Novel biphenyl derivative as PD-l1 inhibitor

Abstract

The present invention relates to a novel compound exhibiting an interaction inhibitory effect between PD-1 and PD-L1. The novel biphenyl derivative of the present invention exhibits excellent cancer prevention and treatment effects through the inhibitory effect.

Description

Novel biphenyl derivatives as PD-L1 inhibitors

[0001] The present invention relates to a novel compound exhibiting an inhibitory effect on the interaction between PD-1 and PD-L1, and the novel biphenyl derivative of the present invention has excellent cancer prevention and treatment through the PD-L1 inhibitory effect.

[0002] Cancer, a leading cause of death worldwide, claimed nearly 10 million lives in 2020. Cancer typically develops when normal cells transform into tumor cells, and treatment typically involves surgery, radiation therapy, or systemic therapies (chemotherapy, hormone therapy, or targeted biological therapy).

[0003] Cancer cells possess the ability to evade the immune system, allowing them to avoid attack by immune cells. Cancer cells express immunosuppressive signaling proteins, which induce immune cell dysfunction and apoptosis. One of the most well-known of these immunosuppressive signaling proteins is programmed death-ligand-1 (PD-L1).

[0004] PD-L1, also known as CD274 or B7-H1, is a transmembrane protein considered a corepressor of the immune response. It binds to programmed cell death protein-1 (PD-1) to reduce the proliferation of PD-1-positive immune cells, suppress the secretion of cytokines required for the immune response, or induce apoptosis.

[0005] PD-1 plays an important role in suppressing immune responses and promoting self-tolerance by regulating T cell activity, activating apoptosis of antigen-specific T cells, and inhibiting apoptosis of regulatory T cells. PD-L1 is known to suppress anticancer immunity by binding to PD-1 expressed on T cells, B cells, dendritic cells, and NK T cells.

[0006] On the one hand, immune checkpoint inhibitors, a form of cancer immunotherapy, are a type of drug that blocks proteins called immune checkpoints, which are expressed on certain immune cells, such as T cells, as well as cancer cells. These immune checkpoints prevent the immune response from becoming too strong, but they can also prevent T cells from killing cancer cells. Therefore, blocking these immune checkpoints can restore immune system function, making them useful in cancer treatment.

[0007] In this regard, PD-1 and PD-L1 inhibitors, representative immune checkpoint inhibitors, inhibit the binding between PD-1 and PD-L1, blocking immune tolerance and stimulating immune cell activity. Since many tumor cells highly express PD-L1, inhibiting the interaction between PD-1 and PD-L1 has been shown through animal and clinical studies to enhance T cell responses and activate the body's anti-tumor activity.

[0008] Accordingly, the present inventors have completed the present invention by developing a novel biphenyl derivative that can be usefully used for cancer prevention and treatment through an inhibitor of PD-1 or PD-L1, or inhibition of the interaction between PD-1 and PD-L1.

[0009] The present inventors studied a compound having an inhibitory effect on the interaction between PD-1 and PD-L1, synthesized a novel biphenyl derivative, identified the structure of the novel compound, and confirmed the inhibitory effect on the interaction between PD-1 and PD-L1, thereby completing the present invention.

[0010] Therefore, the present invention aims to provide a novel compound useful as a cancer prevention or treatment agent by exhibiting an effect of inhibiting the interaction between PD-1 and PD-L1.

[0011] The present invention provides a compound of the following chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0012] [Chemical Formula 1]

[0013]

[0014] In the above formula, X1 and X2 are each independently hydrogen, halo, haloalkyl, cyano, alkyl, alkenyl, alkynyl, -N(Ra)2, -ORa, -SRa, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein Ra is each independently hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl,

[0015] Y1 and Y2 are each independently a single bond, or alkyl, alkenyl, alkynyl, -ORb-, -N(Rb)-, -C(=O)Rb-, -C(=O)N(Rb)-, -C(=S)N(Rb)-, -N(Rb)C(=O)-, -N(Rb)S(=O)-, -N(Rb)S(=O)(=NH)-, -CH=C(Rb)-, -N(Rb)CH(OH)-, or -N(Rb)S(=O)2-, wherein Rb is each independently hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

[0016] Z1 and Z2 are each independently hydrogen, halo, cyano, alkyl, alkenyl, alkynyl, -C(=O)Rc, -C(=O)N(Rc)(Rd), -C(=O)ORc, -N(Rc)(Rd), -N(Rc)C(=O)Rd, -NH(Rc)C(=O)Rd, -NH(Rc)NHC(=O)Rd, -N(Rc)S(=O)Rd, -N(Rc)S(=O)2Rd, -NO2, -ORc, -OC(=O)Rc, -SRc, -S(=O)Rc, -S(=O)N(Rc)(Rd), -S(=O)2Rc, -S(=O)2N(Rc)(Rd), cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein Rc and Rd is each independently hydrogen, hydroxy, -COOH, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl,

[0017] The above alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl may be substituted or unsubstituted.

[0018] In one embodiment, X1 and X2 are each independently hydrogen, halo, C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 It is alkynyl,

[0019] Y1 and Y2 are each independently a single bond, or C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, -ORb-, -N(Rb)-, -C(=O)Rb-, -C(=O)N(Rb)-, -N(Rb)C(=O)-, -N(Rb)S(=O)-, -N(Rb)S(=O)(=NH)-, -CH=C(Rb)-, -N(Rb)CH(OH)- or -N(Rb)S(=O)2-, wherein Rb is each independently hydrogen, halo, C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 It's alkynyl

[0020] Z1 and Z2 are each independently hydrogen, C 1-6 Alkyl, C 2-6Alkenyl, or C 2-6 alkynyl, -C(=O)N(Rc)(Rd), -C(=O)ORc, -N(Rc)(Rd), -N(Rc)C(=O)Rd, -N(Rc)S(=O)Rd, -N(Rc)S(=O)2Rd, -NO2, -ORc, -OC(=O)Rc, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein Rc and Rd are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl,

[0021] The above alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl may be substituted or unsubstituted.

[0022] In one embodiment, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl,

[0023] Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, N(Rb)CH(OH)-, or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo, C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 It is alkynyl,

[0024] Z1 and Z2 are each independently hydrogen; aryl; heterocycloalkyl substituted with 1 to 3 heteroatoms selected from the group consisting of N, O or S; or heteroaryl substituted with 1 to 3 heteroatoms selected from the group consisting of N, O or S,

[0025] The above aryl, heterocycloalkyl, or heteroaryl is halo, -OH, -CN, -C 1-6 Alkyl, -OC 1-6 Alkyl, haloalkyl, -C 1-6 Alkyl-OH, -C 1-6 Alkyl-COOH, -C 1-6 Alkyl-NH-C1-6 Alkyl-COOH, -C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-COOH, -C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-C(=O)-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-OH, -NH-C 1-6 Alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -NH-C 1-6 Alkyl-OH, -N(C 1-6 Alkyl-OH)(C 1-6 Alkyl-OH), -N(C 1-6 Alkyl-COOH)(C 1-6 Alkyl-COOH), -NH-C 1-6 Alkyl-(C 1-6 Alkyl-OH)2, -NH-C 1-6 Alkyl-COOH, -NH-C 1-6 Alkyl-NH-C(=O)C 1-6 Alkyl, -NH-C 1-6 Alkyl-C(=O)-OC 1-6 Alkyl, -NH-C 1-6 Alkyl-OC 1-6 Alkyl, -NH-C 1-6 Alkyl-NH-SO2-C 1-6 Alkyl, heterocycloalkyl, -C 1-6 Alkyl-heterocycloalkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-heterocycloalkyl, -C 1-6 Alkyl-bicycloalkyl-COOH, -NH-heterocycloalkyl, -NH-C 1-6 Alkyl-heterocycloalkyl and -NH-cycloalkyl-OC 1-6 which may be substituted or unsubstituted with one or more substituents selected from the group consisting of alkyl,

[0026] At this time, the heterocycloalkyl and cycloalkyl are halo, =O, -OH, COOH, -C 1-6 Alkyl-OH, and -C(=O)C 1-6It may be substituted or unsubstituted with one or more substituents selected from the group consisting of alkyl.

[0027] In one embodiment, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl,

[0028] Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, -N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl,

[0029] Z1 and Z2 are each independently hydrogen,

[0030]

[0031] or And,

[0032] R1 to R17 are each independently hydrogen, halo, -OH, -CN, -C 1-6 Alkyl, -OC 1-6 Alkyl, haloalkyl, -C 1-6 Alkyl-OH, -C 1-6 Alkyl-COOH, -C 1-6 Alkyl-NH-C 1-6 Alkyl-COOH, -C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-COOH, -C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-C(=O)-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-OH, -NH-C 1-6 Alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -NH-C 1-6 Alkyl-OH, -N(C 1-6 Alkyl-OH)(C 1-6 Alkyl-OH), -N(C 1-6 Alkyl-COOH)(C 1-6 Alkyl-COOH), -NH-C 1-6 Alkyl-(C 1-6Alkyl-OH)2, -NH-C 1-6 Alkyl-COOH, -NH-C 1-6 Alkyl-NH-C(=O)C 1-6 Alkyl, -NH-C 1-6 Alkyl-C(=O)-OC 1-6 Alkyl, -NH-C 1-6 Alkyl-OC 1-6 Alkyl, -NH-C 1-6 Alkyl-NH-SO2-C 1-6 Alkyl, heterocycloalkyl, -C 1-6 Alkyl-heterocycloalkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-heterocycloalkyl, -C 1-6 Alkyl-bicycloalkyl-COOH, -NH-heterocycloalkyl, -NH-C 1-6 Alkyl-heterocycloalkyl, or, -NH-cycloalkyl-OC 1-6 It is alkyl,

[0033] The above heterocycloalkyl and cycloalkyl are halo, =O, -OH, COOH, -C 1-6 Alkyl-OH, and -C(=O)C 1-6 It may be substituted or unsubstituted with one or more substituents selected from the group consisting of alkyl.

[0034] In one embodiment, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl,

[0035] Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl,

[0036] Z1 and Z2 are each independently hydrogen,

[0037]

[0038] or And,

[0039] R1a to R1c, R2a to R2d, R3a to R3b, R4 to R6, R7a to R7b and R8 to R17 are each independently hydrogen, halo, -OH, -CN, -C 1-6 Alkyl, haloalkyl, -C 1-6 Alkyl-OH, -C 1-6 Alkyl-COOH, -C 1-6 Alkyl-NH-C 1-6 Alkyl-COOH, -C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-C(=O)-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-OH, -NH-C 1-6 Alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -NH-C 1-6 Alkyl-OH, -N(C 1-6 Alkyl-OH)(C 1-6 Alkyl-OH), -NH-C 1-6 Alkyl-(C 1-6 Alkyl-OH)2, -NH-C 1-6 Alkyl-COOH, -NH-C 1-6 Alkyl-NH-C(=O)C 1-6 Alkyl, -NH-C 1-6 Alkyl-C(=O)-OC 1-6 Alkyl, -NH-C 1-6 Alkyl-OC 1-6 Alkyl, -NH-C 1-6 Alkyl-NH-SO2-C 1-6 Alkyl, heterocycloalkyl, -C 1-6 Alkyl-heterocycloalkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-heterocycloalkyl, -C 1-6 Alkyl-bicycloalkyl-COOH, -NH-heterocycloalkyl, -NH-C 1-6 Alkyl-heterocycloalkyl, or -NH-cycloalkyl-OC 1-6 It is alkyl,

[0040] The above heterocycloalkyl is pyrrolidine or azetidine, which may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, =O, -OH and -COOH,

[0041] The above cycloalkyl is =O, -OH, COOH, -C 1-6 Alkyl-OH, and -C(=O)C 1-6 It may be substituted or unsubstituted with one or more substituents selected from the group consisting of alkyl.

[0042] In one embodiment, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl,

[0043] Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl,

[0044] Z1 or Z2 When,

[0045] The above R1a, R1b and R1c are each independently hydrogen, halo, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-heterocycloalkyl, -C 1-6 Alkyl-heterocycloalkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-COOH, -C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-C(=O)-C 1-6 Alkyl or -C 1-6 Alkyl-NH-C 1-6 Alkyl-OH,

[0046] The above heterocycloalkyl may be substituted or unsubstituted with one or more substituents selected from the group consisting of =O, -OH and COOH.

[0047] In one embodiment, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl,

[0048] Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl,

[0049] Z1 or Z2 When,

[0050] The above R1a and R1c are each independently hydrogen, halo, -C 1-6 Alkyl, or -OC 1-6 It is alkyl,

[0051] R1b is hydrogen, halo, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-heterocycloalkyl, -C 1-6 Alkyl-heterocycloalkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-COOH, -C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-C(=O)-C 1-6 Alkyl or -C 1-6 Alkyl-NH-C 1-6 Alkyl-OH,

[0052] The above heterocycloalkyl is , or It could be.

[0053] In one embodiment, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl,

[0054] Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl,

[0055] Z1 or Z2 is

[0056] or It could be.

[0057] In one embodiment, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl,

[0058] Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl,

[0059] Z1 or Z2 When,

[0060] The above R2a, R2b, R2c and R2d are each independently hydrogen, halo, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 1-6 Alkyl-heterocycloalkyl or -C 1-6 Alkyl-NH-C 1-6 Alkyl-OH,

[0061] The above heterocycloalkyl may be pyrrolidine, which may be substituted or unsubstituted with OH.

[0062] In one embodiment, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl,

[0063] Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl,

[0064] Z1 or Z2 When,

[0065] The above R2a, R2b, R2c and R2d are each independently hydrogen, halo, -C1-6 Alkyl, -OC 1-6 Alkyl, -C 1-6 Alkyl-heterocycloalkyl or -C 1-6 Alkyl-NH-C 1-6 Alkyl-OH,

[0066] The above heterocycloalkyl is It could be.

[0067] In one embodiment, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl,

[0068] Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl,

[0069] Z1 or Z2 is

[0070] or It could be.

[0071] In one embodiment, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl,

[0072] Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl,

[0073] Z1 or Z2 The above R3a and R3b are each independently hydrogen, -OC 1-6 Alkyl or -C 1-6 Alkyl-NH-C 1-6 Alkyl-heterocycloalkyl,

[0074] The above heterocycloalkyl may be pyrrolidine, which may be substituted or unsubstituted with =O.

[0075] In one embodiment, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl,

[0076] Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl,

[0077] Z1 or Z2 When,

[0078] The above R3a and R3b are each independently hydrogen, -OC 1-6 Alkyl or -C 1-6 Alkyl-NH-C 1-6 Alkyl-heterocycloalkyl,

[0079] The above heterocycloalkyl is It could be.

[0080] In one embodiment, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl,

[0081] Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl,

[0082] Z1 or Z2 is It could be.

[0083] In one embodiment, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl,

[0084] Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl,

[0085] Z1 or Z2 When,

[0086] The above R4 is hydrogen or -C 1-6 Alkyl-heterocycloalkyl,

[0087] The above heterocycloalkyl may be pyrrolidine or azetidine, which may be unsubstituted or substituted with -OH or halo.

[0088] In one embodiment, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl,

[0089] Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl,

[0090] Z1 or Z2 When,

[0091] The above R4 is hydrogen or -C 1-6 It may be at least one selected from the group consisting of alkyl-heterocycloalkyl,

[0092] The above heterocycloalkyl is or It could be.

[0093] In one embodiment, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl,

[0094] Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl,

[0095] Z1 or Z2 is or It could be.

[0096] In one embodiment, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl,

[0097] Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl,

[0098] Z1 or Z2 When,

[0099] The above R5 is hydrogen, -C 1-6 is alkyl or haloalkyl,

[0100] R6 is hydrogen or -C 1-6 Alkyl-heterocycloalkyl,

[0101] The above heterocycloalkyl may be pyrrolidine or azetidine, which may be unsubstituted or substituted with -OH or halo.

[0102] In one embodiment, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl,

[0103] Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl,

[0104] Z1 or Z2 When,

[0105] The above R5 is hydrogen, -C 1-6 is alkyl or haloalkyl,

[0106] R6 is hydrogen or -C 1-6 Alkyl-heterocycloalkyl,

[0107] The above heterocycloalkyl is or It could be.

[0108] In one embodiment, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl,

[0109] Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl,

[0110] Z1 or Z2 is or It could be.

[0111] In one embodiment, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl,

[0112] Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl,

[0113] Z1 or Z2 When,

[0114] The above R7a and R7b are each independently hydrogen, -CN or -C 1-6 Alkyl-heterocycloalkyl,

[0115] The above heterocycloalkyl may be pyrrolidine, which may be substituted or unsubstituted with -COOH.

[0116] In one embodiment, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl,

[0117] Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl,

[0118] Z1 or Z2 is It could be.

[0119] In one embodiment, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl,

[0120] Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl,

[0121] Z1 or Z2 When,

[0122] The above R8 and R9 are each independently hydrogen, -C 1-6 Alkyl or - C 1-6 It may be alkyl-bicycloalkyl-COOH.

[0123] In one embodiment, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl,

[0124] Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl,

[0125] Z1 or Z2 is It could be.

