, and approximately 37.3°.

[0152] In some embodiments, the crystal form of 5-fluoro-N-isopropyl-N-methyl-2-(3-(1-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide mono-(2R,3S,4R,5S)-2,3,4,5-tetrahydroxyhexanoate (mucilage) is characterized by having at least one, at least two, at least three, or at least four XRPD patterns of peaks selected from the following (in terms of 2θ): about 7.2°, about 12.4°, about 17.6°, about 18.4°, about 20.9°, about 21.6°, about 21.8°, about 23.9°, about 24.6°, about 24.8°, and about 29.9°.

[0153] In some embodiments, 5-fluoro-N-isopropyl-N-methyl-2-(3-(1-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide mono-(2R,3S,4R,5S)-2,3,4,5-tetrahydroxyhexadiate (mucilage) is crystalline and characterized in that it is substantially as Figure 1 The XRPD characteristic curve shown in the figure.

[0154] It should be understood that certain features of the invention set forth in a single embodiment for clarity may also be provided in combination with a single embodiment. Conversely, for the sake of brevity, various features of the invention set forth in a single embodiment may also be provided separately or in any suitable combination.

[0155] The phrase “optionally substituted” as used in this application means either unsubstituted or substituted. The term “substituted” as used in this application means that a hydrogen atom is removed and replaced by a substituent. The term “substituted” can also mean that two hydrogen atoms are removed and replaced by a divalent substituent (e.g., an oxo group or a sulfide group). It should be understood that substitution on a given atom is limited by valence.

[0156] Throughout this specification, the substituent systems of the compounds of this invention are disclosed in groups or ranges. This invention is explicitly intended to include each and every sub-combination of members of these groups and ranges. For example, the term "C" 1-6 The term "alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0157] The term "z-membered" (where z is an integer) typically describes the number of cyclic atoms in a portion having z cyclic atoms. For example, piperidinyl is an example of a 6-membered heterocyclic alkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridinyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl ring.

[0158] Linking substituents have been described throughout this specification. Each linking substituent is particularly intended to include both its forward and reverse forms. For example, -NR (CR'R''). n -Including-NR(CR'R'') n - and -(CR'R'') n NR - Both. If the structure explicitly requires a linking group, then the Markush variable listed for that group should be understood as a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl," then it should be understood that "alkyl" or "aryl" represents a linking alkylene or aryl group, respectively.

[0159] Throughout this specification, various aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described. Unless otherwise specified, these rings may be attached to the remainder of the molecule at any ring member permissible by valence. For example, the terms "pyridine ring" or "pyridinyl" may refer to a pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl ring.

[0160] For compounds of the present invention in which a variable appears more than once, each variable can be a different part of a group of self-defined variables. For example, if the described structure has two R groups present simultaneously on the same compound, then the two R groups can represent different parts of a group of variables independently selected for R.

[0161] The term "C" as used in this application i-jWhen used alone or in combination with other terms, "alkyl" refers to a saturated hydrocarbon group that can be straight-chain or branched, having one to one dozen carbon atoms. In some embodiments, the alkyl group contains one to six carbon atoms, one to four carbon atoms, or one to three carbon atoms. Examples of the alkyl moiety include (but are not limited to) chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, dibutyl, and tert-butyl. In some embodiments, if the alkyl group is a linking group, it may be referred to as "C". i-j Alkylene".

[0162] The term "C" as used in this application i-j "Alkoxy" when used alone or in combination with other terms refers to a group of the formula -O-alkyl, wherein the alkyl group has i to j carbon atoms. Examples of alkoxy groups include methoxy, ethoxy, and propoxy (e.g., n-propoxy and isopropoxy). In some embodiments, the alkyl group has 1 to 3 carbon atoms.

[0163] The term "C" as used in this application i-j "Alkenyl" when used alone or in combination with other terms refers to an unsaturated hydrocarbon group having one or more carbon-carbon double bonds and having i to j carbon atoms. In some embodiments, the alkenyl moiety contains 2 to 6 or 2 to 4 carbon atoms. Examples of alkenyl groups include (but are not limited to) vinyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

[0164] The term "C" as used in this application i-j "Alynyl" when used alone or in combination with other terms refers to an unsaturated hydrocarbon group having one or more carbon-carbon triple bonds and having i to j carbon atoms. Examples of alkynyl groups include (but are not limited to) ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6 or 2 to 4 carbon atoms.

[0165] The term "C" as used in this application i-j "Alkylamino" when used alone or in combination with other terms refers to a group of the formula -NH (alkyl), wherein the alkyl group has i to j carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

[0166] The term "di-C" as used in this application i-j "-alkylamino" when used alone or in combination with other terms refers to a group of the formula -N(alkyl)2, wherein each of the two alkyl groups independently has 1 to 1 carbon atom. In some embodiments, each alkyl group independently has 1 to 6 or 1 to 4 carbon atoms. In some embodiments, the dialkylamino group is -N(C 1-4 Alkyl)2, for example, dimethylamino or diethylamino.

[0167] The term "C" as used in this applicationi-j "Alkylthio" when used alone or in combination with other terms refers to a group of the formula -S-alkyl, wherein the alkyl group has i to j carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. In some embodiments, the alkylthio group is C10-C20. 1-4 Alkyl thiols, such as methyl thiols or ethyl thiols.

[0168] The term “thiol” as used in this application refers to -SH when used alone or in combination with other terms.

[0169] The term "amino" as used in this application refers to a group of the formula -NH2, whether used alone or in combination with other terms.

[0170] The term "C" as used in this application i-j "Haloalkoxy" when used alone or in combination with other terms refers to a group of the formula -O-haloalkyl having i to j carbon atoms. An example haloalkoxy is OCF3. Another example is OCHF2. In some embodiments, the haloalkoxy is simply fluorinated. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. In some embodiments, the haloalkoxy is C... 1-4 Halogenated alkoxy groups.

[0171] The term "halogen" as used in this application, when used alone or in combination with other terms, refers to a halogen atom selected from F, Cl, I, or Br. In some embodiments, "halogen" refers to a halogen atom selected from F, Cl, or Br. In some embodiments, the halogenated substituent is F.

[0172] The term "C" as used in this application i-j "Halogenated alkyl" when used alone or in combination with other terms refers to an alkyl group having one to 2s+1 halogen atoms, which may be the same or different, wherein "s" represents the number of carbon atoms in the alkyl group, and the alkyl group has i to j carbon atoms. In some embodiments, the halogenated alkyl group is only fluorinated. In some embodiments, the halogenated alkyl group is fluoromethyl, difluoromethyl, or trifluoromethyl. In some embodiments, the halogenated alkyl group is trifluoromethyl. In some embodiments, the halogenated alkyl group is 2,2,2-trifluoroethyl. In some embodiments, the halogenated alkyl group is 2,2-difluoroethyl. In some embodiments, the halogenated alkyl group has 1 to 6 or 1 to 4 carbon atoms.

[0173] The term "C" as used in this application i-j "Cyanoalkyl" when used alone or in combination with other terms refers to the formula CN-(C i-j Alkyl groups.

[0174] The term "C" as used in this application i-j"Hydroxyalkyl" when used alone or in combination with other terms refers to an alkyl group having one hydroxyl group (i.e., an OH group) to 2s+1 hydroxyl groups that may be the same or different, where "s" is the number of carbon atoms in the alkyl group, and the alkyl group has i to j carbon atoms. In some embodiments, C i-j Hydroxyalkyl groups contain one, two, or three hydroxyl groups. In some embodiments, C i-j The hydroxyalkyl group comprises a hydroxyl group. In some embodiments, the hydroxyalkyl group has 1 to 6 or 1 to 3 carbon atoms. The term "aryl" as used herein, when used alone or in combination with other terms, refers to a monocyclic or polycyclic aromatic hydrocarbon (e.g., having 2, 3, or 4 fused rings), such as (but not limited to) phenyl, 1-naphthyl, 2-naphthyl, anthracene, phenanthrene, and the like. In some embodiments, the aryl group is C10. 6-10 Aryl. In some embodiments, the aryl group is C. 6-14 Aryl group. In some embodiments, the aryl group is a naphthyl ring or a phenyl ring. In some embodiments, the aryl group is phenyl.

[0175] The term "C" as used in this application i-j "Cycloalkyl," when used alone or in combination with other terms, refers to a non-aromatic cyclic hydrocarbon moiety having i to j ring-forming carbon atoms, which may optionally contain one or more alkenyl groups as part of the ring structure. Cycloalkyl groups may include monocyclic or polycyclic ring systems. Polycyclic ring systems may include fused ring systems and spirocyclic systems. Also included within the definition of cycloalkyl are moieties having one or more aromatic rings fused to the cycloalkyl ring (i.e., having the same bonds as cycloalkyl), such as cyclopentane, cyclopentene, cyclohexane, and benzo or pyrido derivatives like these. Heterocyclic alkyl groups including fused aromatic (e.g., aryl or heteroaryl) moieties can be linked to the molecule by atoms from the aromatic or non-aromatic moieties. One or more ring-forming carbon atoms of the cycloalkyl group may be oxidized to form a carbonyl bond. In some embodiments, the cycloalkyl group is C10-C10. 3-10 cycloalkyl, C 3-7 cycloalkyl or C 5-6 Cycloalkyl groups. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptanetrienyl, norcamphenyl, norpinel, norcarnyl, and the like. Other exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Other examples of cycloalkyl groups having a fused aryl or heteroaryl moiety include tetrahydronaphth-2-yl, 2,3-dihydro-1H-inden-2-yl; 2,3,4,9-tetrahydro-1H-carbazole-7-yl; 2,6,7,8-tetrahydrobenzo[cd]indazole-4-yl; and 5,6,7,8,9,10-hexahydrocycloheptane[b]indole-3-yl.

[0176] The term "heteroaryl" as used herein, when used alone or in combination with other terms, refers to a monocyclic or polycyclic aromatic heterocyclic moiety having one or more heteroatom ring members selected from nitrogen, sulfur, and oxygen (e.g., having 2, 3, or 4 fused rings). In some embodiments, the heteroaryl group has 1, 2, 3, or 4 heteroatom ring members. In some embodiments, the heteroaryl group has 1, 2, or 3 heteroatom ring members. In some embodiments, the heteroaryl group has 1 or 2 heteroatom ring members. In some embodiments, the heteroaryl group has 1 heteroatom ring member. In some embodiments, the heteroaryl group is 5 to 10 quinones or 5 to 6 quinones. In some embodiments, the heteroaryl group is 5 quinones. In some embodiments, the heteroaryl group is 6 quinones. In some embodiments, the heteroaryl group is a 9- or 10-quinone bicyclic ring. In some embodiments, the heteroaryl group is a 9-quinone bicyclic ring. When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. The nitrogen atom in the ring of a heteroaryl group can be oxidized to form an N-oxide. Examples of heteroaryl groups include (but are not limited to) pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrroleyl, pyrazolyl, and azoleyl. azole group, iso Azolyl, thiazolyl, isothiazolyl, imidazolyl, furanyl, thiophene, triazolyl, tetrazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, indoleyl, benzothiophene, benzofuranyl, benzoisophene Azolyl, benzimidazolyl, imidazo[1,2-b]thiazolyl, purinyl, triazine, and the like. In some embodiments, the heteroaryl group is 9H-carbazole-2-yl; 1H-benzo[d]imidazo-6-yl; 1H-indol-6-yl; 1H-indazole-6-yl; 2H-indazole-4-yl; 1H-benzo[d][1,2,3]triazol-6-yl; benzo[d] Azol-2-yl; quinoline-6-yl; or benzo[d]thiazol-2-yl.

[0177] The term "heterocyclic alkyl" as used herein, when used alone or in combination with other terms, refers to a non-aromatic heterocyclic ring system that optionally contains one or more unsaturated elements as part of its ring structure and has at least one heteroatom ring member independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heterocyclic alkyl has one, two, three, or four heteroatom ring members. In some embodiments, the heterocyclic alkyl has one, two, or three heteroatom ring members. In some embodiments, the heterocyclic alkyl has one or two heteroatom ring members. In some embodiments, the heterocyclic alkyl has one heteroatom ring member. When the heterocyclic alkyl contains more than one heteroatom in the ring, the heteroatoms may be the same or different. Examples of cyclic members include CH, CH2, C(O), N, NH, O, S, S(O), and S(O)2. Heterocyclic alkyl can comprise monocyclic or polycyclic (e.g., having two, three, or four fused rings) ring systems. Polycyclic systems can comprise fused systems and spirocyclic systems. Also included within the definition of heterocyclic alkyl groups are portions having one or more aromatic rings fused to a non-aromatic ring (i.e., having the same bonds as the aromatic ring), such as 1,2,3,4-tetrahydro-quinoline, dihydrobenzofuran, and the like. Heterocyclic alkyl groups including fused aromatic portions can be linked to the molecule via atoms from the aromatic or non-aromatic portions. The carbon atoms or heteroatoms in the ring of a heterocyclic alkyl group can be oxidized to form a carbonyl, sulfinyl, or sulfonyl group (or other oxidized bonds) or the nitrogen atom can be quaternized. In some embodiments, the heterocyclic alkyl group is 5 to 10-membered, 4 to 10-membered, 4 to 7-membered, 5-membered, or 6-membered. Examples of heterocyclic alkyl groups include 1,2,3,4-tetrahydro-quinoline, dihydrobenzofuran, azaheptanyl, azaheptanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and pyranyl. Examples of heterocyclic alkyl groups comprising one or more fused aromatic groups (e.g., aryl or heteroaryl) include N-(2'-oxospiro[cyclohexane-1,3'-dihydroindole]-6'-yl); 1,2,3,4-tetrahydroisoquinoline-6-yl; 2,3-dihydro-1H-benzo[d]imidazol-5-yl; 1,3-dihydrospiro[indene-2,3'-dihydroindole]-6'-yl; 2,3-dihydrobenzo[d] Azol-5-yl; 1,2-dihydroquinoline-7-yl; dihydroindole-6-yl; spiro[cyclopentane-1,3'-dihydroindole]-6'-yl; spiro[cyclohexane-1,3'-dihydroindole]-6'-yl; chroman-6-yl; 3,4-dihydro-2H-benzo[b][1,4] Azine-6-yl; and benzo[d][1,3]dioxacyclopentenyl-5-yl.

[0178] The term “arylalkyl” as used in this application, when used alone or in combination with other terms, refers to an aryl-substituted alkyl group.

[0179] The term “cycloalkyl alkyl” as used in this application, when used alone or in combination with other terms, refers to an alkyl group that has been substituted with a cycloalkyl group.

[0180] The term “heteroarylalkyl” as used in this application, when used alone or in combination with other terms, refers to an alkyl group that has been substituted with a heteroaryl group.

[0181] The term “heterocyclic alkyl alkyl” as used in this application, when used alone or in combination with other terms, refers to an alkyl group that has been substituted with a heterocyclic alkyl group.

[0182] The term "C" as used in this application i-j "alkylsulfinyl" refers to the formula -S(=O)-(C) when used alone or in combination with other terms. i-j Alkyl groups.

[0183] The term "C" as used in this application i-j "alkylsulfinyl" when used alone or in combination with other terms refers to the formula -S(=O)2-(C i-j Alkyl groups.

[0184] The term “carboxyl group” as used in this application, when used alone or in combination with other terms, refers to the -C(=O)OH group.

[0185] The term "C" as used in this application i-j "alkyl carbonyl" refers to the formula -C(=O)-(C) when used alone or in combination with other terms. i-j Alkyl groups.

[0186] The term "C" as used in this application i-j "Alkoxycarbonyl" refers to the formula -C(=O)O-(C) when used alone or in combination with other terms. i-j Alkyl groups.

[0187] The term "aminocarbonyl" as used in this application, when used alone or in combination with other terms, refers to a group of the formula -C(=O)NH2.

[0188] The compounds described in this application may be asymmetric (e.g., having one or more stereocenters). Unless otherwise shown, all stereoisomers (e.g., mirror-image and non-mirror-image isomers) are indicated. If the compound name or structure does not indicate the stereochemistry of the stereocenter, all possible configurations of the stereocenter are contemplated. Compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic form. Methods for preparing optically active forms from optically inactive raw materials are known in the art, for example, by resolving racemic mixtures or by stereoselective synthesis. Geometric isomers of alkenes, C=N double bonds, and the like may also be present in the compounds described in this application, and all such stable isomers are covered in this invention. Cis and trans geometric isomers of the compounds of the present invention are described, and they can be isolated as mixtures of isomers or as separated isomers.

[0189] When the compounds of the present invention contain a chiral center, these compounds can be any possible stereoisomer. In a compound having a single chiral center, the stereochemistry of the chiral center can be (R) or (S). In a compound having two chiral centers, the stereochemistry of each chiral center can be (R) or (S) independently, and therefore the configuration of the chiral center can be (R) and (R), (R) and (S); (S) and (R) or (S) and (S). In a compound having three chiral centers, the stereochemistry of each of the three chiral centers can be (R) or (S) independently, and therefore the configuration of the chiral center can be (R), (R) and (R); (R), (R) and (S); (R), (S) and (R); (R), (S) and (S); (S), (R) and (R); (S), (R) and (S); (S), (S) and (R); or (S), (S) and (S).

[0190] The resolution of racemic mixtures of compounds can be carried out by any of a variety of methods known in the art. Exemplary methods include fractional recrystallization using chiral resolving acids that are optically active salt-forming organic acids. Resolving agents suitable for fractional recrystallization methods are, for example, optically active acids such as tartaric acid in D and L forms, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids (e.g., β-camphorsulfonic acid). Other resolving agents suitable for fractional recrystallization methods include stereoisomeric pure forms of α-methylbenzylamine (e.g., S and R forms, or non-mirror image isomeric pure forms), 2-phenylglycolamine, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

[0191] Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). A suitable elution solvent composition can be determined by those skilled in the art.

[0192] When a disclosed compound is named or described without showing the stereochemistry of one or more stereocenters, it is intended to cover every stereoisomer that may arise from the stereochemistry at the undefined stereocenter. For example, if the stereocenter is not specified as R or S, either or both are contemplated.

[0193] The compounds of this invention also include tautomer forms. Tautomer forms arise from the interchange of single bonds and adjacent double bonds, as well as the accompanying migration of protons. Tautomer forms include proton-shift tautomers that are isoprotonated states having the same empirical formula and total charge. Examples of proton-shift tautomers include keto-enol pairs, amide-imino pairs, lactam-lactam pairs, amide-imino pairs, enamine-imino pairs, and cyclic forms in which protons can occupy two or more positions in the heterocyclic system, such as 1H- and 3H-imidazolium, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomer forms can be brought into equilibrium by appropriate substitution or stereolocked into a single form.

[0194] The compounds of this invention may also include all isotopes of atoms present in intermediates or the final compound. Isotopes include those atoms with the same atomic number but different mass numbers. The isotopes of the constituent atoms of the compounds of this invention may exist naturally or in non-natural abundances. Examples of hydrogen isotopes include deuterium and tritium. In some embodiments, the compounds of this invention are deuterated, meaning that at least one deuterium atom replaces a hydrogen atom. In some embodiments, one, two, three, four, five, six, seven, or eight hydrogen atoms in the compounds of this invention are replaced by deuterium. Methods for replacing hydrogen in a molecule with deuterium are known in the art.

[0195] The term "compound" as used in this application is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the described structure. Unless otherwise specified, a compound identified by its name or structure as a particular tautomer form in this application is intended to include other tautomer forms (e.g., in the case of a purine ring, unless otherwise shown, when the compound name or structure has a 9H tautomer, it should be understood that the 7H tautomer is also included).

[0196] All compounds and their pharmaceutically acceptable salts may be found together with other substances (e.g., hydrates and solvates) or may be separated.

[0197] In some embodiments, the compounds of the present invention or their salts are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially isolated from the environment in which it is formed or detected. Partial isolation may include, for example, compositions rich in the compounds of the present invention. Substantialtive isolation may include compositions containing at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 90 wt%, at least about 95 wt%, at least about 97 wt%, or at least about 99 wt% of the compounds of the present invention or their salts. Methods for separating the compounds and their salts are conventional methods in the art.

[0198] The phrase “pharmaceutically acceptable” is used in this application to refer to compounds, materials, compositions and / or dosage forms that, to the extent of reasonable medical judgment, are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications and are commensurate with a reasonable benefit / risk ratio.

[0199] The terms “ambient temperature” and “room temperature” as used in this application are understood in the art to mean, and generally refer to, temperature, such as, reaction temperature, which is approximately the temperature of the chamber in which the reaction is carried out, for example, a temperature of about 20°C to about 30°C.

[0200] This invention also includes pharmaceutically acceptable salts of the compounds described in this application. As used herein, “pharmaceutically acceptable salt” refers to a derivative of the disclosed compound, wherein the parent compound is altered by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include (but are not limited to) mineral acid or organic acid salts of basic residues (e.g., amines); alkali metal or organic salts of acidic residues, such as carboxylic acids; and the like. Pharmaceutically acceptable salts of this invention include, for example, conventional nontoxic salts of parent compounds formed from nontoxic inorganic or organic acids. Pharmaceutically acceptable salts of this invention can be synthesized by conventional chemical methods from parent compounds containing a basic or acidic moiety. Typically, these salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of a suitable base or acid in water, in an organic solvent, or in a mixture of both; typically, non-aqueous media (such as ethers, ethyl acetate, alcohols (e.g., methanol, ethanol, isopropanol, or butanol), or acetonitrile (MeCN)) are preferred. For a list of suitable salts, see Remington's Pharmaceutical Sciences, 17th edition (Mack Publishing Company, Easton, 1985), p. 1418; Berge et al., J. Pharm. Sci., 1977, 66(1), 1-19; and Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Wiley, 2002).

[0201] The terms “individual” and “patient” as used in this application are used interchangeably and refer to a mammal in need of treatment, such as companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cattle, pigs, horses, sheep, goats, and the like), and laboratory animals (e.g., rats, mice, guinea pigs, and the like). Generally, an individual or patient is a human being in need of treatment.

[0202] synthesis

[0203] The compounds of the present invention (including their salts) can be prepared using known organic synthesis techniques and can be synthesized according to any of a variety of possible synthetic routes.

[0204] The reactions to prepare the compounds of the present invention can be carried out in suitable solvents that can be readily selected by those skilled in the art of organic synthesis. Suitable solvents are likely to be substantially non-reactive with the starting materials (reactants), intermediates, or products at temperatures in which the reaction is carried out (e.g., temperatures in the range of the solvent's freezing temperature to its boiling point). A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the specific reaction step, those skilled in the art can select a solvent suitable for that particular reaction step.

[0205] The preparation of the compounds of this invention may involve the protection and deprotection of various chemical groups. Those skilled in the art can readily determine the need for protection and deprotection and the selection of appropriate protecting groups (“Pg”). The chemical properties of protecting groups (“Pg”) can be found, for example, in PGM Wuts and TW Greene, Protective Groups in Organic Synthesis, 4th Edition, Wiley & Sons, Inc., New York (2006), the entire contents of which are incorporated herein by reference.

[0206] The compounds of this invention can be prepared using conventional methods with readily available reagents and starting materials. The reagents used in the preparation of the intermediates of this invention are commercially available or can be prepared using standard procedures described in the literature. Intermediates or final compounds can also be synthesized using various techniques (e.g., solid-phase chemistry, microwave chemistry, or flow chemistry). Furthermore, other methods for preparing the compounds of this invention will readily become apparent to those skilled in the art based on the following reactions, schemes, and examples. Unless otherwise shown, all variables are defined below. Suitable synthetic methods are described in the following references: March, Advanced Organic Chemistry, 3rd edition, John Wiley & Sons, 1985; Greene and Wuts, Protective Groups in Organic Chemistry, 2nd edition, John Wiley & Sons 1991; and Larock, Comprehensive Organic Transformations, 4th edition, VCH publishers Inc., 1989. Additionally, in any synthesis, one or more of the reagents, intermediates, or chemicals may be used in excess to ensure the completion of the reaction. Suitable reaction temperatures are generally in the range of about 0°C to about the boiling point of the solvent. More typically, the temperature is high enough to allow reflux, for example, around 68°C (for tetrahydrofuran). In some cases (e.g., under microwave conditions), the reaction temperature can exceed the boiling point of the solvent.

[0207] The compounds of this invention can be synthesized by the methods described in Schemes 1-3 below. Many synthetic steps are well described in FA Carey, RJ Sundberg, Advanced Organic Chemistry, 2nd ed., Plenum publication, 1983. The synthesis of various hydroxyl-substituted heterocycles is well documented in the literature and can be synthesized by known methods. For general synthesis of useful heterocycles, refer to The Handbook of Heterocyclic Chemistry, Alan R. Katritzky, Pergamon Press, NY, USA, 1st ed., 1986. The described intermediates are also available from various suppliers using commercially available reagents.

[0208] The compounds of this invention can be synthesized by a variety of retrosynthetic analytical methods based on the final objective. Exemplary methods are shown in schemes 1-3.

[0209]

[0210] Commercially available starting heterocycles can be reacted with various ketones containing α-acid protons under basic or acidic conditions to give intermediate 2 of scheme 1. Basic conditions can include various organic and inorganic bases and can be carried out in a variety of protic or aprotic solvents at varying temperatures to solvent reflux temperatures. Similarly, various organic or inorganic acids can be used in protic or aprotic solvents at varying temperatures to solvent reflux temperatures. One synthetic method involves the use of one or more inorganic bases and one or more protic solvents. An illustrative reaction can be carried out using NaOH as the base, alcohol solvent, and reflux conditions, as described by Agarwal, Atul et al. in JMC, 36(25), 4006-14; 1993. The intermediates described above can be hydrogenated in various solvents in the presence of various metal catalysts and hydrogen. For example, hydrogenation reactions can be carried out using hydrogen or hydrogen transfer conditions. An illustrative method involves the use of a palladium catalyst in an alcohol solvent under a hydrogen atmosphere.

[0211] Intermediate 3 of Scheme 1 can be arylated under various conditions. For example, the arylation reaction can be selected from SNAr reactions or metal-mediated aromatic coupling. Various methods for N-arylation of nitrogen heterocycles are described in “Copper-Mediated Cross-Coupling Reactions”, Gwilherm Evano (ed.), John Wiley & Sons, 1st ed., 2013. Exemplary methods involve the reaction of a suitably substituted halo-aryl compound with intermediate 3 of Scheme 1 in one or more aprotic solvents and one or more organic or inorganic bases in the presence of a metal catalyst. Exemplary metal catalysts include (but are not limited to) palladium or copper with suitable ligands. Exemplary aprotic polar solvents include (but are not limited to) dihydrogen ions. Alkane, dimethylformamide, and dimethylacetamide. Another example involves suitably substituted chloro-aryl, bromo-aryl, or iodo-aryl compounds with cuprous iodide in the presence of 1,2-diamine in dimethylformamide and potassium phosphate or cesium carbonate in a 1,4-dimethylformamide. The reaction occurs in alkanes. Alternatively, the bromoaryl halide may contain one or more suitable functional groups, which can be further modified after the cross-coupling reaction. The functional group is selected such that it is suitable for cross-coupling and can be further modified to introduce desired substituents. For example, an acid can be selected as the functional group and then further modified to obtain various desired substituents. In some embodiments, the acid is converted to the corresponding amide via a standard amide coupling procedure.

[0212] Option 1A. Synthesis of intermediate A

[0213]

[0214] The first step of Scheme 1A involves the N-arylation of the heterocycle. The procedures and methods used are similar to those described in Scheme 1. The second step involves the reaction of intermediate 5 or 7 of Scheme 2 with an electrophilic halogenating agent to introduce a halogen group into the molecule. This can be achieved by various methods described in "Heterocyclic Chemistry", John A. Joule & Keith Mills (eds.), John Wiley & Sons, 1st ed., 2013. Exemplary methods involve the use of an electrophilic halogenating agent (e.g., N-halosuccinimide) in an aprotic solvent (e.g., a halogenated solvent or formamide), or the use of a halogen as an electrophile in the presence of a base and an aprotic solvent. Another example involves the use of N-bromosuccinimide in an aprotic solvent (e.g., dimethylformamide) at room temperature. Cross-coupling reactions of aryl halides (i.e., intermediates 6 or 8 of Scheme 1A) with various reagents (e.g., boranate (Suzuki), tin reagent (Stille), zinc reagent (Negishi), or magnesium reagent (Grignard)) are well known in the literature. Another option, as is well known in the art, is to convert the halide into a metallizing agent for coupling with various electrophiles. These conversions are described, for example, in “Cross-Coupling Reactions: A Practical Guide”, Norio Miyaura, 1st edition, 2003, Springer. An illustrative method involves the reaction of arylboranate or vinylboranate with intermediates 6 or 8 of Scheme 2 under palladium-catalyzed reaction conditions in the presence of an inorganic base and solvent (e.g., proton or aprotic) at elevated temperatures.

[0215] In some embodiments, intermediate A of scheme 1-1A is a compound of formula I provided in this application or a pharmaceutically acceptable salt thereof.

[0216] Scheme 2A. Synthesis of intermediate A1

[0217]

[0218] Intermediate A1, containing 1,3-dihydro-2H-imidazo or 7,9-dihydro-8H-purine-8-one, can be synthesized from suitable di-halopyridine or pyrimidine or any other suitable starting material, as described in Burgy et al., 2006, Bioorg. Med. Chem. Lett., 16(19): 5052-5056. The halogen can be sequentially amination by appropriately selected amines at the 3 and 4 positions. Substitution of the halogen at the 4 position can be achieved by nucleophilic substitution. Substitution of the halogen at the 3-position of pyridine or the 5-position of pyrimidine can be achieved by cross-coupling reactions using, for example, various palladium or copper-catalyzed reactions, as described in “Synthesis and Modification of Heterocycles by Metal-Catalyzed Cross-coupling Reactions”, Patonay and Kónya (eds.), 1st edition, 2016, Springer.

[0219] Various synthetic methods for the synthesis of intermediate A2 have been reported in the literature (see, for example, Pryde et al., 2013, Bioorg. Med. Chem. Lett., 23(3): 827-833). This involves starting with a suitably substituted 4-halo-3-nitropyridine or 4-halo-5-nitropyrimidine (where X is a halide) and utilizing nucleophilic substitution of the amine. Reduction of the nitro group by hydrogenation or other methods is well known in the literature and to those skilled in the art. The diamine can be further condensed in an aprotic solvent at elevated temperatures in the presence of triphosgene or carbonyl diimidazole, etc.

[0220] Exemplary methods involve the substitution of amines with 4-chloropyridine or 4-chloropyrimidine in DMF in the presence of an inorganic base (e.g., cesium carbonate). Reduction of the nitro group can be achieved via metal / acid-mediated reduction. For example, one exemplary method uses zinc and HCl at elevated temperatures. An exemplary method of cyclization is carried out by the condensation of a diamine with 1,1-carbonyldiimidazole at elevated temperatures in the presence of one or more aprotic solvents (e.g., acetonitrile). The condensation of a thioanalyte with (e.g.) 1,1-thiocarbonyldiimidazole yields intermediate A2.

[0221] Option 2B. Synthesis of intermediate A3

[0222]

[0223] Various aliphatic alcohols can be condensed, for example, via the Mitsunobu reaction or by converting the alcohol to a suitable nucleophilic substitute, each of which is documented and well known to those skilled in the art. Exemplary methods involve the reaction of heterocycles with aliphatic alcohols under Mitsunobu conditions in an aprotic solvent. In some embodiments, the aliphatic alcohol is converted to a suitable leaving group (e.g., trifluoromethanesulfonate) and then reacted with the heterocycle at elevated temperatures in one or more aprotic solvents (e.g., DMF or acetonitrile) in the presence of an inorganic base (e.g., cesium carbonate). Another illustrative method involves the reaction of aliphatic alcohols with heterocycles at room temperature or elevated temperatures in one or more aprotic solvents (e.g., THF) in the presence of triphenylphosphine and diethyl azodicarbonate. Various methods (e.g., as shown in step 2 of scheme 2B) can be used to halogenate the product thus obtained. Another illustrative method involves the use of N-bromosuccinimide in an aprotic solvent, which can be carried out at various temperatures. The bromine product thus obtained can be reacted with a suitable arylboronic ester under standard metal-catalyzed reaction conditions (e.g., the Suzuki reaction). One embodiment involves using an arylboronic ester with a palladium catalyst (e.g., Pd(dppf)₂Cl₂), in the presence of a base (e.g., cesium carbonate), and a combination of an aprotic solvent and water, at elevated temperatures. The product thus obtained can be used as intermediate A or can be further processed by modification of functional groups as set forth in this application. For example, such functional group modification may include converting an acid to an amide or replacing bromine with various alkyl and amide groups and the like. In some embodiments, the functional group is an acid or ester that is subsequently converted to an amide.

[0224] Scheme 2C. Synthesis of intermediate A4

[0225]

[0226] Intermediates A3-A4 containing the pyrazole moiety can be synthesized by, for example, a variety of methods well known in the art. An illustrative synthesis involves the use of an aliphatic acid. For example, the aliphatic acid is converted to an aldehyde or Weinreb amide by procedures well known in the art, and then reacted with a suitably substituted 3-halopyridine or 5-halopyrimidine (where X is a halogen group, scheme 2C) by ortho-lithiation (see, for example, Tetrahedron, Vol. 39, 1983, 2009-2021). The aryl ketone thus obtained is then condensed with a suitably substituted phenylhydrazine to give the desired intermediate A3. Further modification by processing the functional groups of the phenylhydrazine yields intermediate A4.

[0227] Another exemplary method involves converting an aliphatic acid to a Weinleber amide by reacting a suitably substituted acid with an N-methyl-O-methylhydroxylamine in one or more aprotic solvents in the presence of an organic base under coupling conditions (e.g., with HATU). The chloropyrimidine or pyridine can then be lithium-ionized in an aprotic solvent (e.g., THF or diethyl ether) (e.g., at low temperature with lithium diisopropylamino), followed by reaction with the Weinleber amide to give the desired aryl ketone. The aryl ketone is then condensed with a suitably substituted phenylhydrazine to give the indazole intermediate A3. This reaction can be carried out, for example, at elevated temperatures in one or more aprotic solvents (e.g., DMF) or protic solvents (e.g., alcoholic solvents, such as ethanol and the like) in the presence of an inorganic base (e.g., potassium carbonate). In some embodiments, the phenylhydrazine is a suitably substituted 2-hydrazinobenzoic acid, which can be further modified as described in this application to incorporate various functional groups. Another embodiment involves converting the acid to an amide.

[0228] Scheme 3. Synthesis of Compound I

[0229]

[0230] The final compound (e.g., a compound of formula I or a pharmaceutically acceptable salt thereof) can be synthesized from intermediate A by further modification of ring A, as shown in Scheme 3, wherein the protecting group (Pg) is attached to a nitrogen atom of ring A or a nitrogen atom of a functional group attached to ring A, which can be prepared as described in this application. Removal of the protecting group (Pg) is well known in the literature, and protecting groups for amines, alcohols, ketones, etc., are well described in Greene and Wuts, Protective Groups in Organic Chemistry, 2nd ed., John Wiley & Sons 1991. Functional groups can be, for example, acids, alcohols, amines, ketones, and the like. Exemplary functional groups include (but are not limited to) amines, alcohols, and ketones that are appropriately protected during the synthesis of intermediate A. An exemplary protecting group for amines is a tert-butoxycarbonyl. An exemplary protecting group for ketones is a ketal. For amines, after removing the protecting group, the free amine (i.e., the unprotected amino group) can be reacted with an acylating agent (e.g., acyl chlorides, sulfonyl chlorides, isocyanates, and the like) or arylized using procedures well known in the art, such as aryl halides, borate esters, or diazonium salts. The free amine can also be reacted with aldehydes and ketones under reducing amination conditions. Exemplary methods involve the reaction of aldehydes and amines in protic or aprotic solvents under reducing amination conditions (e.g., reaction with sodium cyanoborohydride at room temperature or elevated temperatures).

[0231] Scheme 3A. Synthesis of Compound I

[0232]

[0233] In some embodiments, the protecting group is a carbon protecting group (Scheme 3A). For example, in some embodiments, Pg is a ketone protecting group (e.g., a ketal, alcohol, or acid, and the like). As set forth in this application, these functional groups can be further transformed into various other functional groups, and other modifications to the skeleton can be implemented through various synthetic transformations. These reactions are as set forth in this application and are well known and widely described in the literature, for example, in March, Advanced Organic Chemistry, 3rd Edition, John Wiley & Sons.

[0234] Exemplary reactions involving the protecting groups of Pg-based ketones involve reductive amination with an amine in a solvent (e.g., proton or aproton) in the presence of a reducing agent, and can be carried out under a variety of conditions (ranging from low temperatures to solvent reflux). Another illustrative method involves the reaction of an amine with a ketone in an alcoholic solvent in the presence of a reducing agent (e.g., sodium cyanoborohydride). The product obtained from such reductive amination can be further processed to yield the final compound of formula I or a pharmaceutically acceptable salt thereof, as set forth in this application.

[0235] In some embodiments, one or more intermediates shown in Scheme 3 may be the final desired product (e.g., a compound of Formula I or a pharmaceutically acceptable salt thereof) and may not require any further modification.

[0236] How to use

[0237] The compounds of this invention are inhibitors of the interaction between menin and MLL or MLL fusion proteins. In some embodiments, this invention relates to a method for inhibiting the interaction between menin and MLL or MLL fusion proteins by contacting menin and MLL or MLL fusion proteins with the compounds of this invention. This contact can be performed in vitro or in vivo. In some embodiments, the compounds of this invention can bind to menin, thereby interfering with the binding of MLL to menin. In some embodiments, this invention provides a method for inhibiting the activity of menin by contacting menin with the compounds of this invention in the presence of MLL or MLL fusion proteins. In other embodiments, this invention provides a method for inhibiting the binding of MLL or MLL fusion proteins to menin, which includes contacting menin with the compounds of this invention in the presence of MLL or MLL fusion proteins.

[0238] The compounds of this invention can also be used to treat diseases associated with menin-MLL interactions or menin-MLL fusion protein interactions. For example, diseases and conditions that can be treated according to the methods of this invention include cancer (e.g., leukemia) and other diseases or conditions mediated by menin-MLL interactions or menin-MLL fusion protein interactions (e.g., diabetes).

[0239] Therefore, the compounds of the present invention are believed to be effective against a wide range of cancers, including (but not limited to) hematologic malignancies (e.g., leukemia and lymphoma), bladder cancer, brain cancers (e.g., glioma, diffuse endogenous pontine glioma (DIPG)), breast cancers (e.g., triple-negative breast cancer, estrogen receptor-positive breast cancer (i.e., ER+ breast cancer)), colorectal cancer, cervical cancer, gastrointestinal cancers (e.g., colorectal cancer, stomach cancer), genitourinary cancers, head and neck cancer, liver cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer (e.g., castration-resistant prostate cancer), kidney cancer (e.g., renal cell carcinoma), skin cancer, thyroid cancer (e.g., papillary thyroid carcinoma), testicular cancer, sarcomas (e.g., Ewing's sarcoma), and AIDS-related cancers. In some embodiments, the cancer is associated with rearranged MLL genes. In some embodiments, the pathophysiology of the cancer depends on the MLL gene. In some embodiments, the cancer is associated with gain-of-function mutations in p53.