[0126] In one embodiment, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl,

[0127] Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl,

[0128] Z1 or Z2 When,

[0129] The above R10 is hydrogen, halo, -OH, -C 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -NH-C 1-6 Alkyl-NH-C(=O)C 1-6 Alkyl, -NH-C 1-6 Alkyl-C(=O)-OC 1-6 Alkyl, -NH-C 1-6 Alkyl-OC 1-6 Alkyl, -OC 1-6 Alkyl, heterocycloalkyl, -NH-heterocycloalkyl, -NH-C 1-6 Alkyl-heterocycloalkyl, -NH-cycloalkyl, -NH-C 1-6 Alkyl-COOH, -NH-C 1-6 Alkyl-OH, -N(C 1-6 Alkyl-OH)(C 1-6 Alkyl-OH), -NH-C 1-6 Alkyl-(C 1-6 Alkyl-OH)2 or NH-C 1-6 Alkyl-NH-SO2-C 1-6 It is alkyl,

[0130] The above heterocycloalkyl and cycloalkyl are =O, -OH, COOH, -C 1-6 Alkyl-OH, and -C(=O)C 1-6 It may be substituted or unsubstituted with one or more substituents selected from the group consisting of alkyl.

[0131] In one embodiment, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl,

[0132] Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl,

[0133] Z1 or Z2 When,

[0134] The above R10 is hydrogen, -OH, -C 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -NH-C 1-6 Alkyl-NH-C(=O)C 1-6 Alkyl, -NH-C 1-6 Alkyl-C(=O)-OC 1-6 Alkyl, -NH-C 1-6 Alkyl-OC 1-6 Alkyl, heterocycloalkyl, -NH-heterocycloalkyl, -NH-C 1-6 Alkyl-heterocycloalkyl, -NH-cycloalkyl, -NH-C 1-6 Alkyl-COOH, -NH-C 1-6 Alkyl-OH, -N(C 1-6 Alkyl-OH)(C 1-6 Alkyl-OH), -NH-C 1-6 Alkyl-(C 1-6 Alkyl-OH)2 or NH-C 1-6 Alkyl-NH-SO2-C 1-6 It is alkyl,

[0135] The above heterocycloalkyl and cycloalkyl are or It could be.

[0136] In one embodiment, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl,

[0137] Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl,

[0138] Z1 or Z2 When,

[0139] The above R11 is hydrogen, halo or -C 1-6 It could be an alkyl.

[0140] In one embodiment, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl,

[0141] Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl,

[0142] Z1 or Z2 It could be.

[0143] In one embodiment, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl,

[0144] Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl,

[0145] Z1 or Z2 When,

[0146] The above R12 is -C, which may be substituted or unsubstituted with hydrogen or halo. 1-6 It could be an alkyl.

[0147] In one embodiment, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl,

[0148] Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl,

[0149] Z1 or Z2 or It could be.

[0150] In one embodiment, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl,

[0151] Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl,

[0152] Z1 or Z2 When,

[0153] At this time, the above R13 is hydrogen, or -C 1-6 It could be an alkyl.

[0154] In one embodiment, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl,

[0155] Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl,

[0156] Z1 or Z2 It could be.

[0157] In one embodiment, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl,

[0158] Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl,

[0159] Z1 or Z2 When,

[0160] At this time, the above R14 is hydrogen, -C 1-6 Alkyl or -NH(C 1-6It can be alkyl)COOH.

[0161] In one embodiment, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl,

[0162] Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl,

[0163] Z1 or Z2 It could be.

[0164] In one embodiment, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl,

[0165] Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl,

[0166] Z1 or Z2 When,

[0167] At this time, the above R15 is hydrogen, -C 1-6 Alkyl or -C 1-6 It could be alkyl-OH.

[0168] In one embodiment, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl,

[0169] Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl,

[0170] Z1 or Z2 It could be.

[0171] In one embodiment, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl,

[0172] Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl,

[0173] Z1 or Z2 When,

[0174] At this time, the above R16 is hydrogen, -C 1-6 Alkyl, -C 1-6 Alkyl-OH or -C 1-6 It could be alkyl-COOH.

[0175] In one embodiment, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl,

[0176] Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl,

[0177] Z1 or Z2 or It could be.

[0178] In one embodiment, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl,

[0179] Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl,

[0180] Z1 or Z2 When,

[0181] At this time, the above R17 is hydrogen or -C 1-6 It could be an alkyl.

[0182] In one embodiment, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl,

[0183] Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl,

[0184] Z1 or Z2 It could be.

[0185] The present invention provides a composition for treating or preventing cancer comprising the compound of the present invention.

[0186] The present invention provides the use of a compound or composition of the present invention for the treatment or prevention of cancer.

[0187] The present invention provides a method for treating cancer by administering the compound of the present invention to a cancer patient.

[0188] The present invention provides a compound selected from the group consisting of the following compounds or a pharmaceutically acceptable salt thereof.

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

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[0206]

[0207]

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[0345]

[0346]

[0347]

[0348] Unlike existing anticancer drugs that attack the cancer itself, immunotherapy is a treatment that stimulates the immune system to induce immune cells to selectively attack only cancer cells.

[0349] The novel compound provided according to the present invention exhibits an inhibitory effect on the interaction between PD-1 and PD-L1, enhances T cell response, and as a result, can be used as a novel immuno-oncology agent having anti-tumor activity and minimizing side effects that occur in existing chemotherapeutic agents.

[0350] Figure 1 is a graph showing the tumor growth inhibition effect of the 218 compound administration group.

[0351] Figure 2 is a graph showing the change in body weight in the 218 compound administration group.

[0352] Hereinafter, with reference to the attached drawings, embodiments and examples of the present invention will be described in detail so that those skilled in the art can easily implement the present invention. However, the present invention may be implemented in various forms and is not limited to the embodiments and examples described herein.

[0353] Throughout this specification, whenever a part is said to "include" a component, this means that it may include other components, but not to the exclusion of other components, unless otherwise specifically stated.

[0354] The term "alkyl" as used herein refers to a hydrocarbon group having substituted or unsubstituted primary, secondary, tertiary and / or quaternary carbon atoms, and includes saturated aliphatic groups which may be straight-chain, branched, cyclic, or combinations thereof. For example, an alkyl group may have 1 to 20 carbon atoms (i.e., C1-C20 alkyl), 1 to 10 carbon atoms (i.e., C1-C10 alkyl), or 1 to 6 carbon atoms (i.e., C1-C6 alkyl). Unless otherwise defined, in a preferred embodiment, alkyl refers to C1-C6 alkyl.Examples of suitable alkyl groups include methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-Methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), and octyl (-(CH2)7CH3).

[0355] The term "Cx-y" or "Cx-Cy" as used herein, when used with a chemical moiety such as acyl, acyloxy, alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl or alkoxy, means a group containing x to y carbon atoms in the chain. C0 alkyl means hydrogen when the substituent is at a terminal position, and a bond when it is internal. Also, for example, a C1-C6 alkyl group contains 1 to 6 carbon atoms in the chain.

[0356] The term "alkenyl" as used herein refers to a hydrocarbon having primary, secondary, tertiary and / or quaternary carbon atoms, including straight-chain, branched and cyclic groups, or combinations thereof, and having one or more regions of unsaturation, i.e., carbon-carbon sp2 double bonds. For example, an alkenyl group can have 2 to 20 carbon atoms (i.e., C2-C20 alkenyl), 2 to 12 carbon atoms (i.e., C2-C12 alkenyl), 2 to 10 carbon atoms (i.e., C2-C10 alkenyl), or 2 to 6 carbon atoms (i.e., C2-C6 alkenyl). Examples of suitable alkenyl groups include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), cyclopentenyl (-C5H7), and 5-hexenyl (-CH2CH2CH2CH2CH=CH2).

[0357] The term "alkynyl" as used herein refers to a hydrocarbon group having primary, secondary, tertiary and / or quaternary carbon atoms, including straight-chain, branched and cyclic groups, or combinations thereof, and having one or more carbon-carbon sp triple bonds. For example, an alkynyl group can have 2 to 20 carbon atoms (i.e., C2-C20 alkynyl), 2 to 12 carbon atoms (i.e., C2-C12 alkynyl), 2 to 10 carbon atoms (i.e., C2-C10 alkynyl), or 2 to 6 carbon atoms (i.e., C2-C6 alkynyl). Examples of suitable alkynyl groups include, but are not limited to, acetylenic (-C≡CH) and propargyl (-CH2C≡CH).

[0358] The term "alkoxy" as used herein refers to an alkyl group attached to a parent compound via an oxygen atom, which may be represented by -O-alkyl, wherein the alkyl group is as defined herein and may be substituted or unsubstituted. The alkyl group of the alkoxy group may have, for example, 1 to 20 carbon atoms (i.e., C1-C20 alkoxy), 1 to 12 carbon atoms (i.e., C1-C12 alkoxy), 1 to 10 carbon atoms (i.e., C1-C10 alkoxy), or 1 to 6 carbon atoms (i.e., C1-C6 alkoxy). Examples of suitable alkoxy groups include, but are not limited to, methoxy (-O-CH3 or -OMe), ethoxy (-OCH2CH3 or -OEt), and t-butoxy (-OC(CH3)3 or -O-tBu).

[0359] The term "alkoxyalkyl" used in the present invention refers to an alkyl group substituted with an alkoxy group as defined herein, and may be represented as -alkyl-O-alkyl.

[0360] "used in the present invention " means that the residue or substituent "R" is attached to the skeletal structure, according to the convention used in the art.

[0361] The term "cycloalkyl" as used herein refers to a substituted or unsubstituted monocyclic, bicyclic, or polycyclic, non-aromatic, saturated or unsaturated ring, wherein each ring atom is carbon. The cycloalkyl may be a polycyclic cycloalkyl composed of two or more rings in which at least one carbon atom is common to adjacent rings. The polycyclic cycloalkyl may be a fused ring system, a spirocyclic ring system, or a bridged ring system, wherein at least one of the rings is cycloalkyl, and the other rings may be, for example, cycloalkyl, aryl, heteroaryl, and / or heterocycloalkyl, as defined herein. Examples of suitable cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

[0362] The term "heterocycloalkyl" as used herein refers to a substituted or unsubstituted monovalent or divalent, saturated or partially saturated non-aromatic ring, which is monocyclic, bicyclic or polycyclic, containing one or more heteroatoms, preferably 1 to 4 heteroatoms, more preferably 1 to 2 heteroatoms, within the ring. "Heterocycloalkyl" also refers to a bicyclic or polycyclic ring system having two or more cyclic rings in which two or more carbons are common to two adjacent rings, wherein at least one of the rings is heterocyclic and the other cyclic rings can be, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocycloalkyl. The bicyclic or polycyclic ring system can be a fused, bridged, or spiro ring system. “Heterocycloalkyl” includes, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, etc. (each of which may be substituted or unsubstituted).

[0363] The term "aryl" as used herein includes substituted or unsubstituted monovalent or divalent aromatic hydrocarbon groups, which are monocyclic, bicyclic, or polycyclic, each ring atom being carbon. Preferably, the aryl ring is a 6- to 20-membered ring, a 6- to 14-membered ring, a 6- to 10-membered ring, or more preferably a 6-membered ring. The aryl group may be a polycyclic ring system having two or more cyclic rings in which two or more carbons are common to two adjacent rings, wherein at least one of the rings is aromatic, for example, the other cyclic ring may be a cycloalkyl, a cycloalkenyl, a cycloalkynyl, an aryl, a heteroaryl, and / or a heterocycloalkyl. Examples of aryl groups include benzene, naphthalene, phenanthrene, anthracene, indene, indane, phenol, and aniline.

[0364] The term "heteroaryl" as used herein refers to a substituted or unsubstituted monovalent or divalent aromatic group, which is monocyclic, bicyclic or polycyclic, containing one or more heteroatoms in the ring. Non-limiting examples of suitable heteroatoms that may be contained in the aromatic ring include oxygen, sulfur and nitrogen. "Heteroaryl" refers to a bicyclic or polycyclic ring system having two or more cyclic rings in which two or more carbons are common to two adjacent rings, wherein at least one of the rings is heteroaromatic and the other cyclic rings can be, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. “Heteroaryl” includes, for example, benzofuran, benzothiophene, pyrrole, furan, thiophene, imidazole, indole, isoindole, isoxazole, isothiazole, oxazole, thiazole, quinoline, isoquinoline, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, each of which may be substituted or unsubstituted.

[0365] The term "amino" used in the present invention refers to -NH2 in which a hydrogen atom is substituted or unsubstituted with a substituent such as alkyl or aryl, wherein the substituent such as alkyl or aryl that substitutes the hydrogen atom is as defined herein and may be substituted or unsubstituted. Examples of suitable amino groups include, but are not limited to, -NH2, -N(CH3)2, -N(CH3)-CH2CH2-N(CH3)2, etc.

[0366] The terms “halo” and “halogen” as used herein both mean halogen, and include chloro, fluoro, bromo, and iodo.

[0367] The term “cyano” used in the present invention refers to a -CN group.

[0368] The term “carboxyl” as used in the present invention refers to a -C(O)OH group.

[0369] The term "haloalkyl" as used herein refers to an alkyl group in which at least one hydrogen atom of the alkyl group as defined above is replaced by a halogen atom. The alkyl moiety of the haloalkyl group may have 1 to 20 carbon atoms (i.e., C1-C20 haloalkyl), 1 to 12 carbon atoms (i.e., C1-C12 haloalkyl), 1 to 10 carbon atoms (i.e., C1-C10 haloalkyl), or 1 to 6 carbon atoms (i.e., C1-C6 haloalkyl). Examples of suitable haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CFH2, and -CH2CF3.

[0370] The term "cycloalkenyl," as used herein, refers to a non-aromatic monocyclic or polycyclic hydrocarbon containing at least one carbon-carbon double bond. In some embodiments, the cycloalkenyl comprises 3 to 20 carbon atoms, 3 to 10 carbon atoms, or 3 to 7 carbon atoms. Cycloalkenyl includes monocyclic and polycyclic groups (including fused, bridged, and spirocycles). Examples of suitable cycloalkenyl groups include, but are not limited to, cyclopentenyl (-C5H7).

[0371] The term "substituted" as used herein, e.g., "substituted alkyl", means that one or more hydrogen atoms of the alkyl are each independently replaced by a non-hydrogen substituent. The substituent may include, but is not limited to, any of the substituents described herein, for example, halogen, hydroxyl, alkyl, hydroxyalkyl, haloalkyl, cyanoalkyl, alkoxyalkyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, aryl, or heteroaryl. The substituted moiety on the hydrocarbon chain may itself be substituted, if desired.

[0372] The term "pharmaceutically acceptable salt" as used in the present invention means any acid addition salt or base addition salt that is non-toxic and harmless to the patient and whose side effects due to the salt do not diminish the beneficial effects of the compound of the present invention.

[0373] The present invention will be described in more detail through the following examples; however, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

[0374]

[0375] [Manufacturing Example 1]

[0376] Preparation of N,N'-(2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide), compound 1

[0377]

[0378] Compound 1 of the present invention was prepared according to the following method.

[0379]

[0380]

[0381] 2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diamine (5.0 g, 4.71 mmol) was dissolved in 50 mL of DCM, and 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxylic acid (1.7 g, 9.44 mmol), EDC (2.3 g, 11.78 mmol), and HOBt (1.6 g, 11.78 mmol) were added, and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, the solvent was removed by distillation under reduced pressure, and H2O and ether were added to the resulting crystals, and the mixture was stirred for 30 minutes. The resulting crystals were filtered and dried in a vacuum oven to obtain 2.1 g (82%) of compound 1.

[0382] 1H NMR (500 MHz, DMSO) d 9.90 (s, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.29 (t, J = 7.8 Hz, 1H), 7.26 (s, 1H), 7.01 (d, J = 7.5 Hz, 1H), 4.50 (t, J = 12.0, 2H), 2.82 (t, 6.1 Hz, 2H), 2.34 (dt, J = 12.0, 6.1 Hz, 2H), 1.93 (s, 3H).

[0383]

[0384] [Manufacturing Example 2]

[0385] Preparation of N-(2,2'-dimethyl-3'-(4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)-4-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, Compound 2

[0386]

[0387]

[0388] Compound 2 of the present invention was prepared according to the following method.

[0389]

[0390]

[0391] 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.6 g, 15.44 mmol) was dissolved in 60 mL of DCM, and 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxylic acid (3.34 g, 18.53 mmol), EDC (3.85 g, 20.07 mmol), and HOBt (2.7 g, 20.07 mmol) were added. The mixture was stirred at room temperature for 12 h. After the reaction was completed, the reaction mixture was cooled to room temperature, and the solvent was removed by distillation under reduced pressure. The resulting crystals were extracted with H2O and EA. The organic layer was dried over anhydrous MgSO4, distilled under reduced pressure to remove the solvent, and purified by column chromatography (n-Hexane:EtOAc=2:1) ​​to obtain 4.76 g (78%) of the intermediate product (N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide).

[0392] 1 H NMR (500 MHz, CDCl3) d 9.75 (s, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.23 (s, 1H), 6.89 (d, J = 7.5 Hz, 1H), 4.44 (t, J = 12.0, 2H), 2.81 (t, 6.1 Hz, 2H), 2.36-2.33 (m, 2H), 1.95 (s, 3H), 1.25 (s, 12H)

[0393]

[0394]

[0395] N-(3-bromo-2-methylphenyl)-4-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide (500 mg, 0.29 mmol) was dissolved in 8 mL of dioxane and 2 mL of H2O, and N-(3-(1,5-dimethyl-2,4-dioxa-3-borabicyclo[3.1.0]hexan-3-yl)-2-methylphenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide (390 mg, 0.29 mmol), Na2CO3 (460 mg, 106 mmol), and Pd(PPh3)4 (168 mg, 0.029 mmol) were added, and the mixture was heated under reflux for 6 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and filtered under reduced pressure with EtOAc. The filtrate was distilled under reduced pressure to remove the solvent. The resulting crystals were extracted with H2O and EA, and the organic layer was dried over anhydrous MgSO4 and distilled under reduced pressure to remove the solvent. The resulting mixture was purified by column chromatography (n-Hexane:EtOAc=1:1) to obtain 128 mg (82%) of compound 2.

[0396] 1 H NMR (500 MHz, CDCl3) d 8.70 (s, 2H), 8.12-8.08 (m, 2H), 7.46 (s, 1H), 7.29-7.25 (m, 2H), 7.04-6.92 (m, 2H), 6.89 (s, 1H), 4.98 (d, J = 3.2 Hz, 1H), 4.47 (t, J = 3.2 Hz, 2H), 4.26-4.04 (m, 2H), 2.77-2.72 (m, 2H), 2.47-2.41 (m, 2H), 2.40-2.30 (m, 1H), 2.26-2.20 (m, 1H), 2.15-2.05 (m, 1H), 2.08-2.05 (m, 6H), 205-1.91 (m, 2H).

[0397]

[0398] [Manufacturing Example 3]

[0399] Preparation of N,N'-(2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(4-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide), compound 2-1

[0400]

[0401]

[0402] Compound 2-1 of the present invention was prepared according to the following method.

[0403]

[0404]

[0405] N,N'-(2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide) (600 mg, 1.12 mmol) was dissolved in a mixed solvent (DCM 8 mL, MeOH 8 mL), and NaBH4 (93 mg, 2.46 mmol) was added. The mixture was stirred at room temperature for 4 hours. After the reaction was completed, the solvent was removed by distillation under reduced pressure, and H2O was added to the resulting crystals and stirred for 30 minutes. The resulting crystals were filtered and dried in a vacuum oven to obtain 538.8 mg (89%) of compound 2-1.

[0406] 1H NMR (500 MHz, CDCl3) d 8.70 (d, J = 3.7 Hz, 2H), 8.13 (dd, J = 13.9, 6.9 Hz, 2H), 7.29 (t, J = 7.5 Hz, 2H), 6.96 (d, J = 7.5 Hz, 2H), 6.88 (d, J = 6.9 Hz, 2H), 4.98 (s, 2H), 4.23-4.02 (m, 4H), 2.48 (s, 2H), 2.33-2.35 (m, 2H), 2.15-2.07 (m, 2H), 2.05 (d, J = 2.1 Hz, 6H), 1.99 (d, J = 4.3 Hz, 4H)

[0407]

[0408] [Manufacturing Example 4]

[0409] N-(2,2'-dimethyl-3'-(4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)-4-((2-hydroxyethyl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide), Preparation of Compound 3

[0410]

[0411]

[0412] Compound 3 of the present invention was prepared according to the following method.

[0413]

[0414]

[0415] N,N'-(2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(4-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide) (300 mg, 0.56 mmol) was dissolved in 25 mL of DCM, and PBr3 (0.16 mL, 1.67 mmol) was added. The mixture was heated and refluxed for 3 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and the solvent was removed by distillation under reduced pressure. H2O was added to the formed crystals and stirred for 30 minutes. The resulting crystals were filtered and dried in a vacuum oven to obtain 303 mg (90%) of the intermediate product (N,N'-(2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(4-bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide)).

[0416]

[0417]

[0418] 4-bromo-N-(2,2'-dimethyl-3'-(4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide (150 mg, 0.25 mmol) was dissolved in 10 mL of DMF, and aminoethanol (0.15 mL, 2.5 mmol) was added. The mixture was stirred at 60°C for 12 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and the solvent was removed by distillation under reduced pressure. The resulting mixture was purified by column chromatography (EtOAc:MeOH=5:1) to obtain 80 mg (32%) of compound 3.

[0419] 1H NMR (500 MHz, CDCl3) d 8.69 (s, 2H), 8.23-8.05 (m, 2H), 7.47 (s, 1H), 7.29-7.25 (m, 2H), 6.99-6.92 (m, 2H), 6.86 (s, 1H), 4.48-4.41 (m, 1H), 4.47 (t, J = 6.3 Hz, 2H), 4.17 (t, J = 6.3 Hz, 2H), 4.02-3.95 (m, 1H), 3.69-3.65 (m, 2H), 2.99-2.87 (m, 2H), 2.75 (t, J = 6.3 Hz, 2H), 2.35 (p, J = 5.4 Hz, 2H), 2.28-2.4 (m, 2H) 2.20-2.16 (m, 1H), 2.15-2.05 (m, 6H), 2.04-2.00 (m, 1H), 1.83-1.74 (m, 1H)

[0420]

[0421] [제조예 5]

[0422] 4-hydroxy-N-(3'-(4-((2-hydroxyethyl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, 화합물 3-1의 제조

[0423]

[0424]

[0425] N-(2,2'-dimethyl-3'-(4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)-4-((2-hydroxyethyl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide (11 mg, 0.019 mmol) was dissolved in 1 mL of DCM and 1 mL of MeOH, and NaBH4 (1.1 mg, 0.029 mmol) was added. The mixture was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was removed by distillation under reduced pressure, and H2O was added to the resulting crystals, which were stirred for 30 minutes. The resulting crystals were filtered and dried in a vacuum oven to obtain 3.44 mg (31%) of compound 3-1.

[0426] 1 H NMR (500 MHz, CDCl3) d 8.70 (s, 2H), 8.24-8.04 (m, 2H), 7.45 (s, 1H), 7.29-7.23 (m, 2H), 6.99-6.91 (m, 2H), 6.85 (s, 1H), 5.31 (s, 1H), 4.49-4.35 (m, 3H), 4.46 (t, J = 6.3 Hz, 2H), 4.17 (t, J = 6.3 Hz, 2H), 4.02-3.95 (m, 1H), 3.69-3.65 (m, 2H), 2.99-2.87 (m, 2H), 2.75 (t, J = 6.3 Hz, 2H), 2.35 (p, J = 5.4 Hz, 2H), 2.28-2.4 (m, 2H) 2.20-2.16 (m, 1H), 2.15-2.05 (m, 6H), 2.04-2.00 (m, 1H), 1.83-1.74 (m, 1H)

[0427]

[0428] [Manufacturing Example 6]

[0429] Preparation of N,N'-(2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(4-(methylamino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide), compound 4

[0430]

[0431]

[0432] N,N'-(2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(4-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide) (1.5 g, 2.78 mmol) was dissolved in 25 mL of DCM, and PBr3 (0.8 mL, 8.32 mmol) was added. The mixture was heated and refluxed for 3 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and the solvent was removed by distillation under reduced pressure. H2O was added to the resulting crystals and stirred for 30 minutes. The resulting crystals were filtered and dried in a vacuum oven to obtain 1.57 mg (85%) of the product.

[0433] 1 H NMR (500 MHz, CDCl3) d 8.70 (d, J = 3.7 Hz, 2H), 8.13 (dd, J = 13.9, 6.9 Hz, 2H), 7.29 (t, J = 7.5 Hz, 2H), 6.96 (d, J = 7.5 Hz, 2H), 6.88 (d, J = 6.9 Hz, 2H), 4.98 (s, 2H), 4.23-4.02 (m, 4H), 2.48 (s, 2H), 2.33-2.35 (m, 2H), 2.15-2.07 (m, 2H), 2.05 (d, J = 2.1 Hz, 6H), 1.99 (d, J = 4.3 Hz, 4H)

[0434]

[0435]

[0436] N,N'-(2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(4-bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide) (1.0 eq) was dissolved in DMF, dimethylamine (10 eq) was added, and the mixture was stirred at 60°C for 12 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (EtOAc:MeOH=5:1) to obtain compound 4.

[0437] 1 H NMR (500 MHz, DMSO) d 9.76 (s, 2H), 9.05 (s, 2H), 7.49 (d, J = 6.9 Hz, 2H), 7.29 (t, J = 7.5 Hz, 2H), 7.05 (s, 2H), 6.99 (d, J = 7.3 Hz, 2H), 4.60-4.58 (m, 2H), 4.22-4.20 (m, 4H), 3.38-3.36 (m, 4H) 2.66 (s, 6H), 2.37 (s, 2H), 2.25-2.23 (s, 4H), 2.02-2.00 (s, 4H)

[0438]

[0439] [Manufacturing Example 7]

[0440] Preparation of compound 5, N,N'-(2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(4-((2-acetamidoethyl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide))

[0441]

[0442]

[0443] N,N'-(2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(4-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide) (1.5 g, 2.78 mmol) was dissolved in 25 mL of DCM, and PBr3 (0.8 mL, 8.32 mmol) was added. The mixture was heated and refluxed for 3 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and the solvent was removed by distillation under reduced pressure. H2O was added to the resulting crystals and stirred for 30 minutes. The resulting crystals were filtered and dried in a vacuum oven to obtain 1.57 mg (85%) of the product.

[0444] 1 H NMR (500 MHz, CDCl3) d 8.70 (d, J = 3.7 Hz, 2H), 8.13 (dd, J = 13.9, 6.9 Hz, 2H), 7.29 (t, J = 7.5 Hz, 2H), 6.96 (d, J = 7.5 Hz, 2H), 6.88 (d, J = 6.9 Hz, 2H), 4.98 (s, 2H), 4.23-4.02 (m, 4H), 2.48 (s, 2H), 2.33-2.35 (m, 2H), 2.15-2.07 (m, 2H), 2.05 (d, J = 2.1 Hz, 6H), 1.99 (d, J = 4.3 Hz, 4H)

[0445]

[0446]

[0447] N,N'-(2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(4-bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide) (1.0 eq) was dissolved in DMF, N-(2-aminoethyl)acetamide (10 eq) was added, and the mixture was stirred at 60°C for 12 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (EtOAc:MeOH=5:1) to obtain compound 5.

[0448] 1 H NMR (500 MHz, CDCl3) δ 8.70 (s, 2H), 8.12 (d, J = 7.9 Hz, 2H), 7.28 (t, J = 7.5 Hz, 2H), 6.96 (d, J = 7.5 Hz, 2H), 6.83 (s, 2H), 5.97 (s, 2H), 4.25-4.10 (m, 2H), 3.97-3.95 (m, 2H), 3.37 (q, J = 6.8 Hz, 2H), 2.89-2.87 (m, 2H), 2.28-2.26 (m, 2H), 2.18-2.16 (m, 2H), 2.06 (s, 3H), 2.02 (s, 3H), 1.99 (d, J = 4.6 Hz, 2H), 1.74-1.72 (m, 2H), 1.64-1.62 (m, 2H)

[0449]

[0450] [Manufacturing Example 8]

[0451] N,N'-(2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(4-((2-hydroxyethyl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide), Preparation of Compound 6

[0452]

[0453]

[0454] N,N'-(2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(4-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide) (1.5 g, 2.78 mmol) was dissolved in 25 mL of DCM, and PBr3 (0.8 mL, 8.32 mmol) was added. The mixture was heated and refluxed for 3 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and the solvent was removed by distillation under reduced pressure. H2O was added to the resulting crystals and stirred for 30 minutes. The resulting crystals were filtered and dried in a vacuum oven to obtain 1.57 mg (85%) of the product.

[0455] 1 H NMR (500 MHz, CDCl3) d 8.70 (d, J = 3.7 Hz, 2H), 8.13 (dd, J = 13.9, 6.9 Hz, 2H), 7.29 (t, J = 7.5 Hz, 2H), 6.96 (d, J = 7.5 Hz, 2H), 6.88 (d, J = 6.9 Hz, 2H), 4.98 (s, 2H), 4.23-4.02 (m, 4H), 2.48 (s, 2H), 2.33-2.35 (m, 2H), 2.15-2.07 (m, 2H), 2.05 (d, J = 2.1 Hz, 6H), 1.99 (d, J = 4.3 Hz, 4H)

[0456]

[0457]

[0458] N,N'-(2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(4-bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide) (1.0 eq) was dissolved in DMF, 2-aminoethanol (10 eq) was added, and the mixture was stirred at 60°C for 12 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and the solvent was removed by distillation under reduced pressure. Compound 6 was obtained by purification using column chromatography (EtOAc:MeOH=5:1).

[0459] 1 H NMR (500 MHz, CDCl3) δ 8.71 (d, J = 8.1 Hz, 2H), 7.28-7.26 (m, 2H), 8.11 (d, J = 8.1 Hz, 2H), 6.96 (d, J = 7.5 Hz, 2H), 6.85 (s, 2H), 4.16-4.14 (m, 4H), 3.97 (t, J = 6.0 Hz, 2H), 3.69 (t, J = 5.0 Hz, 4H), 2.92-2.90 (m, 4H), 2.42-2.20 (m, 6H), 2.20-2.08 (m, 2H), 2.02 (s, 6H), 2.08-1.92 (m, 2H), 1.88-1.70 (m, 2H)

[0460]

[0461] [Manufacturing Example 9]

[0462] 2-[[2-[[3-[3-[[4-(carboxymethylamino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carbonyl]amino]-2- chloro-phenyl]-2-chloro-phenyl]carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]amino]acetic Preparation of acid, compound 8

[0463]

[0464]

[0465] N-(3-bromo-2-chloro-phenyl)-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (1 g, 2.71 mmol, 1 eq) and methyl 2-aminoacetate (1.21 g, 9.63 mmol, 3.55 eq) were dissolved in MeOH (15 mL), and then NaBH3CN (1.70 g, 27.13 mmol, 10 eq) and AcOH (1.63 g, 27.13 mmol, 1.55 mL, 10 eq) were added. The reaction mixture was stirred at 60 °C for 12 h. After concentrating the reactant, the residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 1 to 0 / 1) to obtain compound 8-2 (800 mg, 50.1% yield) as a white solid.

[0466] LCMS m / z 443.0 [M+3] + .

[0467]

[0468]

[0469] methyl 2-[[2-[(3-bromo-2-chloro-phenyl)carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]amino]acetate 2 (200 mg, 452.79 μmol, 1 eq) 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (344.94 mg, 1.36 mmol, 3 eq), KOAc (133.31 mg, 1.36 mmol, 3 eq), Pd(dppf)Cl2·CH2Cl2 (36.98 mg, 45.28 μmol, 0.1 eq) of dioxane (5 mL) mixture under nitrogen conditions. The mixture was stirred at 90 °C for 5 hours. After concentration under reduced pressure, the residue was purified by prep-TLC (SiO2, petroleum ether: ethyl acetate = 0:1) to obtain compound 8-3 (257 mg, 81.3% yield) as a white solid.

[0470] LCMS m / z 489.3 [M+1] + .

[0471]

[0472]

[0473] methyl 2-[[2-[[2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]amino]acetate (199.18 mg, 407.51 μmol, 1.2 eq), methyl 2-[[2-[(3-bromo-2-chloro-phenyl)carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]amino]acetate (150 mg, 339.59 μmol, 1 eq), ditert-butyl(cyclopentyl)phosphane;dichloropalladium;iron (22.13 mg, 33.96 μmol, 0.1 eq), A mixture of cesium fluoride (154.76 mg, 1.02 mmol, 37.61 μL, 3 eq) and dioxane (5 mL) / H2O (1 mL) was stirred at 90 °C for 5 h under nitrogen. After concentration under reduced pressure, the residue was purified by prep-TLC (SiO2, DCM: MeOH = 11:1) to obtain compound 8-4 (110 mg, 41.6% yield) as a white solid.

[0474] LCMS m / z 723.1 [M+1] + .

[0475]

[0476]

[0477] LiOHㆍH2O (31.90 mg, 760.08 μmol, 5 eq) was added to a solution of methyl 2-[[2-[[2-chloro-3-[2-chloro-3-[[4-[(2-methoxy-2-oxo-ethyl)amino]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carbonyl]amino]phenyl]phenyl]carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]amino]acetate (110 mg, 152.02 μmol, 1 eq) in H2O (3 mL) / MeOH (3 mL), and the reaction mixture was stirred at room temperature for 12 hours. After concentration under reduced pressure, the residue was purified by reversed-phase HPLC (column: Waters Xbridge Prep OBD C18 150 * 40 mm * 10 um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 8%-38% B over 15 min) to obtain compound 8 (57 mg, 53.37% yield) as a white solid.

[0478] LCMS m / z 695.4 [M+1] + .