[0240] In some embodiments, specific cancers that can be treated by the compounds, compositions, and methods set forth in this application include gastric cardia cancer, such as sarcomas (e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; lung cancer, including (e.g.) bronchial cancer (e.g., squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, and adenocarcinoma), alveolar and bronchiolar carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, non-small cell lung cancer, small cell lung cancer, bronchial adenoma / carcinoid, and pleural pulmonary blastoma; and gastrointestinal cancers, including (e.g.) esophageal cancer (e.g., squamous cell carcinoma, adenocarcinoma, and esophageal cancer). Leiomyoma and lymphoma), gastric cancers (e.g., carcinoma, lymphoma, and leiomyosarcoma), pancreatic cancers (e.g., ductal adenocarcinoma, insulinoma, glucocorticoidoma, gastrinoma, carcinoidoma, and vasoactive intestinal peptide tumor), small intestinal cancers (e.g., adenocarcinoma, lymphoma, carcinoidoma, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, and fibroma), large or colon cancers (e.g., adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, and leiomyoma) and other digestive tract cancers (e.g., anal cancer, rectal and anal canal cancer, appendix cancer, anal canal cancer, tongue cancer, gallbladder cancer, gastrointestinal stromal tumor (GIST), colon cancer, colorectal cancer, extrahepatic bile duct cancer, etc.). Intrahepatic bile duct cancer, rectal cancer, and small bowel cancer; urogenital tract cancers, including (e.g.) kidney cancers (e.g., adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, and leukemia), bladder and urethral cancers (e.g., squamous cell carcinoma, transitional cell carcinoma, and adenocarcinoma), prostate cancers (e.g., adenocarcinoma and sarcoma), testicular cancers (e.g., seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoidoma, and lipoma), as well as transitional cell carcinoma, transitional cell carcinoma of the renal pelvis and ureter and other urinary organs, urethral cancer, and urobladder cancer; liver cancers, including (e.g., hepatocellular carcinoma, biliary tract cancer, etc.). Carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma; bone cancer, including (e.g.) osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondrogenic exostosis), benign chondroma, chondrocyte-derived tumor, chondromycinoid fibroma, osteoid osteoma, and giant cell tumor; cancers of the nervous system, including (e.g.) skull cancers (e.g., osteoma, hemangioma, granuloma, xanthoma, and osteitis deformans); meningeal cancers (e.g., meningioma, meningiosarcoma, and gliomatosis);Brain cancers (e.g., astrocytoma, neuroblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, and congenital tumors); spinal cord cancers (e.g., neurofibroma, meningioma, glioma, and sarcoma); and other nervous system cancers (e.g., brainstem glioma, diffuse endogenous pontine glioma (DIPG), brain tumors, central nervous system cancers, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, pediatric cerebellar astrocytoma, pediatric cerebral astrocytoma, primary central nervous system lymphoma, visual pathway and hypothalamic glioma, nervous system lymphoma, supratentorial primitive neuroectodermal tumor). Neuroectodermal tumors, pineal blastomas, and supratentorial primitive neuroectodermal tumors; gynecological cancers, including (e.g.) uterine cancers (e.g., endometrial cancer), cervical cancers (e.g., cervical cancer and pretumoral cervical dysplasia), ovarian cancers (e.g., ovarian cancer, including serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa cystic cell tumors, Sertoli Leydig cell tumors). Cancers of the vulva (e.g., squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, and melanoma), vaginal cancers (e.g., clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma, and embryonal rhabdomyosarcoma), and fallopian tube cancers (e.g., carcinomas); other reproductive tract cancers, including (e.g.) endometrial cancer, endometrial uterine cancer, germ cell tumors, gestational trophoblastic tumors, gliomas, ovarian epithelial cancer, ovarian germ cell tumors, low-grade malignant potential ovarian tumors, penile cancer, vaginal cancer, vulvar cancer, extracranial germ cell tumors, gonadal germ cell tumors, uterine cancer, endometrial cancer, and uterine sarcoma; lymphatic and hematologic cancers, including (e.g., hematologic cancers such as acute myeloid leukemia (AML), chronic ... The following are considered cancers: CML, acute lymphoblastic leukemia (ALL), chronic lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma and myelodysplastic syndromes, Hodgkin's lymphoma, non-Hodgkin's lymphoma (malignant lymphoma) and Waldenstrom's macroglobulinemia, and other lymphoid or blood cancers, including (e.g.) childhood leukemia, myeloproliferative disorders (e.g., primary myelofibrosis), plasma cell vegetations / multiple myeloma, spinal dysplasia, myelodysplastic syndromes, cutaneous T-cell lymphoma, lymphocysts, AIDS-related lymphomas, thymoma, thymoma and thymic carcinoma, mycosis fungoides and Sézary syndrome;Skin cancers, including (e.g.) malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipomas, hemangiomas, dermatofibromas, keloids, psoriasis, Merkel cell carcinoma, Merkel cell skin carcinoma, melanoma, and carcinoid tumors; adrenal cancers, including (e.g.) neuroblastoma; other cancers associated with the endocrine system, including (e.g.) adrenocortical carcinoma, multiple endocrine neoplasia (e.g., type I multiple endocrine neoplasia), multiple endocrine neoplasia syndrome, parathyroid carcinoma, pituitary tumors, and pheochromocytoma. Chromocytoma, pancreatic islet cell carcinoma, and islet cell tumors; connective tissue cancers (e.g., bone cancer, bone and joint cancer, osteosarcoma, and malignant fibrous histiocytoma); cancers associated with the head, neck, and mouth (e.g., head and neck cancer, paranasal sinus and nasal cavity cancer, metastatic squamous neck cancer, oral cancer, laryngeal cancer, esophageal cancer, laryngeal cancer, pharyngeal cancer, hypopharyngeal cancer, lip and oral cavity cancer, nasopharyngeal cancer, oral cavity cancer, oropharyngeal cancer, and salivary gland cancer); and cancers associated with the eye (e.g., eye cancer, intraocular melanoma). In some embodiments, the cancer is Ewing's sarcoma.

[0241] In some embodiments, the cancer is a blood cancer, such as leukemia or lymphoma. Examples of leukemias and lymphomas that can be treated with the compounds of the present invention include mixed lineage leukemia (MLL), MLL-associated leukemia, MLL-related leukemia, MLL-positive leukemia, MLL-induced leukemia, rearranged mixed lineage leukemia (MLL-r), leukemia associated with MLL rearrangements or MLL gene rearrangements, acute leukemia, chronic leukemia, painless leukemia, lymphoblastic leukemia, lymphocytic leukemia, myeloid leukemia, bone marrow leukemia, childhood leukemia, acute lymphoblastic leukemia (ALL) (also known as acute lymphoblastic leukemia or acute lymphoblastic leukemia), acute myeloid leukemia (AML) (also known as acute bone marrow leukemia or acute myeloblastic leukemia), acute granulocytic leukemia, acute non-lymphocytic leukemia, and chronic lymphocytic leukemia (CLL). (Also known as chronic lymphoblastic leukemia, chronic myeloid leukemia (CML)) (Also known as chronic myeloid leukemia), therapy-related leukemia, myelodyplastic syndrome (MDS), myeloproliferative disorders (MPD) (e.g., primary myelofibrosis (PMF)), myeloproliferative neoplasm (MPN), plasma cell vegetations, multiple myeloma, spinal dysplasia, cutaneous T-cell lymphoma, lymphoproliferative disease, AIDS-related lymphoma, thymoma, thymoma and thymic carcinoma, mycosis fungoides, Alibert-Bazin syndrome, mycosis fungoides, Cezari syndrome, hairy cell leukemia, T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, meningeal leukemia, leukemic meningitis, leukemic meningitis, multiple myeloma, Hodgkin's lymphoma, non-Hodgkin's lymphoma (malignant lymphoma), and Waldenström macroglobulinemia. In some implementations, acute myeloid leukemia (AML) is a major nucleolar phosphoprotein (NPM1)-mutant acute myeloid leukemia (i.e., NPM1-mutant). mut Acute myeloid leukemia.

[0242] In specific embodiments, the compounds of the present invention are used to treat leukemia associated with MLL rearrangement, acute lymphoblastic leukemia associated with MLL rearrangement, acute lymphoblastic leukemia associated with MLL rearrangement, acute lymphoblastic leukemia associated with MLL rearrangement, acute myeloid leukemia associated with MLL rearrangement, or acute myeloid leukemia associated with MLL rearrangement. As used herein, "MLL rearrangement" means rearrangement of the MLL gene.

[0243] In some embodiments, diseases and conditions treatable with the compounds of the present invention include insulin resistance, prediabetes, diabetes (e.g., type 2 or type 1 diabetes), and diabetes risk. In some embodiments, diseases and conditions treatable with the compounds of the present invention include hyperglycemia. In some embodiments, hyperglycemia is associated with diabetes (e.g., type 2 diabetes). In some embodiments, the compounds of the present invention are used to treat loss of response and / or reduced β-cell function in patients or individuals to other antidiabetic agents. In some embodiments, the compounds of the present invention are used to restore response to other antidiabetic agents and / or restore β-cell function and / or reduce insulin requirements in patients or individuals. In some embodiments, the compounds of the present invention are used to reduce insulin resistance, reduce diabetes risk, or reduce statin-induced increases in blood glucose in individuals taking statins. In some embodiments, the compounds of the present invention are used to treat diabetes in individuals taking statins or to prevent diabetes in individuals taking statins. The methods of the present invention include reducing, lowering, inhibiting, suppressing, limiting, or controlling elevated blood glucose levels in a patient. In other aspects, the methods of the present invention include increasing, stimulating, enhancing, promoting, inducing, or activating an individual's insulin sensitivity. Statins include (but are not limited to) atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rousuvastatin, and simvastatin.

[0244] In some embodiments, the compounds of the present invention are used to treat (e.g., administer) a patient in an amount sufficient to treat or improve one or more of the diseases and symptoms listed above (e.g., a therapeutically effective amount). The compounds of the present invention can also be used to prevent one or more of the diseases listed in this application.

[0245] Combination therapy

[0246] This invention further relates to combination therapies for treating the diseases or conditions described in this application. In some embodiments, the combination therapy comprises administering at least one compound of the present invention in combination with one or more other pharmaceutically active agents to treat cancer or other conditions mediated by menin / MLL. In some embodiments, the combination therapy comprises administering at least one compound of the present invention in combination with one or more other pharmaceutically active agents to, for example, treat cancer. The pharmaceutically active agents may be combined with a single dosage form of the compounds of the present invention, or these therapeutic agents may be administered simultaneously or sequentially as individual dosage forms.

[0247] The compounds of the present invention can also be used in combination with immunotherapies to treat the diseases or conditions disclosed in this application, including (but not limited to) cell-based therapies, antibody therapies, and intercellular therapy.

[0248] In some embodiments, the compounds of the present invention are used in combination with one or more passive immunotherapies, including (but not limited to) naked monoclonal antibody drugs and monoclonal antibody conjugates. Examples of naked monoclonal antibody drugs that may be used include (but are not limited to) rituximab. ® Antibodies against the CD20 antigen; trastuzumab (Herceptin) ® Antibodies targeting the HER2 protein; alemtuzumab (Lemtrada) ® Campath ® Antibodies targeting the CD52 antigen; cetuximab (Erbitux) ® Antibodies targeting the EGFR protein; and bevacizumab (Avastin). ® It is an anti-angiogenic inhibitor of VEGF protein.

[0249] Examples of usable conjugated monoclonal antibodies include (but are not limited to) the radiolabeled antibody ibritumomab tiuxetan (Zevalin). ® Radiolabeled antibody tositumomab (Bexxar) ® ); and the immunotoxin gemtuzumab ozogamicin (Mylotarg) ® It contains calicheamicin; BL22, an anti-CD22 monoclonal antibody-immunotoxin conjugate; and radiolabeled antibodies, such as OncoScint. ® and ProstaScint ® Brentuximab vedotin (Adcetris) ® ); ado-trastuzumab emtansine (Kadcyla) ® Also known as TDM-1).

[0250] Other examples of usable therapeutic antibodies include (but are not limited to) REOPRO. ®(abciximab), an antibody targeting platelet glycoprotein IIb / IIIa receptors; ZENAPAX ® (Daclizumab), an immunosuppressive humanized anti-CD25 monoclonal antibody; PANOREX™, a murine anti-17-IA cell surface antigen IgG2a antibody; BEC2, a murine anti-individual genotype (GD3 epitope) IgG antibody; IMC-C225, a chimeric anti-EGFR IgG antibody; VITAXIN™, a humanized anti-αVβ3 integrin antibody; Camppath 1H / LDP-03, a humanized anti-CD52 IgG1 antibody; Smart M195, a humanized anti-CD33 IgG antibody; LYMPHOCIDE™, a humanized anti-CD22 IgG antibody; LYMPHOCIDE™ Y-90; Lymphoscan; Nuvion ® Targets include: CD3; CM3, humanized anti-ICAM3 antibody; IDEC-114, primate-derived anti-CD80 antibody; IDEC-131, humanized anti-CD40L antibody; IDEC-151, primate-derived anti-CD4 antibody; IDEC-152, primate-derived anti-CD23 antibody; SMART anti-CD3, humanized anti-CD3 IgG; 5G1.1, humanized anti-complement factor 5 (C5) antibody; D2E7, humanized anti-TNF-α antibody; CDP870, humanized anti-TNF-α Fab fragment; IDEC-151, primate-derived anti-CD4 IgG1 antibody; MDX-CD4, humanized anti-CD4 IgG antibody; CD20-streptavidin (+biotin-yttrium 90); CDP571, humanized anti-TNF-α IgG4 antibody; LDP-02, humanized anti-α4β7 antibody; OrthoClone OKT4A, humanized anti-CD4... IgG antibody; ANTOVA™, humanized anti-CD40L IgG antibody; ANTEGREN™, humanized anti-VLA-4 IgG antibody; and CAT-152, human anti-TGF-β2 antibody.

[0251] In some embodiments, the compounds of the present invention are used in combination with one or more targeted immunotherapies containing toxins but not antibodies, including (but not limited to) denileukin diftitox (Ontak). ® ), which is linked to diphtheria toxin IL-2.

[0252] The compounds of this invention can also be used in combination with adjuvant immunotherapies to treat the diseases or conditions disclosed in this application. These adjuvant immunotherapies include (but are not limited to) interleukins, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte-macrophage colony-stimulating factor (G-CSF), macrophage inflammatory protein (MIP)-1-α, interleukins (including IL-1, IL-2, IL-4, IL-6, IL-7, IL-12, IL-15, IL-18, IL-21, and IL-27), tumor necrosis factor (including TNF-α), and interferons (including IFN-α, IFN-β, and IFN-γ); aluminum hydroxide; Bacille Calmette-Guérin (BCG); keyhole limpet hemocyanin (KLH); and incomplete Freund's adjuvant. adjuvant (IFA); QS-21; DETOX; levamisole; and dinitrofluorophenyl (DNP) and combinations thereof, such as interleukins (e.g., IL-2) combined with other interleukins (e.g., IFN-α).

[0253] In some embodiments, the compounds of the present invention are used in combination with vaccine therapies, including (but not limited to) autologous and allogeneic tumor cell vaccines, antigen vaccines (including multivalent antigen vaccines), dendritic cell vaccines, and viral vaccines.

[0254] In another embodiment, the invention comprises administering to an individual with cancer an effective amount of the compound of the invention and one or more other anticancer therapies selected from: surgery, anticancer agents / drugs, biotherapy, radiation therapy, anti-angiogenic therapy, immunotherapy, adoptive transfer of effector cells, gene therapy, or hormone therapy. Examples of anticancer agents / drugs are described below.

[0255] In some implementation schemes, the anticancer agents / drugs are, for example, adriamycin, aactinomycin, bleomycin, vinblastine, cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; hexamethylmelamine; ambomycin; and ametatantrone acetate. acetate); aminoglutethimide; amsacrine; anastrozole; antramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequina sodium. sodium); bropirimine; busulfan; actinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carrubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; cristatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride;Droloxifen; Droloxifen Citrate; Drolmostanolone Propionate; Duazomycin; Edatrexate; Eflornithine Hydrochloride; Elsamitrucin; Enloplatin; Enpromate; Epipropidine; Epirubicin Hydrochloride; Erbulozole; Esorubicin Hydrochloride; Estramustine; Estramide Sodium; Etanidazole; Etoposide; Etoposide Phosphate; Etoprine; Fadrozole Hydrochloride hydrochloride; fazarabine; fenretinide; fluxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol Sodium); Lomustine; Loxantrone Hydrochloride; Masoprocol; Maytansine; Nitrogen Mustard Hydrochloride; Medroxyprogesterone Acetate; Melengestrol Acetate; Melphalan; Menogaril; Mercaptopurine; Metoprine; Metoprine Sodium; Metoprine;Meturedepa; Mitindomide; Mitocarcin; Mitocoromin; Mitogillin; Mitomalcin; Mitomycin; Mitosper; Mitotane; Mitoxantrone hydrochloride; Mycophenolic acid (acid); Nocodazole; Nogalamycin; Ormaplatin; Oxisuran; Pegaspargase; Peliomycin; Pentazine; Peplomycin sulfate; Perfosfamide; Pipobroman; Piposulfan; Piroxantrone hydrochloride; plicamycin; Plomestane; Porfimer sodium; Porfiromycin; Prednimustine; Procarbazine hydrochloride hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride hydrochloride; temoporfin; teniposide; teroxirone;Testolactone; Thiamipridine; Thiotepa; Tiazofurin; Tirapazamine; Toremifene Citrate; Tristolon Acetate; Triciribine Phosphate; Trimetrexate; Trimetrexate Glucuronate; Triptorelin; Tubulozole Hydrochloride; Uracil Mustard; Uredepa; Vapreotide; Verteporfin; Vincristine Sulfate; Vindesine Sulfate; Vinpidine Sulfate; Vincrylic Acid Sulfate sulfate); vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride; palbociclib; Yervoy; ® (ipilimumab); Mekinist TM (trametinib); pegylated interferon α-2b, recombinant interferon α-2b; Sylatron TM (Pegylated interferon α-2b); Tafinlar ® (dabrafenib); Zelboraf ® (Vemurafenib); or nivolumab.

[0256] The compounds of the present invention can be administered in combination with existing methods to treat cancer, such as by chemotherapy, irradiation, or surgery. Therefore, the present invention further provides a method for treating cancer comprising administering to an individual requiring the treatment an effective amount of the compound of the present invention or a pharmaceutically acceptable salt form thereof, wherein an effective amount of at least one other cancer chemotherapeutic agent is administered to the individual. Examples of suitable cancer chemotherapy agents include any of the following: abarrelix, adorantrolizumab (Aitansin), interleukin, alenzusumab, atrazonoin, allopurinol, hexamethylmelamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, bleomycin, bortezombi, bortezomib, busulfan (intravenous), busulfan (oral), calutidone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, actinomycin, and dalteparin. sodium, dasatinib, daunorubicin, decitabine, denileukin, interleukin, dexrazoxane, docetaxel, doxorubicin, drotahistamine propionate, eculizumab, estradiol, epirubicin, eribulin, erlotinib, estradiol mustard, etoposide phosphate, etoposide, everolimus, exemestane, fentanyl citrate, filgrastim, fluorouracil, fludarabine, fluorouracil, fruquintinib, fulvestrant, gefitinib, gemcitabine, gesuzumab ozomicin, goserelin acetate Acetate), histamine relin acetate, tiimomab, idarubicin, ifosfamide, imatinib mesylate, interferon alpha-2a, irinotecan, ixabepilone, lapatinib dimethylbenzenesulfonateditosylate), lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, nitrogen mustard, medroxyprogesterone acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin, paclitaxel, paclitaxel albumin-stabilized nanoparticle formulation, pamidronate, panitumumab, pegaspargase, polyethylene glycol filgrastim, pemetrexed disodium Disodium, pentostatin, pertuzumab, piperobromidine, procainamide, procarbazine, quinacrine, rasburicase, rituximab, sorafenib, streptozotocin, sulfatinib, sunitinib, sunitinib maleate, tamoxifen, temozolomide lomide, teniposide, testrolide, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tosimomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vincristine, vinorelbine, volitinib, vorinostat, and zoledronate.

[0257] In specific embodiments, the compounds of the present invention are used in combination with one or more anticancer agents selected from the following to treat breast cancer: methotrexate, paclitaxel albumin-stabilized nanoparticle formulation, adorantrolactam (trastuzumab), azibuvir, doxorubicin, fluorouracil, everolimus, anastrozole, pamidronate disodium, exemestane, capecitabine, cyclophosphamide, docetaxel, epirubicin, toremifene, fulvestrant, letrozole, gemcitabine, gemcitabine hydrochloride, goserelin acetate, trastuzumab, ixaprone, lapatinib xylenesulfonic acid, megestrol acetate, tamoxifen citrate, pamidronate disodium, palbociclib, and pertuzumab.

[0258] Other anticancer agents / drugs include (but are not limited to): 20-epi-1,25-dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; arubicin; acylfulvene; adenypenol; adorexin; interleukin; ALL-TK antagonists; hexamethylmelamine; ambamustine; amidox; aifostine; aminolevulinic acid; amrubicin; acridine; anagrelide; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenesis protein-1 (anti-dorsalizing morphogenesis protein-1). Morphogenetic protein-1; anti-androgen; anti-estrogen; anti-tumor ketone (antineoplaston); antisense oligonucleotide; aphidicolin glycinate; apoptosis gene regulator; apoptosis regulator; purine-free nucleic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1); Marine cyclic peptide 2; Marine cyclic peptide 3; Azasetron; Azatoxin; Diazotyrosine; Gibberellin III derivative; Balanol; Palmastat; BCR / ABL antagonist; Benzochlorins; Benzoyl astrosarcine; β-lactam derivative; β-alethine; Beta-aclamycin B; Betulinic acid; bFGF inhibitor; Bicalutamide; Bismuthrin; Diaziridinylspermethrin; Difenofad; Bistratene A; Bismuthrin; Breflate; Brompilide; Budotitan; Butylthionine sulfoxide; Calcipotriol; Calphostin C C); Camptothecin derivatives; Canarypox IL-2; Capecitabine; Formamide-amino-triazole; Carboxyamine-triazole; CaRest M3; CARN 700; Chondroitin inhibitors; Cazelexin; Casein kinase inhibitors; Castanospermine; Cecropin B;Cetrorelix; chlorins; chloroquine sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogs; clotrimazole; collismycin A; collismycin B; compretastatin A4; compretastatin analogs; conagenin; crabescidin 816; cristatin; cryptophycin 8; cryptophycin A derivatives; curacin A A); Cyclin-dependent kinase inhibitors; Cyclopentaquinone; Cycloplatam; Cypemycin; Cytarabineocfosfate; Cytolysin; Hexestrol phosphate; Dacliximab; Decitabine; Dehydrodidemnin B; Deslorelin; Dexamethasone; Dextromethorphan; Dextrozosin; Dextromethorphan; Dextromethorphan; Dextromethorphan; Dextromethorphan B); didox; diethylnorsemine; dihydro-5-azacytidine; 9-dioxamycin; diphenylspiromostin; docosyl alcohol; dolasetron; doxifluridine; dronabinol; duocarmycin SA SA); ebselen; ecomustine; edelfosine; edrecolomab; fluoroornithine; elemene; emitefur; epirubicin; epristeride; estradiol analog; estrogen agonist; estrogen antagonist; estanidazole; etoposide phosphate; faldazole; fazarabine; fenivel-Amin; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane;Fostracin; Formustine; Gadolinium texaphyrin; Gallium nitrate; Galocitabine; Ganirelix; Gelatinase inhibitor; Gemcitabine; Glutathione inhibitor; Hepsulfam; Heregulin; Hexamethylene diacetamide; Hypericin; Ibandronic acid; Idarubicin; Idoxifene; Idramantone; Emofocin; Ilomastat; Imidazotropin; Imiquimod; Immunostimulatory peptides; Insulin-like growth factor 1 receptor inhibitors; Iobenguane; Iododoxorubicin; 4-Ipomosanol 4-); Iroplact; Irsogladine; Isobengazole; Ishomohalicondrin B; Itasetron; Jasplakinolide; Kahalalide F; Lamellarin-N triacetate; Lanreitide; Leinamycin; Lenograstim; Lentinan sulfate; Leptolstatin; Letrozole; Leukemia inhibitory factor; Leuprorelin + Estrogen + Progesterone; Leuprorelin; Levamisole; Riazol; Linear polyamine analog; Lipophilic disaccharide; Lipophilic platinum compound; Lissoclinamide 7 7); Lobaplatin; Lombricine; Lometroxo; Lonidamine; Loxoanthraquinone; Lovastatin; Loxoribine; Lurtotecan; Lutetium texaphyrin; Lysofylline; Lysozyme; Maitansine; Mannostatin A; Marimastat; Masoprolol; Maspin; Matrix cleavage protein inhibitor; Matrix metalloproteinase inhibitor; Menoliline; Merbarone; Meterelin;Methioninase; Metoclopramide; MIF inhibitors; Mifepristone; Miltefosine; Mirimostim; Mismatched double-stranded RNA; Mitoguazone; Mitolactalol; Mitomycin analogs; Mitonafide; Mitotoxin; Fibroblast growth factor-Saporin; Mitoxantrone; Mofarotene; Molgramostim; Monoclonal antibodies; Human chorionic gonadotropin; Monophospholipid A+ Mycobacterium cell wall SK; Mopidamol; Multidrug resistance gene inhibitors; Therapies based on multiple tumor suppressors; Mustard anticancer agents; Indian Ocean sponge B (mycaperoxide) B); Mycobacterium cell wall extract; Myriaporone; N-acetyldinaline; N-substituted benzamide; Nafarelin; Nagrestip; Naloxone + Pentazocine; Napavin; Naphterpin; Nartograstim; Nedaplatin; Nemorubicin; Neridronic acid acid); neutral peptide chain endopeptidase; nilutamide; nisamycin; nitric oxide regulator; nitric oxide antioxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotide; onapristone; ondansetron; ondansetron; oracin; oral interferon inducer; omaliplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid acid); panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; sodium pentosan polysulfide; pentostatin;Pentrozole; perflubron; pephosphatidyl alcohol; perillyl alcohol; phenazinomycin; phenyl acetate; phosphatase inhibitor; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; Pastine A Placetin A; Placetin B; Plasminogen activator inhibitor; Platinum complex; Platinum compound; Platinum-triamine complex; Porphyrin sodium; Pofibromycin; Prednisone; Propylbisacridone; Prostaglandin J2; Proteosome enzyme inhibitor; Protein A-based immunomodulator; Protein kinase C inhibitor; Microalgae; Protein tyrosine phosphatase inhibitor; Purine nucleoside phosphorylase inhibitor; Red pigment; Pyrazoline acridine; Pyridoxylated heme polyoxyethylene conjugate; RAF antagonist; Raltitrexed; Ramosetron; RAS farnesyl protein transferase inhibitor; RAS inhibitor; RAS-GAP inhibitor; Demethylated retelliptine; Rhenium Re186 (etidroxyphenate Re186) etidronate; rhizobium; ribonuclease; RII retinamide; roguimine; rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimic; semustine; aging-derived inhibitors; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single-stranded antigen-binding proteins; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; interleukin-binding proteins; sonermin; sparfosic acid acid); Spicamycin D; Spiromustin; Splenopentin; Spongistatin 1;Squalamine; stem cell inhibitor; stem cell division inhibitor; stipiamide; matrix lysin inhibitor; sulfinosine; potent vasoactive intestinal peptide antagonist; sulfadiazine; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen iodide; tauromustine; tazarotene; tecogallan sodium; fenfluridine Tellurapyrylium; Telomerase inhibitor; Temoporphen; Temozolomide; Teniposide; Tetrachlorodecaoxide; Tetrazomine; Thaliblastine; Thiocoraline; Thrombopoietin; Thrombopoietin mimic; Thymalfasin; Thymopoietin receptor agonist; Thymotrinan; Thyroid-stimulating hormone; Tinethyl etiopurpurin; terazamine; dicarboxylated titanium dioxide; topsentin; toremifene; pluripotent stem cell factor; translation inhibitor; retinoic acid; triacetyluridine; tricerebroside; trimethotriazine; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitor; tyrphostin; UBC inhibitor; ubenimex; urogenital sinus-derived growth inhibitor; urokinase receptor antagonist; vapeptide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdin; verteporfin; vinorelbine; vinxaltine; integrin antagonist; zanoterone; subbenzylidene vitamin C (zilascorb); zinostatin stimalamer; 5-fluorouracil; and roxithromycin.

[0259] In some implementations, the anticancer agent / drug is a microtubule-stabilizing agent. As used herein, "microtubule stabilizer" means an anticancer agent / drug that prevents G2-M phase cells from functioning due to microtubule stabilization. Examples of microtubule stabilizers include ACLITAXEL. ® and Taxol ®Analogs. Other examples of microtubule stabilizers include (but are not limited to) the following marketed and investigational drugs: Discodermolide (also known as NVP-XX-A-296); Epothilone (e.g., Epothilone A, Epothilone B, Epothilone C (also known as deoxyepothilone A or dEpoA); Epothilone D (also known as KOS-862, dEpoB, and deoxyepothilone B); Epothilone E; Epothilone F; Epothilone B N-oxide; Epothilone A N-oxide; 16-aza-epothilone B; 21-aminoepothilone B (also known as BMS-310705); 21-hydroxyepothilone D (also known as deoxyepothilone F and dEpoF), 26-fluoroepothilone); FR-182877 (Fujisawa, also known as WS-9885B), BSF-223651 (BASF, also known as ILX-651 and LU-223651); AC-7739 (Ajinomoto, also known as AVE-8063A and CS-39.HCl); AC-7700 (Ajinomoto, also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCl and RPR-258062A); Fijianolide B; Laulimalide; Caribaeolin; Taccalonolide; Eleutherobin; Sarcodictyin; Laulimalide; Dictyostatin-1; Jatrophane ester; and their analogues and derivatives.

[0260] In another embodiment, the anticancer agent / drug is a microtubule inhibitor. As used in this application, "tubulin inhibitor" means an anticancer agent that works by inhibiting tubulin polymerization or microtubule assembly. Examples of microtubule inhibitors include (but are not limited to) the following marketed and investigational drugs: irbuprozil (also known as R-55104); dolastatin 10 (also known as DLS-10 and NSC-376128); mivobulin isethionate (also known as CI-980); vincristine; NSC-639829; ABT-751 (Abbott, also known as E-7010); altorhyrtin (e.g., altorhyrtin A and altorhyrtin C); spongistatin (e.g., spongistatin 1, spongistatin 2, spongistatin 3, spongistatin 4, spongistatin 5, spongistatin 6, spongistatin 7, spongistatin 8 and spongistatin 9); cimadodine hydrochloride (Cemadotin). hydrochloride, also known as LU-103793 and NSC-D-669356; Auristatin PE (also known as NSC-654663); Soblidotin (also known as TZT-1027), LS-4559-P (Pharmacia, also known as LS-4577); LS-4578 (Pharmacia, also known as LS-477-P); LS-4477 (Pharmacia), LS-4559 (Pharmacia); RPR-112378 (Aventis); vincristine sulfate; DZ-3358 (Daiichi); GS-164 (Takeda); GS-198 (Takeda); KAR-2 (Hungarian Academy of Sciences); SAH-49960 (Lilly / Novartis); SDZ-268970 (Lilly / Novartis); AM-97 (Armad / Kyowa Hakko); AM-132 (Armad); AM-138 (Armad / KyowaHakko); IDN-5005 (Indena); Kritefixin 52 (also known as LY-355703); Vitilevuamide; Tubulysin A; Canadensol; Centaureidin (also known as NSC-106969); T-138067 (Tularik (also known as T-67, TL-138067 and TI-138067));COBRA-1 (Parker Hughes Institute, also known as DDE-261 and WHI-261); H10 (Kansas State University); H16 (Kansas State University); Oncocidin A1 (also known as BTO-956 and DIME); DDE-313 (Parker Hughes Institute); SPA-2 (Parker Hughes Institute); SPA-1 (Parker Hughes Institute, also known as SPIKET-P); 3-IAABU (Cytoskeleton / Mt. Sinai School of Medicine, also known as MF-569); Narcosine (also known as NSC-5366); Nascapine, D-24851 (Asta Medica), A-105972 (Abbott); Hemiasterlin; 3-BAABU (Cytoskeleton / Mt. Sinai School of Medicine (also known as MF-191); TMPN (Arizona State University); Vanadoceneacetylacetonate; T-138026 (Tularik); Monsatrol; Inanocine (also known as NSC-698666); 3-IAABE (Cytoskeleton / Mt. Sinai School of Medicine); A-204197 (Abbott); T-607 (Tularik, also known as T-900607); RPR-115781 (Aventis); Iridoxine (e.g., demethylideneideneidene, deacetyneideneideneidene, isoideneideneidene A and Z-ideneideneidene); Soft sponge B; D-64131 (Asta Medica); D-68144 (Asta Medica); Diazonead A (Diazonamide A); A-293620 (Abbott); NPI-2350 (Nereus); TUB-245 (Aventis); A-259754 (Abbott); Diozostatin; (-)-Phenylahistin (also known as NSCL-96F037);D-68838 (Asta Medica); D-68836 (Asta Medica); Myoseverin B; D-43411 (Zentaris, also known as D-81862); A-289099 (Abbott); A-318315 (Abbott); HTI-286 (also known as SPA-110, trifluoroacetate) (Wyeth); D-82317 (Zentaris); D-82318 (Zentaris); SC-12983 (NCI); Resverastatin phosphate sodium; BPR-0Y-007 (National Health Research Institutes); SSR-250411 (Sanofi); Comparetacardine A4; Halaven; ® ), and its analogues and derivatives.

[0261] In other embodiments, the compounds of the present invention are used in combination with one or more alkylating agents, antimetabolites, natural products or hormones.

[0262] Examples of alkylating agents that can be used in the methods of the present invention include (but are not limited to) nitrogen mustard (e.g., mechloroethamine hydrochloride, cyclophosphamide, chlorambucil, melphalan, etc.), ethyleneimine and methyl melamine (e.g., hexamethyl melamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, semustine, streptozotocin, etc.) or triazine (decarbazine, etc.).

[0263] Examples of antimetabolites that can be used in the methods of this invention include (but are not limited to) folic acid analogs (e.g., methotrexate) or pyrimidine analogs (e.g., fluorouracil, floxouridine, cytarabine) and purine analogs (e.g., mercaptopurine, thioguanine, pentostatin). Examples of natural products that can be used in the methods of this invention include (but are not limited to) vinca alkaloids (e.g., vincristine, vinblastine), epipodophyllotoxin (e.g., etoposide, teniposide), antibiotics (e.g., actinomycin D, doxorubicin, doxorubicin, bleomycin, purcamycin, mitomycin) or enzymes (e.g., L-asparaginase).

[0264] Examples of hormones and antagonists that can be used to treat cancer include (but are not limited to) corticosteroids (e.g., prasone), progestins (e.g., hydroxyprogesterone acetate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethylstilbestrol, ethinylestradiol), anti-estrogens (e.g., tamoxifen), androgens (e.g., testosterone propionate, flumethyltestosterone), anti-androgens (e.g., flutamide), and gonadotropin-releasing hormone analogs (e.g., leuprolide).

[0265] Other agents that can be used in combination with the compounds of the present invention for the treatment of cancer include platinum coordination complexes (e.g., cisplatin, carboplatin), anthrones (e.g., mitoxantrone), substituted ureas (e.g., hydroxyurea), methylhydrazine derivatives (e.g., procarbazine), and adrenocortical inhibitors (e.g., mitotane, amlumid). Other anticancer agents / drugs that can be used in combination with the compounds of the present invention include (but are not limited to) liver X receptor (LXR) modulators, including LXR agonists and LXR β-selective agonists; aryl hydrocarbon receptor (AhR) inhibitors; poly(ADP-ribose) polymerase (PARP) inhibitors, including olaparib, iniparib, rucaparib, and veliparib; vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitors, including cediranib; and programmed cell death protein 1 (PD-1) inhibitors, including nivorumab (Bristol-Myers Squibb Co.) and pembrolizumab (Merck & Co.). Inc.; MK-3475); MEK inhibitors, including cobimetinib; β-Raf enzyme inhibitors, including vemurafenib; cytotoxic T-lymphocyte antigen (CTLA-4) inhibitors, including tremelimumab; programmed death-ligand 1 (PD-L1) inhibitors, including MEDI4736 (AstraZeneca); Wnt pathway inhibitors; epidermal growth factor receptor (EGFR) inhibitors, including AZD9291 (AstraZeneca), erlotinib, gefitinib, panitumumab, and cetuximab; adenosine A2A receptor inhibitors; adenosine A2B receptor inhibitors; colony-stimulating factor-1 receptor (CSF1R) inhibitors, including PLX3397 (Plexxikon); and CD73 inhibitors.

[0266] The compounds of the present invention can be used in combination with one or more therapeutic strategies including immune checkpoint inhibitors, such as inhibitors of PD-1, PD-L1 and CTLA-4.

[0267] The compounds of the present invention can be used in combination with one or more anticancer agents selected from the following: MCL-1 inhibitors, such as homoharringtonin (HHT) and omacetaxine; BCL-2 inhibitors, such as venetoclax (ABT-199), navitoclax (ABT-263), ABT-737, gossypol (AT-101), apoogossypolone (ApoG2), and obatoclax; selective inhibitors of nuclear export (SINE), such as selinexor (KPT-330).

[0268] In a specific embodiment, the compounds of the present invention are used in combination with one or more anticancer agents selected from the following to treat leukemia: abitrexate ® Folex ® Folex PFS ® Mexate ® Mexate-AQ ® ); Arranon ® ); Blincytobactam (blinatumomab) ® ); rudorubicin hydrochloride or daunorubicin hydrochloride (Cerubidine®); cyclophosphamide (Clafenamide) ® Cytoxan ® Neosar ® ); Clofarex ® Clolar ® ); Cytosar-U ® Tarabine PFS ® ); Dasatinib (Sprycel) ® Doxorubicin hydrochloride; Erwinia chrysanthemi (Erwinaze); Imatinib mesylate (Gleevec) ® ); Ponatinib hydrochloride (Iclusig) ® ); mercaptopurine (Purinethol; Purixan); oncasparase ® ); Prisson; Oncovinyl sulfate ®Vincasar PFS ® Vincrex ® ); Vincristine sulfate liposomes (Marqibo) ® Hyper-CVAD (fractionated cyclophosphamide, vincristine, adenomyomycin, and dexamethasone); Arsenic trioxide (Trisenox) ® ); Idamycin hydrochloride ® ); Mitoxantrone hydrochloride; Tabloid (thioguanine) ® ); ADE (cytarabine, daunomycin, and etoposide); alenzumab (Lemtrada) ® Campath ® ); Ambochlorin ® Amboclorin ® Leukeran ® Linfolizin ® ); ofatumumab (Arzerra ® ); bendamustine hydrochloride (Treanda ® Fludarabine phosphate ® ); obinutuzumab (Gazyva) ® ); ibrutinib (Imbruvica) ® ); Idelalisib (Zydelig ® ); Nitrogen mustard hydrochloride (Mustargen) ® ); Rituxan ® Chlorobutazone-Presson; CVP (cyclophosphamide, vincristine, and presson); Bosutinib ® Busulfex ® Myleran ® ); Omacetaxine mepesuccinate (Synribo) ® ); Nilotinib (Tasigna) ® Intron ®A (recombinant interferon α-2b); DOT1L inhibitors, including EPZ-5676 (Epizyme, Inc.); and inhibitors of bromodomain and outer terminal motif (BET) proteins (BET inhibitors), including MS417, JQ1, I-BET 762, and I-BET 151.

[0269] The compounds of this invention can be used in combination with one or more other agents or therapies to treat insulin resistance, prediabetes, diabetes (e.g., type 2 or type 1 diabetes), and risk of diabetes, including (but not limited to) insulin and insulin analogs such as Humulin® (EIi Lilly), Lantus® (Sanofi Aventis), Novolin® (Novo Nordisk), and Exubera® (Pfizer); Avandamet® (metformin HCl and rosiglitazone maleate, GSK); Avandaryl® (glimepiride and rosiglitazone maleate, GSK); Metalip® (glipizide and metformin hydrochloride, Bristol Myers Squibb); Glucovance® (glyburide and metformin hydrochloride, Bristol Myers Squibb). Squibb); PPARγ agonists, such as Avandia® (rosiglitazone maleate, GSK) and Actos® (pioglitazone hydrochloride, Takeda / Eli Lilly); sulfonylureas, such as Amaryl® (glimepiride, Sanofi Aventis), Diabeta® (glibenclamide, Sanofi Aventis), Micronase® / Glynase® (glibenclamide, Pfizer), and Glucotrol® / Glucotrol XL® (glipizide, Pfizer); meglitinide, such as Prandin® / NovoNorm® (repaglinide, Novo Nordisk), Starlix® (nateglinide, Novartis), and Glufast® (mitiglinide, Takeda); biguanides, such as Glucophase® / Glucophase XR® Metformin hydrochloride (Bristol Myers Squibb) and Glumetza® (Metformin hydrochloride, Depomed); thiazolidinediones; islet amyloid peptide analogs; GLP-1 analogs; DPP-IV inhibitors, such as Januvia® (sitagliptin, Merck) and Galvus® (vildagliptin, Novartis); PTB-1 B inhibitors;Protein kinase inhibitors (including AMP-activated protein kinase inhibitors); glucagon antagonists, glycogen synthase-3β inhibitors; glucose-6-phosphatase inhibitors; glycophosphorylase inhibitors; sodium-glucose cotransporter inhibitors; and α-glucosidase inhibitors, such as Glycet® (miglitol, Pfizer); statins, fibrates, and Zetia® (ezetimibe); α-blockers; β-blockers; calcium channel blockers; diuretics; angiotensin-converting enzyme (ACE) inhibitors; dual ACE and neutral endopeptidase (NEP) inhibitors; angiotensin receptor blockers (ARBs); aldosterone synthase inhibitors; aldosterone receptor antagonists; endothelin receptor antagonists; orlistat; phentermine; Acomplia® Rimonabant; thiazolidinediones (e.g., rosiglitazone, pioglitazone); SGLT 2 inhibitors (e.g., dapagliflozin, remogliflozinetabonate, sergliflozin, canagliflozin, and 1-chloro-4-(β-D-glucan-1-yl)-2-[4-(('S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene); PPAR-γ agonists (e.g., Gl262570) and antagonists; PPAR-γ / α modulators (e.g., KRP 297); α-glucosidase inhibitors (e.g., acarbose, voglibose); DPPIV inhibitors (e.g., Januvia® (sitalactone), Galvus® / Zomelis®). Vidagliptin, Onglyza® (saxagliptin), Nesina® / Vipidia® (alogliptin), and Tradjenta® / Trajenta® (linagliptin); α2-antagonists; glucagon-like protein-1 (GLP-1) receptor agonists and analogues (e.g., exendin-4); pancreatic amyloid peptides; inhibitors of protein tyrosine phosphatase 1; substances affecting disordered glucose production in the liver, such as inhibitors of glucose-6-phosphatase or fructose-1,6-bisphosphatase, and glycophosphorylase; glucagon receptor antagonists; inhibitors of phosphoenolpyruvate carboxylkinase; glycogen synthesis kinase and glucokinase activators; lipid-lowering agents, such as HMG-CoA-reductase inhibitors (e.g., simvastatin, atorvastatin);Fibrates (e.g., bezafibrate, fenofibrate), nicotinic acid and its derivatives, PPAR-α agonists, PPAR-δ agonists; ACAT inhibitors (e.g., avasimibe); cholesterol absorption inhibitors, such as ezetimibe; bile acid conjugates, such as cholestyramine; ileal bile acid transport inhibitors; HDL-elevating compounds, such as CETP inhibitors and ABC1 modulators; active substances used to treat obesity, such as tetrahydrolipostatin (tet...). Rahydrolipostatin; SDRI; axokine; leptin; leptin mimics; cannabinoid I receptor antagonists; and MCH-1 receptor antagonists; MC4 receptor agonists; NPY5 and NPY2 antagonists; β3-adrenergic agonists, such as SB-418790 and AD-9677; 5HT2c receptor agonists; GABA-receptor antagonists; Na-channel blockers; topiramate; protein kinase C inhibitors; advanced glycation end products (AGEs) inhibitors; and aldose reductase inhibitors.

[0270] Pharmaceutical preparations, administration and dosage forms

[0271] When used as a medicine, the compounds of the present invention can be administered in the form of pharmaceutical compositions, which are combinations of the compounds of the present invention or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable carrier. These compositions can be prepared in ways well known in the pharmaceutical industry and can be administered via various routes, depending on whether local or systemic treatment is desired and depending on the area to be treated. Administration can be local (including ocular and mucous membrane delivery, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or blowing of powders or aerosols, including via nebulizers; intratracheal, intranasal, epidermal, and percutaneous), ocular, oral, or parenteral. Methods of ocular delivery can include local administration (eye drops), subconjunctival, perioral, or intravitreal injection, or introduction via a balloon catheter or surgical placement of an ocular insert into the conjunctival sac. Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial administration, for example, intrathecal or intraventricular administration. Parenteral administration can be in the form of a single concentrated dose or can be performed via, for example, a continuous infusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional drug carriers, aqueous solutions, powders or oily bases, thickeners, and the like may be necessary or desirable.

[0272] This invention also includes pharmaceutical compositions comprising one or more of the above-described compounds of the invention as active ingredients and one or more pharmaceutically acceptable carriers. In preparing the compositions of the invention, the active ingredient is typically mixed with an excipient, diluted by the excipient, or encapsulated in such a carrier in the form of, for example, capsules, pouches, paper capsules, or other containers. When the excipient is used as a diluent, it can be a solid, semi-solid, or liquid material, acting as a medium, carrier, or medium for the active ingredient. Therefore, these compositions can be in the following forms: tablets, pills, powders, rhomboid tablets, pouches, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0273] The compounds or compositions described in this application may be administered to a patient in any amount and via any route of administration that is effective in treating or alleviating the severity of one or more of the diseases and conditions described in this application. The exact amount required will vary between individuals, depending on the individual's species, age and general condition, the severity of the infection, the disease or symptom, the specific drug, its administration method, and the like. The provided compounds are preferably formulated into specific unit dosage forms for ease of administration and uniform dosage. The term "unit dosage form" as used in this application refers to a physically discrete unit of the drug suitable for treating the patient.

[0274] The therapeutic dose of the compounds of this invention may vary depending on, for example, the specific use of the treatment, the route of administration of the compound, the patient's health and condition, and the prescribing physician's judgment. The proportion or concentration of the compounds of this invention in the pharmaceutical composition may vary depending on a variety of factors, including dosage, chemical characteristics (e.g., hydrophobicity), and route of administration. For example, the compounds of this invention may be provided for parenteral administration in an aqueous solution containing about 0.1 w / v% to about 10 w / v% of the compound in a physiological buffer solution. Some typical dosage ranges are about 1 µg / kg body weight to about 1 g / kg body weight per day. In some embodiments, the dosage range is about 0.01 mg / kg body weight to about 100 mg / kg body weight per day. The dosage may depend on variables such as the type and extent of disease or disease progression, the overall health status of the particular patient, the relative bioavailability of the selected compound, the formulation of the excipients, and the route of administration. The effective dose can be inferred from dose-response curves derived from in vitro or animal model testing systems.

[0275] Example

[0276] The compounds are prepared according to the following general procedure as described in the examples below. It should be understood that although the general method describes the synthesis of certain compounds of the present invention, the following general method and other methods known to those skilled in the art can be applied to all compounds set forth in this application and to each of the subclasses and types of such compounds.

[0277] Microwave reactions were performed in a CEM reactor using the Discovery SP system. If NMR data are provided, spectra were obtained on a Varian-400 (400 MHz). Spectra are reported in ppm from tetramethylsilane under low magnetic field conditions, with proton number, multiplicity, and coupling constant in some cases shown in parentheses along with a reference to the deuterated solvent. Compounds were also purified using the standard methods described in the manual via the ISCO rapid chromatography system.

[0278] The compound was purified using the acidic, basic, or neutral preparative HPLC methods described below.

[0279] Preparative RP-HPLC Method A

[0280] RP-HPLC (C-18, Boston Green ODS 150*30 mm*5 µm; eluent gradient: water + 0.1% TFA / acetonitrile = 81:19 to 51:49)

[0281] Mobile phase A: Water + 0.1% TFA; Mobile phase B: CH3CN; Flow rate: 30 mL / min; Detection: UV 220 nm / 254 nm; Column: Boston Green ODS 150*30 mm*5 µm; Column temperature: 30℃.

[0282]

[0283] Preparative RP-HPLC Method B

[0284] RP-HPLC (C-18, Phenomenex Synergi C18 250*21.2 mm*4 µm; eluent gradient: water + 0.1% TFA / acetonitrile = 75:25 to 45:55).

[0285] Mobile phase A: Water + 0.1% TFA; Mobile phase B: CH3CN; Flow rate: 25 mL / min; Detection: UV 220 nm / 254 nm; Column: Phenomenex Synergi C18 250*21.2 mm*4 µm; Column temperature: 30℃.

[0286]

[0287] Preparative RP-HPLC Method C

[0288] RP-HPLC (C-18, Phenomenex Synergi C18 250*21.2 mm*4 µm; eluent gradient: water + 0.05 % HCl / acetonitrile = 82:18 to 52:48).

[0289] Mobile phase A: Water containing 0.05% HCl; Mobile phase B: CH3CN; Flow rate: 30 mL / min; Detection: UV 220nm / 254 nm; Column: Phenomenex Gemini 150*30 mm*4 µm; Column temperature: 30℃.

[0290]

[0291] Preparative RP-HPLC method D

[0292] RP-HPLC (C-18, Phenomenex Gemini 150*25 mm*10 µm; eluent gradient: water + 0.05% ammonium hydroxide / acetonitrile = 30:70 to 0:100).

[0293] Mobile phase A: Water containing 0.05% ammonium hydroxide; Mobile phase B: CH3CN; Flow rate: 25 mL / min; Detection: UV 220 nm / 254 nm; Column: Phenomenex Gemini 150*25 mm*10 µm; Column temperature: 30℃.

[0294]

[0295] Preparative RP-HPLC method E

[0296] Mobile phase A: water containing 0.1% TFA; Mobile phase B: acetonitrile containing 0.1% TFA; Flow rate: 25 mL / min; Detection: UV 220 nm / 254 nm; Column: C-18 Synergi Max-RP 150*30 mm*4 µm; Column temperature: 30℃.

[0297]

[0298] Neutral preparative HPLC method F

[0299] Mobile phase A: Water

[0300] Mobile phase B: CH3CN

[0301] Flow rate: 120 mL / min.

[0302] Detection: UV 220 nm / 254 nm

[0303] Column: Phenomenex Synergi Max-RP 250*50 mm*10μm

[0304] Column temperature: 30℃

[0305]

[0306] Preparative HPLC method G

[0307] Mobile phase A: Water (10 mM NH4HCO3)

[0308] Mobile phase B: CH3CN

[0309] Flow rate: 25 mL / min.

[0310] Detection: UV 220 nm / 254 nm

[0311] Column: Xtimate C18 150*25mm*5μm

[0312] Column temperature: 30℃

[0313]

[0314] LCMS data were obtained using the following chromatographic conditions:

[0315] LCMS Method A

[0316] HPLC system: Waters ACQUITY; Column: Waters ACQUITY CSH TM C18 1.7 µm. Guard column: Waters Assy. Frit, 0.2 µm, 2.1 mm; column temperature: 40 °C.

[0317] Mobile phase: A: TFA:water (1:1000, v:v); Mobile phase B: TFA:ACN (1:1000, v:v); Flow rate: 0.65 mL / min; Injection volume: 2 µL; Acquisition time: approximately 1.5 min.

[0318]

[0319] Mass spectrometer: Waters SQD; Ionization: Positron Spray Ionization (ESI); Mode scan (100-1400 m / z, every 0.2 seconds); ES capillary voltage: 3.5 kV; ES cone voltage: 25 V. Source temperature: 120℃; Desolvation temperature: 500℃; Desolvation gas flow rate: Nitrogen set 650 (L / h); Cone gas flow rate: Nitrogen set 50 (L / h).

[0320] LCMS Method B

[0321] HPLC system: Waters ACQUITY; Column: Waters ACQUITY CSH TM C18 1.7 µm. Guard column: Waters Assy. Frit, 0.2 µm, 2.1 mm; column temperature: 40 °C.

[0322] Mobile phase: A: TFA:water (1:1000, v:v); Mobile phase B: TFA:ACN (1:1000, v:v); Flow rate: 0.65 mL / min; Injection volume: 2 µL; Acquisition time: approximately 1.5 min.

[0323]

[0324] Mass spectrometer: Waters SQD; Ionization: Positron Spray Ionization (ESI); Mode scan (100-1400 m / z every 0.2 seconds); ES capillary voltage: 3.5 kV; ES cone voltage: 25 V; Source temperature: 120 °C; Desolvation temperature: 500 °C; Desolvation gas flow rate: Nitrogen set 650 (L / h); Cone gas flow rate: Nitrogen set 50 (L / h).

[0325] LCMS Method C

[0326]

[0327] LCMS Method D

[0328]

[0329] LCMS Method E

[0330]

[0331] LCMS method F

[0332]

[0333] LCMS method G

[0334] HPLC system: Waters ACQUITY; Column: Waters ACQUITY CSH TM C18 1.7 µm. Guard column: Waters Assy. Frit, 0.2 µm, 2.1 mm; column temperature: 40 °C.

[0335] Mobile phase: A: TFA: water (1:1000, v:v); Mobile phase B: TFA: ACN (1:1000, v:v); Flow rate: 1 mL / min; Injection volume: 2 µL; Acquisition time: approximately 115 min.

[0336]

[0337] Mass spectrometer: Waters SQD; Ionization: Positron spray ionization (ESI); Mode scan (100-1400 m / z every 0.2 seconds); ES capillary voltage: 3.5 kV; ES cone voltage: 25 V.

[0338] Source temperature: 120℃; desolvation temperature: 500℃; desolvation gas flow rate: nitrogen set to 650 (L / h); conical gas flow rate: nitrogen set to 50 (L / h).

[0339] The following methods are supercritical fluid chromatography (SFC) separation methods for racemic compounds:

[0340] Method A

[0341] Instrument: Thar SFC 80; Column: AD 250 mm*30 mm, 5 µm; Mobile phase: A: supercritical CO2, B: IPA (0.05 % DEA), A:B = 80:20 (60 mL / min); Column temperature: 38℃; Nozzle pressure: 100 bar; Nozzle temperature: 60℃; Evaporator temperature: 20℃; Trimmer temperature: 25℃; Wavelength: 220 nm.

[0342] Method B

[0343] Instrument: SFC MG2; Column: OJ 250 mm*30 mm, 5 µm; Mobile phase: A: supercritical CO2, B: MeOH (0.05% DEA), A:B = 90:10 (70 mL / min); Column temperature: 38℃; Nozzle pressure: 100 bar; Nozzle temperature: 60℃; Evaporator temperature: 20℃; Fine-tuner temperature: 25℃; Wavelength: 220 nm.

[0344] X-ray powder diffraction (XRPD) method A

[0345]

[0346] This invention is illustrated by the following embodiments, wherein the following abbreviations may be used:

[0347]

[0348]

[0349] Intermediate 1. tert-butyl 4-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidine-1-carboxylic acid ester

[0350]

[0351] Step 1: 4-(1H-pyrrolo[2,3-c]pyridin-3-yl)-5,6-dihydropyridine-1(2H)-formate tert-butyl ester

[0352]

[0353] A solution of 1H-pyrrolo[2,3-c]pyridine (25 g, 21.2 mmol) in ethylene glycol (250 mL) was supplemented with tert-butyl 4-oxopiperidin-1-carboxylate (5 g, 25.4 mmol) and KOH (24 g, 42.4 mmol). The mixture was stirred at 100 °C for 2 days. The mixture was diluted with water and extracted with EtOAc (500 mL × 3). The combined organic layers were washed with brine (2 L × 3), dried over Na2SO4, and filtered. The filtrate was concentrated, and the residue was purified by ISCO column chromatography (from 100% DCM to 6% MeOH in DCM) to give a yellow oil of tert-butyl 4-(1H-pyrrolo[2,3-c]pyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate. Yield: 40 g (47%); LCMS method D: R t = 1.819 min; (M+H) + = 300.2. 1HNMR (DMSO-d6,): δ ppm 11.66 (s, 1H), 8.74 (s,1H), 8.12 (d, J = 7.2 Hz, 1H), 7.77 (d, J = 6.4 Hz, 1H), 7.67 (s, 1H), 6.17 (s, 1H), 4.04-4.05 (m, 2H), 3.56 (t, J = 5.6 Hz, 2H), 3.17 (s, 1H), 2.50-2.55 (m, 1H), 1.43 (s, 9H).

[0354] Step 2: 4-(1H-pyrrolo[2,3-c]pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester

[0355]

[0356] Pd(OH)₂ / C (4 g, 10%) was added to a solution of 4-(1H-pyrrolo[2,3-c]pyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (40 g, 134 mmol) in anhydrous MeOH:THF (500 mL, 1:1). The mixture was purged with H₂ (40 psi) and degassed three times, followed by stirring at 45 °C for 24 h under H₂ (40 psi). The mixture was filtered and the filtrate was concentrated to give 4-(1H-pyrrolo[2,3-c]pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (30 g, 74% yield). LCMS method D:R t = 1.825 min; (M+H) + = 302.2. 1 H NMR (DMSO-d6): δ ppm 11.34 (s,1H), 8.69 (s,1H), 8.05 (d, J = 5.6 Hz, 1H), 7.53 (d, J = 5.2 Hz, 1H), 7.38(s, 1H), 4.06 (d, J = 11.6 Hz, 2H), 2.91-2.98 (m, 3H), 1.92 (d, J = 12.0 Hz, 2H), 1.48-1.57 (m, 2H), 1.41 (s, 9H).

[0357] Step 3: 2-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluorobenzoic acid

[0358]

[0359] To a mixture of tert-butyl 4-(1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-carboxylic acid (10 g, 0.03 mol) in DMF (200 mL), 5-fluoro-2-iodobenzoic acid (8.3 g, 0.03 mol), Cu (384 mg, 0.01 mol), and K₂CO₃ (12 g, 0.09 mol) were added. The mixture was degassed with N₂ and purged three times, followed by heating at 130 °C for 17 h under N₂. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was added to water (500 mL) and 3 M HCl (aq.) was added to pH = 3–4. The mixture was extracted with EtOAc / i-PrOH (v / v, 10 / 3, 3 × 400 mL), and the combined organic layers were dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure to give 2-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluorobenzoic acid as a brown solid. Yield: 14 g (100% crude product); LCMS method C:R t = 0.645 min; (M+H) + = 440.3.

[0360] Step 4: 4-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester

[0361] To a mixture of 2-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluorobenzoic acid (5 g, 0.01 mol) in DMF (100 mL), N-methylpropane-2-amine (1.2 g, 0.02 mol), HATU (7.6 g, 0.02 mol), and DIEA (6.5 g, 0.05 mol) were added. The mixture was degassed with N2 and purged three times, followed by heating at 20–28 °C for 2 h under N2. The reactants were concentrated under reduced pressure. The residue was added to water (50 mL), extracted with EtOAc (3 × 80 mL), and the combined organic layers were washed with water (3 × 60 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with petroleum ether / EtOAc = 1 / 1) to give a yellow oily tert-butyl 4-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-carboxylic acid. Yield: 5.2 g (92%); LCMS method D:Rt =2.574 min; (M+H) + = 495.2. 1 H NMR (CD3OD): δ ppm 8.50-8.65 (m, 1H), 8.15-8.25 (m,1H), 7.70-7.80 (m, 1H), 7.60-7.70 (m, 1H), 7.40-7.50 (m, 2H), 7.35-7.40 (m,1H), 4.40-4.55 (m, 0.5H), 4.15-4.30 (m, 2H), 3.55-3.65 (m, 0.5H), 3.05-3.15(m, 1H), 2.90-3.05 (m, 2H), 2.65-2.70 (m, 1.5H), 2.45-2.50 (m, 1.5H), 2.00-2.10 (m, 2H), 1.60-1.75 (m, 2H), 1.45-1.55 (m, 9H), 0.95-1.15 (m, 3H), 0.15-0.60 (m, 3H). 19 F NMR (CD3OD): δ ppm -113.22 to -113.44.

[0362] Intermediate 2-17.

[0363] The following intermediates were synthesized using the method described above for intermediate 1. Characterization data for intermediates 2-17 are shown in Table 2.

[0364] Table 1.

[0365]

[0366]

[0367]

[0368] Table 2.

[0369]

[0370] Intermediates 17A-17B: 2-(3-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide (intermediate 17A) and 5-fluoro-N-isopropyl-N-methyl-2-(3-(4-oxocyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide (intermediate 17B)

[0371] and

[0372] Step 1: 3-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1H-pyrrolo[2,3-c]pyridine

[0373]

[0374] KOH (28.5 g, 507.87 mmol) was added to a solution of 1H-pyrrolo[2,3-c]pyridine (20.0 g, 169.29 mmol) in 600 mL of ethane-1,2-diol. After all the KOH was completely dissolved, 1,4-dioxaspiro[4.5]dec-8-one (53.0 g, 338.58 mmol) was added. The mixture was degassed and purged with N2. The resulting mixture was stirred under N2 at 100-110°C (oil temperature) for 24 h. The reactants were cooled to 30-40°C, diluted with EtOAc (600 mL), and washed with H2O (3 × 800 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with EtOAc (50 mL) and filtered. The filter cake was collected and dried under reduced pressure to obtain a white solid 3-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1H-pyrrolo[2,3-c]pyridine. Yield: 29.0 g (67%); LCMS method C:R t = 0.547 min; (M+H) + = 257.0. 1H NMR (CD3OD): δ ppm 8.64 (d, J = 1.2 Hz, 1H), 8.07(d, J = 6.0 Hz, 1H), 7.77-7.80 (m, 1H), 7.74-7.78 (m, 1H), 7.52 (s, 1H), 6.08(t, J = 4.0 Hz, 1H), 3.99 (s, 4H), 2.60-2.70 (m, 2H), 2.40-2.50 (m, 2H), 1.89-1.95 (t, J = 6.8 Hz, 2H).

[0375] Step 2: 3-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrrolo[2,3-c]pyridine

[0376] Pd(OH)₂ / C (6.0 g, 10%, dry) was added to a solution of 3-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1H-pyrrolo[2,3-c]pyridine (29.0 g, 113.15 mmol) in 400 mL MeOH and 200 mL THF. The mixture was degassed with H₂ and purged three times. The resulting mixture was hydrogenated at 40-50 °C for 24 h under H₂ (40 Psi). The reaction mixture was then filtered through a diatomaceous earth mat. The filtrate was concentrated under reduced pressure to give a white solid of 3-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrrolo[2,3-c]pyridine, which was used directly in the next step without further purification. Yield: 28.0 g (96%); LCMS method C:R t = 0.560 min; (M+H) + = 259.0. 1 H NMR (CD3OD): δ ppm8.63 (d, J = 0.8 Hz, 1H), 8.04 (d, J = 5.2 Hz, 1H), 7.77-7.80 (dd, J = 0.8,5.2 Hz, 1H), 7.34 (s, 1H), 3.95-4.05 (m, 4H), 2.85-2.95 (m, 1H), 2.00-2.10 (m,2H), 1.80-1.95 (m, 4H), 1.70-1.80 (m, 2H).

[0377] Step 3: 2-(3-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluorobenzoic acid

[0378]

[0379] To a solution of 3-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrrolo[2,3-c]pyridine (9.0 g, 34.84 mmol) in 200 mL of anhydrous DMF, 5-fluoro-2-iodobenzoic acid (9.3 g, 34.84 mmol), Cu (442 mg, 6.97 mmol), and K₂CO₃ (14.4 g, 104.52 mmol) were added. The resulting mixture was degassed and purged three times with N₂, and then stirred at 130 °C for 24 h under N₂. The reaction mixture was then filtered through diatomaceous earth. The filter cake was washed with EtOAc (150 mL), and the filtrate was concentrated under reduced pressure to remove most of the EtOAc and DMF. The resulting residue was poured into water (300 mL). The aqueous layer was adjusted to pH 6-7 with 6 N HCl, extracted with EtOAc (3 × 300 mL), and some white precipitate formed. The suspension was then filtered. The filter cake was collected and dried under reduced pressure to obtain the first batch of white solid 2-(3-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluorobenzoic acid (7.5 g). The organic layer was washed with brine (3 × 300 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the second batch of brown solid 2-(3-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluorobenzoic acid (4.5 g). Yield: 12.0 g (87%); LCMS method E: R t = 0.649 min; (M+H) + = 397.0. 1 H NMR (DMSO-d6): δ ppm8.45 (s, 1H), 8.20-8.22 (d, J = 5.6, 1H), 7.60-7.80 (m, 4H), 7.53 (s, 1H), 3.95 (4, 1H), 2.90-3.00 (m, 1H), 2.03-2.10 (m, 2H), 1.65-1.85 (m, 6H). 19 F NMR (DMSO-d6): δ ppm -112.83.

[0380] Step 4: 2-(3-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide (Intermediate 17A)

[0381] N-methylpropane-2-amine (1.7 g, 22.71 mmol), HATU (6.3 g, 16.65 mmol), and DIEA (5.9 g, 45.42 mmol) were added to a solution of 2-(3-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluorobenzoic acid (6.0 g, 15.14 mmol) in 120 mL of anhydrous CH2Cl2. The resulting mixture was stirred at room temperature for 18 h. The reaction mixture was then concentrated under reduced pressure. The residue was dissolved in H2O (50 mL) and extracted with CH2Cl2 (2 × 100 mL). The organic layer was then concentrated under reduced pressure to obtain crude yellow oily 2-(3-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide (7 g, 98% crude). 2.2 g of crude was then obtained, which was purified by alkaline preparative RP-HPLC method G to obtain white solid 2-(3-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide (intermediate 17A) (1.2 g). LCMS method E:R t = 0.668 min; (M+H) + = 452.1. 1 H NMR (CD3OD): δ ppm 8.52-8.61 (m, 1H), 8.15-8.18 (m, 1H), 7.61-7.73 (m, 2H), 7.33-7.43 (m, 3H), 4.45-4.48 (m, 0.5H), 3.97 (s, 4H), 3.54-3.59 (m, 0.5H), 2.90-3.00 (m, 1H), 2.43-2.66 (m, 3H), 1.70-2.10 (m, 8H), 0.95-1.04 (m, 3H), 0.15-0.60 (m, 3H). 19 FNMR (CD3OD): δ ppm -109.72 to -106.43.

[0382] Step 5: 5-Fluoro-N-isopropyl-N-methyl-2-(3-(4-oxocyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide (intermediate 17B)

[0383] An aqueous solution of HCl (30 mL, 3 N in H2O) was added to a solution of 2-(7-(1,4-dioxaspiro[4.5]dec-8-yl)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-5-fluoro-N-isopropyl-N-methylbenzamide (3.9 g, 8.64 mmol) in THF (30 mL). The resulting mixture was stirred at 40 °C (oil temperature) for 20 h. The reaction mixture was adjusted to pH = 10 by NH3-H2O and extracted with EtOAc (3 × 50 mL). The organic layer was washed with brine (2 × 100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a yellow solid of 5-fluoro-N-isopropyl-N-methyl-2-(7-(4-oxocyclohexyl)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)benzamide. Yield: 2.8 g (80%); LCMS method C:R t =0.616 min; (M+H) + = 408.1. 1 H NMR (CD3OD): δ ppm 8.55-8.65 (m, 1H), 8.20-8.25 (m,1H), 7.80-7.84 (m, 1H), 7.67-7.75 (m, 1H), 7.36-7.50 (m, 3H), 4.43-4.49 (m,0.5H), 3.40-3.60 (m, 1.5H), 2.44-2.80 (m, 9H), 1.90-2.05 (m, 2H), 0.95-1.13(m, 3H), 0.18-0.60 (m, 2H). 19 F NMR (CD3OD): δ ppm -113.62 to -113.11.

[0384] Intermediate 17C. 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1,2,3,4-tetrahydroisoquinoline-6-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide

[0385]

[0386] Step 1: 2-(3-bromo-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluorobenzoic acid

[0387]

[0388] A mixture of 3-bromo-1H-pyrrolo[2,3-c]pyridine (5 g, 25.38 mmol), 5-fluoro-2-iodobenzoic acid (6.8 g, 25.38 mmol), Cu (322 mg, 5.08 mmol), and K₂CO₃ (10.5 g, 76.13 mmol) in anhydrous DMF (50 mL) was stirred at 130 °C for 18 h. The mixture was concentrated under high vacuum, and the residue was diluted with H₂O (50 mL) and acidified to pH 3 to 4 with 3N HCl aqueous solution. The resulting yellow solid was collected by filtration, washed with H₂O (3 × 20 mL), and dried under high vacuum to obtain a yellow solid of 2-(3-bromo-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluorobenzoic acid, which was used directly in the next step without further purification. Yield: 5.8 g (68%); LCMS method C: R t = 0.551 min; (M+H) + = 334.8, 336.8 (bromine isotopes).

[0389] Step 2: 2-(3-bromo-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide

[0390]

[0391] To a solution of 2-(3-bromo-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluorobenzoic acid (4.8 g, 14.32 mmol) in anhydrous DCM (150 mL), (COCl)₂ (18.2 g, 12 mL, 143.23 mmol) and DMF (2 mL) were added sequentially. The mixture was stirred at 19–25 °C for 2 h under N₂. Another (COCl)₂ (2 mL) was added and the mixture was stirred at 19–25 °C for 2 h. The mixture was concentrated under reduced pressure. The residue was diluted with DCM (150 mL). DIEA (7.4 g, 57.28 mmol) and N-methylpropane-2-amine (2.1 g, 28.64 mmol) were added and the mixture was stirred at 19–25 °C for 18 h. The reactants were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting with petroleum ether / EtOAc = 10 / 1 to 2 / 3) to give a brown oily 2-(3-bromo-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide. Yield: 3.8 g (68%); LCMS method C:R t = 0.634 min; (M+H) += 389.9, 391.9 (bromine isotopes).

[0392] Step 3: 6-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester

[0393]

[0394] 2-(3-bromo-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide (100 mg, 0.26 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaboronylcyclopentan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester (138 mg, 0.38 mmol), Pd(dppf)Cl2 (19 mg, 0.026 mmol) and Na2CO3 (68 mg, 0.64 mmol) were reacted with N2 in a 2-dioxane mixture. The mixture in alkyl / H2O (3 mL / 1 mL, v / v) was bubbled for 5 min. The mixture was stirred at 80 °C under N2 for 18 h. The mixture was diluted with H2O (20 mL), extracted with EtOAc (3 × 20 mL), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography on silica gel (eluting with petroleum ether / ethyl acetate = 10 / 1 to 2 / 3) to give a yellow oil of tert-butyl 6-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid (200 mg, 96% yield). LCMS method E:R t = 2.246 min; (M+H) + 543.2; 1H NMR (CD3OD): δ ppm 8.61-8.67 (m,1H), 8.25 (d, J = 1.2 Hz, 1H), 7.95 (d, J = 6.0 Hz, 1H), 7.81 (s, 1H), 7.70-7.75 (m, 1H), 7.45-7.50 (m, 3H), 7.39 (d, J = 2.8 Hz, 1H), 7.25 (d, J = 8.0Hz, 1H), 4.63 (s, 2H), 4.40-4.50 (m, 0.5H), 3.60-3.70 (m, 2.5H), 2.90-2.95(m, 2H), 2.47-2.64 (m, 3H), 1.50 (s, 9H), 0.95-1.05 (m, 3H), 0.30-0.55 (m, 3H). 19 F NMR (CD3OD): δ ppm -111.70.

[0395] Step 4: 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1,2,3,4-tetrahydroisoquinoline-6-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide

[0396] HCl-di(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester (170 mg, 0.31 mmol) was added to a mixture of 6-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester (170 mg, 0.31 mmol) in anhydrous DCM (20 mL) at 0 °C. Alkane (5 mL, 4 N). The mixture was stirred at 16–24 °C for 2 h until LC-MS showed completion. The mixture was concentrated under reduced pressure to give crude yellow oily 5-fluoro-N-isopropyl-N-methyl-2-(3-(1,2,3,4-tetrahydroisoquinoline-6-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide (138 mg, 100% crude yield), which was used directly in the next step without further purification. LCMS method E:R t = 1.935 min; (M+H) + =443.2; 1H NMR (CD3OD): δ ppm 8.59-8.65 (m, 1H), 8.25 (d, J = 1.2 Hz, 1H), 7.93 (d, J = 6.0 Hz, 1H), 7.77 (s, 1H), 7.70-7.75 (m, 1H), 7.35-7.50 (m, 4H), 7.16 (d, J = 8.0 Hz, 1H), 4.45-4.50 (m, 0.5H), 4.00 (s, 2H), 3.60-3.65 (m, 0.5H), 3.13 (t, J = 5.6 Hz, 2H), 2.92 (t, J = 5.6 Hz, 2H), 2.45-2.63 (m, 3H), 1.00-1.05 (m, 3H), 0.30-0.55 (m, 3H). 19 F NMR (CD3OD): δ ppm -112.80.

[0397] Intermediate 18. 4-(5H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidine-1-carboxylic acid tert-butyl ester

[0398]

[0399] Step 1: 4-(5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5,6-dihydropyridine-1(2H)-formate tert-butyl ester

[0400]

[0401] A solution of 5H-pyrrolo[3,2-d]pyrimidine (2 g, 16.8 mmol) in 1,2-ethylene glycol (40 mL) was supplemented with tert-butyl 4-oxopiperidinium-1-carboxylate (6.7 g, 33.5 mmol) and KOH (3.8 g, 6.72 mmol). The mixture was stirred at 95 °C for 18 h. The mixture was then diluted with ethyl acetate (30 mL) and washed with brine (50 mL × 3), dried over Na₂SO₄, and filtered. The filtrate was concentrated and purified by ISCO column chromatography on silica gel (from 100% DCM to DCM / MeOH = 10 / 1) to give a yellow oily tert-butyl 4-(5H-pyrrolo[3,2-d]pyrimidine-7-yl)-5,6-dihydropyridine-1(2H)-carboxylate. Yield: 3 g (60%); LCMS method D: R t = 1.679 min; (M+H) + = 301.2.

[0402] Step 2: tert-butyl 4-(5H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidine-1-carboxylic acid

[0403] Pd(OH)₂ (0.3 g, 10 %) was added to a solution of 4-(5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (3 g, 10 mmol) in anhydrous MeOH-THF (20 mL). The mixture was purged with H₂ and degassed three times, then stirred at 45 °C for 5 days under H₂ (50 psi). The mixture was filtered and the filtrate was concentrated to give crude black solid 4-(5H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidine-1-carboxylic acid tert-butyl ester. Yield: 3 g (99% crude); LCMS method D: R t = 1.585 min; (M+H) + = 303.2.

[0404] Intermediate 19. 6-Formyl-1H-indole-2-carboxynitrile

[0405]

[0406] Step 1: 6-Bromo-1H-indole-2-carboxylic acid

[0407]

[0408] LiOH•H2O (313 mg, 7.46 mmol) was added to a solution of ethyl 6-bromo-1H-indole-2-carboxylate (1.0 g, 3.73 mmol) in THF (15 mL) and H2O (2 mL). The resulting mixture was stirred at 7–20 °C for approximately 20 h. The reaction mixture was then adjusted to pH 7.0 with 3N HCl. The mixture was concentrated under reduced pressure to obtain crude yellow solid 6-bromo-1H-indole-2-carboxylic acid, which was used directly in the next step. Yield: 1.2 g; 1 H NMR (DMSO-d6): δ ppm7.66 (s, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.11 (dd, J = 8.8, 2.0 Hz, 1H), 6.94 (s, 1H).

[0409] Step 2: 6-Bromo-1H-indole-2-carboxamide

[0410]

[0411] (COCl)₂ (1.9 g, 15.0 mmol) and DMF (2 drops, catalyst, anhydrous) were added to a solution of 6-bromo-1H-indole-2-carboxylic acid (1.2 g, 5.0 mmol, crude product) in CH₂Cl₂ (50 mL, anhydrous). The resulting mixture was stirred at 50 °C for about 2 h. Then, NH₃-H₂O (15 mL) was added dropwise over 5 min. The resulting mixture was stirred at 5–15 °C for about 20 h. The reaction mixture was then filtered, and the filter cake was collected and dried under reduced pressure to give crude, pale yellow powder of 6-bromo-1H-indole-2-carboxamide. Yield: 1.0 g (84% crude product); 1 H NMR (DMSO-d6): δ ppm 11.75 (s, 1H), 7.96-8.03 (m, 2H), 7.81 (s, 1H), 7.67 (s, 1H), 7.41 (s, 1H), 7.34-7.37 (m,1H), 7.25-7.28 (m, 1H), 7.08 (s, 1H).

[0412] Step 3: 6-Bromo-1H-indole-2-carboxynitrile

[0413]

[0414] POCl3 (2.2 g, 1.4 mL, 14.7 mmol) was added to a solution of 6-bromo-1H-indole-2-carboxamide (1.0 g, 4.2 mmol, crude) in CHCl3 (15 mL). The resulting mixture was stirred at 70 °C under N2 for about 20 h. The reaction mixture was diluted with water (30 mL) and adjusted to pH = 7.0 by NH3-H2O. The aqueous layer was extracted with EtOAc (2 × 30 mL). The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 20 / 1 to 4 / 1) to give 6-bromo-1H-indole-2-carboxynitrile as a brown powder. Yield: 850 mg (92%); 1 H NMR (CDCl3): δ ppm8.65 (s, 1H), 7.83 (s, 1H), 7.48 (d, J = 8.8, 1H), 7.31 (d, J = 8.8, 1H), 7.14 (s, 1H).