[0479] 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.70 - 1.79 (m, 2 H) 1.91 (br d, J = 7.50 Hz, 2 H) 2.01 (br s, 2 H) 2.19 (br s, 2 H) 3.31 (br s, 4 H) 4.04 (br t, J = 5.88 Hz, 2 H) 4.16 (br t, J=6.00 Hz, 4 H) 6.82 (s, 2 H) 7.17 (d, J = 7.63 Hz, 2 H) 7.49 (t, J=7.94 Hz, 2 H) 8.27 (d, J = 8.26 Hz, 2 H) 9.56 (s, 2 H).

[0480]

[0481] [Manufacturing Example 10]

[0482] Preparation of compounds 11 to 17

[0483]

[0484] 10-1. Preparation of 4-hydroxy-N-(3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, compound 11

[0485]

[0486]

[0487] Starting material 1 (500 mg, 1.26 mmol, 1 eq), 3-bromo-2-methyl-aniline (258.89 mg, 1.39 mmol, 171.45 uL, 1.1 eq), K3PO4 (805.55 mg, 3.79 mmol, 3 eq), Pd(dppf)Cl2 (92.56 mg, 126.50 umol, 0.1 eq) in dioxane (5 mL) / H2O (1 mL) mixture was stirred at 80 °C under nitrogen for 16 h. After concentration under reduced pressure, the residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / 1 to 1 / 1) to obtain compound 11-3 (420 mg, 88.8% yield) as a white solid, which was used in the next reaction without further purification.

[0488]

[0489]

[0490] Starting material 4 (10 g, 51.92 mmol, 1 eq), (3R)-pyrrolidin-3-ol (9.05 g, 103.84 mmol, 8.62 mL, 2 eq) was added to a DCE (500 mL) solution of DIEA (6.71 g, 51.92 mmol, 9.04 mL, 1 eq) and stirred at room temperature for 1 hour. NaBH(OAc)3 (33.01 g, 155.76 mmol, 3 eq) was added in three portions and stirred at room temperature for 16 hours. After concentration under reduced pressure, the residue was purified by column chromatography (SiO2, DCM: MeOH=100 / 1 to 50 / 1) to give compound 11-5 (20 g, 87.64% yield) as a yellow oil.

[0491] 1 H NMR (400 MHz, chloroform-d) δ = 9.12 (d, J = 2.1 Hz, 1H), 8.40 (d, J = 5.6 Hz, 1H), 8.31 (d, J = 2.0 Hz, 1H), 7.65 (d, J = 5.6 Hz, 1H), 5.31 (s, 1H), 4.22 - 4.03 (m, 2H), 3.48 (s, 1H), 3.25 - 3.08 (m, 2H), 2.95 (s, 2H), 1.43 (d, J = 6.7 Hz, 2H)

[0492]

[0493]

[0494] Starting material 3 (420 mg, 1.59 mmol, 1 eq), HCl / dioxane (4 M, 796.28 uL, 2 eq) and t-BuOH (10 mL) mixture were stirred in a microwave reactor at 120° C for 4 h. The mixture was concentrated under reduced pressure, and the residue was purified by reversed-phase HPLC (condition: water (NH4HCO3)-ACN; Column: Waters Xbridge C18 150*50mm* 10um) to obtain compound 11-6 as a yellow solid.

[0495] LCMS 602.2 m / z [M+1] + .

[0496]

[0497]

[0498] To a solution of starting material 11-6 (35 mg, 58.17 μmol, 1 eq) in MeOH (1 mL) / THF (1 mL) was added NaBH4 (11.01 mg, 290.84 μmol, 5 eq), and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and purified by reversed-phase HPLC (column: Waters Xbridge C18 150*50mm* 10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 32%-62%, 10 min) to obtain compound 11 (15 mg, 42.7% yield) as a white solid.

[0499] LCMS 604.3 m / z [M+1] + .

[0500] 1H NMR (400 MHz, DMSO-d6) δ = 9.52 (s, 1H), 9.30 (s, 1H), 8.86 (s, 1H), 8.48 - 8.40 (m, 1H), 8.18 (s, 1H), 8.09 - 8.03 (m, 1H), 7.66 - 7.55 (m, 1H), 7.35 - 7.25 (m, 2H), 7.20 - 7.16 (m, 1H), 7.00 (s, 1H), 6.86 (d, J = 8.0 Hz, 1H), 6.69 (s, 1H), 5.55 (d, J = 5.3 Hz, 1H), 4.79 - 4.70 (m, 1H), 4.22 (dd, J = 3.3, 5.8 Hz, 1H), 4.17 - 4.10 (m, 1H), 3.81 (d, J = 10.9 Hz, 1H), 2.67 (d, J = 1.6 Hz, 3H), 2.39 (d, J = 3.3 Hz, 4H), 2.33 - 2.32 (m, 2H), 2.08 (s, 4H), 1.97 (s, 4H).

[0501]

[0502] 10-2. 4-((2-acetamidoethyl)amino)-N-(3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, 화합물 12의 제조

[0503]

[0504]

[0505] To a solution of starting material 11-6 (35 mg, 58.17 umol, 1 eq) and N-(2-aminoethyl) acetamide (59.41 mg, 581.69 umol, 55.52 uL, 10 eq) in MeOH (2 mL) was added HOAc (104.79 mg, 1.75 mmol, 99.80 uL, 30 eq), and the reaction mixture was stirred at room temperature for 30 min. NaBH3CN (18.28 mg, 290.84 umol, 5 eq) was added to the reaction mixture, and the mixture was stirred at 40 °C for 1 h. After concentrating the reactant under reduced pressure, the residue was purified by reversed-phase HPLC (column: Waters Xbridge C18 150*50mm* 10um; mobile phase: [water (NH-4HCO3)-ACN]; B%: 28%-58%, 10 min) to obtain compound 12 (18 mg, 45.0% yield) as a yellow solid.

[0506] LCMS 688.4 m / z [M+1] + .

[0507] 1H NMR (400 MHz, DMSO-d6) δ = 9.50 (s, 1H), 9.30 (s, 1H), 8.86 (s, 1H), 8.42 (d, J = 8.3 Hz, 1H), 8.18 (s, 1H), 8.05 (d, J = 5.6 Hz, 1H), 7.82 (s, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.34 - 7.25 (m, 2H), 7.18 (d, J = 5.9 Hz, 1H), 7.00 (d, J = 7.3 Hz, 1H), 6.86 (d, J = 7.1 Hz, 1H), 6.73 (s, 1H), 4.72 (d, J = 4.6 Hz, 1H), 4.22 (s, 1H), 4.13 (s, 2H), 3.89 - 3.76 (m, 3H), 3.13 (q, J = 5.9 Hz, 3H), 2.74 (dd, J = 6.3, 9.6 Hz, 1H), 2.68 - 2.63 (m, 4H), 2.41 - 2.30 (m, 3H), 2.20 (s, 2H), 2.10 - 2.06 (m, 3H), 1.97 (s, 4H), 1.80 (s, 3H)

[0508]

[0509] 10-3. 4-((R)-3-hydroxypyrrolidin-1-yl)-N-(3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, 화합물 13의 제조

[0510]

[0511]

[0512] To a solution of starting material 11-6 (100 mg, 166.20 umol, 1 eq), (3R)-pyrrolidin-3-ol (144.79 mg, 1.66 mmol, 137.90 uL, 10 eq) in MeOH (2 mL) was added HOAc (299.41 mg, 4.99 mmol, 285.16 uL, 30 eq), and stirred at room temperature for 30 min. NaBH3CN (52.22 mg, 830.98 umol, 5 eq) was added to the reaction mixture, and stirred at 40 °C for 16 h. After concentrating the reactant under reduced pressure, the residue was purified by reversed-phase HPLC (column: YMC Triart C18 150*25mm*5um; mobile phase: [water (HCl)-ACN]; B%: 2%-32%, 10 min) to obtain compound 13 (62 mg, 55.5% yield) as a yellow solid.

[0513] LCMS 673.4 m / z [M+1] + .

[0514] 1 H NMR (400 MHz, DMSO-d6) δ = 11.98 (s, 1H), 11.59 (s, 1H), 11.35 (s, 1H), 9.73 (d, J = 3.4 Hz, 1H), 9.40 (s, 1H), 8.76 (s, 1H), 7.75 (s, 1H), 7.57 - 7.44 (m, 2H), 7.30 (q, J = 7.1 Hz, 3H), 7.22 (s, 1H), 7.06 (d, J = 7.4 Hz, 1H), 4.93 - 4.79 (m, 2H), 4.72 (d, J = 18.8 Hz, 3H), 4.52 - 4.34 (m, 3H), 4.28 - 4.17 (m, 3H), 3.48 (s, 5H), 3.16 (s, 1H), 3.13 - 3.02 (m, 3H), 2.29 - 2.16 (m, 3H), 2.00 (d, J = 8.6 Hz, 8H)

[0515]

[0516] 10-4. 4-((2-hydroxyethyl)amino)-N-(3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)a mino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, Preparation of Compound 14

[0517]

[0518]

[0519] To a solution of starting material 11-6 (35 mg, 58.17 umol, 1 eq) and 2-aminoethanol (35.53 mg, 581.69 umol, 35.18 uL, 10 eq) in MeOH (2 mL) was added HOAc (104.79 mg, 1.75 mmol, 99.80 uL, 30 eq) and stirred at room temperature for 30 min. NaBH3CN (18.28 mg, 290.84 umol, 5 eq) was added to the reaction mixture and stirred at 40 °C for 2 h. After concentrating the reactant under reduced pressure, the residue was purified by reversed-phase HPLC (column: Waters Xbridge C18 150*50mm* 10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 28%-58%, 10 min) to obtain compound 14 (18 mg, 47.8% yield) as a yellow solid.

[0520] LCMS 647.4 m / z [M+1] + .

[0521] 1H NMR (400 MHz, DMSO-d6) δ = 9.54 - 9.47 (m, 1H), 9.30 (s, 1H), 8.87 (s, 1H), 8.42 (d, J = 8.5 Hz, 1H), 8.18 (s, 1H), 8.06 (s, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.36 - 7.24 (m, 2H), 7.18 (s, 1H), 7.01 (d, J = 7.6 Hz, 1H), 6.90 - 6.83 (m, 1H), 6.72 (s, 1H), 4.72 (d, J = 4.5 Hz, 1H), 4.55 - 4.47 (m, 1H), 4.26 - 4.19 (m, 1H), 4.17 - 4.10 (m, 2H), 3.88 (ddt, J = 1.4, 3.3, 6.3 Hz, 1H), 3.81 (d, J = 11.1 Hz, 1H), 3.48 (d, J = 5.9 Hz, 3H), 2.69 - 2.65 (m, 7H), 2.35 - 2.31 (m, 4H), 2.08 (s, 4H), 1.97 (s, 3H).

[0522]

[0523] 10-5. N-(3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-4-((((S)-5-oxopyrrolidin-2-yl)methyl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, 화합물 15의 제조

[0524]

[0525]

[0526] To a solution of starting material 11-6 (35 mg, 58.17 umol, 1 eq) and (5S)-5-(aminomethyl) pyrrolidin-2-one (66.40 mg, 581.69 umol, 10 eq) in MeOH (2 mL) was added HOAc (104.79 mg, 1.75 mmol, 99.80 uL, 30 eq) and stirred at room temperature for 30 min. NaBH3CN (18.28 mg, 290.84 umol, 5 eq) was added to the reaction mixture and stirred at 40 °C for 2 h. After concentrating the reactant under reduced pressure, the residue was purified by reversed-phase HPLC (column: Waters Xbridge C18 150*50mm* 10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 28%-58%, 10 min) to obtain compound 15 (20 mg, 49.13% yield) as a yellow solid.

[0527] LCMS 700.4 m / z [M+1] +

[0528] 1H NMR (400 MHz, DMSO-d6) δ = 9.50 (d, J = 2.9 Hz, 1H), 9.30 (s, 1H), 8.86 (d, J = 1.9 Hz, 1H), 8.42 (d, J = 8.1 Hz, 1H), 8.18 (d, J = 1.4 Hz, 1H), 8.05 (d, J = 5.8 Hz, 1H), 7.68 (d, J = 19.6 Hz, 1H), 7.59 (br d, J = 7.4 Hz, 1H), 7.35 - 7.25 (m, 2H), 7.18 (d, J = 5.8 Hz, 1H), 7.01 (d, J = 7.4 Hz, 1H), 6.86 (d, J = 7.5 Hz, 1H), 6.76 (d, J = 9.8 Hz, 1H), 4.72 (d, J = 4.5 Hz, 1H), 4.29 - 4.06 (m, 3H), 3.94 - 3.74 (m, 3H), 3.58 (dd, J = 2.1, 3.7 Hz, 1H), 2.74 (dd, J = 6.0, 9.4 Hz, 1H), 2.70 - 2.65 (m, 3H), 2.64 - 2.57 (m, 3H), 2.38 (dd, J = 3.4, 9.6 Hz, 2H), 2.35 - 2.30 (m, 2H), 2.13 - 2.05 (m, 6H), 1.97 (s, 3H), 1.76 - 1.64 (m, 2H), 1.57 (dd, J = 5.1, 8.4 Hz, 1H).

[0529]

[0530] 10-6. 2-((2-((3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl)amino)acetic acid, 화합물 16의 제조

[0531]

[0532] To a solution of starting material 11-6 (100 mg, 166.20 umol, 1 eq) and glycine (124.76 mg, 1.66 mmol, 10 eq) in MeOH (2 mL) was added HOAc (299.41 mg, 4.99 mmol, 285.16 uL, 30 eq) and stirred at room temperature for 30 min. NaBH3CN (52.22 mg, 830.98 umol, 5 eq) was added to the reaction mixture and stirred at 40 °C for 16 h. After concentrating the reactant under reduced pressure, the residue was purified by reversed-phase HPLC (column: Waters Xbridge 150*25mm* 5um; mobile phase: [water (NH4HCO3)-ACN]; B%: 20%-50%, 8 min) to obtain compound 16 (102 mg, 92.88% yield) as a yellow solid.

[0533] LCMS 661.3 m / z [M+1] + .

[0534] 1 H NMR (400 MHz, DMSO-d6) δ = 9.56 (s, 1H), 9.30 (s, 1H), 8.87 (s, 1H), 8.41 (d, J = 7.8 Hz, 1H), 8.19 (s, 1H), 8.06 (d, J = 5.8 Hz, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.36 - 7.24 (m, 2H), 7.18 (d, J = 5.8 Hz, 1H), 7.01 (d, J = 7.9 Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 6.77 (s, 1H), 4.87 - 4.66 (m, 1H), 4.29 - 4.02 (m, 5H), 3.93 - 3.74 (m, 2H), 2.86 - 2.62 (m, 5H), 2.28 - 2.13 (m, 2H), 2.08 (s, 4H), 1.97 (s, 4H), 1.82 - 1.68 (m, 2H), 1.64 - 1.51 (m, 1H), 1.23 (s, 1H).

[0535]

[0536] 10-7. (R)-2-((2-((3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)carbamoyl)pyrazolo[1,5-a]pyridin-4-yl)amino)-2-methylpropanoic acid, compound 17 manufacturing

[0537]

[0538] To a THF (80 mL) solution of N-(3-bromo-2-methyl-phenyl)-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (5 g, 14.36 mmol, 1 eq) was slowly added NaBH4 (1.09 g, 28.72 mmol, 2 eq), and the mixture was stirred at room temperature for 2 hours. Aq. sat'd NH4Cl (200 mL) was added to the mixture, and then extracted with EtOAc (200 mL*2). The organic layer was washed with brine (200 mL), dried over Na2SO4, and concentrated under reduced pressure to obtain compound 17-2 (4.46 g, 70.9% yield) as a yellow solid, which was used in the next reaction without further purification.

[0539] LCMS m / z 352.0 [M+3] + .

[0540]

[0541] To a solution of N-(3-bromo-2-methyl-phenyl)-4-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide (4.46 g, 12.74 mmol, 1 eq) in DCM (80 mL) was slowly added SOCl2 (7.58 g, 63.68 mmol, 4.62 mL, 5 eq), and the mixture was stirred at room temperature for 12 h. Aq. sat'd NH4Cl (200 mL) was added to the mixture, and the mixture was extracted with EtOAc (200 mL*2). The organic layer was washed with brine (200 mL), dried over Na2SO4, and concentrated under reduced pressure to give compound 17-3 (3.78 g, 72.4% yield) as a red solid, which was used in the next reaction without further purification.

[0542] LCMS m / z 369.9 [M+3] + .

[0543]

[0544] DIEA (1.95 g, 15.05 mmol, 2.62 mL, 1.5 eq) and NaI (150.44 mg, 1.00 mmol, 0.1 eq) were added to a mixture of N-(3-bromo-2-methylphenyl)-4-chloro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide (3.7 g, 10.04 mmol, 1 eq) and methyl 2-amino-2-methyl-propanoate (11.76 g, 100.36 mmol, 10 eq), and the mixture was stirred at 90 °C for 12 h. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 3 / 1 to 1 / 1) to obtain compound 17-4 (3.65 g, 72.8% yield) as a white solid.