[0415] Step 4: 6-Formyl-1H-indole-2-carboxynitrile

[0416] NaH (362 mg, 9.04 mmol, 60% in mineral oil) was added in a single addition to a solution of 6-bromo-1H-indole-2-carboxynitrile (500 mg, 2.26 mmol) in THF (20 mL, anhydrous) at 10–15 °C. The mixture was stirred at 10–15 °C for 15 min. The mixture was then cooled to -70 °C, and t-BuLi (4.35 mL, 5.65 mmol, 1.3 M in pentane) was added dropwise via syringe, while the mixture was stirred at -70 °C for 20 min. Anhydrous DMF (991 mg, 1 mL, 13.56 mmol) was added dropwise via syringe at -70 °C, and the mixture was stirred at -70 °C under N2 for 2 h. The mixture was then quenched with saturated NH4Cl solution (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (2 × 40 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc (15 mL), and the suspension was stirred for 10 min. The solid was collected by filtration and concentrated and dried under reduced pressure to give a brown solid, 6-formyl-1H-indole-2-carboxynitrile. Yield: 290 mg (75%). 1 H NMR (CDCl3): δ ppm 10.00 (s, 1H), 8.16 (s, 1H), 7.89 (d, J = 8.4, 1H), 7.47 (d, J = 8.4, 1H), 7.30 (s, 1H).

[0417] Intermediate 20. 6-Formyl-3-methyl-2-oxodihydroindole-3-carboxynitrile

[0418]

[0419] Step 1: Methyl 4-(2-cyano-1-ethoxy-1-oxopropane-2-yl)-3-nitrobenzene

[0420]

[0421] Ethyl 2-cyanoethyl (5.33 mL, 50 mmol) was added dropwise to a 60% suspension of sodium hydride (2.0 g, 50 mmol) in anhydrous DMF (50 mL) at 0 °C. The mixture was stirred at 0 °C for another 30 min. Methyl 4-fluoro-3-nitrobenzene (7.97 g, 40 mmol) was added to the resulting gray suspension at 0 °C. The resulting deep red mixture was stirred at 0 °C for 30 min and then heated to room temperature over 2 h. The reaction mixture was cooled to 0 °C, and MeI (7.8 mL) was added, followed by KOtBu (8.4 g, 75 mmol). After the addition, the mixture was stirred at room temperature for 2 days, followed by quenching with an aqueous NH4Cl solution. The mixture was extracted twice with EtOAc, and the organic layers were combined and washed continuously with H2O and brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by rapid chromatography to give methyl 4-(2-cyano-1-ethoxy-1-oxopropane-2-yl)-3-nitrobenzoate. Yield: 6.04 g. LCMS Method B: R t = 1.42 min.

[0422] Step 2: Methyl 3-cyano-3-methyl-2-oxodihydroindole-6-carboxylate

[0423]

[0424] A solution of methyl 4-(2-cyano-1-ethoxy-1-oxopropan-2-yl)-3-nitrobenzene (6.039 g, 19.72 mmol) in EtOH (60 mL) was mixed with saturated NH4Cl aqueous solution (15 mL) and iron powder (5.803 g, 98.61 mmol). The mixture was heated to reflux overnight. The mixture was then cooled to room temperature and filtered through a short diatomaceous earth mat, washed with EtOAc. The filtrate was washed with H2O and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by rapid chromatography to give methyl 3-cyano-3-methyl-2-oxodihydroindole-6-carboxylate. Yield: 4.404 g. LCMS Method B: R t = 1.07 min; (M+H) + = 231.1.

[0425] Step 3: 6-(hydroxymethyl)-3-methyl-2-oxodihydroindole-3-carboxynitrile

[0426]

[0427] Methyl 3-cyano-3-methyl-2-oxodihydroindole-6-carboxylate (2.101 g, 9.12 mmol) was added sequentially to a solution of methyl 3-cyano-3-methyl-2-oxodihydroindole-6-carboxylate in anhydrous THF (40 mL) under N2 atmosphere, along with a solution of LiBH4 (9.1 mL, 18.2 mmol) and MeOH (0.2 mL). The mixture was heated to reflux and held for 2 h, then quenched with an aqueous NH4Cl solution. The mixture was extracted twice with EtOAc, and the organic layers were combined and washed continuously with H2O and brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by rapid chromatography to give 6-(hydroxymethyl)-3-methyl-2-oxodihydroindole-3-carboxynitrile. Yield: 1.42 g. LCMS Method B: R t = 0.79 min; (M+H) + = 203.1.

[0428] Step 4: 6-Formyl-3-methyl-2-oxodihydroindole-3-carboxynitrile

[0429] Active MnO2 (2.57 g, 29.56 mmol) was added to a solution of 6-(hydroxymethyl)-3-methyl-2-oxodihydroindole-3-carboxynitrile (0.597 g, 2.95 mmol) in DCM. The mixture was stirred overnight at room temperature and then filtered through a short diatomaceous earth pad. The filtrate was concentrated to remove the solvent, and the residue was purified by rapid chromatography to give 6-formyl-3-methyl-2-oxodihydroindole-3-carboxynitrile. Yield: 0.347 g. LCMS Method B: R t = 1.25 min.

[0430] Intermediate 21. N-(trans-4-formylcyclohexyl)methanesulfonamide

[0431]

[0432] Step 1: Methyl trans-4-(methylsulfonamide)cyclohexanecarboxylate

[0433]

[0434] (MeSO₂)₂O (7.5 g, 43.37 mmol) and Et₃N (11.0 g, 108.42 mmol) were added to a solution of trans-4-aminocyclohexanecarboxylate hydrochloride (7.0 g, 36.14 mmol) in 200 mL of anhydrous CH₂Cl₂. The resulting mixture was stirred at 8–18 °C for 18 h. The reaction mixture was adjusted to pH 6–7 with 1 N HCl aqueous solution. The mixture was concentrated under reduced pressure and extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to give a white solid of trans-4-(methylsulfonylamino)cyclohexanecarboxylate. Yield: 9.0 g (100% crude product); 1 H NMR (CD3OD): δ ppm 3.65 (s, 3H), 3.15-3.25 (m, 1H), 2.95 (s, 3H), 2.20-2.35 (m, 1H), 1.95-2.10 (m, 4H), 1.40-1.60 (m, 2H), 1.25-1.40 (m, 2H).

[0435] Step 2: N-(trans-4-formylcyclohexyl)methanesulfonamide

[0436] The solution of methyl trans-4-(methylsulfonamide)cyclohexanecarboxylate (4.0 g, 17.00 mmol) in anhydrous toluene (100 mL) was degassed and purged three times with N2, and then cooled to -75 °C. A solution of DIBAL-H (11.9 mL, 11.90 mol, 1 M in toluene) was added dropwise under N2 (keeping the internal temperature below -70 °C). After the addition, the mixture was vigorously stirred at -75 °C for 3 h. MeOH (5 mL) was added dropwise below -70 °C, followed by a solution of saturated Rochell salt (aqueous solution, 200 mL) and EtOAc (200 mL) dropwise at -70 °C. The mixture was warmed to room temperature and stirred at room temperature for 18 h. The aqueous layer was separated and extracted with EtOAc (2 × 200 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was then purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 1) to give N-(trans-4-formylcyclohexyl)methanesulfonamide as a white solid. Yield: 2.0 g (57%); 1H NMR (MeOD): δ 9.59 (s, 1H), 3.10-3.25 (m, 1H), 2.90-3.00 (m, 3H), 2.10-2.30 (m, 1H), 1.85-2.10 (m, 4H), 1.30-1.45 (m, 2H), 1.10-1.30 (m, 2H).

[0437] Intermediate 22. (trans-3-formylcyclobutyl)carbamate tert-butyl ester

[0438]

[0439] A mixture of tert-butyl (trans-3-(hydroxymethyl)cyclobutyl)carbamate (250 mg, 1.24 mmol) and PCC (535 mg, 2.48 mmol) in anhydrous DCM (12 mL) was stirred at 19–28 °C for 18 h until TLC (petroleum ether: ethyl acetate = 3:1) showed completion. The mixture was filtered and the filtrate was concentrated under reduced pressure at below 35 °C. The residue was purified by silica gel column chromatography (eluting with petroleum ether / EtOAc = 4 / 1 to 2 / 1) to give a colorless oily tert-butyl (trans-3-formylcyclobutyl)carbamate. Yield: 240 mg (96%). 1 H NMR (CDCl3): δ ppm9.76 (d, J = 2.0 Hz, 1H), 4.65-4.70 (m, 1H), 2.95-3.00 (m, 1H), 2.55-2.65 (m,2H), 2.05-2.10 (m, 2H), 1.37 (s, 9H).

[0440] Intermediate 23. (trans-4-(2-oxoethyl)cyclohexyl)tert-butyl carbamate

[0441]

[0442] A mixture of (trans-4-(2-hydroxyethyl)cyclohexyl)carbamate tert-butyl ester (250 mg, 1.03 mmol) and PCC (444 mg, 2.06 mmol) in anhydrous DCM (10 mL) was stirred at 5–17 °C for 2 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with petroleum ether / ethyl acetate = 3 / 1) to give a white solid of (trans-4-(2-oxoethyl)cyclohexyl)carbamate tert-butyl ester. Yield: 190 mg (76%). 1H NMR (CDCl3): δ ppm 9.69 (s, 1H), 4.30-4.34 (m, 1H), 3.32-3.35 (m, 1H), 2.26 (d, J = 6.4 Hz, 2H), 1.93-1.98 (m, 2H), 1.70-1.77 (m, 3H), 1.37 (s, 9H), 1.01-1.09 (m, 4H).

[0443] Intermediate 24-24A. 2-(5-formyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl formic acid (intermediate 24) and 1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-carboxaldehyde (intermediate 24A)

[0444] and

[0445] Step 1. 4-((2-hydroxyethyl)amino)-3-nitrobenzene

[0446]

[0447] K₂CO₃ (37.4 g, 271.2 mmol) was added to a solution of 4-fluoro-3-nitrobenzene (15 g, 90.4 mmol) and 2-aminoethanol (11.0 g, 180.7 mmol) in anhydrous DMF (600 mL) under N₂ conditions, and the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was washed with H₂O (100 mL) and the mixture was extracted with EtOAc (3 × 500 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to give 4-((2-hydroxyethyl)amino)-3-nitrobenzene. The yellow solid residue was used in the next step without further purification. Yield: 17.3 g. LCMS method E:R t = 1.016 min; (M+H) + = 207.9.

[0448] Step 2. 3-Amino-4-((2-hydroxyethyl)amino)benzonitrile

[0449]

[0450] Fe (23.4 g, 418.0 mmol) and NH4Cl (44.8 g, 836.0 mmol) were added to a solution of 4-((2-hydroxyethyl)amino)-3-nitrobenzene (17.3 g, 83.6 mmol) in EtOH (800 mL) and H2O (400 mL) under N2 conditions, and the reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in EtOAc (500 mL), washed with H2O (2 × 100 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give 3-amino-4-((2-hydroxyethyl)amino)benzonison. The brownish-red solid residue was used in the next step without further purification. Yield: 11.6 g. LCMS method D: R t = 0.941 min; (M+H) + =178.2.

[0451] Step 3. 3-Amino-4-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)benzonitrile

[0452]

[0453] Imidazole (11.14 g, 163.65 mmol) was added to a solution of 3-amino-4-((2-hydroxyethyl)amino)benzonitrile (11.6 g, 65.46 mmol) and tert-butylchlorodimethylsilane (11.84 g, 78.55 mmol) in anhydrous DMF (300 mL), and the reaction mixture was stirred at 35 °C for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The reaction mixture was added to water (1000 mL) and extracted with EtOAc (3 × 500 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give a black oily 3-amino-4-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)benzonitrile, which was used in the next step without further purification. Yield: 25 g. LCMS method C: R t = 0.878 min; (M+H) + = 292.1

[0454] Step 4. 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-carboxynitrile

[0455]

[0456] A solution of bis(trichloromethyl) carbonate (BTC, 28.5 g, 96.2 mmol) was added to a solution of 3-amino-4-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)benzonitrile (14 g, 48.1 mmol) in anhydrous THF (400 mL) at 0 °C. Then, Et3N (33 mL) was added dropwise to the mixture at 0 °C. After the addition, the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into a saturated aqueous solution of NaHCO3 (500 mL) and extracted with EtOAc (3 × 300 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluting with petroleum ether:EtOAc = 5:1 to 1:1) to give 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazolium-5-carboxynitrile. Yield: 4.8 g (31%). LCMS method F:R t = 1.378 min. (M+H) + = 318.3 1 H NMR (CDCl3): δ 10.06 (brs, 1 H), 7.31 (d, J = 8.4 Hz, 1H), 7.16 (s, 1H), 7.11 (d, J = 8.0 Hz, 1 H), 3.94-3.96 (m, 2 H), 3.83-3.85(m, 2 H), 0.67 (s, 9 H), -0.198 (s, 6H).

[0457] Step 5. 1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-carboxaldehyde (intermediate 24A) and 2-(5-formyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl formic acid (intermediate 24)

[0458] Ni-Al (8.27 g, 96.2 mmol) was added to a solution of 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazolium-5-carboxynitrile (6.1 g, 19.2 mmol) in HCOOH (120 mL) and H2O (40 mL) under N2 conditions. The reaction mixture was then stirred at 90 °C for 16 h. The reaction mixture was then filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with DCM:MeOH = 10:1) to give a white solid 1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-carboxaldehyde (intermediate 24A) and a yellow solid 2-(5-formyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl carbamate (intermediate 24).

[0459] Intermediate 24. Ethyl formate 2-(5-formyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl) formate: Yield: 1.7 g (27%). LCMS method F:R t = 0.858 min; (M+H) + = 235.2 1 H NMR (DMSO-d6): δ11.27 (brs, 1 H), 9.87 (s, 1 H), 8.12 (s, 1H), 7.63 (dd, J = 8.0, 1.2 Hz, 1H), 7.42 (s, 1H), 7.37 (d, J = 8.0 Hz, 1 H), 4.35-4.38 (m, 2 H), 4.12-4.14 (m, 2 H).

[0460] Intermediate 24A. 1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-carboxaldehyde: Yield: 1.5 g (27%). LCMS method F:R t = 0.788 min; (M+H) + = 207.2 1 H NMR (DMSO-d6): δ 11.20(brs, 1 H), 9.86 (s, 1 H), 7.60 (d, J = 8.0 Hz, 1 H), 7.40 (s, 1H), 7.31 (d,J = 8.0 Hz, 1 H), 4.86 (s, 1 H), 3.85-3.86 (m, 2 H), 3.63-3.65 (m, 2 H).

[0461] Example 1. 5-((7-(5-(4-fluoro-2-(trifluoromethyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one

[0462]

[0463] Step 1: 5-Fluoro-N-isopropyl-N-methyl-2-(3-(piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide

[0464]

[0465] HCl-di(2,3-c)pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-carboxylic acid tert-butyl ester (intermediate 1, 840 mg, 1.69 mmol) was added to a mixture of 4-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-carboxylic acid tert-butyl ester (intermediate 1, 840 mg, 1.69 mmol) in CH2Cl2 (20 mL) under ice-cold water. Alkane (3 mL). The mixture was stirred at room temperature for 2 h. The mixture was then concentrated under reduced pressure and the residue was alkalized to pH = 10-12 with 10% NaOH solution and extracted with DCM / isopropanol = 10 / 1 (3 × 40 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow oily 5-fluoro-N-isopropyl-N-methyl-2-(3-(piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide, which was used directly in the next step without further purification. Yield: 640 mg (96% crude); LCMS Method B: R t = 0.758 min; (M+H) + = 395.4. 1H NMR (CD3OD): δ ppm 8.53-8.61 (m, 1H), 8.15-8.19 (m, 1H), 7.74-7.76 (d, J = 5.2 Hz, 1H), 7.62-7.68 (m, 1H), 7.33-7.45 (m, 3H), 4.43-4.47 (m,0.5H), 3.55-3.58 (m, 0.5H), 3.15-3.25 (m, 2H), 3.00-3.10 (m, 1H), 2.85-2.95(m, 2H), 2.43-2.65 (m, 3H), 2.09 (d, J = 12.8 Hz, 2H), 1.70-1.85 (m, 2H), 0.95-1.05 (m, 3H), 0.20-0.55 (m, 3H). 19 F NMR (CD3OD): δ ppm -113.21 to -113.49.

[0466] Step 2: 2-(3-(1-benzylpiperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide

[0467] 5-fluoro-N-isopropyl-N-methyl-2-(3-(piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide (25 mg, 0.06 mmol), benzaldehyde (13 mg, 0.13 mmol), and NaBH3CN were added. A mixture of 15 mg (0.24 mmol) in MeOH (4 mL) was stirred at 70 °C for 17 h. The mixture was then concentrated under reduced pressure. The residue was purified by alkaline preparative RP-HPLC method D to give a white solid 2-(3-(1-benzylpiperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide. Yield: 7.6 mg (25%); LCMS method E:R t =0.907 min; (M+H) + = 485.4. 1H NMR (CD3OD): δ ppm 8.50-8.60 (m, 1H), 8.13-8.17 (m,1H), 7.73-7.74 (d, J = 5.2 Hz, 1H), 7.55-7.65 (m, 1H), 7.20-7.45 (m, 8H),4.43-4.46 (m, 1H), 3.61 (s, 2H) 3.00-3.07 (m, 2H) 2.85-2.94 (m, 1H), 2.42-2.63 (m, 3H), 2.20-2.30 (m, 2H), 1.84-2.04 (m, 4H), 0.98-1.03 (m, 3H), 0.20-0.51 (m, 3H). 19 F NMR (CD3OD): δ ppm -113.33 to -113.62.

[0468] Examples 2 to 17.

[0469] The following embodiments were synthesized using the method described above for Embodiment 1.

[0470] Table 3.

[0471]

[0472] Examples 18-18A. (trans-4-(2-(4-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)ethyl)cyclohexyl)tert-butyl carbamate (Example 18A) and 2-(3-(1-(2-(trans-4-acetamidocyclohexyl)ethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide (Example 18)

[0473] and

[0474] Step 1: (trans-4-(2-(4-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)ethyl)cyclohexyl)tert-butyl carbamate (Example 18A)

[0475]

[0476] A mixture of 5-fluoro-N-isopropyl-N-methyl-2-(3-(piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide (Example 1, Step 1, 120 mg, 0.24 mmol, HCl salt), intermediate 23 (87 mg, 0.36 mmol), Et3N (121 mg, 0.17 mL, 1.2 mmol), and NaBH3CN (75 mg, 1.2 mmol) in anhydrous MeOH (6 mL) was stirred at 70 °C for 18 h. The mixture was then concentrated under reduced pressure. The residue was added to H2O (20 mL) and extracted with EtOAc (3 × 40 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with CH2Cl2 / MeOH = 9 / 1) to give a white solid (trans-4-(2-(4-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)ethyl)cyclohexyl)tert-butyl carbamate (100 mg, 68% yield). LCMS method E:R t =0.836 min; (M+H) + = 620.5. 1 H NMR (CD3OD): δ ppm 8.52-8.61 (m, 1H), 8.14-8.18 (m,1H), 7.74-7.75 (m, 1H), 7.60-7.7 (m, 1H), 7.30-7.45 (m, 3H), 4.40-4.49 (m,1H), 3.50-3.60 (m, 1H), 2.85-3.25 (m, 5H), 2.40-2.66 (m, 5H), 2.15-2.25 (m,2H), 2.00-2.10 (m, 2H), 1.75-1.95 (m, 6H), 1.40-1.60 (m, 10H), 0.95-1.35 (m,7H), 0.20-0.55 (m, 3H). 19 F NMR (CD3OD δ ppm -117.52 to -113.25).

[0477] Step 2: 2-(3-(1-(2-(trans-4-aminocyclohexyl)ethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide

[0478]

[0479] Add HCl-di(2-(4-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)ethyl)cyclohexyl)tert-butyl carbamate (60 mg, 0.1 mmol) to a mixture in anhydrous DCM (5 mL). Alkane (1 mL, 4 N). The mixture was stirred at 5–18 °C for 1 h. A white solid formed. The mixture was concentrated under reduced pressure to give a white solid of 2-(3-(1-(2-(trans-4-aminocyclohexyl)ethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide in the form of an HCl salt, which was used directly in the next step without further purification. Yield: 60 mg (100% crude); LCMS method B: R t =0.474 min; (M+H) + = 520.2

[0480] Step 3: 2-(3-(1-(2-(trans-4-acetamidocyclohexyl)ethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide (Example 18)

[0481] Ac2O (20 mg, 0.2 mmol) was added to a mixture of 2-(3-(1-(2-(trans-4-aminocyclohexyl)ethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide (60 mg, 0.1 mmol, HCl salt) and Et3N (61 mg, 0.08 mL, 0.6 mmol) in anhydrous CH2Cl2 (5 mL). The mixture was stirred at 5–18 °C for 18 h. The mixture was concentrated under reduced pressure. The residue was purified by preparative RP-HPLC method A to give a white solid 2-(3-(1-(2-(trans-4-acetamicyclohexyl)ethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide (TFA salt). Yield: 13 mg (23%); LCMS method E:R t= 0.440 min; (M+H) + = 562.5. 1 H NMR (CD3OD): δ ppm 8.90-9.00 (m, 1H), 8.30-8.40 (m, 2H), 8.10-8.20 (m, 1H), 7.70-7.80 (m, 1H), 7.45-7.55 (m, 2H), 4.35-4.45 (m, 0.6H), 3.70-3.80 (m, 2.6H), 3.50-3.65 (m, 1H), 3.40-3.50 (m, 1H), 3.15-3.25 (m, 4H), 2.65 (s, 3H), 2.05-2.40 (m, 4H), 1.70-2.00 (m, 10H), 0.50-1.50 (m, 10H). 19 F NMR (CD3OD): δ ppm -110.66 to -110.48, -77.44 to -76.67.

[0482] Example 19. 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1-(2-(trans-4-(methanesulfonylamino)cyclohexyl)ethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide

[0483]

[0484] 2-(3-(1-(2-(trans-4-aminocyclohexyl)ethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide (Example 18, step 2, 34 mg, 0.065 mmol, HCl salt), (MeSO2)2O (34 mg, 0.20 mmol), and Et3N (33 mg, 0.33 mmol) were stirred for 0.5 h in anhydrous DCM (20 mL) at 3-16 °C. The mixture was concentrated under reduced pressure. The residue was purified by alkaline preparative RP-HPLC method D to obtain a white solid, 5-fluoro-N-isopropyl-N-methyl-2-(3-(1-(2-(trans-4-(methanesulfonylamino)cyclohexyl)ethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide. Yield: 12.3 mg (31%); LCMS method E:R t = 2.011 min; (M+H) + = 598.3 1H NMR (CD3OD): δ ppm 8.54-8.63 (m,1H), 8.15-8.25 (m, 1H), 7.76 (d, J = 5.6 Hz, 1H), 7.60-7.70 (m, 1H), 7.40-7.50 (m, 2H), 7.35-7.37 (m, 1H), 4.37-4.51 (m, 0.5H), 3.55-3.65 (m, 0.5 H), 3.11-3.20 (m, 3H), 2.60-3.00 (m, 6 H), 2.40-2.51 (m, 3H), 1.75-2.30 (m, 10H),0.90-1.52 (m, 10H), 0.20-0.60 (m, 3H). 19 F NMR (CD3OD): δ ppm -113.24 to 113.58.

[0485] Examples 20-20A. (trans-4-((4-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)methyl)cyclohexyl)tert-butyl carbamate (Example 20A) and 2-(3-(1-(1-(trans-4-acetamidocyclohexyl)methyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide (Example 20)

[0486] and

[0487] Step 1: ((1r,4r)-4-((4-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)methyl)cyclohexyl)tert-butyl carbamate (Example 20A)

[0488]

[0489] TEA (75 mg, 0.75 mmol) was added to a solution of 5-fluoro-N-isopropyl-N-methyl-2-(3-(piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide (Example 1, Step 1, 60 mg, 0.15 mmol, hydrochloride) and (trans-4-formylcyclohexyl)carbamate tert-butyl ester (35 mg, 0.15 mmol) in MeOH (2 mL, anhydrous). The resulting mixture was stirred at 2–18 °C for 20 min, and then NaBH3CN (29 mg, 0.45 mmol) was added. The resulting mixture was stirred at 2–18 °C for approximately 16 h. The mixture was concentrated, and the residue was purified by preparative RP-HPLC method A to give tert-butyl carbamate ((1r,4r)-4-((4-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)methyl)cyclohexyl)carbamate. Yield: 80 mg (88%); LCMS method E:R t =0.816 min; (M+H) + = 606.5. 1 H NMR (CD3OD): δ ppm 8.86-9.01 (m, 1 H), 8.25-8.39 (m, 2 H), 8.14 (d, J = 11.6 Hz, 1 H), 7.74 (dd, J = 8.4, 4.0 Hz, 1 H), 7.43-7.56 (m, 2 H), 4.35-4.45 (s, 1 H), 3.70-3.80 (m, 3 H), 3.35-3.50 (m, 2 H), 3.05-3.30 (m, 4 H), 2.55- 2.65 (m, 3 H), 2.05-2.40 (m, 5 H), 1.80-2.05 (m, 5H), 1.44 (s, 6H), 1.05-1.38 (m, 6H), 0.55-0.95 (m, 5H). 19 F NMR (CD3OD): δppm -77.07, -110.41 to -110.60.

[0490] Step 2: 2-(3-(1-(((1r,4r)-4-aminocyclohexyl)methyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide

[0491]

[0492] Add HCl to a solution of (trans-4-((4-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)methyl)cyclohexyl)tert-butyl carbamate (80 mg, 0.13 mmol) in DCM (3 mL). Alkane (0.6 mL, 4 M). The mixture was stirred at 5–18 °C for 4 h. The mixture was concentrated to give crude 2-(3-(1-((trans-4-aminocyclohexyl)methyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide (HCl salt), which was used directly in the next step without purification. Yield: 80 mg (100% crude); LCMS method E:R t = 0.756 min; (M+H) + = 506.5

[0493] Step 3: 2-(3-(1-(((1r,4r)-4-acetamidocyclohexyl)methyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide (Example 20)

[0494] Pyridine (101 mg, 1.28 mmol) and Ac₂O (18 mg, 0.17 mmol) were added to a solution of 2-(3-(1-((trans-4-aminocyclohexyl)methyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide (80 mg, 0.16 mmol, HCl salt) in DCM (2 mL, anhydrous). The mixture was stirred at room temperature for 16 h. The mixture was concentrated, and the residue was purified by preparative RP-HPLC method A to give a white solid of 2-(3-(1-((trans-4-acetamicyclohexyl)methyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide (TFA salt). Yield: 15 mg (17%); LCMS method E:R t = 0.849 min; (M+H) + = 548.4. 1H NMR (CD3OD): δ ppm 8.85-9.04 (m, 1H), 8.30-8.40 (m, 2H), 8.10-8.21(m, 1H), 7.76 (dd, J = 8.8, 4.8 Hz, 1H), 7.43-7.58 (m, 2H), 4.33-4.45 (m,1H), 3.70-3.85 (m, 2H), 3.55-3.70 (m, 1H), 3.40-3.50 (m, 1H), 3.15-3.25 (m,2H), 3.10 (d, J = 6.4 Hz, 2H), 2.58-2.68 (m, 3H), 2.12-2.40 (m, 4H), 1.87-2.04 (m, 8H), 1.07-1.40 (m, 6H), 0.49-1.01 (m, 4H). 19 FNMR (CD3OD): δ ppm -76.92, -110.45 to 110.63.

[0495] Example 21. 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1-((trans-4-(methanesulfonylamino)cyclohexyl)methyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide

[0496]

[0497] Et3N (86 mg, 0.85 mmol) and (MeSO2)2O (89 mg, 0.51 mmol) were added to a mixture of 2-(3-(1-((trans-4-(methanesulfonylamino)cyclohexyl)methyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide (Example 20, Step 2, 85 mg, 0.17 mmol) in CH2Cl2 (15 mL), and the mixture was stirred at room temperature for 0.5 h. The mixture was then concentrated under reduced pressure and the residue was purified by alkaline preparative RP-HPLC method G to obtain a white solid 5-fluoro-N-isopropyl-N-methyl-2-(3-(1-((trans-4-(methanesulfonylamino)cyclohexyl)methyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide. Yield: 38.3 mg (27%); LCMS method E:R t = 0.859 min; (M+H) + = 584.4. 1H NMR (CD3OD): δ ppm 8.30-8.41 (m, 1H), 7.94-7.98 (m, 1H), 7.54 (d, J = 5.2 Hz, 1H), 7.41-7.48 (m, 1H), 7.13-7.23 (m, 3H), 4.24-4.27 (m, 0.5H), 3.35-3.38 (m, 0.5H), 2.95-3.00 (m, 1H), 2.80-2.90 (m,2H), 2.60-2.75 (m, 4H), 2.23-2.46 (m, 3H), 1.90-2.10 (m, 2H) 1.90-2.00 (m,2H) 1.75-1.85 (m, 4H), 1.55-1.75 (d, J = 13.2 Hz, 4H), 1.25-1.35 (m, 1H), 1.05-1.15 (m, 2H), 0.75-0.90 (m, 5H), 0.00-0.35 (m, 3H). 19 F NMR (CD3OD): δ ppm -113.59 to -113.32.

[0498] Example 22. 2-(3-(1-(4-acetamidobenzyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide

[0499]

[0500] Step 1: (4-((4-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)methyl)phenyl)tert-butyl carbamate

[0501]

[0502] 5-Fluoro-N-isopropyl-N-methyl-2-(3-(piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide (Example 1, Step 1, 200 mg, 0.51 mmol, HCl salt), (4-formylphenyl)carbamate tert-butyl ester (244 mg, 1.01 mmol), and Et3N (258 mg, 2.55 mmol) were stirred in anhydrous MeOH (20 mL) for 0.5 h at room temperature. NaBH3CN (128 mg, 2.04 mmol) was added, and the mixture was then stirred at 60 °C for 18 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with DCM / MeOH = 1 / 0 to 10 / 1) to give a yellow oil of tert-butyl carbamate (4-((4-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)methyl)phenyl)carbamate. Yield: 110 mg (36%); LCMS method B: R t = 0.615min; (M+H) + = 600.1

[0503] Step 2: 2-(3-(1-(4-aminobenzyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide

[0504]

[0505] HCl-di(2,3-c)pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)methyl)phenyl)carbamate tert-butyl ester (110 mg, 0.18 mmol) in anhydrous DCM (20 mL) was added at 0 °C. Alkane (4 mL, 4 N) solution. The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure to give a white solid 2-(3-(1-(4-aminobenzyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide, which was used without further purification. Yield: 91 mg (100% crude product).

[0506] Step 3: 2-(3-(1-(4-acetamidobenzyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide

[0507] A solution of 2-(3-(1-(4-aminobenzyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide (41 mg, 0.082 mmol, HCl salt), Ac₂O (25 mg, 0.25 mmol), and pyridine (32 mg, 0.41 mmol) in anhydrous DCM (20 mL) was stirred at 2–15 °C for 18 h. The mixture was concentrated under reduced pressure. The residue was purified by alkaline preparative RP-HPLC method D to give 2-(3-(1-(4-acetamidobenzyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide. LCMS method E:R t = 1.806 min; (M+H) + = 542.3. 1 H NMR (CD3OD): δ ppm 8.53-8.62 (m, 1H), 8.19 (dd, J = 5.6,8.0 Hz, 1H), 7.76 (d, J = 5.6 Hz, 1H), 7.63-7.69 (m, 1H), 7.56 (d, J = 8.4Hz, 2H), 7.40-7.47 (m, 2H), 7.33-7.36 (m, 3H), 4.45-4.48 (m, 0.5H), 3.61 (s,2H), 3.50-3.60 (m, 0.6H), 3.06-3.09 (m, 2H), 2.90-3.00 (m, 1H), 2.40-2.60 (m,3H), 2.25-2.35 (m, 2H), 2.17 (s, 3H), 2.00-2.07 (m, 2H), 1.80-1.95 (m, 2H), 0.95-1.05 (m, 3H), 0.22-0.52 (m, 3H). 19 FNMR (CD3OD): δ ppm -111.27 to -113.55.

[0508] Example 23. 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1-(4-(methanesulfonylamino)benzyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide

[0509]

[0510] The title compound was prepared according to the method described in Example 22. Methanesulfonic anhydride was used instead of acetic anhydride in step 3. LCMS method D:Rt = 1.749 min; (M+H) + = 578.2. 1 H NMR (CD3OD): δ ppm 8.54-8.63 (m, 1H), 8.18 (dd, J = 5.6, 8.0 Hz, 1H), 7.76 (d, J = 5.2 Hz, 1H), 7.60-7.70 (m, 1H), 7.34-7.45 (m, 5H), 7.26 (d, J = 8.4 Hz, 1H), 4.40-4.50 (m,0.5H), 3.62 (s, 2H), 3.50-3.60 (m, 0.5H), 3.06-3.09 (m, 2H), 2.97 (s, 3H), 2.90-2.95 (m, 1H), 2.40-2.70 (m, 3H), 2.25-2.35 (m, 2H), 2.00-2.07 (m, 2H), 1.80-1.95 (m, 2H), 0.95-1.10 (m, 3H), 0.22-0.60 (m, 3H). 19 F NMR (CD3OD): δ ppm -113.24 to 113.53.

[0511] Example 24. 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1-(4-(methanesulfonyl)phenethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide

[0512]

[0513] Step 1: 1-(2-methoxyvinyl)-4-(methylsulfonyl)benzene

[0514]

[0515] n-BuLi (2.2 mL, 5.43 mmol, 2.5 mol / L in hexane) was added dropwise to a solution of MeOCH2PPh3Cl (1.9 g, 5.43 mmol) in anhydrous THF (40 mL) at -78 °C under N2. After 30 min, 4-(methylsulfonyl)benzaldehyde (500 mg, 2.71 mmol) dissolved in anhydrous THF (10 mL) was added dropwise. The reaction mixture was stirred at -78 °C for 2 h and then heated to 7-22 °C and maintained for 18 h. The mixture was quenched with saturated NH4Cl (10 mL) solution. The mixture was diluted with H2O (40 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with petroleum ether / EtOAc = 10 / 1 to 1 / 1) to give a yellow solid (1-(2-methoxyvinyl)-4-(methylsulfonyl)benzene (approximately 90% purity, E and Z mixture, 1 / 1 ratio). Yield: 200 mg (35%). 1 H NMR (CDCl3): δ ppm 7.80-7.85 (m, 4H), 7.73 (d, J = 8.8 Hz, 2H), 7.39 (d, J = 8.8 Hz, 2H), 7.22 (d, J = 13.2 Hz, 1H), 6.32 (d, J = 6.8 Hz, 1H), 5.85 (d, J = 12.8 Hz, 1H), 5.29 (d, J = 7.2 Hz, 1H), 3.86 (s, 3H), 3.74 (s, 3H), 3.04 (s, 6H).

[0516] Step 2: 2-(4-(methylsulfonyl)phenyl)acetaldehyde

[0517]

[0518] An aqueous solution of HCl (5 mL, 3N) was added to a solution of 1-(2-methoxyvinyl)-4-(methanesulfonyl)benzene (200 mg, 0.94 mmol) in anhydrous THF (20 mL). The reaction mixture was stirred at 70 °C for 2 h. The mixture was diluted with H₂O (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow solid 2-(4-(methanesulfonyl)phenyl)acetaldehyde (150 mg, 80%, crude product), which was used directly in the next step without further purification. Yield: 150 mg (80% crude product);

[0519] Step 3: 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1-(4-(methanesulfonyl)phenethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide

[0520]

[0521] A solution of 5-fluoro-N-isopropyl-N-methyl-2-(3-(piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide (Example 1, Step 1, 50 mg, 0.13 mmol, HCl salt), 2-(4-(methanesulfonyl)phenyl)acetaldehyde (50 mg, 0.25 mmol, crude product) and Et3N (64 mg, 0.63 mmol) in anhydrous MeOH (20 mL) was stirred at 3–17 °C for 0.5 h. Then, NaBH3CN (33 mg, 0.52 mmol) was added, and the reaction mixture was stirred at 60 °C for 18 h. The mixture was then concentrated under reduced pressure. The residue was purified by preparative RP-HPLC to obtain a white solid, 5-fluoro-N-isopropyl-N-methyl-2-(3-(1-(4-(methanesulfonyl)phenylethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide. Yield: 20.0 mg (27%); LCMS method: E:R t = 1.874 min; (M+H) + = 577.2. 1HNMR (CD3OD): δ ppm 8.50-8.65 (m, 1H), 8.20 (dd, J = 5.6, 8.0 Hz, 1H), 7.91 (d,J = 8.4 Hz, 2H), 7.77 (d, J = 5.6 Hz, 1H), 7.63-7.70 (m, 1H), 7.56 (d, J =8.0 Hz, 2H), 7.42-7.48 (m, 2H), 7.34-7.37 (m, 1H), 4.40-4.50 (m, 0.5H), 3.58-4.47 (m, 0.5H), 3.15-3.23 (m, 2H), 3.12 (s, 3H), 2.90-3.05 (m, 3H), 2.70-2.76(m, 2H), 2.40-2.65 (m, 3H), 2.32-2.38 (m, 2H), 2.05-2.14 (m, 2H), 1.80-1.95(m, 2H), 0.96-1.10 (m, 3H), 0.20-0.60 (m, 3H). 19 F NMR (CD3OD): δ ppm -113.25 to 113.53.

[0522] Example 25. 2-(3-(1-(3-cyanophenylethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide

[0523]

[0524] The title compound was prepared starting with 3-cyanobenzaldehyde according to the method described in Example 24. LCMS method E:R t = 0.716 min; (M+H) + = 524.3. 1 H NMR (CD3OD): δ ppm 8.85-8.90 (m, 1H), 8.15-8.45 (m, 3H), 7.43-7.77 (m, 7H), 4.37 (s, 1H), 3.36-3.84 (m, 8H), 2.22-2.63 (m, 7H), 0.53-1.11 (m, 6H). 19 F NMR (CD3OD): δ ppm -110.49 to -110.67.