[0545] LCMS m / z 449.1 [M+1] + .

[0546] 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.32 (d, J=4.63 Hz, 6 H) 1.52 - 1.64 (m, 1 H) 1.87 - 1.99 (m, 3 H) 2.12 - 2.18 (m, 1 H) 2.27 (s, 3 H) 3.65 (s, 3 H) 3.88 (br d, J=2.63 Hz, 1 H) 4.06 - 4.19 (m, 2 H) 6.67 (s, 1 H) 7.15 (t, J=8.00 Hz, 1 H) 7.42 (d, J=7.75 Hz, 1 H) 7.48 (d, J=8.00 Hz, 1 H) 9.80 (s, 1 H).

[0547]

[0548]

[0549] methyl 2-[[2-[(3-bromo-2-methyl-phenyl)carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]amino]-2-methyl-propanoate (300 mg, 667.65 μmol, 1 eq), 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (186.76 mg, 801.17 μmol, 1.2 eq), K2CO3 (276.83 mg, 2.00 mmol, 3 eq), Pd(dppf)Cl2 (48.85 mg, 66.76 μmol, 0.1 eq) of dioxane (10 mL) / H2O (2 mL) mixture under nitrogen conditions at 90 °C. The mixture was stirred for 12 hours. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 0 / 1 to 1 / 1) to obtain compound 17-5 (314 mg, 86.0% yield) as a white solid.

[0550] LCMS m / z 476.2 [M+1] + .

[0551]

[0552]

[0553] To a solution of methyl 2-[[2-[[3-(3-amino-2-methyl-phenyl)-2-methyl-phenyl]carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]amino]-2-methyl-propanoate (300 mg, 630.81 μmol, 1 eq) and (3R)-1-[(8-chloro-1,7-naphthyridin-3-yl)methyl]pyrrolidin-3-ol (415.89 mg, 1.58 mmol, 2.5 eq) in t-BuOH (10 mL) was added HCl / dioxane (4 M, 968.21 μL, 6.14 eq), and the mixture was stirred in a microwave reactor at 120 °C for 12 h. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase HPLC (column: Waters Xbridge Prep OBD C18 150 * 40 mm * 10 um; mobile phase: [water (NH4HCO3) - ACN]; gradient: 15% - 45% B over 20 min) to obtain 17 (23 mg, 5.19% yield) as a yellow solid.

[0554] LCMS m / z 689.3 [M+1] + .

[0555] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.30 (d, J=3.25 Hz, 6 H) 1.54 - 1.75 (m, 3 H) 1.87 - 1.95 (m, 1 H) 1.97 (s, 3 H) 2.03 (br dd, J=13.07, 6.82 Hz, 2 H) 2.08 (s, 3 H) 2.11 - 2.18 (m, 1 H) 2.39 (dd, J=9.57, 3.56 Hz, 1 H) 2.44 - 2.48 (m, 1 H) 2.66 (q, J=7.75 Hz, 1 H) 2.75 (dd, J=9.63, 6.13 Hz, 1 H) 3.75 - 3.87 (m, 3 H) 3.94 (br dd, J=7.32, 5.19 Hz, 1 H) 4.08 - 4.14 (m, 2 H) 4.23 (tt, J=6.71, 3.42 Hz, 1 H) 4.65 - 4.86 (m, 1 H) 6.75 (s, 1 H) 6.87 (d, J=7.00 Hz, 1 H) 7.01 (d, J=6.88 Hz, 1 H) 7.18 (d, J=5.75 Hz, 1 H) 7.30 (dt, J=13.79, 7.74 Hz, 2 H) 7.58 (d, J=7.75 Hz, 1 H) 8.06 (d, J=5.75 Hz, 1 H) 8.18 (d, J=1.75 Hz, 1 H) 8.43 (d, J=7.75 Hz, 1 H) 8.87 (d, J=2.00 Hz, 1 H) 9.30 (s, 1 H) 9.52 (s, 1 H).

[0556]

[0557] [Manufacturing Example 11]

[0558] Preparation of compounds 18 to 27

[0559]

[0560] 11-1. (3R)-1-(2-((2,2'-dichloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)- [1,1'-biphenyl]-3-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl)pyrrolidine-3-carboxylic Preparation of acid, compound 22

[0561]

[0562]

[0563] A dioxane (10 mL) / H2O (2.5 mL) mixture of N-[2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (900 mg, 2.17 mmol, 1.1 eq), 3-bromo-2-chloro-aniline (406.39 mg, 1.97 mmol, 1 eq), K2CO3 (816.10 mg, 5.90 mmol, 3 eq), and Pd(dppf)Cl2 (144.02 mg, 196.83 umol, 0.1 eq) was stirred at 80 °C under nitrogen for 16 h. After concentrating the mixture under reduced pressure, the residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / 1 to 1 / 1) to obtain compound 22-3 (400 mg, 38.7% yield) as a yellow solid.

[0564] LCMS m / z 415.0 [M+1] + .

[0565]

[0566]

[0567] To a solution of (3R)-1-[(8-chloro-1,7-naphthyridin-3-yl)methyl]pyrrolidin-3-ol (317.53 mg, 1.20 mmol, 2.5 eq) and N-[3-(3-amino-2-chloro-phenyl)-2-chloro-phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (200 mg, 481.61 μmol, 1 eq) in t-BuOH (10 mL) was added HCl / dioxane (4 M, 240.81 μL, 2 eq), and the mixture was stirred at 120 °C for 12 h. The mixture was concentrated under reduced pressure to obtain compound 22-5 (380 mg, 87.1% yield) as a brown solid, which was used in the next reaction without further purification.

[0568] LCMS m / z 642.3 [M+1] + .

[0569]

[0570]

[0571] To a solution of N-[2-chloro-3-[2-chloro-3-[[3-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]-1,7-naphthyridin-8-yl]amino]phenyl]phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (200 mg, 311.27 μmol, 1 eq) and pyrrolidine-3-carboxylic acid (179.18 mg, 1.56 mmol, 5 eq) in MeOH (15 mL), AcOH (37.38 mg, 622.54 μmol, 35.64 μL, 2 eq) and NaBH3CN (97.80 mg, 1.56 mmol, 5 eq) were added, and the mixture was stirred at 60 °C for 12 h. After concentrating the mixture under reduced pressure, the residue was purified by reversed-phase HPLC ((0.1%NH3ㆍH2O condition) column: Waters Xbridge 150*25mm* 5um; mobile phase: [water(NH4HCO3)-ACN]; B%: 22%-52%, 9 min) to obtain compound 22 (33 mg, 14.2% yield) as a white solid.

[0572] LCMS m / z 741.3 [M+1] + .

[0573] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54 - 1.64 (m, 1 H) 1.88 - 1.98 (m, 4 H) 1.99 - 2.04 (m, 1 H) 2.15 - 2.30 (m, 1 H) 2.57 - 2.64 (m, 1 H) 2.65 - 2.75 (m, 3 H) 2.77 - 2.80 (m, 1 H) 2.81 - 2.87 (m, 1 H) 2.88 - 2.96 (m, 2 H) 3.79 - 3.94 (m, 4 H) 4.12 - 4.19 (m, 3 H) 4.20 - 4.25 (m, 2 H) 4.69 - 4.83 (m, 1 H) 6.70 - 6.75 (m, 1 H) 7.00 - 7.06 (m, 1 H) 7.17 - 7.23 (m, 1 H) 7.32 - 7.37 (m, 1 H) 7.46 - 7.55 (m, 2 H) 8.16 - 8.22 (m, 1 H) 8.24 - 8.31 (m, 2 H) 8.90 - 8.95 (m, 1 H) 9.09 - 9.17 (m, 1 H) 9.52 - 9.58 (m, 1 H) 9.85 - 9.92 (m, 1 H).

[0574]

[0575] 11-2. N-(2,2'-dichloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-[1,1'-biphenyl]-3-yl)-4-((R)-3-hydroxypyrrolidin-1-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, 화합물 25의 제조

[0576]

[0577]

[0578] To a solution of N-[2-chloro-3-[2-chloro-3-[[3-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]-1,7-naphthyridin-8-yl]amino]phenyl]phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (200 mg, 311.27 μmol, 1 eq), (3R)-pyrrolidin-3-ol (135.59 mg, 1.56 mmol, 129.38 μL, 5 eq) in MeOH (15 mL), AcOH (37.38 mg, 622.54 μmol, 35.64 μL, 2 eq), NaBH3CN (97.80 mg, 1.56 mmol, 5 eq) were added, and the mixture was stirred at 60 °C. The mixture was stirred for 12 hours. After concentrating the mixture under reduced pressure, the residue was purified by reversed-phase HPLC ((0.1% HCl condition) column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water(HCl)-ACN]; gradient: 10%-40% B over 8 min) to obtain compound 25 (17 mg, 7.6% yield) as a brown solid.

[0579] LCMS m / z 713.3 [M+1] + .

[0580] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.94 - 2.04 (m, 2 H) 2.05 - 2.11 (m, 1 H) 2.12 - 2.21 (m, 1 H) 2.23 - 2.36 (m, 2 H) 2.97 - 3.13 (m, 2 H) 3.15 - 3.18 (m, 2 H) 3.27 - 3.37 (m, 3 H) 3.44 - 3.52 (m, 2 H) 3.55 - 3.63 (m, 3 H) 4.22 - 4.27 (m, 2 H) 4.40 - 4.48 (m, 2 H) 4.64 - 4.74 (m, 2 H) 4.82 - 4.93 (m, 1 H) 7.24 (br s, 2 H) 7.33 - 7.44 (m, 2 H) 7.48 - 7.63 (m, 2 H) 8.03 - 8.23 (m, 2 H) 8.64 - 8.74 (m, 1 H) 9.20 - 9.34 (m, 1 H) 9.61 - 9.73 (m, 1 H) 11.18 - 11.38 (m, 1 H) 11.79 - 11.98 (m, 1 H).

[0581]

[0582] 11-3. 2-((2-((2,2'-dichloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-[1,1'-biphenyl]-3-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl)amino)acetic acid, 화합물 26의 제조

[0583]

[0584]

[0585] To a solution of N-[2-chloro-3-[2-chloro-3-[[3-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]-1,7-naphthyridin-8-yl]amino]phenyl]phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (180 mg, 280.14 μmol, 1 eq) and 2-aminoacetic acid (105.15 mg, 1.40 mmol, 5 eq) in MeOH (15 mL), AcOH (33.64 mg, 560.28 μmol, 32.07 μL, 2 eq) and NaBH3CN (88.02 mg, 1.40 mmol, 5 eq) were added, and the mixture was stirred at 60 °C for 12 h. After concentrating the mixture under reduced pressure, the residue was purified by reversed-phase HPLC ((0.1%NH3ㆍH2O condition) column: Waters Xbridge 150*25mm* 5um; mobile phase: [water(NH4HCO3)-ACN]; B%: 20%-50%, 9 min) to obtain compound 26 (30 mg, 15.7% yield) as a white solid.

[0586] LCMS m / z 701.3 [M+1] + .

[0587] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.60 (br dd, J=8.00, 4.88 Hz, 1 H) 1.68 - 1.81 (m, 1 H) 1.91 (br dd, J=13.57, 6.57 Hz, 1 H) 1.98 - 2.06 (m, 2 H) 2.20 (br dd, J=13.63, 6.00 Hz, 1 H) 2.63 - 2.83 (m, 3 H) 3.17 (s, 4 H) 3.81 - 3.94 (m, 3 H) 4.07 (br t, J=5.88 Hz, 1 H) 4.15 (br t, J=6.00 Hz, 2 H) 4.24 (br d, J=6.63 Hz, 1 H) 6.83 (s, 1 H) 7.03 (dd, J=7.50, 1.00 Hz, 1 H) 7.20 (dd, J=7.57, 1.44 Hz, 1 H) 7.35 (d, J=5.88 Hz, 1 H) 7.51 (q, J=8.05 Hz, 2 H) 8.20 (d, J=5.88 Hz, 1 H) 8.25 - 8.30 (m, 2 H) 8.93 (d, J=1.88 Hz, 1 H) 9.13 (dd, J=8.38, 1.38 Hz, 1 H) 9.57 (s, 1 H) 9.89 (s, 1 H)

[0588]

[0589] 11-4. N-(2,2'-dichloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-[1,1'-biphenyl]-3-yl)-4-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, 화합물 18의 제조

[0590]

[0591]

[0592] To a solution of N-[2-chloro-3-[2-chloro-3-[[3-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]-1,7-naphthyridin-8-yl]amino]phenyl]phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (100 mg, 155.63 umol, 1 eq) in MeOH (1 mL) / THF (1 mL) was added NaBH4 (778.17 umol, 5 eq), and the mixture was stirred at 20 °C for 2 hours. The mixture was concentrated under reduced pressure and purified by reversed-phase HPLC (column: Waters Xbridge C18 150*50mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 44%-74%, 10 min) to obtain compound 18 (20 mg, 19.1% yield) as a white solid.

[0593] LCMS m / z 644.3 [M+1] + .

[0594] 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.00 - 2.03 (m, 3 H) 2.33 - 2.34 (m, 4 H) 2.40 - 2.76 (m, 3 H) 3.81 - 3.87 (m, 2 H) 4.13 - 4.22 (m, 3 H) 4.72 - 4.77 (m, 2 H) 5.60 - 5.61 (m, 1 H) 6.75 (s, 1 H) 7.02 - 7.04 (m, 1 H) 7.20 - 7.21 (m, 1 H) 7.34 - 7.36 (m, 2 H) 8.19 - 8.20 (m, 1 H) 8.26 - 8.31 (m, 2 H) 8.92 (s, 1 H) 9.13 - 9.15 (s, 1 H) 9.57 (s, 1 H) 9.89 (s, 1 H)

[0595]

[0596] 11-5. 4-((2-acetamidoethyl)amino)-N-(2,2'-dichloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naph thyridin-8-yl)amino)-[1,1'-biphenyl]-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, Preparation of Compound 19

[0597]

[0598]

[0599] N-[2-chloro-3-[2-chloro-3-[[3-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]-1,7-naphthyridin-8-yl]amino]phenyl]phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (25 mg, 38.91 umol, 1 eq), NaBH3CN (12.23 mg, 194.54 umol, 5 eq), HOAc (70.09 mg, 1.17 mmol, After adding 66.76 uL, 30 eq), mix the mixture to 60 °C for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by reversed-phase HPLC (column: Waters Xbridge 150*25mm* 5um; mobile phase: [water (NH4HCO3)-ACN]; B%: 45%-75%, 8 min) to obtain compound 19 (15 mg, 51.5% yield) as a yellow solid.

[0600] LCMS m / z 728.2 [M+1] + .

[0601] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.80 (s, 3 H) 2.33 - 2.65 (m, 3 H) 2.66 - 2.76 (m, 7 H) 3.12 - 3.14 (m, 2 H) 3.37 - 3.39 (m, 2 H) 3.80 - 4.14 (m, 3 H) 4.14 - 4.23 (m, 3 H) 4.72 - 4.73 (m, 1 H) 6.79 (s, 1 H) 7.02 - 7.04 (m, 1 H) 7.20 - 7.21 (m, 1 H) 7.34 - 7.36 (m, 2 H) 8.19 - 8.20 (m, 1 H) 8.26 - 8.31 (m, 2 H) 8.92 (s, 1 H) 9.13 - 9.15 (s, 1 H) 9.57 (s, 1 H) 9.89 (s, 1 H).

[0602]

[0603] 11-6. N-(2,2'-dichloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-[1,1'-biphenyl]-3-yl)-4-((2-hydroxyethyl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, 화합물 20의 제조

[0604]

[0605]

[0606] To a solution of N-[2-chloro-3-[2-chloro-3-[[3-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]-1,7-naphthyridin-8-yl]amino]phenyl]phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (30 mg, 46.69 umol, 1 eq), 2-aminoethanol (28.52 mg, 466.90 umol, 28.24 uL, 10 eq) in MeOH (3 mL), NaBH3CN (14.67 mg, 233.45 umol, 5 eq), HOAc (84.12 mg, 1.40 mmol, 80.11 uL, 30 eq) were added, and the mixture was stirred at 60 °C for 2 h. The mixture was concentrated under reduced pressure, and the residue was purified by reversed-phase HPLC (column: Waters Xbridge 150*25mm* 5um; mobile phase: [water (NH4HCO3)-ACN]; B%: 45%-75%, 8 min) to obtain compound 20 (21 mg, 62.1% yield) as a yellow solid.

[0607] LCMS m / z 687.2 [M+1] + .

[0608] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.59 - 1.98 (s, 2 H) 2.01 - 2.18 (m, 4 H) 2.20 - 2.22 (m, 4 H) 2.32 - 2.351 (m, 5 H) 2.36 - 2.50 (m, 3 H) 2.67 - 3.01 (m, 3 H) 3.60 - 3.68 (m, 3 H) 7.02 - 7.04 (m, 1 H) 7.20 - 7.21 (m, 1 H) 7.34 - 7.36 (m, 2 H) 8.19 - 8.20 (m, 1 H) 8.26 - 8.31 (m, 2 H) 8.92 (s, 1 H) 9.13 - 9.15 (s, 1 H) 9.57 (s, 1 H) 9.89 (s, 1 H).

[0609]

[0610] 11-7. N-(2,2'-dichloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-[1,1'-biphenyl]-3-yl)-4-((((S)-5-oxopyrrolidin-2-yl)methyl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, 화합물 21의 제조

[0611]

[0612]

[0613] To a solution of N-[2-chloro-3-[2-chloro-3-[[3-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]-1,7-naphthyridin-8-yl]amino]phenyl]phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (35 mg, 54.47 umol, 1 eq) and (5S)-5-(aminomethyl)pyrrolidin-2-one (62.18 mg, 544.72 umol, 10 eq) in MeOH (3 mL) was added HOAc (98.13 mg, 1.63 mmol, 93.46 uL, 30 eq) and stirred at 60°C for 10 min. After adding NaBH3CN (17.12 mg, 272.36 umol, 5 eq) to the mixture, the mixture was stirred at 60 °C for 4 hours. The mixture was concentrated under reduced pressure, and the residue was purified by reversed-phase HPLC (column: Waters Xbridge 150*25mm* 5um; mobile phase: [water (NH4HCO3)-ACN]; B%: 45%-75%, 8 min) to obtain compound 21 (25 mg, 61.9% yield) as a yellow solid.

[0614] LCMS m / z 740.2 [M+1] + .

[0615] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.68 - 1.70 (m, 2 H) 2.11 - 2.18 (m, 1 H) 2.32 - 2.40 (m, 7 H) 2.67 - 2.75 (m, 5 H) 3.05 - 3.1 (m, 1 H) 3.78 - 3.88 (m, 3 H) 4.12 - 4.21 (m, 3 H) 4.72 - 4.73 (m, 3 H ) 6.82 - 6.85 (m, 2 H) 7.02 - 7.04 (m, 1 H) 7.20 - 7.21 (m, 1 H) 7.34 - 7.36 (m, 2 H) 8.19 - 8.20 (m, 1 H) 8.26 - 8.31 (m, 2 H) 8.92 (s, 1 H) 9.13 - 9.15 (s, 1 H) 9.57 (s, 1 H) 9.89 (s, 1 H).

[0616]

[0617] 11-8. 1-(2-((2,2'-dichloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-[1,1'-biphenyl]-3-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl)piperidine-4-carboxylic acid, 화합물 24의 제조

[0618]

[0619]

[0620] A dioxane (1.5 mL) / H2O (0.4 mL) mixture of methyl 1-[2-[(3-bromo-2-chloro-phenyl)carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]piperidine-4-carboxylate (100 mg, 201.70 μmol, 1 eq), 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (51.14 mg, 201.70 μmol, 1 eq), Pd(dppf)Cl2 (147.58 mg, 201.70 μmol, 1 eq), and K2CO3 (27.88 mg, 201.70 μmol, 1 eq) was stirred at 90 °C under nitrogen for 12 h. The mixture was concentrated under reduced pressure, and the residue was purified by prep-TLC (SiO2, DCM: MeOH = 10:1) to obtain compound 24-3 (80 mg, 73.1% yield) as a yellow solid.

[0621] LCMS m / z 542.2 [M+1] + .

[0622]

[0623]

[0624] (3R)-1-[(8-chloro-1,7-naphthyridin-3-yl)methyl]pyrrolidin-3-ol (109.39 mg, 414.78 μmol, 3 eq), methyl 1-[2-[[3-(3-amino-2-chloro-phenyl)-2-chloro-phenyl]carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]piperidine-4-carboxylate (75 mg, 138.26 μmol, 1 eq), and t-BuOH (10 mL) mixture of HCl / dioxane (4 M, 34.57 μL, 1 eq) were stirred in a microwave reactor at 120 °C for 3 h. After filtering the mixture, the filtrate was concentrated under reduced pressure to obtain compound 24-5 (80 mg, 75.1% yield) as a black solid, which was used in the next reaction without further purification.

[0625] LCMS m / z 729.4 [M+1] + .

[0626]

[0627]

[0628] A solution of methyl 1-[2-[[2-chloro-3-[2-chloro-3-[[3-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]-1,7-naphthyridin-8-yl]amino]phenyl]phenyl]carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]piperidine-4-carboxylate (100 mg, 129.92 μmol, 1 eq) and LiOH (9.33 mg, 389.75 μmol, 3 eq) in MeOH (6 mL) / H2O (2 mL) was stirred at room temperature for 12 h. The mixture was washed with aq. The pH range was adjusted to 6-7 with 1N HCl solution, and the residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 22%-52% B over 15 min) to obtain compound 24 (35 mg, 33.8% yield) as a white solid.

[0629] LCMS m / z 755.4 [M+1] + .

[0630] 1H NMR (400 MHz, DMSO-d6) δ = 9.90 (s, 1H), 9.56 (s, 1H), 9.18 - 9.11 (m, 1H), 8.92 (d, J = 1.9 Hz, 1H), 8.31 - 8.23 (m, 2H), 8.20 (d, J = 5.9 Hz, 1H), 7.58 - 7.45 (m, 2H), 7.35 (d, J = 5.9 Hz, 1H), 7.20 (d, J = 6.9 Hz, 1H), 7.03 (d, J = 7.5 Hz, 1H), 6.67 (s, 1H), 4.21 (br d, J = 7.0 Hz, 2H), 4.10 - 3.94 (m, 2H), 3.88 - 3.77 (m, 2H), 2.81 - 2.72 (m, 2H), 2.70 - 2.63 (m, 2H), 2.48 - 2.36 (m, 3H), 2.30 - 2.12 (m, 3H), 2.06 - 1.94 (m, 2H), 1.91 - 1.76 (m, 3H), 1.73 - 1.49 (m, 4H), 1.39 (br d, J = 11.4 Hz, 1H).

[0631]

[0632] 11-9. N-(2,2'-dichloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-[1,1'-biphenyl]-3-yl)-4-(4-hydroxypiperidin-1-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, 화합물 23의 제조

[0633]

[0634]

[0635] A dioxane (20 mL) / H2O (5 mL) mixture of N-(3-bromo-2-chloro-phenyl)-4-(4-hydroxy-1-piperidyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide (150 mg, 330.57 μmol, 1 eq), 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (125.72 mg, 495.86 μmol, 1.5 eq), K2CO3 (137.06 mg, 991.71 μmol, 3 eq), and Pd(dppf)Cl2 (24.19 mg, 33.06 μmol, 0.1 eq) was stirred at 90 °C under nitrogen for 8 h. The mixture was concentrated under reduced pressure and purified by column chromatography (SiO2, DCM: MeOH= 10 / 1) to obtain compound 23-2 (160 mg, 94.7% yield) as a black solid.

[0636] LCMS m / z 500.2 [M+1] + .

[0637]

[0638]

[0639] To a solution of N-[3-(3-amino-2-chloro-phenyl)-2-chloro-phenyl]-4-(4-hydroxy-1-piperidyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide 23-2 (160 mg, 319.73 μmol, 1 eq) in t-BuOH (10 mL) was added (3R)-1-[(8-chloro-1,7-naphthyridin-3-yl)methyl]pyrrolidin-3-ol (252.96 mg, 959.20 μmol, 3 eq) and 4 M HCl (in dioxane (0.1 mL)), and the mixture was stirred in a microwave reactor at 120 °C for 12 h. After concentrating the mixture under reduced pressure, the residue was purified by reversed-phase HPLC (column: Waters X bridge 150 * 25 mm * 5 um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 48%- 78% B over 9 min) to obtain compound 23 (71 mg, 30.5% yield) as a yellow solid.

[0640] LCMS m / z 727.3 [M+1] + .

[0641] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.32 - 1.47 (m, 2 H) 1.53 - 1.61 (m, 1 H) 1.73 (br s, 2 H) 1.89 (br d, J=7.38 Hz, 1 H) 1.95 - 2.06 (m, 2 H) 2.12 (br s, 1 H) 2.27 (br t, J=9.07 Hz, 1 H) 2.38 (br dd, J=9.76, 3.75 Hz, 2 H) 2.61 - 2.69 (m, 2 H) 2.74 (br dd, J=9.69, 6.19 Hz, 2 H) 3.46 (br d, J=3.88 Hz, 1 H) 3.76 - 3.89 (m, 2 H) 3.92 - 4.10 (m, 2 H) 4.20 (br d, J=7.25 Hz, 2 H) 4.56 (d, J=4.13 Hz, 1 H) 4.73 (d, J=4.50 Hz, 1 H) 6.65 (s, 1 H) 7.03 (d, J=7.50 Hz, 1 H) 7.20 (d, J=7.38 Hz, 1 H) 7.35 (d, J=5.88 Hz, 1 H) 7.51 (q, J=8.05 Hz, 2 H) 8.19 (d, J=5.75 Hz, 1 H) 8.24 - 8.31 (m, 2 H) 8.92 (d, J=1.75 Hz, 1 H) 9.13 (d, J=8.50 Hz, 1 H) 9.55 (s, 1 H) 9.89 (s, 1 H).

[0642]

[0643] 11-10. 2-((2-((2,2'-dichloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-[1,1'-biphenyl]-3-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl)amino)-2-methylpropanoic acid, 화합물 27의 제조

[0644]

[0645]

[0646] methyl 2-[[2-[(3-bromo-2-chloro-phenyl)carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]amino]-2-methyl-propanoate (200 mg, 425.75 μmol, 1 eq), 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (161.91 mg, 638.63 μmol, 1.5 eq), K2CO3 (176.53 mg, 1.28 mmol, 3 eq), Pd(dppf)Cl2 (31.15 mg, 42.58 μmol, 0.1 eq) of dioxane (10 mL) / H2O (2 mL) mixture under nitrogen conditions at 90 °C for 12 hours. The mixture was stirred for a while. After concentrating the mixture under reduced pressure, the residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 0 / 1 to 1 / 1) to obtain compound 27-2 (216 mg, 78.5% yield) as a white solid.

[0647] LCMS m / z 516.2 [M+1] + .

[0648]

[0649]

[0650] To a mixture of methyl 2-[[2-[[3-(3-amino-2-chloro-phenyl)-2-chloro-phenyl]carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]amino]-2-methyl-propanoate (200 mg, 387.28 μmol, 1 eq) and (3R)-1-[(8-chloro-1,7-naphthyridin-3-yl)methyl]pyrrolidin-3-ol (306.41 mg, 1.16 mmol, 3 eq) in t-BuOH (10 mL) was added HCl / dioxane (4 M, 968.21 μL, 10 eq), and the mixture was stirred in a microwave reactor at 120 °C for 12 h. The mixture was concentrated under reduced pressure to obtain compound 27-3 (200 mg, 69.4% yield) as a black solid, which was used in the next reaction without further purification.

[0651] LCMS m / z 743.3 [M+1] + .

[0652]

[0653]

[0654] To a solution of methyl 2-[[2-[[2-chloro-3-[2-chloro-3-[[3-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]-1,7-naphthyridin-8-yl]amino]phenyl]phenyl]carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]amino]-2-methyl-propanoate 6 (200 mg, 268.93 μmol, 1 eq) in MeOH (5 mL) / H2O (5 mL) was added LiOHㆍH2O (33.86 mg, 806.80 μmol, 3 eq), and the mixture was stirred at room temperature for 12 h. After concentrating the mixture under reduced pressure, the residue was purified by reversed-phase HPLC (column: Waters Xbridge 150 * 25 mm * 5 um; mobile phase: [water (NH4HCO3) - ACN]; gradient: 24% - 54% B over 9 min. column: Phenomenex luna C18 150 * 25 mm * 10 um; mobile phase: [water (HCl) - ACN]; gradient: 5% - 35% B over 10 min) to obtain compound 27 (44 mg, 21.3% yield) as a yellow solid.

[0655] LCMS m / z 729.2 [M+1] + .

[0656] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.30 (d, J=3.25 Hz, 6 H) 1.54 - 1.69 (m, 2 H) 1.90 - 2.06 (m, 3 H) 2.09 - 2.18 (m, 1 H) 2.31 - 2.42 (m, 3 H) 2.62 - 2.78 (m, 3 H) 3.78 - 3.89 (m, 2 H) 3.94 (br dd, J=6.88, 5.38 Hz, 1 H) 4.06 - 4.18 (m, 2 H) 4.19 - 4.25 (m, 1 H) 4.73 (br d, J=1.63 Hz, 1 H) 6.80 (s, 1 H) 7.04 (dd, J=7.57, 1.31 Hz, 1 H) 7.20 (dd, J=7.63, 1.50 Hz, 1 H) 7.36 (d, J=5.88 Hz, 1 H) 7.52 (q, J=8.13 Hz, 2 H) 8.20 (d, J=5.75 Hz, 1 H) 8.27 (d, J=1.63 Hz, 1 H) 8.31 (d, J=7.75 Hz, 1 H) 8.93 (d, J=1.88 Hz, 1 H) 9.14 (dd, J=8.38, 1.38 Hz, 1 H) 9.55 (s, 1 H) 9.90 (s, 1 H).

[0657]

[0658] [Manufacturing Example 12]

[0659] Preparation of compounds 28 to 36

[0660]

[0661] 12-1. N-(2-chloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2'-methyl-[1, 1'-biphenyl]-3-yl)-4-((2-hydroxyethyl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, Preparation of Compound 28

[0662]

[0663]

[0664] A dioxane (30 mL) / H2O (3 mL) mixture of N-[2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (3 g, 7.22 mmol, 1 eq), 3-bromo-2-methyl-aniline (2.01 g, 10.83 mmol, 1.33 mL, 1.5 eq), K2CO3 (2.79 g, 20.21 mmol, 2.8 eq), and Pd(dppf)Cl2 (528.09 mg, 721.71 μmol, 0.1 eq) was stirred at 90 °C under nitrogen for 2 h. The mixture was extracted with ethyl acetate (30 mL x 3) containing water (40 mL). The organic layer was washed with brine (60 mL), dried over Na2SO4, concentrated under reduced pressure, and purified by flash silica gel chromatography (Petroleum ether / Ethyl acetate=100 / 1 to 1 / 1) to obtain compound 28-3 (2.5 g, 78.9% yield) as a white solid.

[0665] LCMS m / z 395.3 [M+1] + .

[0666] 1H NMR (400 MHz, DMSO-d6) δ = 9.74 (s, 1H), 8.04 (dd, J = 1.4, 8.1 Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.28 (s, 1H), 7.07 (dd, J = 1.5, 7.6 Hz, 1H), 7.00 - 6.86 (m, 1H), 6.75 - 6.60 (m, 1H), 6.43 - 6.24 (m, 1H), 4.95 (s, 2H), 4.55 - 4.38 (m, 2H), 2.80 - 2.63 (m, 2H), 2.41 - 2.24 (m, 2H), 1.77 (s, 3H).

[0667]

[0668]

[0669] To a solution of (3R)-1-[(8-chloro-1,7-naphthyridin-3-yl)methyl]pyrrolidin-3-ol (133.58 mg, 506.52 μmol, 2 eq) and N-[3-(3-amino-2-methyl-phenyl)-2-chloro-phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (100 mg, 253.26 μmol, 1 eq) in t-BuOH (10 mL) was added HCl / dioxane (4 M, 253.26 μL, 4 eq) and stirred at 120 °C for 12 h. The pH of the mixture was adjusted to aq. After adjusting to 8 using 1 N NaOH solution, the precipitated solid was filtered to obtain compound 28-6 (126 mg, 63.9% yield) as a white solid, which was used in the next reaction without further purification.

[0670]

[0671]

[0672] A mixture of N-[2-chloro-3-[3-[[3-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]-1,7-naphthyridin-8-yl]amino]-2-methyl-phenyl]phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (100 mg, 160.74 μmol, 1 eq), 2-aminoethanol (98.19 mg, 1.61 mmol, 97.21 μL, 10 eq), and HOAc (96.53 mg, 1.61 mmol, 92.02 μL, 10 eq) in MeOH (10 mL) was stirred at 60 °C for 2 h. After adding NaBH3CN (30.30 mg, 482.23 μmol, 3 eq) to the mixture, the mixture was stirred at 60°C for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 35%-65% B over 9 min) to obtain compound 28 (23 mg, 20.3% yield) as a white solid.

[0673] LCMS m / z 677.4 [M+1] + .

[0674] 1H NMR (400 MHz, METHANOL-d4) δ = 8.88 (d, J = 2.0 Hz, 1H), 8.39 (dd, J = 1.5, 8.3 Hz, 1H), 8.23 - 8.09 (m, 2H), 7.94 (d, J = 5.9 Hz, 1H), 7.43 (t, J = 7.9 Hz, 1H), 7.34 (t, J = 7.8 Hz, 1H), 7.14 (dd, J = 1.5, 7.6 Hz, 1H), 7.08 (d, J = 6.0 Hz, 1H), 7.00 (d, J = 6.8 Hz, 1H), 6.89 (s, 1H), 4.44 - 4.32 (m, 1H), 4.25 - 4.16 (m, 2H), 4.04 (dd, J = 5.4, 7.4 Hz, 1H), 3.96 - 3.81 (m, 2H), 3.70 (t, J = 5.7 Hz, 2H), 2.91 - 2.79 (m, 4H), 2.64 - 2.53 (m, 2H), 2.41 - 2.25 (m, 1H), 2.23 - 2.16 (m, 2H), 2.14 (s, 3H), 2.10 - 1.97 (m, 1H), 1.92 - 1.68 (m, 2H).