[0525] Example 26. 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1-(3-(methylcarbamoyl)phenethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide

[0526]

[0527] Step 1: Methyl 3-(2-(4-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)ethyl)benzoate

[0528]

[0529] Et3N (126 mg, 1.25 mmol) was added to a mixture of 5-fluoro-N-isopropyl-N-methyl-2-(3-(piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide (Example 1, Step 1, 100 mg, 0.25 mmol) in MeOH (10 mL), and the mixture was stirred at 7-19 °C for 10 min. Methyl 3-(2-oxoethyl)benzoate (90 mg, 0.51 mmol), prepared from methyl 4-formylbenzoate by a method similar to steps 1-2 of Example 24, was added to the mixture, followed by the addition of NaBH3CN. (62 mg, 1.00 mmol). The mixture was degassed and purged three times with N2, followed by heating at 70 °C for 17 h under N2 atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with DCM / MeOH = 10 / 1) to give a white oily methyl 3-(2-(4-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)ethyl)benzoate. Yield: 135 mg (95%); LCMS method E: R t = 0.585 min; (M+H) + = 557.1

[0530] Step 2: 3-(2-(4-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)ethyl)benzoic acid

[0531]

[0532] Add 10% NaOH solution (2 mL) to a mixture of methyl 3-(2-(4-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)ethyl)benzoate (50 mg, 0.09 mmol) in MeOH (5 mL). Degas the mixture with N2 and purge three times, then heat at 8–18 °C for 17 h under N2 atmosphere. Extract the mixture with EtOAc (20 mL × 3). Add 1N HCl to the aqueous solution to adjust the pH to 3–4. Then extract the aqueous solution with EtOAc (20 mL × 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to give a yellow solid 3-(2-(4-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)ethyl)benzoic acid. Yield: 49 mg (100% crude); LCMS method E: R t = 0.578 min; (M+H) + = 543.0

[0533] Step 3: 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1-(3-methylcarbamoyl)phenethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide

[0534] To a mixture of 3-(2-(4-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)ethyl)benzoic acid (49 mg, 0.09 mmol) in DMF (8 mL), HATU (103 mg, 0.27 mmol), MeNH2 in THF (0.23 mL, 0.45 mmol), and Et3N (36 mg, 0.36 mmol) were added. The mixture was degassed with N2 and purged three times, followed by heating at 11–18 °C for 2 h under N2 atmosphere. The mixture was then extracted with EtOAc (20 mL × 3) and the combined organic layers were washed with water (20 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by alkaline preparative RP-HPLC method D to obtain a white solid, 5-fluoro-N-isopropyl-N-methyl-2-(3-(1-(3-(methylcarbamoyl)phenylethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide. LCMS method E: R t = 0.873 min; (M+H)+ = 556.4. 1 HNMR (CD3OD): δ ppm 8.55-8.64 (m, 1H), 8.20-8.25 (m, 1H), 7.65-7.79 (m, 4H), 7.35-7.50 (m, 5H), 4.47-4.64 (m, 0.5H), 3.54-3.62 (m, 0.5H), 3.19-3.26 (m,2H) 2.94-3.04 (m, 3H), 2.94 (s, 3H), 2.75-2.84 (m, 2H), 2.47-2.69 (m, 3H),2.38-2.47 (m, 2H), 2.11-2.15 (m, 2H), 1.91-1.96 (m, 2H), 0.90-1.09 (m, 3H), 0.12-0.59 (m, 3H). 19 F NMR (CD3OD) δ ppm -113.23 to -113.50.

[0535] Examples 27-27A. trans-(5-fluoro-2-(3-(1-((4-hydroxycyclohexyl)methyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropyl-N-methylbenzamide (Example 27) and cis-(5-fluoro-2-(3-(1-((4-hydroxycyclohexyl)methyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropyl-N-methylbenzamide) (Example 27A)

[0536] and

[0537] Step 1: 2-(3-(1-(1,4-dioxaspiro[4.5]dec-8-ylmethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide

[0538]

[0539] To a solution of 5-fluoro-N-isopropyl-N-methyl-2-(3-(piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide (Example 1, Step 1, 100 mg, 0.25 mmol) in MeOH (3 mL, anhydrous), 1,4-dioxaspiro[4.5]decane-8-carboxaldehyde (65 mg, 0.38 mmol) and NaCNBH3 (32 mg, 0.50 mmol) were added. The resulting mixture was stirred under N2 at 6–10 °C for 20 h. The reaction mixture was then concentrated under reduced pressure. The residue was purified by alkaline preparative RP-HPLC method D to obtain a white solid 2-(3-(1-(1,4-dioxaspiro[4.5]dec-8-ylmethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide (40 mg, 28%). Yield: 40 mg (28%); LCMS method D: R t = 1.567 min; (M+H) + = 549.3.

[0540] Step 2: 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1-((4-oxocyclohexyl)methyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide

[0541]

[0542] An aqueous solution of HCl (2 mL, 3 M in H2O) was added to a solution of 2-(3-(1-(1,4-dioxaspiro[4.5]dec-8-ylmethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide (40 mg, 0.073 mmol) in THF (4 mL, anhydrous). The resulting mixture was stirred at 40 °C (oil temperature) under N2 for 20 h. The reaction mixture was then neutralized with an aqueous solution of NaOH (2 N in H2O) and the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The organic layer was washed with brine (2 × 30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a colorless oily 5-fluoro-N-isopropyl-N-methyl-2-(3-(1-((4-oxocyclohexyl)methyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide (25 mg, 68% crude yield), which was used directly in the next step.

[0543] Step 3: trans-(5-fluoro-2-(3-(1-((4-hydroxycyclohexyl)methyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropyl-N-methylbenzamide) and cis-(5-fluoro-2-(3-(1-((4-hydroxycyclohexyl)methyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropyl-N-methylbenzamide)

[0544] To a solution of 5-fluoro-N-isopropyl-N-methyl-2-(3-(1-((4-oxocyclohexyl)methyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide (25 mg, 0.050 mmol) in MeOH (3 mL, anhydrous), NaBH4 (2.8 mg, 0.075 mmol) was added, and the resulting mixture was stirred at room temperature for 30 min. The reaction mixture was then neutralized with 1N HCl (0.5 mL). The reaction mixture was purified by preparative RP-HPLC method A to obtain trans-(5-fluoro-2-(3-(1-((4-hydroxycyclohexyl)methyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropyl-N-methylbenzamide (TFA salt) and cis-(5-fluoro-2-(3-(1-((4-hydroxycyclohexyl)methyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropyl-N-methylbenzamide (TFA salt), both of which were colorless solids.

[0545] Example 27 (trans-isomer): LCMS method D:R t = 1.254 min; (M+H) + = 507.3. 1H NMR(CD3OD): δ ppm 8.81-9.12 (m, 1H), 8.32-8.42 (m, 2H), 8.14-8.18 (m, 1H), 7.74-7.78 (m, 1H), 7.43-7.57 (m, 2H), 4.33-4.44 (m, 0.5H), 3.68-3.84 (m, 2.5H), 3.52-3.58 (m, 1H), 3.40-3.45 (m, 1H), 3.22 (t, J = 12.0 Hz, 2H), 3.08 (d, J =6.4 Hz, 2H), 2.59-2.67 (m, 3H), 2.15-2.38 (m, 4H), 1.87-2.07 (m, 5H), 1.30-1.40 (m, 2H), 1.08-1.26 (m, 4H), 0.51-1.05 (m, 4H). 19 F NMR (CD3OD): δ ppm -110.67 to -110.48, -76.88.

[0546] Example 27A (cis-isomer): LCMS method D:R t = 1.312 min; (M+H) + = 507.3. 1 H NMR(CD3OD): δ ppm 8.90-8.99 (m, 1H), 8.33-8.38 (m, 2H), 8.12-8.18 (m, 1H), 7.74-7.78 (m, 1H), 7.46-7.58 (m, 2H), 4.40-4.42 (m, 0.5H), 3.95-4.01 (m, 0.5H), 3.60-3.80 (m, 2.0H), 3.43-3.50 (m, 1H), 3.15-3.30 (m, 4H), 3.11 (d, J = 6.8Hz, 1H), 2.56-2.69 (m, 3H), 2.09-2.45 (m, 5H), 1.74-2.08 (m, 3H), 1.53-1.69 (m, 4H), 0.34-1.32 (m, 7H). 19 F NMR (CD3OD): δ ppm -110.71 to -110.51, -76.90.

[0547] Example 28. 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1-(2-(1-(methanesulfonyl)piperidin-4-yl)ethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide

[0548]

[0549] Step 1: 4-(2-(4-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)ethyl)piperidin-1-carboxylic acid tert-butyl ester

[0550]

[0551] A mixture of 5-fluoro-N-isopropyl-N-methyl-2-(3-(piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide (Example 1, Step 1, 120 mg, 0.28 mmol, HCl salt), tert-butyl 4-(2-oxoethyl)piperidin-1-carboxylic acid (95 mg, 0.42 mmol, HCl salt), and NaBH3CN (70 mg, 1.12 mmol) in MeOH (5 mL) was stirred at 70 °C for 18 h. The mixture was then concentrated under reduced pressure. The residue was added to H2O (20 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with DCM / MeOH = 10 / 1) to give tert-butyl 4-(2-(4-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)ethyl)piperidin-1-carboxylic acid as a yellow oil, which was used directly in the next step.

[0552] Step 2: 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1-(2-(piperidin-4-yl)ethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide

[0553]

[0554] Add HCl / di(2-(4-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)ethyl)piperidin-1-carboxylic acid tert-butyl ester (70 mg, 0.12 mmol) to a mixture of 4-(2-(4-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)piperidin-1-carboxylic acid tert-butyl ester (70 mg, 0.12 mmol) in anhydrous DCM (5 mL). The mixture was stirred at room temperature for 1 h with 1 mL of alkylene (4 N). The mixture was then concentrated under reduced pressure to give crude white solid 5-fluoro-N-isopropyl-N-methyl-2-(3-(1-(2-(piperidin-4-yl)ethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide (HCl salt), which was used directly in the next step without further purification.

[0555] Step 3: 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1-(2-(1-(methanesulfonyl)piperidin-4-yl)ethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide

[0556] Add (MeSO2)2O (63 mg, 0.36 mmol) to a mixture of 5-fluoro-N-isopropyl-N-methyl-2-(3-(1-(2-(piperidin-4-yl)ethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide (70 mg crude, 0.12 mmol, HCl salt) and Et3N (61 mg, 0.08 mL, 0.6 mmol) in anhydrous DCM (5 mL), and stir the mixture at 6–20 °C for 30 min. The mixture was then concentrated under reduced pressure, and the residue was purified by preparative RP-HPLC to give a white solid, 5-fluoro-N-isopropyl-N-methyl-2-(3-(1-(2-(1-(methanesulfonyl)piperidin-4-yl)ethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide. Yield: 14.6 mg (21%); LCMS method: E:R t = 0.878 min; (M+H) + = 584.4. 1H NMR (CD3OD): δ ppm 8.55-8.64 (m, 1H), 8.17-8.21 (m, 1H), 7.76-7.79 (m, 1H), 7.65-7.69 (m, 1H), 7.35-7.46 (m, 3H), 4.46-4.50 (m, 0.5H), 3.71-3.74 (m, 2H), 3.56-3.58 (m, 0.5H), 3.10-3.20 (m,2H), 2.90-3.05 (m, 1H), 2.83-2.85 (m, 3H), 2.70-2.80 (m, 2H), 2.68 (s, 1.5H),2.50-2.60 (m, 2H), 2.45 (s, 1.5H), 2.20-2.30 (m, 2H), 2.00-2.10 (m, 2H), 1.80-2.00 (m, 4H), 1.40-1.60 (m, 3H), 1.25-1.35 (m, 2H), 0.95-1.10 (m, 3H), 0.20-0.60 (m, 3H). 19 F NMR (CD3OD): δ ppm -115.84 to -113.23.

[0557] Example 29. 2-(3-(1-(4-(2-cyanopropane-2-yl)phenethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide

[0558]

[0559] Step 1: 2-(4-(bromomethyl)phenyl)ethanol

[0560]

[0561] BH3-THF (20.7 mL, 20.7 mmol, 1 M) was added dropwise to a solution of 2-(4-(bromomethyl)phenyl)acetic acid (3.2 g, 13.9 mmol) in anhydrous THF (30 mL) at 0 °C for 30 min. After addition, the mixture was stirred at 9–20 °C for 2 h. The mixture was then added dropwise to an aqueous HCl solution (2 M, 30 mL) and stirred at 9–20 °C for 20 min. The mixture was then extracted with EtOAc (30 mL × 2) and the combined organic layers were washed with brine (50 mL × 2), dried over Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by ISCO column (from 100% DCM to 5% MeOH in DCM) to give a white solid 2-(4-(bromomethyl)phenyl)ethanol. Yield: 3.1 g (100%). 1 H NMR(CDCl3): δ ppm 7.35 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 4.50 (s,2H), 3.87 (t, J = 6.4 Hz, 2H), 2.87 (t, J = 6.4 Hz, 2H), 1.45 (brs, 1H).

[0562] Step 2: 2-(4-(2-hydroxyethyl)phenyl)acetonitrile

[0563]

[0564] KCN (1.17 g, 18.0 mmol) was added to a solution of 2-(4-(bromomethyl)phenyl)ethanol (3.0 g, 13.8 mmol) in DMSO (30 mL), and the solution was stirred at room temperature for 4 h. The mixture was then poured into tert-butyl methyl ether / NaHCO3 (100 mL, 1 / 1) and stirred at 5–20 °C for 20 min. The organic layer was separated and washed with brine (50 mL × 3), dried over Na2SO4, filtered, and the filtrate was concentrated to give a yellow oily 2-(4-(2-hydroxyethyl)phenyl)acetonitrile, which was used directly in the next step.

[0565] Step 3: 2-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)acetonitrile

[0566]

[0567] TBSCl (1.68 g, 11.2 mmol) and imidazole (1.26 g, 18.6 mmol) were added to a solution of 2-(4-(2-hydroxyethyl)phenyl)acetonitrile (1.5 g, 9.3 mmol) in anhydrous DMF (30 mL), and the mixture was stirred at 6–20 °C for 6 h. The mixture was then diluted with EtOAc (30 mL) and washed with brine (30 mL × 2), dried over Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by ISCO column chromatography (from 100% petroleum ether to 10% EtOAc in petroleum ether) to give colorless oily 2-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)acetonitrile. Yield: 2.2 g (86%); 1 H NMR (CDCl3): δ ppm 7.24-7.29 (m, 4H), 3.82 (t, J = 7.2 Hz, 2H), 3.75 (s,2H), 2.84 (t, J = 6.8 Hz, 2H), 0.90 (s, 9H), 0.08 (s, 6H).

[0568] Step 4: 2-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)-2-methylpropionitrile

[0569]

[0570] NaH (378 mg, 9.4 mmol) was added to a solution of 2-(4-(2-(tert-butyldimethylsilyl)oxy)ethyl)phenyl)acetonitrile (1.3 g, 4.7 mmol) in anhydrous DMF (10 mL) at 0 °C and stirred for 10 min. MeI (1.34 g, 9.4 mmol) was then added dropwise to the mixture and stirred at room temperature for 2 h. The mixture was quenched with NH4Cl (20 mL) aqueous solution and extracted with EtOAc (20 mL × 2). The combined organic layers were washed with brine (30 mL × 3), dried over Na2SO4, filtered, and the filtrate was concentrated for purification by ISCO column (10% EtOAc in petroleum ether) to obtain a colorless oily 2-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)-2-methylpropionitrile. Yield: 750 mg (53%). 1H NMR (CDCl3): δ ppm 7.40 (d, J = 8.0 Hz, 2H), 7.26 (t, J = 8.0 Hz, 2H), 3.82 (t, J = 6.8 Hz, 2H), 2.84 (t, J = 6.8 Hz, 2H), 1.73 (s, 6H), 0.88 (s, 9H),0.00 (s, 6H).

[0571] Step 5: 2-(4-(2-hydroxyethyl)phenyl)-2-methylpropionitrile

[0572]

[0573] A solution of 2-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)acetonitrile (750 mg, 2.5 mmol) in 1 M TBAF solution (THF solution, 3 mL) was stirred at 2–17 °C for 2 h. The mixture was then quenched with NH4Cl (10 mL) aqueous solution and extracted with EtOAc (10 mL × 2). The combined organic layers were washed with brine (20 mL × 2), dried over Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by acidic (TFA) preparative RP-HPLC method A to give a yellow oily 2-(4-(2-hydroxyethyl)phenyl)-2-methylpropionitrile (TFA salt). Yield: 150 mg (33%); 1 H NMR(CDCl3): δ ppm 7.41-7.44 (m, 2H), 7.25-7.28 (m, 2H), 3.90 (t, J = 6.4 Hz, 2H), 3.06 (br s, 1H), 2.89 (t, J = 6.4 Hz, 2H), 1.72 (s, 6H).

[0574] Step 6: 4-(2-cyanopropane-2-yl)phenethyl methanesulfonate

[0575]

[0576] Et3N (85 mg, 0.84 mmol) and MsCl (58 mg, 0.51 mmol) were added to a solution of 2-(4-(2-hydroxyethyl)phenyl)-2-methylpropionitrile (80 mg, 0.42 mmol) in anhydrous CH2Cl2 (5 mL), and the mixture was stirred at room temperature for 18 h. The mixture was diluted with DCM (10 mL) and washed with brine (10 mL × 2), dried over Na2SO4, filtered, and the filtrate was concentrated to give colorless oily 4-(2-cyanopropane-2-yl)phenethyl methanesulfonate. Yield: 70 mg (62%); LCMS Method B: R t = 0.727 min; (M+H) + = 285.0.

[0577] Step 7: 2-(3-(1-(4-(2-cyanopropane-2-yl)phenethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide

[0578] 5-fluoro-N-isopropyl-N-methyl-2-(7-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)benzamide (Example 63, step 3, 52 mg, 0.13 mmol) and Et3N (66 mg, 0.65 mmol) were added to a solution of 4-(2-cyanopropan-2-yl)phenethyl methanesulfonate (70 mg, 0.26 mmol) in anhydrous DMF (2 mL), and the mixture was stirred at 100 °C for 18 h. The mixture was then diluted with MeCN (3 mL) and purified by RP-HPLC to obtain a white solid 2-(3-(1-(4-(2-cyanopropan-2-yl)phenethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide. Yield: 1.2 mg (1%); LCMS method D:R t = 1.747 min; (M+H) + = 556.3. 1H NMR (CD3OD): δ ppm 8.83-9.91 (m, 1H), 8.34-8.39 (s, 1H), 8.30 (d, J = 5.6 Hz, 1H), 8.05-8.15 (m, 1H), 7.70-7.80 (m, 1H), 7.44-7.57 (m,4H), 7.40 (d, J = 8.4 Hz, 2H), 3.85 (d, J = 11.6 Hz, 2H), 3.42-3.50 (m, 3H), 3.10-3.20 (m, 2H), 2.57-2.66 (m, 3H), 2.38-2.41 (m, 2H), 2.00-2.20 (m, 3H), 1.72 (s, 6H), 1.30 (s, 3H), 1.02-1.18 (m, 2H), 0.55-0.95 (m, 3H). 19 F NMR (CD3OD): δ ppm -76.94, -110.51.

[0579] Example 30. 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1-(1-phenylethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide

[0580]

[0581] To a solution of 5-fluoro-N-isopropyl-N-methyl-2-(3-(piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide (Example 1, Step 1, 50 mg, 0.13 mmol) in DMF (3 mL), (1-bromoethyl)benzene (26 mg, 0.14 mmol) and K₂CO₃ (36 mg, 0.26 mmol) were added, and the reaction mixture was stirred at 100 °C for 16 h. The mixture was then diluted with H₂O (100 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated. The residue was purified by acidic RP-HPLC to give a white solid 5-fluoro-N-isopropyl-N-methyl-2-(3-(1-(1-phenylethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide (HCl salt). Yield: 10.9 mg (17% crude); LCMS method E: R t = 0.743 min; (M+H) + = 499.3. 1HNMR (CD3OD): δ ppm 8.80-9.00 (m, 1H), 8.25-8.40 (m, 2H), 8.05-8.20 (m, 1 H), 7.70-7.80 (m, 1H), 7.40-7.60 (m, 7H), 4.50-4.60 (m, 1H), 4.30-4.40 (m, 0.5H), 3.85-3.95 (m, 1H), 3.60-3.75 (m, 0.5H), 3.45-3.55 (m, 1H), 3.30-3.40 (m, 1H), 3.00-3.25 (m, 2H), 2.55-2.65 (m, 3H), 2.25-2.40 (m, 2H), 2.00-2.20 (m, 2H), 1.75-1.90 (m, 3H), 0.50-1.20 (m, 6H). 19 F NMR (CD3OD): δ ppm -110.68 to -110.50.

[0582] Example 31. 2-(3-(2-benzylpiperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide

[0583]

[0584] Step 1: 2-Benzyl-4-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester

[0585]

[0586] The title compound was prepared by starting with tert-butyl 2-benzyl-4-oxoperpiperidine-1-carboxylic acid according to the method described for the synthesis of intermediate 1. LCMS method B: R t = 0.805 min; (M+H) + = 585.1.

[0587] Step 2: 2-(3-(2-benzylpiperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide

[0588] Add HCl / di(2-benzyl-4-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-carboxylic acid tert-butyl ester (100 mg, 0.14 mmol) to a solution of 2-benzyl-4-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-carboxylic acid tert-butyl ester (100 mg, 0.14 mmol) in DCM (3 mL). Alkane (1.0 mL) was added, and the reaction mixture was stirred at room temperature for 16 h. The mixture was then concentrated and purified by acidic RP-HPLC method A to give a white solid 2-(3-(2-benzylpiperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide (HCl salt). Yield: 31.1 mg (47%); LCMS method E: R t =0.726 min; (M+H) + = 485.3. 1 H NMR (CD3OD): δ ppm 8.85-9.05 (m, 1 H), 8.15-8.40 (m, 3 H), 7.70-7.80 (m, 1 H), 7.50-7.60 (m, 7 H), 4.30-4.40 (m, 0.5 H), 3.80-4.00 (m, 1 H), 3.55-3.80 (m, 2.5 H), 2.95-3.30 (m, 2 H), 2.60 (s, 3 H), 2.10-2.45 (m, 3 H), 1.80-2.10 (m, 2 H), 1.40-1.20 (m, 6 H). 19 F NMR (CD3OD): δ ppm -110.64 to -110.45 (m, 1F).

[0589] Example 32. 2-(3-(1-benzylpiperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-ethyl-5-fluoro-N-isopropylbenzamide

[0590]

[0591] The title compound was prepared from intermediate 7 according to the method described in Example 1. LCMS method D:R t =1.740 min; (M+H) + = 499.3. 1H NMR (CD3OD): δ ppm 8.53-8.57 (m, 1H), 8.15-8.17 (m, 1H), 7.70-7.75 (m, 1H), 7.50-7.60 (m, 1H), 7.25-7.45 (m, 8H), 3.55-3.60 (m,3H), 3.35-3.45 (m, 1H), 3.00-3.10 (m, 2H), 2.90-2.94 (m, 2H), 2.24 (t, J =12.0 Hz, 2H), 1.95-2.04 (m, 2H), 1.80-1.95 (m, 2H), 0.95-1.05 (m, 3H), 0.70-0.85 (m, 4H), 0.25-0.35 (m, 2H). 1 F NMR (CD3OD): δ ppm -113.26.

[0592] Example 33. 2-(3-(1-benzylpiperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N,N-diisopropylbenzamide

[0593]

[0594] The title compound was prepared from intermediate 8 according to the method described in Example 1. LCMS method D:R t =2.341 min; (M+H) + = 5133. 1 H NMR (CD3OD): δ ppm 8.58 (s, 1H), 8.16 (d, J = 5.6Hz, 1H), 7.76 (dd, J = 0.8, 6.4 Hz, 1H), 7.55-7.74 (m, 1H), 7.44 (s, 1H), 7.30-7.44 (m, 5H), 7.20-7.30 (m, 2H), 3.60 (s, 2H), 3.50-3.60 (m, 1H), 3.35-3.35 (m, 1H), 3.04-3.08 (m, 2H), 2.85-2.95 (m, 1H), 2.22-2.28 (m, 2H), 2.00-2.10 (m, 2H), 1.80-1.95 (m, 2H), 1.44 (d, J = 6.8 Hz, 3H), 1.02 (d, J = 6.4Hz, 6H), 0.28 (d, J = 5.6 Hz, 3H). 19F NMR (CD3OD): δ ppm -113.37.

[0595] Example 34. N-(trans-4-(2-(4-(1-(2-(cyclopropylmethoxy)-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)ethyl)cyclohexyl)methanesulfonamide

[0596]

[0597] Step 1: 2-(cyclopropylmethoxy)-4-fluoro-1-iodobenzene

[0598]

[0599] A mixture of 5-fluoro-2-iodophenol (200 mg, 0.84 mmol), (bromomethyl)cyclopropane (227 mg, 1.68 mmol), and K₂CO₃ (464 mg, 3.36 mmol) in CH₃CN (5 mL) was stirred under reflux for 2 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with petroleum ether) to give a colorless oily 2-(cyclopropylmethoxy)-4-fluoro-1-iodobenzene. Yield: 220 mg (90%). 1 H NMR (CDCl3): δ ppm 7.59-7.64 (m, 1H), 6.41-6.49 (m, 2H), 3.80 (d, J = 6.4 Hz, 2H), 1.21-1.26 (m, 1H), 0.56-0.62 (m, 2H), 0.33-0.38 (m, 2H).

[0600] Step 2: 4-(1-(2-(cyclopropylmethoxy)-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester

[0601]

[0602] A mixture of tert-butyl 4-(1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-carboxylic acid (intermediate 1, step 2, 150 mg, 0.5 mmol), 2-(cyclopropylmethoxy)-4-fluoro-1-iodobenzene (220 mg, 0.75 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (28 mg, 0.2 mmol), CuI (10 mg, 0.05 mmol), and K3PO4 (317 mg, 1.5 mmol) in anhydrous DMF (5 mL) was stirred at 130 °C for 18 h. The mixture was cooled and then added to H2O (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with H₂O (3 × 20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with EtOAc) to give a yellow oily tert-butyl 4-(1-(2-(cyclopropylmethoxy)-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidine-1-carboxylic acid. Yield: 110 mg (36%); LCMS method E:R t = 1.029 min; (M+H) + = 466.3. 1 H NMR (CD3OD): δ ppm 7.76-8.27 (m, 3H), 7.43-7.47 (m, 2H), 7.04-7.08 (m, 1H), 6.86-6.89 (m, 1H), 4.22-4.26 (m, 2H), 3.90 (d, J = 6.4 Hz,2H), 3.01-3.16 (m, 3H), 2.09-2.13 (m, 2H), 1.65-1.77 (m, 2H), 1.50 (s, 9H),1.04-1.07 (m, 1H), 0.42-0.46 (m, 2H), 0.17-0.22 (m, 2H). 19 F NMR (CD3OD): δ ppm-112.46.

[0603] Step 3: 1-(2-(cyclopropylmethoxy)-4-fluorophenyl)-3-(piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridine

[0604]

[0605] HCl-di(2-(1-(1-(2-(cyclopropylmethoxy)-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-carboxylic acid tert-butyl ester (90 mg, 0.19 mmol) in CH2Cl2 (10 mL) was added under ice-cold water. Alkane (2 mL). The mixture was degassed and purged three times with N2. The mixture was stirred at room temperature under N2 atmosphere for 2 h. The mixture was then concentrated under reduced pressure, alkalized to pH = 10-12 with 10% NaOH solution and extracted with CH2Cl2 (3 × 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow oily 1-(2-(cyclopropylmethoxy)-4-fluorophenyl)-3-(piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridine, which was used directly in the next step without further purification. Yield: 70 mg (98% crude); LCMS Method B: R t = 0.573 min; (M+H) + = 366.0

[0606] Step 4: N-(trans-4-(2-(4-(1-(2-(cyclopropylmethoxy)-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)ethyl)cyclohexyl)methanesulfonamide

[0607] The title compound was prepared according to the methods described in steps 2 and 3 of Example 28. LCMS method D:R t = 2.395 min; (M+H) + = 569.3. 1H NMR (CD3OD): δ ppm 8.38 (s, 1H), 8.14 (d, J = 6.0Hz, 1H), 7.74 (d, J = 6.0 Hz, 1H), 7.40-7.50 (m, 2H), 7.06 (d, J = 10.0 Hz, 1H), 6.85-6.91 (m, 1H), 3.90 (d, J = 6.8 Hz, 2H), 3.10-3.19 (m, 3H), 2.96 (s,3H), 2.50-2.60 (m, 2H), 2.25-2.40 (m, 2H), 2.13-2.16 (m,2H), 2.04-2.07 (m,2H), 1.92-1.99 (m, 2H), 1.85-1.88 (m, 2H), 1.45-1.55 (m, 2H), 1.20-1.40 (m,4H), 1.04-1.17 (m, 3H), 0.40-0.45 (m, 2H), 0.10-0.18 (m, 2H). 19 F NMR (CD3OD): δ ppm -112.01.

[0608] Example 35. 1-(2-(cyclopropylmethoxy)-4-fluorophenyl)-3-(1-(4-fluorobenzyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridine

[0609]

[0610] Add 4-fluorobenzaldehyde (17 mg, 0.14 mmol) and NaBH3CN to a mixture of 1-(2-(cyclopropylmethoxy)-4-fluorophenyl)-3-(piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridine (Example 34, Step 3, 25 mg, 0.06 mmol, HCl salt) in MeOH (4 mL). (17 mg, 0.28 mmol). The mixture was degassed and purged three times with N2. The mixture was stirred at 70 °C for 17 h under N2 atmosphere. The mixture was then concentrated under reduced pressure and purified by preparative RP-HPLC method D to give a white solid 1-(2-(cyclopropylmethoxy)-4-fluorophenyl)-3-(1-(4-fluorobenzyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridine. Yield: 5.6 mg (18%); LCMS method E:R t = 0.999 min; (M+H) + = 474.3. 1H NMR (CD3OD): δ ppm 8.37 (s, 1H), 8.13 (d, J = 6.0 Hz, 1H), 7.73-7.74 (m, 1H), 7.40-7.50 (m, 4H), 7.04-7.12 (m, 3H), 6.86-6.90 (m, 1H),3.89 (d, J = 6.8 Hz, 2H), 3.63 (s, 2H), 3.00-3.09 (m, 2H), 2.90-2.99 (m, 1H),2.25-2.32 (m, 2H), 2.05-2.11 (m, 2H), 1.85-1.97 (m, 2H), 0.95-1.06 (m, 1H), 0.40-0.46 (m, 2H), 0.15-0.20 (m, 2H). 19 F NMR (CD3OD): δ ppm -117.53, -112.06.

[0611] Example 36. 2-(3-(1-benzylpiperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-(2-hydroxyethyl)-N-isopropylbenzamide

[0612]

[0613] Step 1. 4-(1-(2-((2-((tert-butyldiphenylsilyl)oxy)ethyl)(isopropyl)carbamoyl)-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester

[0614]

[0615] A mixture of 2-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluorobenzoic acid (intermediate 1, step 3, 100 mg, 0.23 mmol), N-(2-((tert-butyldiphenylsilyl)oxy)ethyl)propane-2-amine (synthesized as described in the European Journal of Organic Chemistry, 2013(11), 2179-2187;2013) (120 mg, 0.35 mmol), HATU (133 mg, 0.35 mmol), and Et3N (116 mg, 0.16 mL, 1.15 mmol) in anhydrous DMF (8 mL) was stirred at 10–15 °C for 18 h. The mixture was added to H2O (20 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with H₂O (3 × 20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with ethyl acetate) to give a yellow solid, tert-butyl 4-(1-(2-((2-((tert-butyldiphenylsilyl)oxy)ethyl)(isopropyl)carbamoyl)-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidine-1-carboxylic acid. Yield: 150 mg (86% crude); LCMS method B: R t = 0.883 min; (M+H) + = 763.3.

[0616] Step 2: 2-(3-(1-benzylpiperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-(2-hydroxyethyl)-N-isopropylbenzamide

[0617] The title compound was prepared according to the method described in step 2 of Example 1, yielding 2-(3-(1-benzylpiperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-(2-hydroxyethyl)-N-isopropylbenzamide. LCMS method E:R t = 0.875 min; (M+H) + = 515.4. 1H NMR (CD3OD): δ ppm 8.88-8.96 (m, 1H), 8.15-8.38 (m, 3H), 7.48-7.75 (m, 8H), 4.43 (s, 2H), 3.41-3.84 (m, 5H), 2.90-3.29 (m, 5H), 2.30-2.39 (m, 2H), 2.00-2.18 (m, 2H), 0.50-1.15 (m, 6H). 19 F NMR (CD3OD): δ ppm -77.43 to -76.65, -110.86 to -110.48.

[0618] Example 37. 5-((4-(1-(4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)methyl)-4-methyl-1H-indole-2-carboxynitrile

[0619]

[0620] Step 1. 4-(1-(4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester

[0621]

[0622] 4-(1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-carboxylic acid tert-butyl ester (intermediate 1, step 2, 200 mg, 0.66 mmol) in anhydrous CH2Cl2 (5 mL) was mixed with (4-fluorophenyl)boronic acid (85 mg, 1.32 mmol), Cu(OAc)2 (240 mg, 1.32 mmol) and Et3N (134 mg, 1.32 mmol) and stirred at room temperature for 2 days. The mixture was filtered and the filtrate was concentrated and purified by Isco column (100% DCM in 15% MeOH) to give a brown oily 4-(1-(4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-carboxylic acid tert-butyl ester. Yield: 100 mg (38%); LCMS Method B: R t = 0.739 min; (M+H) + = 396.1.

[0623] Step 2. 5-((4-(1-(4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)methyl)-4-methyl-1H-indole-2-carboxynitrile

[0624] The title compound was prepared using 5-formyl-4-methyl-1H-indole-2-carboxynitrile according to the methods described in steps 1 and 2 of Example 1, yielding 5-((4-(1-(4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)methyl)-4-methyl-1H-indole-2-carboxynitrile. LCMS method F:R t = 0.764 min; (M+H) + = 464.3. 1 H NMR(CD3OD): δ ppm 9.06 (s, 1H), 8.34 (t, J = 6.8 Hz, 2H), 8.27 (s, 1H), 7.68 (dd,J = 8.0 5.6 Hz, 2H), 7.49 (t, J = 8.8 Hz, 1H), 7.40-7.44 (m, 4H), 4.58 (s,2H), 3.72 (d, J = 12.4 Hz, 2H), 3.35-3.50 (m, 3H), 2.72 (s, 3H), 2.37 (d, J =15.2 Hz, 2H), 2.05-2.20 (m, 2H). 1 F NMR (CD3OD): δ ppm -77.04, -113.78.

[0625] Examples 38-40.

[0626] The following embodiments were synthesized using the method described above for Embodiment 37.

[0627] Table 4.

[0628]

[0629] Examples 41-41A. 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1-(((1r,4r)-4-(methanesulfonylamino)cyclohexyl)methyl)azacyclohept-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide and 2-(3-(azacyclohept-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide (Example 41A)

[0630] and

[0631] Step 1: 2-(3-(azacyclohepta-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide (Example 41A)

[0632] HCl-MeOH (1 mL) was added to a mixture of 4-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)azacycloheptane-1-carboxylic acid tert-butyl ester (intermediate 14, 40 mg, 0.07 mmol) in CH2Cl2 (1 mL, anhydrous). The resulting mixture was stirred at room temperature for 2 h to give a yellow oily 2-(3-(azacycloheptane-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide) (TFA salt). Yield: 4.5 mg (16%); LCMS method D: R t = 0.961 min; (M+H) + = 409.3. 1 H NMR (CD3OD): δppm 8.85-9.00 (m, 1H), 8.25-8.35 (m, 2H), 8.05-8.15 (m, 1H), 7.65-7.80 (m,1H), 7.35-7.65 (m, 2H), 4.30-4.45 (m, 0.5H), 3.60-3.75 (m, 0.5H), 3.30-3.50(m, 5H), 2.55-2.65 (m, 3H), 1.80-2.35 (m, 6H), 0.25-1.25 (m, 6H). 19 F NMR (CD3OD): δ ppm -76.94, -110.63.

[0633] Step 2: 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1-((trans-4-(methanesulfonylamino)cyclohexyl)methyl)azacyclohept-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide (Example 41)

[0634] NaBH3CN (10 mg, 0.16 mmol) was added to a solution of 2-(3-(azacyclohepta-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide (20 mg, 0.04 mmol, crude product) and N-(trans-4-formylcyclohexyl)methanesulfonamide (intermediate 21.8 mg, 0.04 mmol) in anhydrous MeOH (3 mL). The reaction mixture was stirred at 23–28 °C for 16 h. The reaction mixture was concentrated and purified by preparative HPLC to obtain a white solid of 5-fluoro-N-isopropyl-N-methyl-2-(3-(1-((trans-4-(methanesulfonylamino)cyclohexyl)methyl)azacyclohepta-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide. Yield: 6.9 mg (30%); LCMS method D:R t =2.153 min; (M+H) + = 598.3. 1 H NMR (CD3OD): δ ppm 8.50-8.65 (m, 1H), 8.10-8.25 (m,1H), 7.60-7.75 (m, 2H), 7.30-7.50 (m, 3H), 4.40-4.50 (m, 0.5H), 3.45-3.60 (m,0.5H), 3.10-3.25 (m, 2H), 2.94 (s, 3H), 2.75-2.90 (m, 4H), 2.40-2.70 (m, 3H),2.39 (d, J = 6.4 Hz, 2H), 1.75-2.20 (m, 10H), 1.40-1.55 (m, 1H), 1.20-1.35(m, 2H), 1.05-1.15(m, 3H), 0.90-1.00(m, 2H), 0.10-0.65(m, 3H). 19 F NMR (CD3OD): δ ppm -113.46.

[0635] Example 42. 5-((4-(1-(4-fluoro-2-isobutylphenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)methyl)-4-methyl-1H-indole-2-carboxynitrile

[0636]

[0637] Step 1: 4-(1-(4-fluoro-2-formylphenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester

[0638]

[0639] A mixture of tert-butyl 4-(1H-pyrrolo[2,3-c]pyridin-3-yl)piperidine-1-carboxylic acid (intermediate 1, step 2, 400 mg, 1.33 mmol), 2,5-difluorobenzaldehyde (378 mg, 2.66 mmol), and Cs₂CO₃ (1.73 g, 5.32 mmol) in CH₃CN (20 mL) was stirred at 50 °C for 18 h. Water (30 mL) was added and the mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with H₂O (3 × 30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with petroleum ether / EtOAC = 1 / 1) to give a brown solid, tert-butyl 4-(1-(4-fluoro-2-formylphenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidine-1-carboxylic acid. Yield: 320 mg (51%); LCMS method C:R t = 0.662 min; (M+H) + = 423.9. 1 H NMR (CDCl3): δ ppm 9.51 (s, 1H), 8.48 (s, 1H), 8.29 (d, J = 6.0 Hz, 1H), 7.70-7.73 (m, 1H), 7.54-7.56 (m, 1H), 7.42-7.45 (m, 2H), 7.08 (s, 1H), 4.20-4.23 (m, 2H), 2.85-3.00 (m, 4H), 1.97-2.02 (m, 3H), 1.42 (s, 9H).

[0640] Step 2: 4-(1-(4-fluoro-2-(2-methylprop-1-en-1-yl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester

[0641]

[0642] n-BuLi (0.42 mL, 1.04 mmol, 2.5 M in hexane) was added to a mixture of isopropyltriphenylphosphonium iodide (450 mg, 1.04 mmol) and anhydrous THF (10 mL) at -78 °C. The mixture was stirred at -78 °C for 1 h. 4-(1-(4-fluoro-2-formylphenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-carboxylic acid tert-butyl ester (220 mg, 0.52 mmol) was added to anhydrous THF (5 mL), and the mixture was stirred at -78 °C for 2 h, then at room temperature for 18 h. The mixture was quenched with saturated NH4Cl solution (20 mL) at -30 °C and concentrated under reduced pressure to remove THF. The residue was then extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with petroleum ether / EtOAc = 1 / 1) to give a yellow oily tert-butyl 4-(1-(4-fluoro-2-(2-methylprop-1-en-1-yl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-carboxylic acid. Yield: 200 mg (70%); LCMS method D:R t = 0.726 min; (M+H) + = 450.1.

[0643] Step 3: 4-(1-(4-fluoro-2-isobutylphenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester

[0644]

[0645] A mixture of tert-butyl 4-(1-(4-fluoro-2-(2-methylprop-1-en-1-yl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-carboxylic acid (60 mg, 0.13 mmol) and dried Pd-C (20 mg, 10%) in MeOH (6 mL) was stirred at room temperature under H2 (15 psi) for 3 h. The mixture was filtered through a diatomaceous earth mat and the filtrate was concentrated under reduced pressure to give a colorless oily tert-butyl 4-(1-(4-fluoro-2-isobutylphenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-carboxylic acid (60 mg, 100% crude), which was used directly in the next step without further purification. Yield: 60 mg (100% crude); LCMS method C: R t = 0.740 min; (M+H) + = 452.1.

[0646] Step 4. 5-((4-(1-(4-fluoro-2-isobutylphenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)methyl)-4-methyl-1H-indole-2-carboxynitrile

[0647] The title compound was prepared from 5-formyl-4-methyl-1H-indole-2-carboxynitrile according to the methods described in steps 1 and 2 of Example 1, yielding 5-((4-(1-(4-fluoro-2-isobutylphenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)methyl)-4-methyl-1H-indole-2-carboxynitrile. LCMS method E:R t = 1.782 min; (M+H) + = 520.3. 1 H NMR (CD3OD): δ ppm 8.11-8.19 (m, 2H), 7.74 (d, J = 5.2 Hz, 1H), 7.12-7.35(m, 7H), 3.67 (s, 2H), 3.06-3.09 (m, 2H), 2.92-2.98 (m, 1H), 2.58 (s, 3H), 2.28-2.34 (m, 3H), 2.01-2.10 (m, 3H), 1.84-1.91 (m, 2H), 1.16-1.48 (m, 1H), 0.62-0.66 (m, 6H). 19 F NMR (CD3OD): δ ppm -113.87 to -116.24.

[0648] Example 43. 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide (mixture of isomers)

[0649]

[0650] The title compound was synthesized from intermediate 2 as a mixture of isomers according to the method described in Example 1. In step 2, 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-carboxaldehyde was used. LCMS method C:R t = 0.762 min; (M+H) + = 541.3.

[0651] Examples 43A-43B. 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide (isomers 1-2)

[0652]

[0653] The compound of Example 43 was separated by SFC method A to obtain two isomers of 5-fluoro-N-isopropyl-N-methyl-2-(3-(1-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide.

[0654] Isomer 1: LCMS method D: R t = 0.998 min; (M+H) + = 541.2. 1 H NMR (CD3OD): δ ppm8.53-8.62 (m, 1H), 8.12-8.19 (m, 1H), 7.63-7.70 (m, 2H), 7.34-7.50 (m, 3H), 6.95-7.15 (m, 3H), 4.30-4.40 (m, 0.5H), 3.52-3.70 (m, 2.5H), 2.85-3.30 (m,3H), 2.30-2.60 (m, 3H), 2.05-2.25 (m, 3H), 1.75-1.90 (m, 2H), 1.45-1.65 (m,1H), 0.95-1.10 (m, 3H), 0.10-0.45 (m, 3H). 19 FNMR (CD3OD): δ ppm -113.43 to -113.08.

[0655] Isomer 2: LCMS method D: R t = 0.966 min; (M+H) + = 541.2. 1H NMR (CD3OD): δ ppm8.53-8.62 (m, 1H), 8.12-8.19 (m, 1H), 7.63-7.70 (m, 2H), 7.34-7.50 (m, 3H), 6.95-7.15 (m, 3H), 4.30-4.40 (m, 0.5H), 3.52-3.70 (m, 2.5H), 2.85-3.30 (m,3H), 2.30-2.60 (m, 3H), 2.05-2.25 (m, 3H), 1.75-1.90 (m, 2H), 1.45-1.65 (m,1H), 0.95-1.10 (m, 3H), 0.10-0.45 (m, 3H). 19 FNMR (CD3OD): δ ppm -113.42 to -113.07.

[0656] Example 44. 5-Fluoro-2-(3-(1-((1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropyl-N-methylbenzamide (mixture of isomers)

[0657]

[0658] Et3N (6.5 g, 63.87 mmol) was added to a solution of 5-fluoro-N-isopropyl-N-methyl-2-(3-(piperidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide (8.4 g, 21.29 mmol, crude product, HCl salt) obtained by acid deprotection of intermediate 2 in MeOH (250 mL). After stirring for 15 min, a mixture of 1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-carboxaldehyde, 2-(5-formyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl) ethyl formic acid (intermediate 24-24A, 8.8 g, 42.58 mmol), and NaBH3CN (2.7 g, 42.58 mmol) was added sequentially. The resulting mixture was stirred at 50 °C (oil temperature) under N2 for 24 h. The reaction mixture was concentrated under reduced pressure to obtain a crude product. The residue was diluted with H2O (300 mL) and extracted with EtOAc (2 × 300 mL). The organic layer was washed with brine (2 × 400 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The residue was purified by silica gel column chromatography (CH2Cl2 / MeOH = 30:1 to CH2Cl2 / MeOH = 6 / 1, containing 1% NH3-H2O) to give a yellow solid, 5-fluoro-2-(3-(1-((1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropyl-N-methylbenzamide. Yield: 6.5 g (52%); LCMS method B: R t = 0.566 min; (M+H) + = 585.2.

[0659] Examples 44A-44B. 5-Fluoro-2-(3-(1-((1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropyl-N-methylbenzamide (isomers 1-2)

[0660]

[0661] The compound of Example 44 was further purified by SFC method A to give two isomers of 5-fluoro-2-(3-(1-((1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropyl-N-methylbenzamide.

[0662] Isomer 1: LCMS method D: R t = 1.644 min; (M+H) + = 585.3. 1 H NMR (CD3OD): δ ppm8.55-8.62 (m, 1H), 8.12-8.18 (m, 1H), 7.63-7.69 (m, 2H), 7.34-7.45 (m, 3H), 7.10-7.15 (m, 3H), 4.35-4.40 (m, 0.5H), 3.95-4.00 (m, 2H), 3.80-3.85 (m, 2H), 3.52-3.70 (m, 2.5H), 2.85-3.30 (m, 3H), 2.25-2.60 (m, 3H), 2.05-2.25 (m, 3H),1.45-1.90 (m, 3H), 0.95-1.10 (m, 3H), 0.10-0.45 (m, 3H). 19 F NMR (CD3OD): δ ppm -113.34 to -113.00.

[0663] Isomer 2: LCMS method B: R t = 1.638 min; (M+H) + = 585.3. 1 H NMR (CD3OD): δ ppm8.55-8.62 (m, 1H), 8.12-8.18 (m, 1H), 7.63-7.69 (m, 2H), 7.34-7.45 (m, 3H), 7.10-7.15 (m, 3H), 4.35-4.40 (m, 0.5H), 3.95-4.00 (m, 2H), 3.80-3.85 (m, 2H), 3.52-3.70 (m, 2.5H), 2.85-3.30 (m, 3H), 2.25-2.60 (m, 3H), 2.05-2.25 (m, 3H),1.45-1.90 (m, 3H), 0.95-1.10 (m, 3H), 0.10-0.45 (m, 3H).19 F NMR (CD3OD): δ ppm -113.41 to -113.08.

[0664] Examples 45-50.

[0665] The following examples were synthesized starting with intermediate 2 and appropriate raw materials using the methods described in steps 1 and 2 of Example 1.

[0666] Table 5.

[0667]

[0668] Example 51. 2-(3-(2-azaspiro[3.5]nonyl-7-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide

[0669]

[0670] Example 51 is synthesized from intermediate 3 using the method described in step 1 of Example 1. LCMS method C:R t = 0.773 min; (M+H) + = 435.3.

[0671] Example 51A. 5-Fluoro-N-isopropyl-N-methyl-2-(3-(2-methyl-2-azaspiro[3.5]nonyl-7-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide

[0672]

[0673] The title compound was prepared from intermediate 3 according to the method described in Example 1. In step 2, formaldehyde was used. LCMS method C:R t = 0.893 min; (M+H) + = 449.3. 1H NMR (CD3OD): δ ppm 8.80-9.00 (m, 1H), 8.20-8.35 (m, 2H), 8.00-8.10 (m, 1H), 7.65-7.75 (m, 1H), 7.35-7.55 (m, 2H), 4.35-4.45 (m, 0.5H), 4.20-4.30 (m, 1H), 4.00-4.10 (m, 1H), 3.80-3.95 (m, 2H), 3.60-3.75 (m, 0.5H), 3.00-3.10 (m, 1H), 2.96 (s, 3H),2.50-2.65 (m, 3H), 2.05-2.30 (m, 4H), 1.75-1.95 (m, 2H), 1.45-1.70 (m, 2H), 0.35-1.20 (m, 6H). 19 F NMR (CD3OD): δ ppm -76.96, -110.73 to -110.88.

[0674] Example 52. 5-Fluoro-N-isopropyl-N-methyl-2-(3-(2-methyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide

[0675]

[0676] A solution of 5-fluoro-N-isopropyl-N-methyl-2-(3-(1,2,3,4-tetrahydroisoquinoline-6-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide (intermediate 17b, 50 mg, 0.11 mmol, HCl salt), oligooxymethylene (34 mg, 1.13 mmol), and Et3N (57 mg, 0.56 mmol) in anhydrous MeOH (10 mL) was stirred for 0.5 h at room temperature. Then, NaBH3CN (28 mg, 0.45 mmol) was added, and the reaction mixture was stirred at 60 °C for 18 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by alkaline preparative HPLC method D to give a white solid 5-fluoro-N-isopropyl-N-methyl-2-(3-(2-methyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide. Yield: 28.3 mg (55%); LCMS method B: R t = 1.930 min; (M+H) + = 457.2. 1H NMR (CD3OD): δppm 8.59-8.65 (m, 1H), 8.20-8.30 (m, 1H), 7.93 (d, J = 5.6 Hz, 1H), 7.78 (s,1H), 7.70-7.75 (m, 1H), 7.35-7.50 (m, 4H), 7.18 (d, J = 8.8 Hz, 1H), 4.40-4.50 (m, 0.5H), 3.60-3.70 (m, 2H), 3.03 (t, J = 5.6 Hz, 2H), 2.79 (t, J = 6.0Hz, 2H), 2.40-2.65 (m, 6H), 0.95-1.05 (m, 3H), 0.25-0.55 (m, 3H). 19 F NMR (CD3OD): δ ppm -112.79.

[0677] Examples 53-53A. 5-Fluoro-2-(3-(4-hydroxycyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropyl-N-methylbenzamide (isomers 1-2)

[0678]

[0679] To a solution of 5-fluoro-N-isopropyl-N-methyl-2-(3-(4-oxocyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide (intermediate 17B, 50 mg, 0.12 mmol) in MeOH (3 mL, anhydrous), NaBH4 (7 mg, 0.18 mmol) was added. The resulting mixture was stirred at room temperature for 30 min. The reaction mixture was neutralized to pH 7.0 with 6N HCl and concentrated under reduced pressure. The residue was purified by preparative RP-HPLC method A to obtain 5-fluoro-2-(3-(trans-4-hydroxycyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropyl-N-methylbenzamide (15 mg) and 5-fluoro-2-(3-(cis-4-hydroxycyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropyl-N-methylbenzamide.

[0680] Example 53 (Isomer 1): Yield: 9.50 mg; LCMS method D: R t = 0.799 min; (M+H) + =410.2. 1H NMR (CD3OD): δ ppm 8.54-8.62 (m, 1H), 8.16-8.21 (m, 1H), 7.73-7.75(m, 1H), 7.65-7.73 (m, 1H), 7.40-7.50 (m, 1H), 7.35-7.40 (m, 2H), 4.44-4.52(m, 0.5H), 3.55-3.70 (m, 1.6H), 2.70-2.85 (m, 1H), 2.44-2.67 (m, 3H), 2.05-2.15 (m, 4H), 1.40-1.65 (m, 4H), 0.95-1.10 (m, 3H), 0.20-0.55 (m, 3H). 19 FNMR (CD3OD): δ ppm -113.61 to -113.36.

[0681] Example 53A (Isomer 2): Yield: 1.80 mg (4%); LCMS method D: R t = 0.851 min; (M+H) + = 410.2. 1 H NMR (CD3OD): δ ppm 8.54-8.64 (m, 1H), 8.16-8.21 (m, 1H), 7.60-7.75 (m, 2H), 7.34-7.45 (m, 3H), 4.44-4.53 (m, 0.5H), 4.00-4.05 (m, 1H),3.55-3.60 (m, 0.5H), 2.90-3.00 (m, 1H), 2.45-2.70 (m, 3H), 1.76-1.86 (m, 6H),1.30-1.49 (m, 2H), 1.00-1.20 (m, 3H), 0.21-0.55 (m, 3H). 19 FNMR (CD3OD): δ ppm -113.73 to -113.45.

[0682] Examples 54-54A. 2-(3-(4-(dimethylamino)cyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide (isomers 1-2, TFA salts)

[0683]

[0684] Dimethylamine hydrochloride (10 mg, 0.12 mmol), Et3N (30 mg, 0.30 mmol), and NaBH3CN (12 mg, 0.20 mmol) were added to a solution of 5-fluoro-N-isopropyl-N-methyl-2-(3-(4-oxocyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide (intermediate 17B, 40 mg, 0.10 mmol) in 5 mL of anhydrous MeOH. The resulting mixture was stirred at 50 °C for 18 h. The mixture was purified by preparative RP-HPLC method A to obtain white solid 2-(3-(trans-4-(dimethylamino)cyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide and 2-(3-(cis-4-(dimethylamino)cyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide.

[0685] Example 54 (Isomer 1): Yield: 5.0 mg (11%); LCMS method D: R t = 2.192 min; (M+H) + = 437.2. 1 H NMR (CD3OD): δ ppm 8.83-8.93 (m, 1H), 8.26-8.32 (m, 2H), 8.06 (d, J= 11.2 Hz 1H), 7.65-7.75 (m, 1H), 7.42-7.55 (m, 2H), 4.36-4.40 (m 0.5H), 3.65-3.75 (m 0.5H), 3.35-3.45 (m 2H), 2.55-3.20 (m, 9H), 2.23-2.35 (m, 3H), 1.65-1.85 (m, 3H), 0.45-1.15 (m, 8H). 19 F NMR (CD3OD): δ ppm -111.17 to -110.73, -76.64 to -76.93.

[0686] Example 54A (Isomer 2): Yield: 6.4 mg (14%); LCMS method D: R t = 2.145 min; (M+H) + = 437.2. 1H NMR (CD3OD): δ ppm 8.90-9.00 (m, 1H), 8.24-8.33 (m, 3H), 7.76-7.77 (m, 1H), 7.44-7.53 (m, 2H), 4.35-4.41 (m, 0.5H), 3.70-3.72 (m, 0.5H), 3.35-3.53 (m, 2H), 2.59-2.62 (m, 9H), 2.02-2.20 (m, 8H), 050-1.11 (m, 6H). 19 FNMR (CD3OD): δ ppm -110.72 to -110.60, -76.94.

[0687] Examples 55-58.

[0688] The following embodiments were synthesized according to the methods described for Examples 54-54A.

[0689] Table 6.

[0690]

[0691]

[0692] Example 59. 5-Fluoro-N-isopropyl-N-methyl-2-(3-(4-phenoxycyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide

[0693]

[0694] Step 1: 5-Fluoro-2-(3-(4-hydroxycyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropyl-N-methylbenzamide

[0695]

[0696] To a solution of 5-fluoro-N-isopropyl-N-methyl-2-(3-(4-oxocyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide (intermediate 17B, 100 mg, 0.25 mmol) in MeOH (5 mL, anhydrous), NaBH4 (15 mg, 0.37 mmol) was added, and the resulting mixture was stirred at 14–20 °C for 15 min. The reaction mixture was then concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc) on silica gel to give a colorless solid of 5-fluoro-2-(3-(4-hydroxycyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropyl-N-methylbenzamide. Yield: 60 mg (59%); LCMS Method B: R t = 0.625 min; (M+H) + = 410.1

[0697] Step 2: 5-Fluoro-N-isopropyl-N-methyl-2-(3-(4-phenoxycyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide

[0698] Under N2, a solution of PPh3 (197 mg, 0.75 mmol) in THF (2 mL, anhydrous) and DIAD (152 mg, 0.75 mmol) was added dropwise to a solution of 5-fluoro-2-(3-(4-hydroxycyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropyl-N-methylbenzamide (60 mg, 0.15 mmol) and phenol (71 mg, 0.75 mmol) in THF (6 mL, anhydrous) and DIAD (152 mg, 0.75 mmol) via syringe. The resulting mixture was stirred under N2 at 13–22 °C for approximately 4 h. The reaction mixture was then concentrated under reduced pressure to remove THF. The residue was purified by preparative TLC (petroleum ether / ethyl acetate = 1 / 3) on silica gel to give crude 5-fluoro-N-isopropyl-N-methyl-2-(3-(4-phenoxycyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide (80 mg), which was further purified by RP-HPLC to give a white solid of 5-fluoro-N-isopropyl-N-methyl-2-(3-(4-phenoxycyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide. Yield: 18.5 mg (25%); LCMS method: R t = 1.801 min; (M+H) + = 486.3. 1H NMR (CD3OD): δppm 8.33-8.42 (m, 1H), 7.95-8.00 (m, 1H), 7.41-7.55 (m, 2H), 7.03-7.25 (m,5H), 6.67-6.77 (m, 3H), 4.39-4.50(m, 1H), 4.14-4.32(m, 0.5H), 3.31-3.37 (m,0.5H), 2.75-2.85 (m, 1H), 2.22-2.49 (m, 3H), 1.42-2.08 (m, 8H), 0.74-0.92 (m,3H), 0.04-0.46 (m, 3H). 19 F NMR (CD3OD): δ ppm -113.71 to -113.45.

[0699] Examples 60-60A. 5-Fluoro-N-isopropyl-N-methyl-2-(3-(4-(((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)amino)cyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide (isomers 1-2)

[0700]

[0701] Step 1: 2-(3-(4-aminocyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide

[0702]

[0703] A solution of 5-fluoro-N-isopropyl-N-methyl-2-(3-(4-oxocyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide (intermediate 17B, 220 mg, 0.54 mmol) in MeOH (10 mL, anhydrous) was mixed with NH4OAc (83 mg, 1.08 mmol) and NaBH3CN (68 mg, 1.08 mmol), and the resulting mixture was stirred at 50 °C under N2 for 20 h. The mixture was purified by preparative RP-HPLC method A to obtain a white solid 2-(3-(4-aminocyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide (TFA salt). Yield: 110 mg (50%); LCMS method E: R t = 0.494 min; (M+H) + = 409.1 1H NMR (CD3OD): δ ppm 8.80-9.10 (m,1H), 8.25-8.40 (m, 2H), 8.05-8.20 (m, 1H), 7.70-7.80 (m, 1H), 7.40-7.60 (m,2H), 4.30-4.45 (m, 0.5H), 3.70-3.80 (m, 0.5H), 3.20-3.30 (m, 1H), 3.05-3.15(m, 1H), 2.55-2.70 (m, 3H), 2.15-2.30 (m, 3H), 1.90-2.10 (m, 2H), 1.60-1.80(m, 3H), 0.35-1.20 (m, 6H). 19 F NMR (CD3OD): δ ppm -110.86 to -110.60.

[0704] Step 2. 5-Fluoro-N-isopropyl-N-methyl-2-(3-(trans-4-(((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)amino)cyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide

[0705] The title compound was prepared according to the method described in Example 45, and separated by SFC method A to obtain two isomers of 5-fluoro-N-isopropyl-N-methyl-2-(3-(4-(((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)amino)cyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide.

[0706] Example 60 (Isomer 1): LCMS Method D: R t = 1.164 min; (M+H) + = 555.3. 1H NMR(CD3OD): δ ppm 8.54-8.62 (m, 1H), 8.17-8.21 (m, 1H), 7.66-7.74(m, 2H), 7.35-7.50 (m, 3H), 7.04-7.15 (m, 3H), 4.44-4.51 (m, 0.5H), 3.89 (s, 2H), 3.51-3.60(m, 0.5H), 2.89-2.95 (m, 1H), 2.44-2.67 (m, 4H), 2.06-2.17 (m, 4H), 1.45-1.58(m, 4H), 0.95-1.06 (m, 3H), 0.15-0.54 (m, 3H). 19 F NMR (CD3OD): δ ppm -113.58 to -113.35.

[0707] Example 60A (Isomer 2): LCMS Method D: R t = 1.231 min; (M+H) + = 555.3. 1 H NMR(CD3OD): δ ppm 8.53-8.61(m, 1H), 8.16-8.18 (m, 1H), 7.66-7.73 (m, 2H), 7.34-7.47 (m, 3H), 7.00-7.12 (m, 3H), 4.43-4.47 (m, 0.5H), 3.84 (s, 2H), 3.52-3.58 (m, 0.5H), 3.05-3.15 (m, 1H), 2.90-2.95 (m, 1H), 2.43-2.66 (m, 3H), 1.75-2.05(m, 8H), 0.95-1.05 (m, 3H), 0.15-0.50 (m, 3H). 19 F NMR (CD3OD): δ ppm -113.56 to -113.33.

[0708] Examples 61-62.

[0709] The following embodiments were synthesized using the methods described above for embodiments 60-60A.

[0710] Table 7.

[0711]

[0712] Example 63. 2-(7-(1-((2-cyano-4-methyl-1H-indol-5-yl)methyl)piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-5-fluoro-N-isopropyl-N-methylbenzamide

[0713]

[0714] Step 1: 4-(5-(4-fluoro-2-(methoxycarbonyl)phenyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidin-1-carboxylic acid tert-butyl ester and 2-(7-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-5-fluorobenzoic acid

[0715] and

[0716] A solution of tert-butyl 4-(5H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidine-1-carboxylic acid (intermediate 18, 300 mg, 0.99 mmol), methyl 2,5-difluorobenzoate (205 mg, 1.19 mmol), and Cs₂CO₃ (646 mg, 1.98 mmol) in anhydrous DMF (20 mL) was stirred at 100 °C for 18 h. The mixture was then concentrated under high vacuum. The residue was diluted with 1 N HCl (50 mL) and extracted with DCM (50 mL × 3) and DCM / propanol (v / v, 80 / 20 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by acidic preparative RP-HPLC method A to yield 2-(7-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-5-fluorobenzoic acid (TFA salt) and 4-(5-(4-fluoro-2-(methoxycarbonyl)phenyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidin-1-carboxylic acid tert-butyl ester, both yellow solids. Yield: 211 mg (48% yield); LCMS method C:R t =0.725 min; (M+H) + = 441.0.

[0717] Step 2: 4-(5-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidine-1-carboxylic acid tert-butyl ester

[0718]

[0719] A solution of 2-(7-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-5-fluorobenzoic acid (80 mg, 0.16 mmol, 88.6% purity), N-methylpropane-2-amine (18 mg, 0.24 mmol), HATU (92 mg, 0.24 mmol), and DIEA (103 mg, 0.80 mmol) in anhydrous DMF (20 mL) was stirred for 18 h at room temperature. The mixture was concentrated under high vacuum, the residue was diluted with H2O (20 mL) solution, and extracted with DCM (3 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (eluting with petroleum ether / EtOAc = 1 / 1 to 0 / 1) to give tert-butyl 4-(5-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidine-1-carboxylic acid by tert-butyl ester, a yellow oil. Yield: 55 mg (54%); LCMS method C:R t = 0.774 min; (M+H) + = 496.1.

[0720] Step 3: 5-Fluoro-N-isopropyl-N-methyl-2-(7-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)benzamide

[0721]

[0722] HCl / di(2-ethylhexyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidine-1-carboxylic acid tert-butyl ester (55 mg, 0.11 mmol) in anhydrous DCM (10 mL) was added at 0 °C. Alkane (3 mL, 4 N). The reaction mixture was stirred at room temperature for 2 h. The mixture was then concentrated under reduced pressure. The residue was diluted with 1 N NaOH (20 mL) solution and extracted with CH2Cl2 (3 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow oily 5-fluoro-N-isopropyl-N-methyl-2-(7-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)benzamide (40 mg, 91%, crude), which was used without further purification. Yield: 55 mg (91% crude);

[0723] Step 4: 2-(7-(1-((2-cyano-4-methyl-1H-indol-5-yl)methyl)piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-5-fluoro-N-isopropyl-N-methylbenzamide

[0724] A solution of 5-fluoro-N-isopropyl-N-methyl-2-(7-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)benzamide (40 mg, 0.10 mmol, crude product), 5-formyl-4-methyl-1H-indole-2-carboxynitrile (37 mg, 0.20 mmol), and HOAc (10 μL) in anhydrous MeOH (10 mL) was stirred at 6–20 °C for 0.5 h. Then, NaBH3CN (25 mg, 0.40 mmol) was added, and the reaction mixture was stirred at 55 °C for 4 h. The mixture was concentrated under reduced pressure. The residue was purified by preparative RP-HPLC to obtain a white solid, 2-(7-(1-((2-cyano-4-methyl-1H-indol-5-yl)methyl)piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-5-fluoro-N-isopropyl-N-methylbenzamide. Yield: 14.7 mg (26%); LCMS method: E:R t = 2.140 min; (M+H) + = 564.3. 1 H NMR(CD3OD): δ ppm 8.87 (d, J = 6.0 Hz, 1H), 8.70-8.85 (m, 1H), 7.60-7.75 (m, 2H), 7.40-7.50 (m, 1H), 7.30-7.40 (m, 2H), 7.31 (s, 1H), 7.27 (d, J = 8.4 Hz, 1H), 4.42-4.45 (m, 0.5H), 3.75 (s, 2H), 3.59-3.66 (m, 0.5H), 3.05-3.15 (m, 3H), 2.45-2.70 (m, 6H), 2.30-2.45 (m, 2H), 2.05-2.20 (m, 2H), 1.80-1.95 (m, 2H), 1.05 (d, J = 6.8 Hz, 3H), 0.35-0.65 (m, 3H).

[0725] 19 F NMR (CD3OD): δ ppm -112.50 to 112.80.

[0726] Example 64. 2-(7-(1-((2-cyano-4-methyl-1H-indol-5-yl)methyl)piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-5-fluoro-N,N-dimethylbenzamide

[0727]

[0728] The title compound was prepared according to a method similar to that of Example 63. In step 2, dimethylamine was used. LCMS method E:R t = 2.008 min; (M+H) + = 536.3. 1 H NMR (CD3OD): δ ppm 8.85 (s, 1H), 8.72 (s, 1H), 7.66-7.71 (m, 2H), 7.45-7.50 (m, 1H), 7.36-7.41 (m, 2H), 7.26-7.31 (m, 2H), 3.69 (s, 2H), 3.00-3.10 (m, 3H), 2.73 (s, 3H), 2.62 (s, 3H), 2.57 (s, 3H), 2.25-35 (m, 2H), 2.10-2.10 (m, 2H), 1.75-1.90(m, 2H). 19 F NMR (CD3OD): δ ppm -112.92.

[0729] Example 65. 5-(4-fluorophenyl)-7-(1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine

[0730]

[0731] Step 1: 4-(5-(4-fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidine-1-carboxylic acid tert-butyl ester

[0732]

[0733] A solution of tert-butyl 4-(5-(5-fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidin-1-carboxylic acid (intermediate 18, 300 mg, 1.0 mmol) in anhydrous CH2Cl2 (5 mL) was mixed with (4-fluorophenyl)boronic acid (280 mg, 2.0 mmol), Cu(OAc)2 (305 mg, 2.0 mmol), and Et3N (202 mg, 2.0 mmol) and stirred at room temperature for 3 days. The mixture was filtered, the filtrate was concentrated, and purified by ISCO column (DCM / MeOH = 10 / 1) to give a brown oily tert-butyl 4-(5-(4-fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidin-1-carboxylic acid (60 mg, 15% yield). Yield: 60 mg (15%); LCMS method E: R t = 2.126 min; (M+H) + = 397.2. 1 H NMR (CD3OD): δ ppm 8.80-9.00(m, 2H), 7.88 (s, 1H), 7.58-7.62 (m ,2H), 7.29-7.33 (m, 2H), 4.20 (d, J =13.2 Hz, 2H), 3.16-3.22 (m, 1H), 2.85-3.00 (m, 2H), 2.09 (d, J = 12.0 Hz, 2H), 1.65-1.84 (m, 2H), 1.46 (s, 9H). 1 F NMR (CD3OD): δ ppm -115.84 to 115.87.

[0734] Step 2: 5-(4-fluorophenyl)-7-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine

[0735]

[0736] Add HCl to a solution of tert-butyl 4-(5-(4-fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidine-1-carboxylic acid (60 mg, 0.15 mmol) in anhydrous CH2Cl2 (2 mL). Alkane (1 mL) was added and the mixture was stirred at room temperature for 2 h. The mixture was concentrated and adjusted to pH = 10 by NH3-H2O and then lyophilized to give a white solid of 5-(4-fluorophenyl)-7-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine. Yield: 45 mg (99% crude yield); LCMS method C:R t= 0.865 min; (M+H) + = 297.1. 1 H NMR (CD3OD): δ ppm 8.85-9.00 (m, 2H),8.00 (s, 1H), 7.64-7.68 (m, 2H), 7.35-7.40 (m, 2H), 3.55 (d, J = 13.2 Hz,2H), 3.35-3.45 (m, 1H), 3.15-3.25 (m, 2H), 2.38 (t, J = 13.6 Hz, 2H), 2.13-2.24 (m, 2H). 19 F NMR (CD3OD): δ ppm -115.75.

[0737] Step 3: 5-(4-fluorophenyl)-7-(1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine

[0738] Tetrahydro-2H-pyran-4-carboxaldehyde (10 mg, 0.084 mmol) and NaBH3CN (16 mg, 0.25 mol) were added to a solution of 5-(4-fluorophenyl)-7-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine (25 mg, 0.084 mmol) in anhydrous MeOH (2 mL). The mixture was stirred at room temperature for 16 h. The mixture was purified by preparative RP-HPLC method A to obtain a white solid of 5-(4-fluorophenyl)-7-(1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine (TFA salt). Yield: 19 mg (57%); LCMS method C: R t = 0.629 min; (M+H) + = 395.3. 1H NMR (CD3OD z): δ ppm 9.23 (s, 1H), 9.09 (s, 1H), 8.39 (s, 1H), 7.71 (q, J =4.4 Hz, 2H), 7.41 (t, J = 8.4 Hz, 2H), 3.97 (dd, J = 7.2 3.6 Hz, 2H), 3.79(d, J = 12.4 Hz, 2H), 3.46-3.51 (m, 3H), 3.23 (t, J = 6.4 Hz, 2H), 3.11 (d, J= 7.2 Hz, 2H), 2.41-2.47 (m, 4H), 2.33-2.40 (m, 1H), 1.76 (d, J = 12.8 Hz, 2H), 1.40-1.46 (m, 2H). 19 F NMR (CD3OD): δ ppm -77.19, -114.33.

[0739] Examples 66-73.

[0740] The following embodiments were synthesized using the method described above for Embodiment 65.

[0741] Table 8.

[0742]

[0743]

[0744]

[0745] Example 74. 5-Fluoro-N-isopropyl-N-methyl-2-(1-(1-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidin-3-yl)-1H-pyrrolo[3,2-c]pyridin-3-yl)benzamide

[0746]

[0747] Step 1: tert-butyl 3-(3-iodo-1H-pyrrolo[3,2-c]pyridin-1-yl)piperidine-1-carboxylic acid

[0748]

[0749] NaH (26 mg, 0.65 mmol, 60% in mineral oil) was added to a solution of 3-iodo-1H-pyrrolo[3,2-c]pyridine (150 mg, 0.62 mmol) in DMF (3 mL) at room temperature. The suspension was stirred at room temperature for 15 min, followed by the addition of tert-butyl 3-((methanesulfonyl)oxy)piperidine-1-carboxylic acid (273 mg, 0.98 mmol) at room temperature. The reaction mixture was then heated at 80 °C for 5 h. After cooling to room temperature, saturated aqueous NH4Cl solution (5 mL) and EtOAc (10 mL) were added sequentially. The aqueous layer was separated and extracted with EtOAc (2 × 5 mL). The organic layers were combined, washed with brine, dried over Na2SO4, and evaporated. The crude product was purified by ISCO rapid column chromatography (100% hexane to 100% EtOAc) to give tert-butyl 3-(3-iodo-1H-pyrrolo[3,2-c]pyridin-1-yl)piperidin-1-carboxylic acid (53 mg, 20%). LCMS method C:t R = 5.194; [M + H] + = 428.40.

[0750] Step 2: 2-(1-(1-(tert-butoxycarbonyl)piperidin-3-yl)-1H-pyrrolo[3,2-c]pyridin-3-yl)-5-fluorobenzoic acid

[0751]

[0752] 3-(3-iodo-1H-pyrrolo[3,2-c]pyridin-1-yl)piperidin-1-carboxylic acid tert-butyl ester (90 mg, 0.21 mmol), (5-fluoro-2-(methoxycarbonyl)phenyl)boronic acid (83 mg, 0.42 mmol), Pd(PPh3)4 (20 mg, 10 mol%) and 2M Na2CO3 aqueous solution (1 mL) were mixed in a two-component immersion reactor. The suspension in alkane (3 mL) was heated at 70 °C for 5 h. After cooling to room temperature, standard treatment was performed using EtOAc and water. The EtOAc layer was dried over Na₂SO₄ and evaporated to obtain crude tert-butyl 3-(3-(4-fluoro-2-(methoxycarbonyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-1-yl)piperidin-1-carboxylic acid. This crude material was absorbed into 2 mL THF and 1 mL MeOH. 1 mL of 4 N NaOH solution was added at room temperature and the reaction mixture was stirred for 4 h. The reaction mixture was diluted with 5 mL of water and washed with EtOAc. The aqueous layer was cooled to 0 °C and acidified with 2 N HCl to pH = approximately 4. The product was extracted from the acidified aqueous layer using EtOAc (3 × 5 mL). The EtOAc layer was dried and evaporated with Na2SO4 to obtain nearly pure 2-(1-(1-(tert-butoxycarbonyl)piperidin-3-yl)-1H-pyrrolo[3,2-c]pyridin-3-yl)-5-fluorobenzoic acid (40 mg, 42% %, in 2 steps). LCMS method C: t R = 5.489 min; [M + H] + = 440.50.

[0753] Step 3: 3-(3-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0754]

[0755] HATU (58 g, 0.18 mmol) was added to a solution of 2-(1-(1-(tert-butoxycarbonyl)piperidin-3-yl)-1H-pyrrolo[3,2-c]pyridin-3-yl)-5-fluorobenzoic acid (40 mg, 0.091 mmol), N-methylpropane-2-amine (20 mg, 0.27 mmol), and iPr2NEt (0.05 mL, 0.29 mmol) in DMF (2 mL) at room temperature. The reaction mixture was stirred for 1 h at room temperature. H2O (3 mL) and EtOAc (5 mL) were added, and the aqueous layer was extracted with EtOAc (2 × 2 mL). The organic layers were combined, washed with H2O, dried over Na2SO4, and evaporated. Purification was performed using ISCO rapid column chromatography (elution with 10% MeOH in DCM) to give tert-butyl 3-(3-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[3,2-c]pyridin-1-yl)piperidin-1-carboxylic acid (16 mg, 36%). LCMS Method B: t R = 1.035 min; [M + H]+ =495.32.

[0756] Step 4: 5-Fluoro-N-isopropyl-N-methyl-2-(1-(1-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidin-3-yl)-1H-pyrrolo[3,2-c]pyridin-3-yl)benzamide

[0757] The title compound was prepared using 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-carboxaldehyde according to the method described in Example 4. LCMS method C: t R = 2.661 min; [M+H] + = 541.58. 1 ¹H NMR (CD₃OD): Mixture of rotational isomers δ 9.03 (s, ¹H), 8.45 (d, J = 6.8, ¹H), 8.16 (d, J = 6.6 Hz, ¹H), 8.05–8.01 (m, ¹H), 7.71–7.60 (m, ¹H), 7.39–7.35 (m, ¹H), 7.25–7.30 (m, ¹H), 7.18–7.16 (m, 2H), 7.13–7.02 (m, ¹H), 5.19–5.10 (m, ¹H), 4.84–4.79 (m, ¹H), 4.52–4.48 (m, ¹H), 4.30–4.17 (m, 2H), 3.58–3.40 (m, 3H), 3.15-2.90 (m,2H), 2.67 (s, 3H), 2.25-2.02 (m, 2H), 1.33-1.29 (m, 3H), 1.02-0.99 (m, 3H).

[0758] Example 78. 5-Fluoro-N-isopropyl-N-methyl-2-(1-(1-(2-((1r,4r)-4-(methylsulfonylamino)cyclohexyl)ethyl)piperidin-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)benzamide

[0759]

[0760] Step 1: 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylic acid tert-butyl ester and 1-(1-(tert-butoxycarbonyl)piperidine-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-carboxylic acid tert-butyl ester

[0761] and

[0762] Et3N (4.5 mL, 33.24 mmol) was added to a suspension of 1-(piperidin-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (4.23 g, 16.62 mmol, synthesized by the method described in BMCL, 16(19), 5052-5056; 2006) in MeOH (30 mL). The mixture was gently heated until the starting material was observed to be completely dissolved. The solvent was then evaporated and the substance was thoroughly dried under high vacuum. The substance was absorbed into MeOH (30 mL) and Boc2O (4.34 g, 19.92 mmol) was added at room temperature, and the reaction mixture was stirred at room temperature for 5 h. Evaporation of the solvent yielded crude tert-butyl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidin-1-carboxylic acid (5.3 g, >95%), containing approximately 20% 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-carboxylic acid tert-butyl ester. This crude product was used directly in the next step without further purification. LCMS Method B: t R =0.748 min; [M+H] + = 319.29. 1 H NMR (CD3OD): δ 8.41-8.36 (m, 2H), 7.72 (d, J = 6.0Hz, 1H), 4.58-4.50 (m, 1H), 4.30-4.26 (m, 2H), 3.02-2.85 (m, 2H), 2.41-2.30(m, 2H), 1.88-1.84 (m, 2H), 1.49 (s, 9H).