[0675]

[0676] 12-2. N-(2-chloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-4-((R)-3-hydroxypyrrolidin-1-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, 화합물 29의 제조

[0677]

[0678]

[0679] A mixture of N-[2-chloro-3-[3-[[3-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]-1,7-naphthyridin-8-yl]amino]-2-methyl-phenyl]phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (100 mg, 160.74 μmol, 1 eq), 2-aminoethanol (98.19 mg, 1.61 mmol, 97.21 μL, 10 eq), and HOAc (96.53 mg, 1.61 mmol, 92.02 μL, 10 eq) in MeOH (10 mL) was stirred at 60 °C for 2 h. After adding NaBH3CN (30.30 mg, 482.23 μmol, 3 eq) to the mixture, the mixture was stirred at 60°C for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 35%-65% B over 9 min) to obtain compound 28 (23 mg, 20.3% yield) as a white solid.

[0680] LCMS m / z 677.4 [M+1] + .

[0681] 1H NMR (400 MHz, METHANOL-d4) δ = 8.88 (d, J = 2.0 Hz, 1H), 8.39 (dd, J = 1.5, 8.3 Hz, 1H), 8.23 - 8.09 (m, 2H), 7.94 (d, J = 5.9 Hz, 1H), 7.43 (t, J = 7.9 Hz, 1H), 7.34 (t, J = 7.8 Hz, 1H), 7.14 (dd, J = 1.5, 7.6 Hz, 1H), 7.08 (d, J = 6.0 Hz, 1H), 7.00 (d, J = 6.8 Hz, 1H), 6.89 (s, 1H), 4.44 - 4.32 (m, 1H), 4.25 - 4.16 (m, 2H), 4.04 (dd, J = 5.4, 7.4 Hz, 1H), 3.96 - 3.81 (m, 2H), 3.70 (t, J = 5.7 Hz, 2H), 2.91 - 2.79 (m, 4H), 2.64 - 2.53 (m, 2H), 2.41 - 2.25 (m, 1H), 2.23 - 2.16 (m, 2H), 2.14 (s, 3H), 2.10 - 1.97 (m, 1H), 1.92 - 1.68 (m, 2H).

[0682]

[0683] 12-3. 4-((2-acetamidoethyl)amino)-N-(2-chloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, 화합물 30의 제조

[0684]

[0685] A solution of N-[2-chloro-3-[3-[[3-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]-1,7-naphthyridin-8-yl]amino]-2-methyl-phenyl]phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (80 mg, 128.59 μmol, 1 eq), N-(2-aminoethyl)acetamide (131.34 mg, 1.29 mmol, 123.21 μL, 10 eq), and HOAc (77.22 mg, 1.29 mmol, 73.61 μL, 10 eq) in MeOH (15 mL) was stirred at 60 °C for 2 h. After adding NaBH3CN (24.24 mg, 385.78 μmol, 3 eq) to the mixture, the mixture was stirred at 60 °C for 2 hours. The mixture was concentrated under reduced pressure and purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 30%-60% B over 15 min) to obtain compound 30 (26 mg, 27.12% yield) as a white solid.

[0686] LCMS m / z 708.4 [M+1] + .

[0687] 1H NMR (400 MHz, METHANOL-d4) δ = 8.88 (d, J = 1.9 Hz, 1H), 8.39 (dd, J = 1.5, 8.3 Hz, 1H), 8.22 - 8.10 (m, 2H), 7.94 (d, J = 5.9 Hz, 1H), 7.43 (t, J = 7.9 Hz, 1H), 7.34 (t, J = 7.9 Hz, 1H), 7.14 (dd, J = 1.5, 7.6 Hz, 1H), 7.08 (d, J = 5.9 Hz, 1H), 7.00 (d, J = 7.4 Hz, 1H), 6.87 (s, 1H), 4.45 - 4.33 (m, 1H), 4.27 - 4.15 (m, 2H), 4.02 (dd, J = 5.3, 7.4 Hz, 1H), 3.96 - 3.81 (m, 2H), 2.89 - 2.78 (m, 4H), 2.63 - 2.52 (m, 2H), 2.37 - 2.16 (m, 3H), 2.14 (s, 3H), 2.10 - 2.01 (m, 1H), 1.96 (s, 3H), 1.87 - 1.70 (m, 2H).

[0688]

[0689] 12-4. N-(2-chloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-4-((((S)-5-oxopyrrolidin-2-yl)methyl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, 화합물 31의 제조

[0690]

[0691] N-[2-chloro-3-[3-[[3-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]-1,7-naphthyridin-8-yl]amino]-2-methyl-phenyl]phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (100 mg, 160.74 μmol, 1 eq), (5S)-5-(aminomethyl)pyrrolidin-2-one (183.48 mg, 1.61 mmol, 297.04 uL, 10 eq, HCl), DIPEA (207.74 mg, 1.61 mmol, 279.98 μL, 10 eq) in MeOH (15 mL) / HOAc (193.05 mg, 3.21 in DMF (3 mL) solution mmol, 184.03 μL, 20 eq) was added to the mixture, and the mixture was stirred at 50 °C for 2 hours. NaBH3CN (50.51 mg, 803.71 μmol, 5 eq) was added to the mixture, and the mixture was stirred at 50 °C for 2 hours. The mixture was concentrated under reduced pressure and purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 35%-65% B over 9 min) to obtain compound 31 (32 mg, 26.2% yield) as a white solid.

[0692] LCMS m / z 720.3 [M+1] + .

[0693] 1H NMR (400 MHz, DMSO-d6) δ = 9.54 (br s, 1H), 9.30 (br s, 1H), 8.85 (br s, 1H), 8.49 (br d, J = 7.4 Hz, 1H), 8.27 (br d, J = 7.1 Hz, 1H), 8.17 (br s, 1H), 8.05 (br d, J = 4.6 Hz, 1H), 7.71 (br d, J = 19.3 Hz, 1H), 7.54 - 7.45 (m, 1H), 7.40 - 7.27 (m, 1H), 7.24 - 7.07 (m, 2H), 6.97 - 6.78 (m, 2H), 4.74 (br s, 1H), 4.28 - 4.07 (m, 3H), 3.96 - 3.73 (m, 3H), 3.58 (br s, 1H), 2.72 (br d, J = 6.1 Hz, 1H), 2.63 (br dd, J = 7.4, 14.1 Hz, 3H), 2.50 (br s, 3H), 2.37 (br d, J = 7.4 Hz, 1H), 2.27 (br s, 2H), 2.11 (br s, 4H), 2.05 - 1.86 (m, 3H), 1.79 - 1.48 (m, 3H).

[0694]

[0695] 12-5. 2-((2-((2-chloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl)amino)acetic acid, 화합물 32의 제조

[0696]

[0697]

[0698] To a solution of N-[2-chloro-3-[3-[[3-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]-1,7-naphthyridin-8-yl]amino]-2-methyl-phenyl]phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (100 mg, 160.74 μmol, 1 eq) and 2-aminoacetic acid (120.66 mg, 1.61 mmol, 297.04 μL, 10 eq) in MeOH (5 mL) / DMF (1 mL) was added HOAc (193.05 mg, 3.21 mmol, 184.03 μL, 20 eq), and the mixture was stirred at 60 °C for 2 h. After adding NaBH3CN (50.51 mg, 803.71 μmol, 5 eq) to the mixture, the mixture was stirred at 60 °C for 2 hours. The mixture was concentrated under reduced pressure and purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 12%-42% B over 15 min) to obtain compound 32 (33 mg, 28.6% yield) as a white solid.

[0699] LCMS m / z 681.3 [M+1] + .

[0700] 1H NMR (400 MHz, DMSO-d6) δ = 9.57 (s, 1H), 9.30 (s, 1H), 8.87 (d, J = 1.9 Hz, 1H), 8.48 (d, J = 8.0 Hz, 1H), 8.30 - 8.22 (m, 1H), 8.18 (d, J = 1.8 Hz, 1H), 8.06 (d, J = 5.8 Hz, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7.34 (t, J = 7.9 Hz, 1H), 7.23 - 7.10 (m, 2H), 6.91 (d, J = 7.5 Hz, 1H), 6.82 (s, 1H), 4.26 - 4.19 (m, 1H), 4.15 (br t, J = 6.1 Hz, 2H), 4.04 (br t, J = 6.1 Hz, 1H), 3.81 (br d, J = 10.6 Hz, 2H), 3.31 (s, 2H), 3.17 (s, 3H), 2.76 - 2.63 (m, 2H), 2.38 (dd, J = 3.6, 9.6 Hz, 1H), 2.27 - 2.16 (m, 1H), 2.14 - 2.07 (m, 3H), 2.05 - 1.86 (m, 3H), 1.82 - 1.49 (m, 2H).

[0701]

[0702] 12-6. (3R)-1-(2-((2-chloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl)pyrrolidine-3-carboxylic acid, 화합물 33의 제조

[0703]

[0704]

[0705] A solution of N-[2-chloro-3-[3-[[3-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]-1,7-naphthyridin-8-yl]amino]-2-methyl-phenyl]phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (100 mg, 160.74 μmol, 1 eq) and (3R)-pyrrolidine-3-carboxylic acid (185.06 mg, 1.61 mmol, 10 eq) in MeOH (15 mL) / DMF (1 mL) was added with HOAc (193.05 mg, 3.21 mmol, 184.03 μL, 20 eq) and stirred at 60 °C for 2 h. After adding NaBH3CN (50.51 mg, 803.71 μmol, 5 eq) to the mixture, the mixture was stirred at 60 °C for 2 hours. The mixture was concentrated under reduced pressure and purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 12%-42% B over 15 min) to obtain compound 33 (28 mg, 22.9% yield) as a white solid.

[0706] LCMS m / z 721.2 [M+1] + .

[0707] 1H NMR (400 MHz, DMSO-d6) δ = 9.56 (s, 1H), 9.30 (s, 1H), 8.86 (s, 1H), 8.48 (br d, J = 8.0 Hz, 1H), 8.32 - 8.23 (m, 1H), 8.17 (s, 1H), 8.06 (d, J = 5.8 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 7.34 (br t, J = 7.8 Hz, 1H), 7.21 - 7.10 (m, 2H), 6.97 - 6.88 (m, 1H), 6.73 (d, J = 8.8 Hz, 1H), 4.81 - 4.67 (m, 2H), 4.26 - 4.15 (m, 3H), 3.80 (br d, J = 10.4 Hz, 3H), 3.17 (d, J = 4.8 Hz, 4H), 2.90 - 2.72 (m, 2H), 2.70 - 2.58 (m, 2H), 2.46 - 2.34 (m, 2H), 2.23 (br s, 1H), 2.11 (s, 3H), 1.88 (br s, 2H), 1.57 (br d, J = 3.4 Hz, 2H).

[0708]

[0709] 12-6. N-(2-chloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-4-(4-hydroxypiperidin-1-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, 화합물 34의 제조

[0710]

[0711] A dioxane (10 mL) / H2O (4 mL) mixture of N-(3-bromo-2-chloro-phenyl)-4-(4-hydroxy-1-piperidyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide (150 mg, 330.57 μmol, 1 eq), 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (115.59 mg, 495.86 μmol, 1.5 eq), K2CO3 (137.06 mg, 991.71 μmol, 3 eq), and Pd(dppf)Cl2 (24.19 mg, 33.06 μmol, 0.1 eq) was stirred at 90 °C under nitrogen for 12 h. The mixture was concentrated under reduced pressure and purified by column chromatography (SiO2, DCM: MeOH = 10 / 1) to obtain compound 34-1 (156 mg, 97.3% yield) as a black solid.

[0712] LCMS m / z 480.3 [M+1] + .

[0713]

[0714] To a solution of N-[3-(3-amino-2-methyl-phenyl)-2-chloro-phenyl]-4-(4-hydroxy-1-piperidyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide 3 (156 mg, 325.00 μmol, 1 eq) in t-BuOH (10 mL) was added (3R)-1-[(8-chloro-1,7-naphthyridin-3-yl)methyl]pyrrolidin-3-ol (257.13 mg, 975.00 μmol, 3 eq) and 4 M HCl (in dioxane (0.1 mL)), and the mixture was stirred in a microwave reactor at 120 °C for 8 h. The mixture was concentrated under reduced pressure and purified by reversed-phase HPLC (column: Waters X bridge 150 * 25 mm * 5 um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 40%- 70% B over 9 min) to obtain compound 34 (85 mg, 36.6% yield) as a yellow solid.

[0715] LCMS m / z 707.4 [M+1] + .

[0716] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34 - 1.46 (m, 2 H) 1.54 - 1.61 (m, 1 H) 1.72 (br s, 2 H) 2.02 (br dd, J=12.76, 6.88 Hz, 2 H) 2.11 (s, 3 H) 2.28 (br d, J=9.01 Hz, 1 H) 2.37 (br dd, J=9.63, 3.75 Hz, 2 H) 2.62 - 2.67 (m, 2 H) 2.74 (br dd, J=9.51, 6.38 Hz, 2 H) 3.46 (br d, J=4.88 Hz, 1 H) 3.75 - 3.87 (m, 2 H) 3.96 (br dd, J=10.44, 5.32 Hz, 1 H) 4.05 (br s, 1 H) 4.22 (br s, 2 H) 4.57 (d, J=4.13 Hz, 1 H) 4.74 (d, J=4.63 Hz, 1 H) 6.65 (s, 1 H) 6.92 (d, J=7.38 Hz, 1 H) 7.13 (d, J=7.63 Hz, 1 H) 7.19 (d, J=5.88 Hz, 1 H) 7.34 (t, J=7.88 Hz, 1 H) 7.47 (t, J=7.88 Hz, 1 H) 8.06 (d, J=5.75 Hz, 1 H) 8.19 (s, 1 H) 8.23 (t, J=7.86 Hz, 1 H) 8.48 (d, J=8.13 Hz, 1 H) 8.87 (d, J=2.00 Hz, 1 H) 9.31 (s, 1 H) 9.56 (d, J=3.88 Hz, 1 H).

[0717]

[0718] 12-7. 1-(2-((2-chloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl)piperidine-4-carboxylic acid, 화합물 35의 제조

[0719]

[0720] A dioxane (4 mL) / H2O (1 mL) mixture of methyl 1-[2-[(3-bromo-2-chloro-phenyl)carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]piperidine-4-carboxylate (200 mg, 403.39 μmol, 1 eq), 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (141.05 mg, 605.09 μmol, 1.5 eq), Pd(dppf)Cl2 (29.52 mg, 40.34 μmol, 0.1 eq), and K2CO3 (167.25 mg, 1.21 mmol, 3 eq) was stirred at 90 °C under N2 conditions for 12 h. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, DCM: MeOH = 20:1) to obtain the compound methyl 1-[2-[[3-(3-amino-2-methyl-phenyl)-2-chloro-phenyl]carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]piperidine-4-carboxylate (150 mg, 71.2% yield) as a white solid.

[0721] LCMS m / z 522.3 [M+1] +.

[0722]

[0723]

[0724] (3R)-1-[(8-chloro-1,7-naphthyridin-3-yl)methyl]pyrrolidin-3-ol (197.02 mg, 747.07 μmol, 3 eq), methyl 1-[2-[[3-(3-amino-2-methyl-phenyl)-2-chloro-phenyl]carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]piperidine-4-carboxylate (130 mg, 249.02 μmol, 1 eq), and t-BuOH (5 mL) mixture of HCl / dioxane (4 M, 0.5 mL, 8.03 eq) were stirred in a microwave reactor at 120 °C for 12 h. After cooling the mixture to room temperature, the precipitated solid was filtered and washed with ethyl acetate (30 mL) to obtain compound 35-1, which was used in the next reaction without further purification.

[0725]

[0726]

[0727] (3R)-1-[(8-chloro-1,7-naphthyridin-3-yl)methyl]pyrrolidin-3-ol (197.02 mg, 747.07 μmol, 3 eq), methyl 1-[2-[[3-(3-amino-2-methyl-phenyl)-2-chloro-phenyl]carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]piperidine-4-carboxylate (130 mg, 249.02 μmol, 1 eq), and t-BuOH (5 mL) mixture of HCl / dioxane (4 M, 0.5 mL, 8.03 eq) were stirred in a microwave reactor at 120 °C for 12 h. After cooling the mixture to room temperature, the precipitated solid was filtered and washed with ethyl acetate (30 mL) to obtain compound 35-1, which was used in the next reaction without further purification.