[0763] Step 2: 2-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)-5-fluorobenzoic acid

[0764]

[0765] A suspension of crude 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidin-1-carboxylic acid tert-butyl ester (containing approximately 20% of 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-carboxylic acid tert-butyl ester) (1 g, 3.14 mmol), 2-bromo-5-fluorobenzoic acid (800 mg, 3.65 mmol), CuI (200 mg, 1.04 mmol), Cs₂CO₃ (1.5 g, 4.6 mmol), and 1,10-phenanthroline (50 mg, 10 mol%) in DMF (8 mL) was heated at 70 °C for 24 h. The reaction mixture was cooled to room temperature and filtered through a diatomaceous earth stopper under EtOAc washing. Solvent removal yielded crude 2-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)-5-fluorobenzoic acid, which was used directly in the next step without further purification. LCMS method C: t R = 4.658 min; [M+H] + = 457.52.

[0766] Step 3: 4-(3-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0767]

[0768] HATU (1.8 g, 4.5 mmol) was added to a solution of crude 2-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)-5-fluorobenzoic acid, N-methylpropane-2-amine (459 mg, 6.30 mmol), and iPr2NEt (1.6 mL, 9.2 mmol) in DMF (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 12 h. Then, H2O (10 mL) and EtOAc (20 mL) were added to the reaction mixture. The EtOAc layer was separated, dried over Na2SO4, and evaporated. The crude compound was purified by ISCO rapid column chromatography (using 10% MeOH elution in DCM) to give tert-butyl 4-(3-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidin-1-carboxylic acid (610 mg, 54% in 2 steps).1 ¹H NMR (CDCl₃): Mixture of rotational isomers δ 8.32 (d, J = 5.2 Hz, 1H), 8.18 (s, 1H), 7.49–7.43 (m, 1H), 7.29–7.25 (m, 1H), 7.20–7.17 (m, 1H), 7.08 (d, J = 5.2 Hz, 1H), 4.64–4.57 (m, 1H), 4.45–4.22 (m, 3H), 2.86–2.80 (m, 2H), 2.79 (s, 3H), 2.37–2.22 (m, 2H), 1.90–1.72 (m, 2H), 1.51 (s, 9H), 1.15–1.04 (m, 3H). 0.91 (d, J = 6.4 Hz, 3H).

[0769] Step 4: 5-Fluoro-N-isopropyl-N-methyl-2-(2-oxo-1-(piperidin-4-yl)-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)benzamide hydrochloride

[0770]

[0771] A 5N HCl solution in iPrOH (5 mL) was added to tert-butyl 4-(3-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylic acid (610 mg, 1.19 mmol). After stirring at room temperature for 2 h, the solvent was evaporated to give crude 5-fluoro-N-isopropyl-N-methyl-2-(2-oxo-1-(piperidine-4-yl)-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)benzamide HCl salt. This substance was used directly in the next step without further purification.

[0772] Step 5: ((1r,4r)-4-(2-(4-(3-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidin-1-yl)ethyl)cyclohexyl)tert-butyl carbamate

[0773]

[0774] NaBH3CN (6 mg, 0.088 mmol) was added to a solution of 5-fluoro-N-isopropyl-N-methyl-2-(2-oxo-1-(piperidin-4-yl)-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)benzamide HCl salt (20 mg, 0.044 mmol), Et3N (0.02 mL, 0.13 mmol), and (trans)-4-(2-oxoethyl)(cyclohexyl)carbamate tert-butyl ester (21 mg, 0.088 mmol) in MeOH at room temperature, and the reaction mixture was stirred at room temperature for 24 h. The solvent was evaporated and purified using ISCO rapid column chromatography (eluting with 15% MeOH in DCM) to give ((trans)-4-(2-(4-(3-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidin-1-yl)ethyl)cyclohexyl)tert-butyl carbamate (30 mg, >95%). LCMS method C: t R = 4.842 min; [M + H] + = 637.70

[0775] Step 6: 2-(1-(1-(2-((1r,4r)-4-aminocyclohexyl)ethyl)piperidin-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)-5-fluoro-N-isopropyl-N-methylbenzamide

[0776]

[0777] The title compound was prepared according to a method similar to that described in step 4 of Example 1, and is used directly in the next step. LCMS: Method A: t R = 0.438 min; [M + H] + = 537.39.

[0778] Step 7: 5-Fluoro-N-isopropyl-N-methyl-2-(1-(1-(2-((1r,4r)-4-(methylsulfonylamino)cyclohexyl)ethyl)piperidin-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)benzamide

[0779] The title compound was synthesized using a method similar to that of Example 21. LCMS method C:t R = 3.161 min; [M+H] + = 615.53. 1¹H NMR (CD₃OD): Mixture of rotational isomers δ 8.56 (d, J = 6.4 Hz, 1H), 8.35 (s, 1H), 7.93 (d, J = 6.4, 1H), 7.72–7.68 (m, 1H), 7.52–7.43 (m, 2H), 4.83–4.75 (m, 1H), 4.58–4.51 (m, 1H), 3.81–3.70 (m, 2H), 3.22–3.14 (m, 5H), 2.94 (s, 3H), 2.94–2.80 (m, 2H), 2.87 (s, 3H), 2.30–2.18 (m, 2H), 2.06–2.02 (m, 2H). 1.87-1.80 (m, 2H), 1.72-1.66 (m, 2H), 1.36-1.09 (m, 8H), 1.04 (d, J = 6.8 Hz, 3H).

[0780] Example 79. 5-Fluoro-N-isopropyl-N-methyl-2-(2-oxo-1-(1-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidin-4-yl)-1,2-dihydro-3H-imidazol[4,5-c]pyridin-3-yl)benzamide

[0781]

[0782] The title product was synthesized by the method described in Example 74. In step 1, tert-butyl 4-((methanesulfonyl)oxy)piperidine-1-carboxylic acid was used. LCMS method C: t R = 2.421 min, within 16 min; [M+H] + =558.62. 1¹H NMR (CD₃OD): Mixture of rotational isomers δ 8.35 (bs, ¹H), 8.14 (bs, ¹H), 7.66–7.62 (m, ¹H), 7.58–7.50 (m, ¹H), 7.49–7.38 (m, 2H), 7.23–7.06 (m, 3H), 4.69–4.60 (m, ¹H), 4.52–4.46 (m, ¹H), 4.38 (s, 2H), 3.69–3.60 (m, 2H), 3.27–3.20 (m, 4H), 2.90–2.84 (m, 2H), 2.84 (s, 3H), 2.21–2.10 (m, 2H), 1.33–1.13 (m,3H), 0.97 (d, J = 6.0 Hz, 3H).

[0783] Example 80. 5-((4-(3-(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidin-1-yl)methyl)-4-methyl-1H-indole-2-carboxynitrile

[0784]

[0785] Step 1: 4-(3-(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0786]

[0787] A suspension of crude tert-butyl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidin-1-carboxylic acid (Example 78, Step 1, 100 mg, 0.31 mmol), (4-fluorophenyl)boronic acid (100 mg, 0.71 mmol), Cu(OAc)₂ (165 mg, 0.92 mmol), Et₃N (0.15 ml, 1.07 mmol), and 4 Å molecular sieve (150 mg) in DCM (3 mL) was stirred at room temperature for 24 h. The reaction mixture was filtered through a diatomaceous earth plug while being washed in DCM. The DCM solution was washed with saturated NH₄Cl aqueous solution, dried over Na₂SO₄, and evaporated. The crude compound was purified by ISCO rapid column chromatography (using 10% MeOH elution in DCM) to give tert-butyl 4-(3-(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidin-1-carboxylic acid (56 mg, 44%). LCMS method C: t R= 5.508; [M+H] + = 413.58.

[0788] Step 2: 5-((4-(3-(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidin-1-yl)methyl)-4-methyl-1H-indole-2-carboxynitrile

[0789] The title compound was prepared according to the method described in Example 74. In the final step, 5-formyl-1H-indole-2-carboxynitrile was utilized. LCMS method C:t R = 3.623 min; [M+H] + = 481.56 1 H NMR (CD3OD): δ8.54 (d, J = 6.0 Hz, 1H), 8.47 (s, 1H), 7.92 (d, J = 6.0 Hz, 1H), 7.64-7.61(m, 2H), 7.50-7.36 (m, 5H), 4.89-4.90 (m, 1H), 4.57 (s, 2H), 3.76-3.72 (m,2H), 3.42-3.31 (m, 2H), 2.90-2.84 (m, 2H), 2.71 (s, 3H), 2.27-2.22 (m, 2H).

[0790] Example 81. 2-(1-(1-(cyclohexylmethyl)piperidin-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)-5-fluoro-N-isopropyl-N-methylbenzamide

[0791]

[0792] The title compound was synthesized using the method described in Example 79. In final step 5, 1-cyclohexanealdehyde was utilized. LC-M method C:t R = 4.159 min, [M+H] + = 508.2. 1¹H NMR (CD₃OD): Mixture of rotational isomers δ 8.41 (d, J = 6.0 Hz, 1H), 8.19 (s, 1H), 7.69–7.63 (m, 2H), 7.51–7.40 (m, 2H), 4.74–4.71 (m, 1H), 4.55–4.50 (m, 1H), 3.80–3.75 (m, 2H), 3.28–3.17 (m, 2H), 3.03 (d, J = 6.8 Hz, 2H), 2.92–2.81 (m, 2H), 2.84 (s, 3H), 2.22–2.12 (m, 2H), 1.90–1.72 (m, 6H), 1.43–1.05 (m, 8H), 1.00 (d, J = 6.4 Hz, 3H).

[0793] Example 82. 2-(1-(1-((2-cyano-4-methyl-1H-indol-5-yl)methyl)piperidin-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)-5-fluoro-N-isopropyl-N-methylbenzamide

[0794]

[0795] The title compound was synthesized by the method described in Example 79. In the final step, 5-formyl-4-methyl-1H-indole-2-carboxynitrile was utilized. LCMS method C:t R = 4.251 min; [M+H] + = 580.60, 1 ¹H NMR (CD₃OD): Mixture of rotational isomers δ 8.53 (d, J = 6.4 Hz, 1H), 8.32–8.29 (m, 1H), 7.88–7.85 (m, 1H), 7.70–7.66 (m, 1H), 7.50–7.40 (m, 5H), 4.82–4.76 (m, 1H), 4.56 (s, 2H), 4.56–4.49 (m, 1H), 3.74–3.70 (m, 2H), 3.40–3.31 (m, 2H), 2.90–2.80 (m, 2H), 2.84 (s, 3H), 2.69 (s, 3H), 2.22–2.17 (m, 2H). 1.14-1.11 (m,3H), 1.00 (d, J = 6.8 Hz, 3H).

[0796] Example 83. 5-Fluoro-2-(1-(1-(4-fluorobenzyl)piperidin-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)-N-isopropyl-N-methylbenzamide

[0797]

[0798] The title compound was synthesized using the method described in Example 79. In the final step, 4-fluorobenzaldehyde was utilized. LCMS method C:t R = 3.660; [M+H] + = 520.65. 1 ¹H NMR (CD₃OD): Mixture of rotational isomers δ 8.60–8.50 (m, ¹H), 8.32–8.28 (m, ¹H), 7.85–7.81 (m, ¹H), 7.69–7.66 (m, ¹H), 7.60–7.57 (m, 2H), 7.50–7.45 (m, 2H), 7.29–7.24 (m, 2H), 4.87–4.70 (m, ¹H), 4.55–4.51 (m, ¹H), 4.39 (s, 2H), 3.70–3.65 (m, 2H), 3.26–3.20 (m, 2H), 2.86–2.75 (m, 2H), 2.85 (s, 3H). 2.22-2.10 (m, 2H), 1.16-1.13 (m, 3H), 1.01 (d, J= 6.4 Hz, 3H).

[0799] Example 84. 5-Fluoro-2-(3-(1-((1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N,N-diisopropylbenzamide

[0800]

[0801] Step 1: 5-Fluoro-2-(1H-pyrrolo[2,3-c]pyridin-1-yl)benzoic acid

[0802]

[0803] A 500 mL flask was filled with 6-aza-indole (10.0 g, 84.65 mmol), 5-fluoro-2-iodobenzoic acid (24.77 g, 93.12 mmol), Cu powder (5.38 g, 84.65 mmol), K₂CO₃ (29.2 g, 211.6 mmol, 2.5 equivalents), and N-methylpyrrolidone (NMP) (200 mL). The mixture was degassed three times and refilled with N₂, then heated to 150 °C and maintained for 2 h. The reaction mixture was cooled to room temperature, filtered through a short diatomaceous earth pad, and washed with MeCN and EtOAc (50 mL each). The filtrate was concentrated to remove MeCN and EtOAc. 6M HCl aqueous solution (28 mL) was slowly added with stirring until the final pH = 6. The resulting precipitate was collected by filtration and washed with H₂O to give 43.3 g of product. LCMS Method B: Rt = 0.58 min, 257 (M+H) + = 257.1

[0804] Step 2: 5-Fluoro-N,N-Diisopropyl-2-(1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide

[0805]

[0806] iPr₂NH (0.55 mL, 3.90 mmol, 5 equivalents) was added to a suspension of 5-fluoro-2-(1H-pyrrolo[2,3-c]pyridin-1-yl)benzoic acid (0.200 g, 0.78 mmol), benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate (PyBOP) (489 mg, 0.94 mmol, 1.2 equivalents) in DMF (2 mL), forming a clear, dark solution. The mixture was then stirred for 6 h. The reaction mixture was diluted with EtOAc and washed with a saturated aqueous solution of NaHCO₃. The combined organic phases were washed with brine, dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated to dryness. The residue was purified by rapid chromatography to give 165 mg of the desired product, which was used directly in the next step.

[0807] Step 3: 2-(3-bromo-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N,N-diisopropylbenzamide

[0808]

[0809] N-bromosuccinimide (NBS) (441 mmol, 2.48 mmol, 1.2 equivalence) was added in a single addition to a solution of 5-fluoro-N,N-diisopropyl-2-(1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide (700 mg, 2.06 mmol) in EtOAc (15 mL) cooled to 0 °C, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0 °C, quenched with aqueous Na₂S₂O₃ solution, and extracted with EtOAc. The organic phase was washed with brine, dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated to dryness and purified by rapid chromatography to give 0.873 g of the desired product. LCMS Method B: t R : 0.97 min; (M+H) + = 418.1.

[0810] Step 4: 5-(1-(2-(diisopropylcarbamoyl)-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[0811]

[0812] Under a N2 atmosphere, a mixture containing 2-(3-bromo-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N,N-diisopropylbenzamide (305 mg, 0.73 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaboronylcyclopentan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (248 mg, 0.80 mmol), K3PO4 (310 mg, 1.46 mmol), SPhos-Pd-G2 (16 mg, 0.022 mmol), and di... A 10 mL CEM microwave test tube containing alkane (3 mL) and H2O (1 mL) was heated to 110 °C and maintained for 15 min. The reaction mixture was diluted with EtOAc, washed with H2O and brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to dryness and the residue was purified by rapid chromatography to give 342 mg of tert-butyl 5-(1-(2-(diisopropylcarbamoyl)-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid. LCMS Method B: t R 1.18 min; (M+H) + = 521.1

[0813] Step 5: 3-(1-(2-(diisopropylcarbamoyl)-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester

[0814]

[0815] 5-(1-(2-(diisopropylcarbamoyl)-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (336 mg, 0.645 mmol) was hydrogenated for 24 h in MeOH (30 mL) with 10% Pd / C (100 mg). The reaction mixture was then filtered through a diatomaceous earth mat. The resulting residue was concentrated to dryness and purified by rapid chromatography on silica gel with hexane / EtOAc to give 263 mg of 3-(1-(2-(diisopropylcarbamoyl)-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester. LCMS Method B: t R 1.17 min; (M+H) + = 523.1.

[0816] Step 6: 5-Fluoro-N,N-Diisopropyl-2-(3-(piperidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide

[0817]

[0818] Add 4 M HCl to a solution of tert-butyl 3-(1-(2-(diisopropylcarbamoyl)-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-carboxylic acid (260 mg, 0.50 mmol) in MeOH (2 mL). Alkane (2 mL) and the mixture was stirred for 30 min at room temperature. The reaction mixture was concentrated to dryness to give 247 mg of 5-fluoro-N,N-diisopropyl-2-(3-(piperidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide in the form of a diHCl salt. LCMS Method B: t R : 0.60 min; (M+H) + = 423.1.

[0819] Step 7: 5-Fluoro-2-(3-(1-((1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N,N-diisopropylbenzamide

[0820] TEA (30 µL), HOAc (1 drop), 2-(5-formyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide (50 mg, 0.10 mmol) in MeOH (2.5 mL) were added to a solution of 5-fluoro-N,N-diisopropyl-2-(3-(piperidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)ethyl formic acid (intermediate 24, 35 mg, 0.14 mmol), and NaBH3CN (70 mg, 1.11 mmol). The mixture was heated at 40 °C for 24 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC method A to give 43.5 mg of the desired product in the form of TFA salt. LCMS method B: t R : 0.62 min; (M+H) + = 613.1. 1 H NMR (CD3OD) δ: 8.58 (s, 1H), 8.18 (d, J = 5.6 Hz, 1H), 7.72 (d, J = 5.6 Hz, 1H), 7.62 (m, 1H), 7.46 (m,1H), 7.40 (td, J = 8.4, 2.8 Hz, 1H), 7.30 (dd, J = 8.4, 2.8 Hz, 1H), 3.54 (m,1H), 3.36 (m, 1H), 3.21-3.10 (m, 3 H), 2.95 (m,1H), 2.93 (s, 3H), 2.22 (m,2H), 2.13-1.81 (m, 10H), 1.52 (m, 2H), 1.45 (d, J = 6.4 Hz, 3H), 1.29 (m, 2H), 1.07-1.01 (m, 8H), 0.25 (m, 2H).

[0821] Example 84A. 5-Fluoro-N,N-Diisopropyl-2-(3-(1-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide

[0822]

[0823] This compound was synthesized using a method similar to that of Example 84. In step 7, 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-carboxaldehyde was used. LCMS Method B: tR : 0.61 min; (M+H) + = 569.2. 1 H NMR (CD3OD)δ: 8.99 (brs, 1H), 8.37 (d, J = 6.4 Hz, 1H), 8.31 (d, J = 6.4 Hz, 1H), 8.20(s, 1H), 7.71 (m, 1H), 7.48 (td, J = 8.4, 2.8 Hz, 1H), 7.41(td, J = 8.0, 2.8Hz, 1H), 7.23-7.16 (m, 2H), 7.10 (m, 1H), 4.45 (m,1H), 4.36 (m, 1H), 3.61 (m,4H), 3.30-3.14 (m, 3H), 2.95 (s, 1H), 2.20-1.87 (m, 4H), 1.38 (m, 3H), 1.09(m, 3H), 0.90-0.51 (m, 6H).

[0824] Example 84B. 5-Fluoro-N,N-Diisopropyl-2-(3-(piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide

[0825]

[0826] The title compound was synthesized by the method described in Example 84 from steps 1 to 6. In step 4, tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid was used. LCMS Method B: t R : 0.58 min; (M+H) + = 423.2.

[0827] Example 85. Acetic acid (R)-2-(5-((3-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)methyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl ester

[0828]

[0829] At 0 °C, pyridine (3 drops) and Ac₂O (3 drops) were successively added to a solution of 5-fluoro-2-(3-(1-((1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropyl-N-methylbenzamide (Example 44, 50 mg, 0.085 mmol) in DCM (2 mL). The mixture was stirred for 30 min and MeOH (1 mL) was added to quench the reaction. The mixture was stirred for another 20 min, and then the reaction mixture was concentrated to dryness. The residue was extracted with EtOAc and washed continuously with aqueous NaHCO₃ solution and brine. The organic phase was dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated to dryness and the residue was purified by rapid chromatography to give 36 mg of (R)-2-(5-((3-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)methyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl acetate. LCMS Method B: t R : 0.61 min; (M+H) + = 627.1. 1 H NMR (CD3OD) δ: 8.62 and 8.54 (brs, 1H), 8.17 (brs, 1H), 7.67 (m, 2H), 7.45-7.37 (m, 3H), 7.15 (m, 3H), 4.84-4.74 (m, 2H), 4.37 (m, 2H), 4.15 (m, 2H), 3.77-3.52 (m, 2H), 3.24-3.03 (m, 4H), 2.60 and 2.57 (m, 1H), 2.38 (m, 1H), 2.22-2.10 (m, 2H), 1.90-1.73 (m, 5H), 1.58 (m, 1H), 0.98 (m, 3H), 0.40 (m, 1H), 0.14 (m, 1H).

[0830] Example 86. (R)-Stearic acid 2-(5-((3-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)methyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl ester

[0831]

[0832] Step 1: Stearoyl chloride

[0833]

[0834] Oxaloyl chloride (0.21 mL, 2.88 mmol) was added to a suspension of stearic acid (409 mg, 1.44 mmol) in anhydrous DCM (6 mL) cooled to 0 °C, followed by a drop of DMF. The mixture was stirred at room temperature for 16 h. The reaction mixture was evaporated to dryness, and the resulting residue was dissolved in anhydrous DCM (10 mL) to give a stearoyl chloride solution in DCM (approximately 0.144 M).

[0835] Step 2: (R)-Stearic acid 2-(5-((3-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)methyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl ester

[0836] A solution of stearoyl chloride (0.6 mL, approximately 0.086 mmol) was added dropwise to a solution of (R)-5-fluoro-2-(3-(1-((1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropyl-N-methylbenzamide (Example 44A, 50 mg, 0.085 mmol) described above. The mixture was stirred for 10 min and then quenched with MeOH (0.2 mL). The reaction mixture was diluted with EtOAc (10 mL) and washed continuously with aqueous NaHCO3 solution and brine. The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to dryness, and the residue was purified by rapid chromatography to give 47 mg of (R)-stearic acid 2-(5-((3-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)methyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl ester. LCMS Method B: t R 1.48 min; (M+H) + =851.2. 1H NMR (CD3OD) δ: 8.60 and 8.52 (brs, 1H), 8.15 (m, 1H), 7.67 (m, 2H), 7.67-7.45 (m, 3H), 7.13-7.09 (m, 3H), 4.37 (m, 2H), 4.13 (m, 2H), 0.98 (d, J = 7.2 Hz, 3H), 0.88 (d, J = 7.2 Hz, 1H), 0.40 (m, 1H), 0.11 (m, 1H).

[0837] Example 87. 5-Fluoro-N,N-Diisopropyl-2-(3-(1-(((1r,4r)-4-(methylsulfonylamino)cyclohexyl)methyl)piperidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide

[0838]

[0839] The title compound was synthesized using a method similar to Example 72, employing 5-fluoro-N,N-diisopropyl-2-(3-(piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide (Example 84B) and N-((1r,4r)-4-formylcyclohexyl)methanesulfonamide. LCMS Method B: t R : 0.67 min; (M+H) + = 612.2. 1H NMR (CD3OD) δ: 8.58(s, 1H), 8.18 (d, J = 5.6 Hz, 1H), 7.72 (d, J = 5.6 Hz, 1H), 7.62 (m, 1H), 7.46 (m, 1H), 7.40 (td, J = 8.4, 2.8 Hz, 1H), 7.30 (dd, J = 8.4, 2.8 Hz, 1H),3.54 (m, 1H), 3.36 (m, 1H), 3.21-3.10 (m, 3 H), 2.95 (m,1H), 2.93 (s, 3H),2.22 (m, 2H), 2.13-1.81 (m, 10H), 1.52 (m, 2H), 1.45 (d, J = 6.4 Hz, 3H), 1.29 (m, 2H), 1.07-1.01 (m, 8H), 0.25 (m, 2H).

[0840] Example 88. 2-(3-(1-((3-cyano-3-methyl-2-oxodihydroindole-6-yl)methyl)piperidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide

[0841]

[0842] The title compound was prepared from 6-formyl-3-methyl-2-oxodihydroindole-3-carboxynitrile (intermediate 20) by a method similar to that of Example 84A. LCMS Method B: t R : 0.68 min; (M+H) + = 579.2. 1H NMR (CD3OD)δ: 8.58 (s, 1H), 8.18 (d, J = 5.6 Hz, 1H), 7.72 (d, J = 5.6 Hz, 1H), 7.62 (m,1H), 7.46 (m, 1H), 7.40 (td, J = 8.4, 2.8 Hz, 1H), 7.30 (dd, J = 8.4, 2.8 Hz,1H), 3.54 (m, 1H), 3.36 (m, 1H), 3.21-3.10 (m, 3 H), 2.95 (m,1H), 2.93 (s,3H), 2.22 (m, 2H), 2.13-1.81 (m, 10H), 1.52 (m, 2H), 1.45 (d, J = 6.4 Hz, 3H), 1.29 (m, 2H), 1.07-1.01 (m, 8H), 0.25 (m, 2H).

[0843] Example 89. 5-Fluoro-N-isopropyl-N-methyl-2-(3-(2-((trans-3-(methanesulfonylamino)cyclobutyl)methyl)octahydrocyclopentadiene[c]pyrrolo-5-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide

[0844]

[0845] Step 1: 5-Fluoro-N-isopropyl-N-methyl-2-(3-(octahydrocyclopentadien[c]pyrrolo-5-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide

[0846]

[0847] Add HCl / di(2,3-c)pyrrolo[2,3-c]pyridin-3-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (intermediate 15, 300 mg, 0.58 mmol) to a mixture of 5-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (intermediate 15, 300 mg, 0.58 mmol) in anhydrous DCM (6 mL). Alkane (2 mL, 4 N) was added, and the mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure, and the residue was alkalized to pH = 12-14 with 10% NaOH solution, followed by extraction with DCM / i-PrOH (v / v = 10 / 1, 3 × 80 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a white solid of 5-fluoro-N-isopropyl-N-methyl-2-(3-(octahydrocyclopentadien[c]pyrrolo-5-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide, which was used directly in the next step without further purification. Yield: 240 mg (99% crude); LCMS Method B: t R : 0.86 min; (M+H) + = 421.3. 1 H NMR (CD3OD): δ ppm 8.50-8.65 (m,1H), 8.15-8.25 (m, 1H), 7.76 (d, J = 5.2 Hz, 1H), 7.65-7.70 (m, 1H), 7.35-7.50 (m, 3H), 4.40-4.55 (m, 0.5H), 3.55-3.65 (m, 0.5H), 3.25-3.30 (m, 1H), 2.90-3.00 (m, 6H), 2.40-2.70 (m, 5H), 1.00-1.50 (m, 5H), 0.20-0.55 (m, 3H). 19 FNMR (CD3OD): δ ppm -113.35.

[0848] Step 2: (trans-3-((5-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)hexahydrocyclopentan[c]pyrrolo-2(1H)-yl)methyl)cyclobutyl)tert-butyl carbamate

[0849]

[0850] A mixture of 5-fluoro-N-isopropyl-N-methyl-2-(3-(octahydrocyclopentadien[c]pyrrolo-5-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide (60 mg, 0.14 mmol), (trans-3-formylcyclobutyl)carbamate tert-butyl ester (intermediate 22, 56 mg, 0.28 mmol), and NaBH3CN (44 mg, 0.7 mmol) in anhydrous MeOH (4 mL) was stirred at 70 °C for 18 h. The mixture was concentrated under reduced pressure, and H2O (20 mL) was added to the residue, followed by extraction with EtOAc (3 × 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with DCM / MeOH = 10 / 1) to give a colorless oil of (trans-3-((5-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)hexahydrocyclopenta[c]pyrrolo-2(1H)-yl)methyl)cyclobutyl)carbamate. Yield: 65 mg (76%); LCMS Method B: t R : 0.620 min; (M+H) + = 604.3.

[0851] Step 3: 2-(3-(2-((trans-3-aminocyclobutyl)methyl)octahydrocyclopentadiene[c]pyrrolo-5-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide

[0852]

[0853] TFA (1 mL) was added to (trans-3-((5-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)hexahydrocyclopenta[c]pyrrolo-2(1H)-yl)methyl)cyclobutyl)carbamate (65 mg, 0.11 mmol) at 0 °C, and the mixture was stirred at 22–27 °C for 2 h. The mixture was alkalized to pH = 12–14 with 10% NaOH solution and extracted with DCM / i-PrOH (v / v = 10 / 1.4 × 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a colorless oily substance of 2-(3-(2-((trans-3-aminocyclobutyl)methyl)octahydrocyclopentadiene[c]pyrrolo-5-yl)-1H-pyrrolo[2,3-c]pyridinolo-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide, which was used directly in the next step without further purification. Yield: 40 mg (74% crude product);

[0854] Step 4: 5-Fluoro-N-isopropyl-N-methyl-2-(3-(2-((trans-3-(methanesulfonylamino)cyclobutyl)methyl)octahydrocyclopentadiene[c]pyrrolo-5-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide

[0855] At 0 °C, (MeSO₂)₂O (38 mg, 0.24 mmol) was added to a mixture of 2-(3-(2-((trans-3-aminocyclobutyl)methyl)octahydrocyclopentadiene[c]pyrrolo-5-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide (40 mg, 0.08 mmol) and Et₃N (40 mg, 0.56 mL, 0.4 mmol) in anhydrous DCM (3 mL), and the mixture was stirred at room temperature for 1 h. The mixture was then added to H₂O (20 mL) and extracted with DCM (3 × 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by alkaline preparative HPLC method D to obtain a white solid, 5-fluoro-N-isopropyl-N-methyl-2-(3-(2-((trans-3-(methanesulfonylamino)cyclobutyl)methyl)octahydrocyclopentadiene[c]pyrrolo-5-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide. Yield: 6.3 mg (14%); LCMS method D: t R 1.965 min; (M+H) + = 582.2. 1H NMR (CD3OD): δ ppm8.50-8.65 (m, 1H), 8.15-8.20 (m, 1H), 7.76 (d, J = 5.2 Hz, 1H), 7.65-7.70 (m,1H), 7.35-7.50 (m, 3H), 4.45-4.55 (m, 0.5H), 3.90-4.00 (m, 1H), 3.55-3.65 (m,0.5H), 3.25-3.30 (m, 1H), 2.90 (s, 3H), 2.75-2.85 (m, 2H), 2.40-2.70 (m,12H), 2.15-2.25 (m, 4H), 1.55-1.65 (m, 2H), 1.00-1.10 (m, 3H), 0.20-0.60 (m, 3H). 19 F NMR (CD3OD): δ ppm -113.53.

[0856] Examples 90-91.

[0857] The following embodiments were synthesized using the method described above for Embodiment 89.

[0858] Table 9.

[0859]

[0860] Example 92. 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1-((cis-3-(methanesulfonylamino)cyclobutyl)methyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide

[0861]

[0862] The title compound was synthesized by means of the method described in Example 1, starting with 5-fluoro-N-isopropyl-N-methyl-2-(3-(piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide (Example 1, step 1) and N-((1r,3r)-3-formylcyclobutyl)methanesulfonamide. LCMS method D:t R 1.757 min; (M+H) + = 556.2. 1H NMR(CD3OD): δ ppm 8.50-8.70 (m, 1H), 8.15-8.25 (m, 1H), 7.75-7.80 (m, 1H), 7.60-7.70 (m, 1H), 7.30-7.50 (m, 3H), 4.35-4.55 (m, 0.5H), 3.70-3.85 (m, 1H), 3.55-3.65 (m, 0.5H), 3.00-3.10 (m, 2H), 2.92-3.00 (m, 1H), 2.91 (s, 3H), 2.70-2.95 (m, 3H), 2.40-2.70 (m, H), 2.20-2.35 (m, 3H), 2.00-2.10 (m, 2H), 1.80-2.00 (m, 2H), 1.65-1.80 (m, 2H), 0.95-1.15 (m, 3H), 0.15-0.60 (m, 3H). 19 FNMR (CD3OD): δ ppm -113.39.

[0863] Example 93. 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1-(2-(4-(methanesulfonylamino)piperidin-1-yl)ethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide

[0864]

[0865] Step 1: 2-(3-(1-(2,2-dimethoxyethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide

[0866]

[0867] To a mixture of 5-fluoro-N-isopropyl-N-methyl-2-(3-(piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide (Example 1, Step 1, 200 mg, 0.51 mmol, HCl salt) in DMF (10 mL), 2-bromo-1,1-dimethoxyethane (171 mg, 1.01 mmol) and K₂CO₃ (211 mg, 1.53 mmol) were added. The mixture was degassed with N₂ and purged three times, then heated at 110 °C for 17 h under N₂. The mixture was added to water (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with DCM / MeOH = 10 / 1) to give a red oily 2-(3-(1-(2,2-dimethoxyethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide. Yield: 115 mg (47%); LCMS Method B: t R : 0.528 min; (M+H) + = 483.1.

[0868] Step 2: 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1-(2-oxoethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide

[0869]

[0870] An aqueous solution of HCl (4 mL, 3 M) was added to a mixture of 2-(3-(1-(2,2-dimethoxyethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide (115 mg, 0.24 mmol) in THF (10 mL). The mixture was degassed with N2 and purged three times, and then heated at 70 °C for 17 h under N2. The mixture was concentrated under reduced pressure to give a red solid of 5-fluoro-N-isopropyl-N-methyl-2-(3-(1-(2-oxoethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide (211 mg crude, 100% crude yield) (HCl salt). Yield: 211 mg (100% crude); LCMS Method B: t R : 0.474 min; (M+H) + = 455.1.

[0871] Step 3: (1-(2-(4-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)ethyl)piperidin-4-yl)tert-butyl carbamate

[0872]

[0873] Add Et3N (146 mg, 1.44 mmol), tert-butyl piperidinium-4-yl)-1H-pyrrolo[2,3-c]pyridinium-1-yl)benzamide (211 mg, 0.48 mmol, HCl salt) to a mixture of 5-fluoro-N-isopropyl-N-methyl-2-(3-(1-(2-oxoethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridinium-1-yl)benzamide (211 mg, 0.48 mmol, HCl salt) and NaBH3CN to MeOH (15 mL). (119 mg, 1.92 mmol). The mixture was degassed with N2 and purged three times, then heated at 70 °C for 15 h under N2. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluting with DCM / MeOH = 10 / 1) to give a red solid (1-(2-(4-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)ethyl)piperidin-4-yl)tert-butyl carbamate. Yield: 156 mg (51%); LCMS Method B: t R : 0.572 min; (M+H) + = 621.3.

[0874] Step 4: 2-(3-(1-(2-(4-aminopiperidin-1-yl)ethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide

[0875]

[0876] HCl-di(2-(4-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)ethyl)piperidin-4-yl)carbamate tert-butyl ester (156 mg, 0.25 mmol) in CH2Cl2 (15 mL) was added at 0 °C. Alkane (3 mL). The mixture was degassed and purged with N2 and then stirred at room temperature under N2 for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC method A to give a red solid 2-(3-(1-(2-(4-aminopiperidin-1-yl)ethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide (TFA salt). Yield: 118 mg (90%); LCMS method B: t R : 0.790 min; (M+H) + = 521.5.

[0877] Step 5: 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1-(2-(4-(methanesulfonylamino)piperidin-1-yl)ethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide

[0878] Et3N (76 mg, 0.75 mmol) and (MeSO2)2O (80 mg, 0.46 mmol) were added to a mixture of 2-(3-(1-(2-(4-aminopiperidin-1-yl)ethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide (80 mg, 0.15 mmol, TFA salt) in CH2Cl2 (10 mL). The mixture was degassed with N2 and purged three times, and then stirred at room temperature under N2 atmosphere for 0.5 h. The mixture was concentrated under reduced pressure, and the residue was purified by alkaline preparative HPLC method D to give a white solid 5-fluoro-N-isopropyl-N-methyl-2-(3-(1-(2-(4-(methanesulfonylamino)piperidin-1-yl)ethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide. Yield: 19.3 mg (21%); LCMS method D: t R : 0.820 min; (M+H) + = 599.3. 1H NMR (CD3OD): δ ppm8.50-8.65 (m, 1H), 8.15-8.25 (m, 1H), 7.75-7.80 (m, 1H), 7.60-7.70 (m, 1H), 7.30-7.50 (m, 3H), 4.40-4.55 (m, 0.5H), 3.50-3.65 (m, 0.5H), 3.20-3.30 (m,2H), 3.05-3.20 (m, 2H), 2.98 (s, 3H), 2.90-2.96 (m, 2H), 2.40-2.70 (m, 7H),2.15-2....

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, I in: Ring A is C 6-10 Aryl, 5- to 14-membered heteroaryl, C 3-14 Cycloalkyl or 4- to 14-membered heterocyclic alkyl; U is N or CR U , where R U H, halogen, CN, OH, C 1-4 Alkyl, C 1-4 Alkoxy, amino, C 1-4 Alkylamino or C 2-8 Dialkylamino; Partially selected from: , , , and , where R Y H, halogen, CN, OH, C 1-4 Alkyl, C 1-4 Alkoxy, amino, C 1-4 Alkylamino or C 2-8 Dialkylamino; X is either F or Cl; L is selected from -C 1-6 Alkylene- and -(C 1-4 Alkylene) a -Q-(C 1-4 Alkylene) b -, where C is mentioned 1-6 Alkylene and -(C 1-4 Alkylene) a -Q-(C 1-4 Alkylene) b -Any C in the group 1-4 The alkylene group is optionally substituted by one, two, or three independent substituents selected from the following: halogen, CN, OH, C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, amino, C 1-3 Alkylamino and di(C) 1-3 alkyl)amino; Q is -O-, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, -C(=O)NR q1 -、-C(=O)O-、-OC(=O)NR q1 -、-NR q1 -、-NR q1 C(=O)O-、-NR q1 C(=O)NR q1 -、-S(=O)2NR q1 -、-C(=NR q2 - or -C(=NR) q2 )-NR q1 -, where each R q1 Independently selected from H and C 1-6 Alkyl and C 1-3 Hydroxyalkyl, wherein each R q2 Independently selected from H and C 1-6 Alkyl groups and CN; Cy represents connectivity C. 6-14 Aryl, Connecting C 3-18 Cycloalkyl, linked 5- to 16-membered heteroaryl, or linked 4- to 18-membered heterocycloalkyl, each optionally selected independently by one, two, three, or four from R Cy Substituents of the substituents; Each R Cy Independently selected from halogens, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, CN, NO2, OR a1 SR a1 C(O)R b1 C(O)NR c1 R d1 C(O)OR a1 OC(O)R b1 OC(O)NR c1 R d1 C(=NR) e1 )NR c1 R d1 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 S(O)R b1 S(O)NR c1 R d1 S(O)2R b1 and S(O)2NR c1 R d1 The C mentioned therein 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 The cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl groups are each optionally substituted by one, two, three, or four independent substituents selected from the following: CN, NO2, OR a1 SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , NR c1 C(=NR e1 )NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O)2R b1 , NR c1 S(O)2NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 and S(O)2NR c1 R d1 ; R 1 For H, Cy 1 Halogen, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl, C 2-6 alkenyl, C 2-6 Alkyne, CN, NO2, OR a2 SR a2 C(O)R b2 C(O)NR c2 R d2 C(O)OR a2 OC(O)R b2 OC(O)NR c2 R d2 C(=NR) e2 )NR c2 R d2 NR c2 C(=NR e2 )NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 NR c2 S(O)2NR c2 R d2 S(O)R b2 S(O)NR c2 R d2 S(O)2R b2 and S(O)2NR c2 R d2 The C mentioned therein 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Each of the alkynyl groups may be optionally substituted by one, two, three, or four independent substituents selected from the following: halogen, CN, NO2, OR. a2 SR a2 C(O)R b2 C(O)NR c2 R d2 C(O)OR a2 OC(O)R b2 , OC(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , NR c2 C(=NR e2 )NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O)2R b2 , NR c2 S(O)2NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 and S(O)2NR c2 R d2 ; Z is Cy 2 Halogen, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl, C 2-6 alkenyl, C 2-6 Alkyne, CN, NO2, OR a3 SR a3 C(O)R b3 C(O)NR c3 R d3 C(S)NR c3 R d3 C(O)OR a3 OC(O)R b3 OC(O)NR c3 R d3 C(=NR) e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)OR a3 NR c3 C(O)NR c3 R d3 NR c3 S(O)R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 S(O)R b3 S(O)NR c3 R d3 S(O)2R b3 S(O)2NR c3 R d3 and P(O)R c3 R d3 The C mentioned therein 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Each of the ynyl groups is optionally substituted by one, two, three, or four independent substituents selected from the following: Cy 2 Halogen, CN, NO2, CN, NO2, OR a3 SR a3 C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , C(=NR e3 )NR c3 R d3 , NR c3 C(=NR e3 )NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)OR a3 , NR c3 C(O)NR c3 R d3 , NR c3 S(O)R b3 , NR c3 S(O)2R b3 , NR c3 S(O)2NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 and S(O)2NR c3 R d3 ; Each R 2 R 3 R 4 and R 5 Independently selected from H, halogen, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl, C 2-6 alkenyl, C 2-6 Alkyne, CN, NO2, OR a4 SR a4 C(O)R b4 C(O)NR c4 R d4 C(O)OR a4 OC(O)R b4 OC(O)NR c4 R d4 C(=NR) e4 )NR c4 R d4 NR c4 C(=NR e4 )NR c4 R d4 NR c4 R d4 NR c4 C(O)R b4 NR c4 C(O)OR a4 NR c4 C(O)NR c4 R d4 NR c4 S(O)R b4 NR c4 S(O)2R b4 NR c4 S(O)2NR c4 R d4 S(O)R b4 S(O)NR c4 R d4 S(O)2R b4 and S(O)2NR c4 R d4 The C mentioned therein 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Each of the alkynyl groups may be optionally substituted by one, two, three, or four independent substituents selected from the following: halogen, CN, NO2, OR. a4 SR a4 C(O)R b4 C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , C(=NR e4 )NR c4 R d4 , NR c4 , C(=NR e4 )NR c4 R d4 , NR c4 R d4 , NR c4 , C(O)R b4 , NR c4 , C(O)OR a4 , NR c4 , C(O)NR c4 R d4 , NR c4 , S(O)R b4 , NR c4 , S(O)2R b4 , NR c4 , S(O)2NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O)2R b4 and S(O)2NR c4 R d4 ; Each Cy 1 Selected independently from C 6-14 Aryl, C 3-18 Cycloalkyl, 5- to 16-membered heteroaryl, and 4- to 18-membered heterocycloalkyl, each optionally selected independently by one, two, three, or four from R Cy1 Substituents of the substituents; Each Cy 2 Selected independently from C 6-14 Aryl, C 3-18 Cycloalkyl, 5- to 16-membered heteroaryl, and 4- to 18-membered heterocycloalkyl, each optionally selected independently by one, two, three, or four from R Cy2 Substituents of the substituents; Each R Cy1 and R Cy2 Independently selected from halogens, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl, CN, NO2, OR a5 SR a5 C(O)R b5 C(O)NR c5 R d5 C(O)OR a5 OC(O)R b5 OC(O)NR c5 R d5 C(=NR) e5 )NR c5 R d5 NR c5 C(=NR e5 )NR c5 R d5 NR c5 R d5 NR c5 C(O)R b5 NR c5 C(O)OR a5 NR c5 C(O)NR c5 R d5 NR c5 S(O)R b5 NR c5 S(O)2R b5 NR c5 S(O)2NR c5 R d5 S(O)R b5 S(O)NR c5 R d5 S(O)2R b5 and S(O)2NR c5 R d5 The C mentioned therein 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 The cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl groups are each optionally substituted by one, two, three, or four independent substituents selected from the following: CN, NO2, OR a5 SR a5 C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5 , C(=NR e5 )NR c5 R d5 , NR c5 C(=NR e5 )NR c5 R d5 , NR c5 R d5 , NR c5 C(O)R b5 , NR c5 C(O)OR a5 , NR c5 C(O)NR c5 R d5 , NR c5 S(O)R b5 , NR c5 S(O)2R b5 , NR c5 S(O)2NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O)2R b5 and S(O)2NR c5 R d5 ; Each R a1 R b1 R c1 R d1 R a2 R b2 R c2 R d2 R a3 R b3 R c3 R d3 R a4 R b4 R c4 R d4 R a5 R b5 R c5 and R d5 Independently selected from H and C 1-6 Alkyl, C 1-4 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl, C 3-10 cycloalkyl-C 1-6 Alkyl, (5 to 10-membered heteroaryl)-C 1-6 Alkyl and (4 to 10-membered heterocyclic alkyl)-C 1-6 Alkyl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl, C 3-10 cycloalkyl-C 1-6 Alkyl, (5 to 10-membered heteroaryl)-C 1-6 Alkyl and (4 to 10-membered heterocyclic alkyl)-C 1-6 Each alkyl group is optionally selected independently from R by one, two, three, four, or five alkyl groups. g Substituents of the substituents; Each R e1 R e2 R e3 R e4 and R e5 Independently selected from H and C 1-4 Alkyl groups and CN; Each R g Choose independently the following groups: OH, NO2, CN, halogens, C 1-20 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-4 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, cyano-C 1-3 Alkyl, HO-C 1-3 Alkyl, amino, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, mercapto, C 1-6 Alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carboxyl, C 1-6 alkyl carbonyl and C 1-6 alkoxycarbonyl; n is 0 or 1; m is 0 or 1; p is 0, 1, 2 or 3; r is 0, 1, or 2; a is 0 or 1; and b is 0 or 1. Any of the cycloalkyl or heteroalkyl groups may optionally be further substituted with one or two oxo groups. And the compound in question is not: , , or 。 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein: Ring A is C 6-10 Aryl, 5- to 14-membered heteroaryl, C 3-14 Cycloalkyl or 4- to 14-membered heterocyclic alkyl; U is N or CR U , where R U H, halogen, CN, OH, C 1-4 Alkyl, C 1-4 Alkoxy, amino, C 1-4 Alkylamino or C 2-8 Dialkylamino; Partially selected from: , , , and , where R Y H, halogen, CN, OH, C 1-4 Alkyl, C 1-4 Alkoxy, amino, C 1-4 Alkylamino or C 2-8 Dialkylamino; X is either F or Cl; L is selected from -C 1-6 Alkylene- and -(C 1-4 Alkylene) a -Q-(C 1-4 Alkylene) b -, where C is mentioned 1-6 Alkylene and -(C 1-4 Alkylene) a -Q-(C 1-4 Alkylene) b -Any C in the group 1-4 The alkylene group is optionally substituted by one, two, or three independent substituents selected from the following: halogen, CN, OH, C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, amino, C 1-3 Alkylamino and di(C) 1-3 alkyl)amino; Q is -O-, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, -C(=O)NR q1 -、-C(=O)O-、-OC(=O)NR q1 -、-NR q1 -、-NR q1 C(=O)O-、-NR q1 C(=O)NR q1 -、-S(=O)2NR q1 -、-C(=NR q2 - or -C(=NR) q2 )-NR q1 -, where each R q1 Independently selected from H and C 1-6 Alkyl groups, wherein each R q2 Independently selected from H and C 1-6 Alkyl groups and CN; Cy represents connectivity C. 6-14 Aryl, Connecting C 3-18 Cycloalkyl, linked 5- to 16-membered heteroaryl, or linked 4- to 18-membered heterocycloalkyl, each optionally selected independently by one, two, three, or four from R Cy Substituents of the substituents; Each R Cy Independently selected from halogens, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, CN, NO2, OR a1 SR a1 C(O)R b1 C(O)NR c1 R d1 C(O)OR a1 OC(O)R b1 OC(O)NR c1 R d1 C(=NR) e1 )NR c1 R d1 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 S(O)R b1 S(O)NR c1 R d1 S(O)2R b1 and S(O)2NR c1 R d1 The C mentioned therein 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 The cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl groups are each optionally substituted by one, two, three, or four independent substituents selected from the following: CN, NO2, OR a1 SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , NR c1 C(=NR e1 )NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O)2R b1 , NR c1 S(O)2NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 and S(O)2NR c1 R d1 ; R 1 For H, Cy 1 Halogen, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl, C 2-6 alkenyl, C 2-6 Alkyne, CN, NO2, OR a2 SR a2 C(O)R b2 C(O)NR c2 R d2 C(O)OR a2 OC(O)R b2 OC(O)NR c2 R d2 C(=NR) e2 )NR c2 R d2 NR c2 C(=NR e2 )NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 NR c2 S(O)2NR c2 R d2 S(O)R b2 S(O)NR c2 R d2 S(O)2R b2 and S(O)2NR c2 R d2 The C mentioned therein 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Each of the alkynyl groups may be optionally substituted by one, two, three, or four independent substituents selected from the following: halogen, CN, NO2, OR. a2 SR a2 C(O)R b2 C(O)NR c2 R d2 C(O)OR a2 OC(O)R b2 , OC(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , NR c2 C(=NR e2 )NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O)2R b2 , NR c2 S(O)2NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 and S(O)2NR c2 R d2 ; Z is Cy 2 C 2-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl, C 2-6 alkenyl, C 2-6 Alkyne, CN, NO2, OR a3 SR a3 C(O)R b3 C(O)NR c3 R d3 C(S)NR c3 R d3 C(O)OR a3 OC(O)R b3 OC(O)NR c3 R d3 C(=NR) e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)OR a3 NR c3 C(O)NR c3 R d3 NR c3 S(O)R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 S(O)R b3 S(O)NR c3 R d3 S(O)2R b3 S(O)2NR c3 R d3 and P(O)R c3 R d3 The C mentioned therein 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Each of the ynyl groups is optionally substituted by one, two, three, or four independent substituents selected from the following: Cy 2 Halogen, CN, NO2, CN, NO2, OR a3 SR a3 C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , C(=NR e3 )NR c3 R d3 , NR c3 C(=NR e3 )NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)OR a3 , NR c3 C(O)NR c3 R d3 , NR c3 S(O)R b3 , NR c3 S(O)2R b3 , NR c3 S(O)2NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 and S(O)2NR c3 R d3 ; Each R 2 R 3 R 4 and R 5 Independently selected from H, halogen, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl, C 2-6 alkenyl, C 2-6 Alkyne, CN, NO2, OR a4 SR a4 C(O)R b4 C(O)NR c4 R d4 C(O)OR a4 OC(O)R b4 OC(O)NR c4 R d4 C(=NR) e4 )NR c4 R d4 NR c4 C(=NR e4 )NR c4 R d4 NR c4 R d4 NR c4 C(O)R b4 NR c4 C(O)OR a4 NR c4 C(O)NR c4 R d4 NR c4 S(O)R b4 NR c4 S(O)2R b4 NR c4 S(O)2NR c4 R d4 S(O)R b4 S(O)NR c4 R d4 S(O)2R b4 and S(O)2NR c4 R d4 The C mentioned therein 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Each of the alkynyl groups may be optionally substituted by one, two, three, or four independent substituents selected from the following: halogen, CN, NO2, OR. a4 SR a4 C(O)R b4 C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , C(=NR e4 )NR c4 R d4 , NR c4 C(=NR e4 )NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)OR a4 , NR c4 C(O)NR c4 R d4 , NR c4 S(O)R b4 , NR c4 S(O)2R b4 , NR c4 S(O)2NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O)2R b4 and S(O)2NR c4 R d4 ; Each Cy 1 Selected independently from C 6-14 Aryl, C 3-18 Cycloalkyl, 5- to 16-membered heteroaryl, and 4- to 18-membered heterocycloalkyl, each optionally selected independently by one, two, three, or four from R Cy1 Substituents of the substituents; Each Cy 2 Selected independently from C 6-14 Aryl, C 3-18 Cycloalkyl, 5- to 16-membered heteroaryl, and 4- to 18-membered heterocycloalkyl, each optionally selected independently by one, two, three, or four from R Cy2 Substituents of the substituents; Each R Cy1 and R Cy2 Independently selected from halogens, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl, CN, NO2, OR a5 SR a5 C(O)R b5 C(O)NR c5 R d5 C(O)OR a5 OC(O)R b5 OC(O)NR c5 R d5 C(=NR) e5 )NR c5 R d5 NR c5 C(=NR e5 )NR c5 R d5 NR c5 R d5 NR c5 C(O)R b5 NR c5 C(O)OR a5 NR c5 C(O)NR c5 R d5 NR c5 S(O)R b5 NR c5 S(O)2R b5 NR c5 S(O)2NR c5 R d5 S(O)R b5 S(O)NR c5 R d5 S(O)2R b5 and S(O)2NR c5 R d5 The C mentioned therein 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 The cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl groups are each optionally substituted by one, two, three, or four independent substituents selected from the following: CN, NO2, OR a5 SR a5 C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5 , C(=NR e5 )NR c5 R d5 , NR c5 C(=NR e5 )NR c5 R d5 , NR c5 R d5 , NR c5 C(O)R b5 , NR c5 C(O)OR a5 , NR c5 C(O)NR c5 R d5 , NR c5 S(O)R b5 , NR c5 S(O)2R b5 , NR c5 S(O)2NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O)2R b5 and S(O)2NR c5 R d5 ; Each R a1 R b1 R c1 R d1 R a2 R b2 R c2 R d2 R a3 R b3 R c3 R d3 R a4 R b4 R c4 R d4 R a5 R b5 R c5 and R d5 Independently selected from H and C 1-6 Alkyl, C 1-4 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl, C 3-10 cycloalkyl-C 1-6 Alkyl, (5 to 10-membered heteroaryl)-C 1-6 Alkyl and (4 to 10-membered heterocyclic alkyl)-C 1-6 Alkyl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl, C 3-10 cycloalkyl-C 1-6 Alkyl, (5 to 10-membered heteroaryl)-C 1-6 Alkyl and (4 to 10-membered heterocyclic alkyl)-C 1-6 Each alkyl group is optionally selected independently from R by one, two, three, four, or five alkyl groups. g Substituents of the substituents; Each R e1 R e2 R e3 R e4 and R e5 Independently selected from H and C 1-4 Alkyl groups and CN; Each R g Choose independently the following groups: OH, NO2, CN, halogens, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-4 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, cyano-C 1-3 Alkyl, HO-C 1-3 Alkyl, amino, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, mercapto, C 1-6 Alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carboxyl, C 1-6 alkyl carbonyl and C 1-6 alkoxycarbonyl, wherein the C 1-6 alkyl groups further via C 1-6 Alkyl substitution; n is 0 or 1; m is 0 or 1; p is 0, 1, 2 or 3; r is 0, 1, or 2; a is 0 or 1; and b is 0 or 1. Any of the cycloalkyl or heterocycloalkyl groups may optionally be further substituted with one or two oxo groups.

3. The compound of claim 1 or 2, wherein U is N.

4. The compound of claim 1 or 2, wherein U is CR U .

5. The compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein X is F.

6. The compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein X is Cl.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein... Part of .

8. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein Part of .

9. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein... Part of .

10. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein Part of .

11. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein Part of .

12. The compound of any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein ring A is a 5- to 10-membered heteroaryl group, and C... 3-10 Cycloalkyl or 4 to 10-membered heterocyclic alkyl.

13. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein ring A is a group having the following formula: , , , , , , , , or , where e and f show the connection points with the remaining part of the molecule.

14. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein ring A is a group having the following formula: , , or , where e and f show the connection points with the remaining part of the molecule.

15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein L is a -C group optionally substituted with one, two, or three substituents independently selected from the group consisting of... 1-6 Alkylene: Halogen, CN, OH, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, amino, C 1-3 Alkylamino and di(C) 1-3 Alkyl)amino.

16. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein L is -C 1-6 Alkylene-.

17. The compound of any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein L is selected from methylene, ethylene, and butylene.

18. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein L is -(C 1-4 Alkylene) a -Q-(C 1-4 Alkylene) b -, where -(C) 1-4 Alkylene) a -Q-(C 1-4 Alkylene) b -Any C in the group 1-4 The alkylene group is optionally substituted by one, two, or three independent substituents selected from the following: halogen, CN, OH, C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, amino, C 1-3 Alkylamino and di(C) 1-3 Alkyl)amino.

19. The compound of any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein L is selected from -NH2CH2-, -N(CH3)CH2-, -NHC(O)-, -O-, -C(O)- and -C(O)CH2-.

20. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein Cy is a linking C. 6-10 Aryl, Connecting C 3-10 Cycloalkyl, linked 5- to 10-membered heteroaryl, or linked 4- to 10-membered heterocycloalkyl, each optionally selected independently by one, two, three, or four from R Cy Substituents are substituted.

21. The compound of any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, wherein Cy is a linked phenyl group, a linked C group, or a C-terminal group. 3-10 Cycloalkyl, linked 5- to 10-membered heteroaryl, or linked 4- to 10-membered heterocycloalkyl, each optionally selected independently by one, two, three, or four from R Cy Substituents are substituted.

22. The compound of any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, wherein Cy is a linking group having the following formula: , , , , , , , , , , , , , , , , or Each of them is optionally selected independently from R by one, two, three or four. Cy Substituents are substituted.

23. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein Cy is a linking group having the following formula: , , or Each of them is optionally selected independently from R by one, two, three or four. Cy Substituents are substituted.

24. The compound of any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, wherein Z is C(O)NR c3 R d3 .

25. The compound of any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, wherein Z is C(O)NR c3 R d3 And R c3 and R d3 Independently selected from H and C 1-6 alkyl.

26. The compound of any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, wherein Z is C(O)NR c3 R d3 And R c3 and R d3 All are C 1-6 alkyl.

27. The compound of any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, wherein Z is C(O)NR c3 R d3 And R c3 and R d3 It is independently selected from methyl and isopropyl.

28. The compound of any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof, wherein R 3 For H.

29. The compound of any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof, wherein R 4 For H.

30. The compound of any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof, wherein n is 0.

31. The compound of any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof, wherein n is 1.

32. The compound of any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof, wherein m is 0.

33. The compound of any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof, wherein m is 1.

34. The compound of any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof, wherein p is 0.

35. The compound of any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof, wherein p is 1.

36. The compound of any one of claims 1 to 35 or a pharmaceutically acceptable salt thereof, wherein r is 0.

37. The compound of any one of claims 1 to 35 or a pharmaceutically acceptable salt thereof, wherein r is 1.

38. The compound of any one of claims 1 to 37 or a pharmaceutically acceptable salt thereof, wherein a is 0.

39. The compound of any one of claims 1 to 37 or a pharmaceutically acceptable salt thereof, wherein a is 1.

40. The compound of any one of claims 1 to 39 or a pharmaceutically acceptable salt thereof, wherein b is 0.

41. The compound of any one of claims 1 to 39 or a pharmaceutically acceptable salt thereof, wherein b is 1.

42. The compound of claim 1 or a pharmaceutically acceptable salt thereof, having the formula IIa, IIb, IIc, IId, IIe, IIIa, IIIb, IIIc or IIId: 。 43. The compound of claim 1 or a pharmaceutically acceptable salt thereof, having the formula IVa, IVb, IVc, IVd, Va, Vb, or Vc: 。 44. The compound of claim 1, wherein the compound is selected from: 5-((7-(5-(4-fluoro-2-(trifluoromethyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one; 2-(3-(1-((2-cyano-4-methyl-1H-indol-5-yl)methyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide; 5-((7-(5-(2,4-dichlorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one; 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 2-(3-(1-((2-cyano-1H-indol-5-yl)methyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide; 2-(3-(1-((2-cyano-1H-indol-6-yl)methyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide; 5-Fluoro-2-(3-(1-(4-fluorobenzyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropyl-N-methylbenzamide; 2-(3-(1-(4-chlorobenzyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide; 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 2-(3-(1-(4-cyanobenzyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide; 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1-(4-(methanesulfonyl)benzyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1-(2-methylbenzyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 2-(3-(1-(2-chlorobenzyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide; 2-(3-(1-((3,3-difluorocyclobutyl)methyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide; 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1-methylpiperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; (trans-4-(2-(4-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)ethyl)cyclohexyl)tert-butyl carbamate; 2-(3-(1-(2-(trans-4-acetamidocyclohexyl)ethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide; 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1-(2-(trans-4-(methanesulfonylamino)cyclohexyl)ethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; (trans-4-((4-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)methyl)cyclohexyl)tert-butyl carbamate; 2-(3-(1-(1-(trans-4-acetamidocyclohexyl)methyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide; 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1-((trans-4-(methanesulfonylamino)cyclohexyl)methyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 2-(3-(1-(4-acetamidobenzyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide; 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1-(4-(methanesulfonylamino)benzyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1-(4-(methanesulfonyl)phenethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 2-(3-(1-(3-cyanophenylethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide; 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1-(3-(methylcarbamoyl)phenethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; trans-(5-fluoro-2-(3-(1-((4-hydroxycyclohexyl)methyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropyl-N-methylbenzamide); cis-(5-fluoro-2-(3-(1-((4-hydroxycyclohexyl)methyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropyl-N-methylbenzamide); 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1-(2-(1-(methanesulfonyl)piperidin-4-yl)ethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 2-(3-(1-(4-(2-cyanopropan-2-yl)phenethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide; 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1-(1-phenylethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 2-(3-(2-benzylpiperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide; 2-(3-(1-benzylpiperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-ethyl-5-fluoro-N-isopropylbenzamide; 2-(3-(1-benzylpiperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N,N-diisopropylbenzamide; N-(trans-4-(2-(4-(1-(2-(cyclopropylmethoxy)-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)ethyl)cyclohexyl)methanesulfonamide; 1-(2-(cyclopropylmethoxy)-4-fluorophenyl)-3-(1-(4-fluorobenzyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridine; 2-(3-(1-benzylpiperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-(2-hydroxyethyl)-N-isopropylbenzamide; 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1-(((1r,4r)-4-(methylsulfonamide)cyclohexyl)methyl)azacyclohept-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 2-(3-(azacyclohepta-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide; 5-((4-(1-(4-fluoro-2-isobutylphenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)methyl)-4-methyl-1H-indole-2-carboxynitrile; 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 5-Fluoro-2-(3-(1-((1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropyl-N-methylbenzamide; 2-(3-(1-benzylpiperidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide; 2-(3-(1-(cyclohexylmethyl)piperidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide; N-Ethyl-5-fluoro-N-isopropyl-2-(3-(1-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; (S)-N-ethyl-5-fluoro-N-isopropyl-2-(3-(1-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; (R)-N-ethyl-5-fluoro-N-isopropyl-2-(3-(1-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; N-Ethyl-5-fluoro-2-(3-(1-((1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropylbenzamide; (S)-N-ethyl-5-fluoro-2-(3-(1-((1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropylbenzamide; (R)-N-ethyl-5-fluoro-2-(3-(1-((1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropylbenzamide; 2-(3-(2-azaspiro[3.5]nonyl-7-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide; 5-Fluoro-N-isopropyl-N-methyl-2-(3-(2-methyl-2-azaspiro[3.5]nonyl-7-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 5-Fluoro-N-isopropyl-N-methyl-2-(3-(2-methyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 5-Fluoro-2-(3-(4-hydroxycyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropyl-N-methylbenzamide; 2-(3-(4-(dimethylamino)cyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide; 5-Fluoro-N-isopropyl-N-methyl-2-(3-(trans-4-(pyrrolidin-1-yl)cyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 5-Fluoro-N-isopropyl-N-methyl-2-(3-(cis-4-(pyrrolidin-1-yl)cyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 2-(3-(trans-4-aminocyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide; 2-(3-(cis-4-aminocyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide; 5-Fluoro-N-isopropyl-N-methyl-2-(3-(4-phenoxycyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 5-Fluoro-N-isopropyl-N-methyl-2-(3-(4-(((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)amino)cyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 5-Fluoro-N-isopropyl-N-methyl-2-(3-(4-(((4-(methanesulfonylamino)cyclohexyl)methyl)amino)cyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 2-(7-(1-((2-cyano-4-methyl-1H-indol-5-yl)methyl)piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-5-fluoro-N-isopropyl-N-methylbenzamide; 2-(7-(1-((2-cyano-4-methyl-1H-indol-5-yl)methyl)piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-5-fluoro-N,N-dimethylbenzamide; 5-(4-fluorophenyl)-7-(1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine; 5-((4-(5-(4-fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidin-1-yl)methyl)-4-methyl-1H-indole-2-carboxynitrile; 5-((4-(5-(4-fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one; 7-(1-((1H-indol-6-yl)methyl)piperidin-4-yl)-5-(4-fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidine; 7-(1-((1H-indol-5-yl)methyl)piperidin-4-yl)-5-(4-fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidine; 5-((4-(5-(4-fluoro-2-methylphenyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidin-1-yl)methyl)-4-methyl-1H-indole-2-carboxynitrile; 5-((4-(5-(3-fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidin-1-yl)methyl)-4-methyl-1H-indole-2-carboxynitrile; 4-Methyl-5-((4-(5-phenyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidin-1-yl)methyl)-1H-indol-2-carboxynitrile; 5-((4-(5-phenyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one; 5-Fluoro-N-isopropyl-N-methyl-2-(1-(1-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidin-3-yl)-1H-pyrrolo[3,2-c]pyridin-3-yl)benzamide; 5-Fluoro-N-isopropyl-N-methyl-2-(1-(1-(2-((1r,4r)-4-(methylsulfonylamino)cyclohexyl)ethyl)piperidin-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)benzamide; 5-Fluoro-N-isopropyl-N-methyl-2-(2-oxo-1-(1-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidin-4-yl)-1,2-dihydro-3H-imidazol[4,5-c]pyridin-3-yl)benzamide; 5-((4-(3-(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidin-1-yl)methyl)-4-methyl-1H-indole-2-carboxynitrile; 2-(1-(1-(cyclohexylmethyl)piperidin-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)-5-fluoro-N-isopropyl-N-methylbenzamide; 2-(1-(1-((2-cyano-4-methyl-1H-indol-5-yl)methyl)piperidin-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)-5-fluoro-N-isopropyl-N-methylbenzamide; 5-Fluoro-2-(1-(1-(4-fluorobenzyl)piperidin-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)-N-isopropyl-N-methylbenzamide; 5-Fluoro-2-(3-(1-((1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N,N-diisopropylbenzamide; 5-Fluoro-N,N-Diisopropyl-2-(3-(1-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 5-Fluoro-N,N-Diisopropyl-2-(3-(piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; Ethyl acetate (R)-2-(5-((3-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)methyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl) ester; Stearic acid (R)-2-(5-((3-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)methyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl ester; 5-Fluoro-N,N-Diisopropyl-2-(3-(1-(((1r,4r)-4-(methylsulfonylamino)cyclohexyl)methyl)piperidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 2-(3-(1-((3-cyano-3-methyl-2-oxodihydroindol-6-yl)methyl)piperidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide; 5-Fluoro-N-isopropyl-N-methyl-2-(3-(2-((trans-3-(methanesulfonylamino)cyclobutyl)methyl)octahydrocyclopentadien[c]pyrrolo-5-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 5-Fluoro-N-isopropyl-N-methyl-2-(3-(2-((trans-4-(methanesulfonylamino)cyclohexyl)methyl)octahydrocyclopentadien[c]pyrrolo-5-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 5-Fluoro-N-isopropyl-N-methyl-2-(3-(2-((1-(methanesulfonyl)piperidin-4-yl)methyl)octahydrocyclopentadien[c]pyrrolo-5-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1-((cis-3-(methanesulfonylamino)cyclobutyl)methyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1-(2-(4-(methanesulfonylamino)piperidin-1-yl)ethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1-(pyridin-2-yl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 5-Fluoro-2-(3-(4-(3-hydroxypyrrolidin-1-yl)cyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropyl-N-methylbenzamide; 5-Fluoro-2-(3-(trans-4-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)cyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropyl-N-methylbenzamide; 5-Fluoro-2-(3-(cis-4-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)cyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropyl-N-methylbenzamide; 5-Fluoro-2-(3-(trans-4-(3-(hydroxymethyl)azacyclobut-1-yl)cyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropyl-N-methylbenzamide; 5-Fluoro-2-(3-(cis-4-(3-(hydroxymethyl)azacyclobut-1-yl)cyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropyl-N-methylbenzamide; 5-Fluoro-2-(3-(trans-4-((R)-2-(hydroxymethyl)pyrrolidin-1-yl)cyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropyl-N-methylbenzamide; 5-Fluoro-2-(3-(cis-4-((R)-2-(hydroxymethyl)pyrrolidin-1-yl)cyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropyl-N-methylbenzamide; 5-Fluoro-2-(3-(trans-4-((R)-3-(hydroxymethyl)pyrrolidine-1-yl)cyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropyl-N-methylbenzamide; 5-Fluoro-2-(3-(cis-4-((R)-3-(hydroxymethyl)pyrrolidin-1-yl)cyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropyl-N-methylbenzamide; 5-Fluoro-2-(3-(trans-4-((S)-3-(hydroxymethyl)pyrrolidin-1-yl)cyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropyl-N-methylbenzamide; 5-Fluoro-2-(3-(cis-4-((S)-3-(hydroxymethyl)pyrrolidin-1-yl)cyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropyl-N-methylbenzamide; 5-Fluoro-N-isopropyl-N-methyl-2-(3-(trans-4-(piperidin-1-yl)cyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 5-Fluoro-N-isopropyl-N-methyl-2-(3-(cis-4-(piperidin-1-yl)cyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 5-Fluoro-2-(3-(trans-4-(4-hydroxypiperidin-1-yl)cyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropyl-N-methylbenzamide; 5-Fluoro-2-(3-(cis-4-(4-hydroxypiperidin-1-yl)cyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropyl-N-methylbenzamide; 2-(3-(trans-4-(4,4-difluoropiperidin-1-yl)cyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide; 2-(3-(cis-4-(4,4-difluoropiperidin-1-yl)cyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide; 5-Fluoro-2-(3-(trans-4-(3-hydroxypiperidin-1-yl)cyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropyl-N-methylbenzamide; 5-Fluoro-2-(3-(cis-4-(3-hydroxypiperidin-1-yl)cyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropyl-N-methylbenzamide; 5-Fluoro-2-(3-(trans-4-(4-(2-hydroxyethyl)piperazin-1-yl)cyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropyl-N-methylbenzamide; 5-Fluoro-2-(3-(cis-4-(4-(2-hydroxyethyl)piperazin-1-yl)cyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropyl-N-methylbenzamide; 5-Fluoro-N-isopropyl-N-methyl-2-(3-(4-(3-oxopiperazin-1-yl)cyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 5-Fluoro-N-isopropyl-N-methyl-2-(3-(trans-4-morpholinocyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 5-Fluoro-N-isopropyl-N-methyl-2-(3-(cis-4-morpholinocyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 1-(trans-4-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)cyclohexyl)piperidin-4-carboxylic acid; 1-(cis-4-(1-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)cyclohexyl)piperidin-4-carboxylic acid; 5-((3-(1-(2-(3-cyclopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one; 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)pyrrolidine-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 5-Fluoro-2-(3-(1-((1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)pyrrolidine-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-isopropyl-N-methylbenzamide; N-Methyl-5-fluoro-N-isopropyl-2-(3-(1-((trans-4-(methanesulfonylamino)cyclohexyl)methyl)pyrrolidine-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; N-Ethyl-5-fluoro-N-isopropyl-2-(3-(1-((trans-4-(methanesulfonylamino)cyclohexyl)methyl)pyrrolidine-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 5-Fluoro-2-(3-(1-((1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)pyrrolidine-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N,N-diisopropylbenzamide; 5-Fluoro-N,N-Diisopropyl-2-(3-(1-((trans-4-(methanesulfonylamino)cyclohexyl)methyl)pyrrolidine-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 5-Fluoro-N-isopropyl-N-methyl-2-(3-(4-(methyl((4-(methanesulfonylamino)cyclohexyl)methyl)amino)cyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 2-(3-(trans-4-benzoylaminocyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide; 2-(3-(trans-4-(cyclohexanecarbamoyl)cyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide; 2-(3-(trans-4-benzoylaminocyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide; 2-(3-(1-(2,3-dihydro-1H-indene-2-carbonyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide; 5-Fluoro-N-isopropyl-N-methyl-2-(3-(1-(2-phenylacetyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 5-Fluoro-2-(3-(1-((1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-N,N-diisopropylbenzamide; 5-Fluoro-N-isopropyl-N-methyl-2-(1-(1-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidin-3-yl)-2-thio-1,2-dihydro-3H-imidazol[4,5-c]pyridin-3-yl)benzamide; ((1r,4r)-4-(2-(3-(1-(2-(diisopropylcarbamoyl)-4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)azacyclobut-1-yl)ethyl)cyclohexyl)tert-butyl carbamate; 5-Fluoro-N,N-Diisopropyl-2-(3-(1-(2-((1r,4r)-4-(methylsulfonylamino)cyclohexyl)ethyl)azacyclobut-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 5-Fluoro-N,N-Diisopropyl-2-(3-(1-(((1r,4r)-4-(methylsulfonylamino)cyclohexyl)methyl)azacyclobut-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 5-Fluoro-N,N-Diisopropyl-2-(3-(4-(2-(methanesulfonylamino)-6-azaspiro[3.4]octane-6-yl)cyclohexyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 5-Fluoro-N,N-Diisopropyl-2-(3-(1-((2-oxo-2,3-dihydrobenzo[d])) 5-azolyl)methyl)pyrrolidone-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; Or its pharmaceutically acceptable salt.

45. A compound selected from the group consisting of: 5-Fluoro-N-isopropyl-N-methyl-2-(3-(piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 2-(3-((2S,6R)-2,6-dimethylpiperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-isopropyl-N-methylbenzamide; 5-Fluoro-N,N-Diisopropyl-2-(3-(piperidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 5-Fluoro-N-isopropyl-N-methyl-2-(3-(octahydrocyclopentadien[c]pyrrolo-5-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide; 5-((4-(1-(4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)methyl)-4-methyl-1H-indole-2-carboxynitrile; 5-((4-(1-(4-chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidin-1-yl)methyl)-4-methyl-1H-indole-2-carboxynitrile; 1-(4-fluorophenyl)-3-(1-isopentylpiperidin-4-yl)-1H-pyrrolo[2,3-c]pyridine; 1-(4-fluorophenyl)-3-(1-phenylethylpiperidin-4-yl)-1H-pyrrolo[2,3-c]pyridine; 5-(4-fluorophenyl)-7-(1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine; 5-((4-(5-(4-fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidin-1-yl)methyl)-4-methyl-1H-indole-2-carboxynitrile; 5-((4-(5-(4-fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one; 7-(1-((1H-indol-6-yl)methyl)piperidin-4-yl)-5-(4-fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidine; 7-(1-((1H-indol-5-yl)methyl)piperidin-4-yl)-5-(4-fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidine; 5-((4-(5-(3-fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidin-1-yl)methyl)-4-methyl-1H-indole-2-carboxynitrile; Methyl-5-((4-(5-phenyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidin-1-yl)methyl)-1H-indol-2-carboxynitrile; 4-Methyl-5-((4-(5-phenyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidin-1-yl)methyl)-1H-indol-2-carboxynitrile; 5-((4-(3-(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidin-1-yl)methyl)-4-methyl-1H-indole-2-carboxynitrile; Or its pharmaceutically acceptable salt.

46. ​​The compound of claim 1, wherein it is 5-fluoro-N-isopropyl-N-methyl-2-(3-(1-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidin-3-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)benzamide or a pharmaceutically acceptable salt thereof.

47. A pharmaceutically acceptable salt of the compound of claim 46, which is mono-(2R,3S,4R,5S)-2,3,4,5-tetrahydroxyhexanoate.

48. The crystal form of the salt of claim 47.

49. A pharmaceutical composition comprising a compound of any one of claims 1 to 46 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

50. A pharmaceutical composition comprising the salt of claim 47 or the crystal form of claim 48 and at least one pharmaceutically acceptable carrier.

51. A method for inhibiting the interaction between menin and MLL, comprising contacting menin and MLL with a compound of any one of claims 1 to 46 or a pharmaceutically acceptable salt thereof.

52. A method for suppressing the interaction between menin and MLL, comprising contacting menin and MLL with the salt of claim 47 or the crystal form of claim 48.

53. A method of treating a patient with cancer, comprising administering to the patient a therapeutically effective amount of the compound of any one of claims 1 to 46 or a pharmaceutically acceptable salt thereof.

54. A method of treating a patient with cancer, comprising administering to the patient a therapeutically effective amount of the salt of claim 47 or the crystal form of claim 48.

55. The method of claim 53 or 54, wherein the cancer is a blood cancer.

56. The method of claim 53 or 54, wherein the cancer is leukemia.

57. The method of claim 53 or 54, wherein the cancer is lymphoma.

58. The method of claim 53 or 54, wherein the cancer is mixed lineage leukemia (MLL), MLL-associated leukemia, MLL-related leukemia, MLL-positive leukemia, MLL-induced leukemia, rearranged mixed lineage leukemia (MLL-r), leukemia associated with MLL rearrangement or MLL gene rearrangement, acute leukemia, chronic leukemia, slow-onset leukemia, lymphoblastic leukemia, lymphocytic leukemia, myeloid leukemia, bone marrow leukemia, childhood leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute granulocytic leukemia, acute non-lymphocytic leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CLL). CML), therapy-related leukemia, myelodysplastic syndrome (MDS), myeloproliferative disorders (MPD), myeloproliferative neoplasm (MPN), plasma cell vegetations, multiple myeloma, spinal dysplasia, cutaneous T-cell lymphoma, lymphoid vegetations, AIDS-related lymphoma, thymoma, thymic carcinoma, mycosis fungoides, Al-Barré syndrome, mycosis fungoides, Cezari syndrome, hairy cell leukemia, T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, meningeal leukemia, leukemic meningitis, leukemic meningitis, multiple myeloma, Hodgkin's lymphoma, non-Hodgkin's lymphoma (malignant lymphoma), or Waldenström macroglobulinemia.

59. A method of treating a patient with insulin resistance, prediabetes, diabetes, or risk of diabetes, comprising administering to the patient a therapeutically effective amount of the compound of any one of claims 1 to 46 or a pharmaceutically acceptable salt thereof.

60. A method of treating a patient with insulin resistance, prediabetes, diabetes, or risk of diabetes, comprising administering to the patient a therapeutically effective amount of the salt of claim 47 or the crystalline form of claim 48.

61. A method of treating a patient with hyperglycemia, comprising administering to the patient a therapeutically effective amount of the compound of any one of claims 1 to 46 or a pharmaceutically acceptable salt thereof.

62. A method of treating a patient with hyperglycemia, comprising administering to the patient a therapeutically effective amount of the salt of claim 47 or the crystalline form of claim 48.

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