[0728]

[0729]

[0730] To a solution of N-[2-chloro-3-[3-[[3-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]-1,7-naphthyridin-8-yl]amino]-2-methyl-phenyl]phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (100 mg, 160.74 μmol, 1 eq) in MeOH (6 mL) was added NaBH4 (20.20 mg, 321.48 μmol, 2 eq) at 0 °C, and the mixture was stirred at room temperature for 2 hours. After concentrating the mixture under reduced pressure, the residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 38%-68% B over 9 min) to obtain compound 36 (42 mg, 39.7% yield) as a white solid.

[0731] LCMS m / z 624.3 [M+1] + .

[0732] 1H NMR (400 MHz, DMSO-d6) δ = 9.56 (s, 1H), 9.30 (s, 1H), 8.86 (d, J = 1.9 Hz, 1H), 8.48 (d, J = 8.0 Hz, 1H), 8.26 (d, J = 8.3 Hz, 1H), 8.18 (d, J = 1.8 Hz, 1H), 8.06 (d, J = 5.8 Hz, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7.34 (t, J = 7.9 Hz, 1H), 7.24 - 7.11 (m, 2H), 6.91 (d, J = 7.4 Hz, 1H), 6.74 (s, 1H), 5.61 (dd, J = 1.9, 5.5 Hz, 1H), 4.82 - 4.66 (m, 2H), 4.31 - 4.07 (m, 3H), 3.91 - 3.71 (m, 2H), 2.77 - 2.61 (m, 2H), 2.38 (dd, J = 3.6, 9.6 Hz, 1H), 2.26 - 2.15 (m, 1H), 2.11 (s, 3H), 2.05 - 1.89 (m, 3H), 1.79 - 1.51 (m, 2H).

[0733]

[0734] [Manufacturing Example 13]

[0735] Preparation of compounds 37 to 44

[0736]

[0737] 13-1. N-(2'-chloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2-methyl-[1, 1'-biphenyl]-3-yl)-4-((2-hydroxyethyl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, Preparation of Compound 37

[0738]

[0739]

[0740] A dioxane (20 mL) / H2O (2 mL) mixture of N-[2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (2.82 g, 7.14 mmol, 1 eq), 3-bromo-2-chloro-aniline (2.95 g, 14.27 mmol, 2 eq), K3PO4 (4.54 g, 21.41 mmol, 3 eq), and Pd(dppf)Cl2 (261.04 mg, 356.76 μmol, 0.05 eq) was stirred at 80 °C under nitrogen for 8 h. After concentrating the mixture under reduced pressure, the residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 1) to obtain compound 37-3 (2.2 g, 69.0% yield) as a brown solid.

[0741] LCMS m / z 395.2 [M+1] + .

[0742] 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.94 - 1.98 (m, 3 H) 2.31 - 2.36 (m, 2 H) 2.69 - 2.73 (m, 2 H) 4.42 - 4.48 (m, 2 H) 5.40 - 5.45 (m, 2 H) 6.38 - 6.43 (m, 1 H) 6.79 - 6.85 (m, 1 H) 6.96 - 7.01 (m, 1 H) 7.04 - 7.10 (m, 1 H) 7.21 - 7.29 (m, 2 H) 7.42 - 7.49 (m, 1 H) 9.79 - 9.85 (m, 1) H).

[0743]

[0744]

[0745] To a solution of (3R)-1-[(8-chloro-1,7-naphthyridin-3-yl)methyl]pyrrolidin-3-ol (500.92 mg, 1.90 mmol, 2.5 eq) and N-[3-(3-amino-2-chloro-phenyl)-2-methyl-phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (300 mg, 759.78 μmol, 1 eq) in t-BuOH (10 mL) was added HCl / dioxane (4 M, 379.89 μL, 2 eq) and stirred at 120 °C for 12 h. The mixture was concentrated under reduced pressure to obtain compound 37-5 (648 mg, 86.1% yield) as a brown solid, which was used in the next reaction without further purification.

[0746] LCMS m / z 622.3 [M+1] + .

[0747]

[0748]

[0749] To a solution of N-[3-[2-chloro-3-[[3-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]-1,7-naphthyridin-8-yl]amino]phenyl]-2-methyl-phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (100 mg, 160.74 umol, 1 eq) and 2-aminoethanol (98.19 mg, 1.61 mmol, 97.21 uL, 10 eq) in MeOH (4 mL) were added HOAc (96.53 mg, 1.61 mmol, 91.93 uL, 10 eq) and NaBH3CN (50.51 mg, 803.71 umol, 5 eq), and the mixture was stirred at 60 °C for 4 h. After concentrating the mixture under reduced pressure, the residue was purified by reversed-phase HPLC (column: Waters Xbridge BEH C18 150*25mm*5um; mobile phase: [water (NH4HCO3)-ACN]; B%: 42%-72%, 9 min) to obtain compound 37 (23 mg, 20.7% yield) as a white solid.

[0750] LCMS m / z 667.4 [M+1] + .

[0751] 1H NMR ( 400 MHz, DMSO-d6) δ ppm 1.56 - 1.58 (m, 1 H) 1.70 - 2.01 (m, 1 H) 2.20 - 2.32 (M, 3 H) 2.32 - 2.33 (m, 2 H) 2.33 - 2.39 (m, 3 H) 2.66 - 2.69 (m, 5 H) 3.47 - 3.48 (m, 2 H) 3.81 - 3.87 (m, 2 H) 3.89 - 4.00 (m, 2 H) 4.15 - 4.50 (m, 1 H) 4.71 - 4.73 (m, 1 H) 6.73 (d, J=7.38 Hz, 1 H) 6.94 -6.96 (m, 1 H) 7.05 - 7.07 (d, J=7.75 Hz, 1 H) 7.30 - 7.34 (m, 2 H) 7.46 - 7.49 (m, 1 H) 7.61 - 7.63 (m, 1 H) 8.18 - 8.20 (br s, 1 H) 8.25 (s, 1 H) 8.92 (m, 1 H) 9.05 - 9.11 (m, 1 H) 9.54 (br s, 1 H) 9.91 (s, 1 H).

[0752]

[0753] 13-2. N-(2'-chloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2-methyl-[1,1'-biphenyl]-3-yl)-4-((R)-3-hydroxypyrrolidin-1-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, 화합물 38의 제조

[0754]

[0755]

[0756] To a solution of N-[3-[2-chloro-3-[[3-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]-1,7-naphthyridin-8-yl]amino]phenyl]-2-methyl-phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (400 mg, 642.97 μmol, 1 eq), (3R)-pyrrolidin-3-ol (560.15 mg, 6.43 mmol, 534.50 μL, 10 eq) in MeOH (10 mL), AcOH (77.22 mg, 1.29 mmol, 73.62 μL, 2 eq), NaBH3CN (202.03 mg, 3.21 mmol, 5 eq) were added and stirred at 60 °C. The mixture was stirred for 12 hours. After concentrating the mixture under reduced pressure, the residue was purified by reversed-phase HPLC ((0.1% HCl condition) column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water (HCl)-ACN]; gradient: 5%-35% B over 8 min) to obtain compound 38 (34 mg, 7.42% yield) as a brown solid.

[0757] LCMS m / z 693.5 [M+1] + .

[0758] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.88 - 1.94 (m, 1 H) 2.04 (s, 4 H) 2.18 - 2.30 (m, 2 H) 3.00 - 3.13 (m, 1 H) 3.27 - 3.37 (m, 2 H) 3.48 (br s, 1 H) 3.56 - 3.61 (m, 1 H) 4.19 - 4.30 (m, 3 H) 4.43 (s, 3 H) 4.47 (s, 3 H) 4.67 - 4.78 (m, 5 H) 4.87 (br dd, J=12.63, 6.25 Hz, 2 H) 7.12 (br d, J=7.13 Hz, 1 H) 7.19 - 7.28 (m, 1 H) 7.30 - 7.39 (m, 2 H) 7.53 - 7.62 (m, 2 H) 8.00 (br s, 1 H) 8.36 (br s, 1 H) 8.73 (br d, J=19.51 Hz, 1 H) 9.27 - 9.38 (m, 1 H) 9.70 - 9.77 (m, 1 H) 11.23 - 11.59 (m, 1 H) 11.88 - 12.18 (m, 1 H)

[0759]

[0760] 13-3. 4-((2-acetamidoethyl)amino)-N-(2'-chloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2-methyl-[1,1'-biphenyl]-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, 화합물 39의 제조

[0761]

[0762]

[0763] N-[3-[2-chloro-3-[[3-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]-1,7-naphthyridin-8-yl]amino]phenyl]-2-methyl-phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (200 mg, 321.48 μmol, 1 eq), N-(2-aminoethyl)acetamide (328.35 mg, 3.21 mmol, 308.02 μL, 10 eq) in MeOH (10 mL) solution of AcOH (38.61 mg, 642.97 μmol, 36.81 μL, 2 eq), NaBHCN. (101.01 mg, 1.61 mmol, 5 eq) was added at 60 °C. The mixture was stirred for 12 hours. After concentration under reduced pressure, the mixture was purified by reversed-phase HPLC ((0.1% HCl condition) column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water(HCl)-ACN]; gradient: 6%-36% B over 8 min) to obtain compound 39 (47 mg, 20.5% yield) as a brown solid.

[0764] LCMS m / z 708.4 [M+1] + .

[0765] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.84 (s, 3 H) 2.03 (s, 3 H) 2.20 - 2.27 (m, 1 H) 2.30 - 2.38 (m, 1 H) 3.08 (br d, J=5.88 Hz, 3 H) 3.16 (s, 2 H) 3.40 - 3.49 (m, 1 H) 3.40 - 3.50 (m, 3 H) 3.55 - 3.63 (m, 1 H) 4.17 - 4.23 (m, 5 H) 4.40 - 4.49 (m, 3 H) 4.69 (br dd, J=13.38, 5.38 Hz, 3 H) 7.11 (d, J=7.25 Hz, 1 H) 7.15 (s, 1 H) 7.16 - 7.24 (m, 1 H) 7.32 (t, J=7.82 Hz, 1 H) 7.34 - 7.39 (m, 1 H) 7.54 - 7.60 (m, 2 H) 7.97 - 8.07 (m, 1 H) 8.33 (br t, J=5.13 Hz, 1 H) 8.65 - 8.75 (m, 1 H) 9.25 - 9.36 (m, 1 H) 9.72 (s, 2 H)

[0766]

[0767] 13-4. N-(2'-chloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2-methyl-[1,1'-biphenyl]-3-yl)-4-((((S)-5-oxopyrrolidin-2-yl)methyl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, 화합물 40의 제조

[0768]

[0769]

[0770] N-[3-[2-chloro-3-[[3-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]-1,7-naphthyridin-8-yl]amino]phenyl]-2-methyl-phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (100 mg, 160.74 μmol, 1 eq), AcOH (19.31 mg, 321.48 μmol, 18.40 μL, 2 eq), DIEA (207.75) in MeOH (10 mL) solution of (5S)-5-(aminomethyl)pyrrolidin-2-one (183.48 mg, 1.61 mmol, 10 eq, HCl) mg, 1.61 mmol, 279.98 μL, 10 eq), After adding NaBH3CN (50.51 mg, 803.71 μmol, 5 eq), the mixture was stirred at 60 °C for 12 hours. The mixture was concentrated under reduced pressure, and the residue was purified by reversed-phase HPLC ((0.1% NH3ㆍH2O condition) column: Waters Xbridge Prep OBD C18 150*40 mm*10 um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 30%-60% B over 15 min) to obtain compound 40 (18 mg, 15.27% yield) as a white solid.

[0771] LCMS m / z 720.4 [M+1] + .

[0772] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.52 - 1.62 (m, 1 H) 1.63 - 1.77 (m, 2 H) 1.87 - 1.96 (m, 1 H) 1.98 - 2.06 (m, 5 H) 2.06 - 2.11 (m, 2 H) 2.35 - 2.41 (m, 1 H) 2.58 - 2.70 (m, 3 H) 2.71 - 2.77 (m, 1 H) 3.53 - 3.63 (m, 1 H) 3.80 - 3.88 (m, 2 H) 4.07 - 4.12 (m, 7 H) 4.18 - 4.26 (m, 1 H) 4.70 - 4.75 (m, 1 H) 6.74 - 6.80 (m, 1 H) 6.93 - 6.98 (m, 1 H) 7.03 - 7.08 (m, 1 H) 7.27 - 7.35 (m, 2 H) 7.45 - 7.52 (m, 1 H) 7.60 - 7.73 (m, 2 H) 8.16 - 8.21 (m, 1 H) 8.23 - 8.27 (m, 1 H) 8.90 - 8.94 (m, 1 H) 9.07 - 9.13 (m, 1 H) 9.50 - 9.56 (m, 1 H) 9.88 - 9.95 (m, 1 H)

[0773]

[0774] 13-5. 2-((2-((2'-chloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl)amino)acetic acid, 화합물 41의 제조

[0775]

[0776]

[0777] To a solution of N-[3-[2-chloro-3-[[3-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]-1,7-naphthyridin-8-yl]amino]phenyl]-2-methyl-phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (150 mg, 241.11 μmol, 1 eq) and 2-aminoacetic acid (180.99 mg, 2.41 mmol, 10 eq) in MeOH (10 mL), AcOH (28.96 mg, 482.23 μmol, 27.61 μL, 2 eq) and NaBH3CN (75.76 mg, 1.21 mmol, 5 eq) were added, and the mixture was stirred at 60 °C for 12 h. After concentrating the mixture under reduced pressure, the residue was purified by reversed-phase HPLC ((0.1% NH3ㆍH2O condition) column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 12%-42% B over 15 min) to obtain compound 41 (14 mg, 8.21% yield) as a white solid.

[0778] LCMS m / z 681.3 [M+1] + .

[0779] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54 - 1.62 (m, 1 H) 1.71 - 1.80 (m, 1 H) 1.83 - 1.97 (m, 2 H) 1.99 - 2.02 (m, 4 H) 2.04 (br d, J=6.97 Hz, 2 H) 2.11 - 2.27 (m, 2 H) 2.30 - 2.36 (m, 1 H) 2.38 - 2.44 (m, 1 H) 2.65 - 2.72 (m, 1 H) 2.73 - 2.80 (m, 1 H) 3.79 - 3.91 (m, 3 H) 4.03 - 4.10 (m, 2 H) 4.12 - 4.17 (m, 2 H) 4.19 - 4.26 (m, 1 H) 6.76 - 6.79 (m, 1 H) 6.94 - 6.98 (m, 1 H) 7.04 - 7.08 (m, 1 H) 7.27 - 7.35 (m, 2 H) 7.46 - 7.52 (m, 1 H) 7.58 - 7.64 (m, 1 H) 8.16 - 8.21 (m, 1 H) 8.24 - 8.28 (m, 1 H) 8.90 - 8.94 (m, 1 H) 9.07 - 9.12 (m, 1 H) 9.56 (br d, J=2.45 Hz, 1 H) 9.89 - 9.92 (m, 1 H).

[0780]

[0781] 13-6. (3R)-1-(2-((2'-chloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl)pyrrolidine-3-carboxylic acid, 화합물 42의 제조

[0782]

[0783]

[0784] To a solution of N-[3-[2-chloro-3-[[3-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]-1,7-naphthyridin-8-yl]amino]phenyl]-2-methyl-phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (400 mg, 642.97 μmol, 1 eq) and (3R)-pyrrolidine-3-carboxylic acid (740.25 mg, 6.43 mmol, 10 eq) in MeOH (10 mL), AcOH (77.22 mg, 1.29 mmol, 73.62 μL, 2 eq) and NaBH3CN (202.03 mg, 3.21 mmol, 5 eq) were added, and the mixture was stirred at 60 °C for 12 h. After concentrating the mixture under reduced pressure, the residue was purified by reversed-phase HPLC ((0.1% HCl condition) column: Welch Xtimate C18 150 * 25mm * 5 um; mobile phase: [water (HCl)-ACN]; gradient: 5%-35% B over 8 min) to obtain compound 42 (14 mg, 2.88% yield) as a brown solid.

[0785] LCMS m / z 721.5 [M+1] + .

[0786] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.95 - 2.12 (m, 7 H) 2.17 - 2.37 (m, 4 H) 3.08 (br d, J=11.76 Hz, 1 H) 3.16 (s, 1 H) 3.26 - 3.37 (m, 2 H) 3.50 (br d, J=12.76 Hz, 1 H) 3.54 - 3.62 (m, 3 H) 4.19 (dt, J=12.94, 6.28 Hz, 3 H) 4.27 (br s, 1 H) 4.42 (br s, 1 H) 4.48 (br s, 1 H) 4.65 - 4.74 (m, 2 H) 4.86 (br s, 1 H) 7.11 (d, J=7.38 Hz, 1 H) 7.18 - 7.24 (m, 2 H) 7.32 (t, J=7.75 Hz, 1 H) 7.37 (t, J=6.72 Hz, 1 H) 7.53 - 7.60 (m, 2 H) 8.03 (br d, J=6.75 Hz, 1 H) 8.47 (br s, 1 H) 8.64 - 8.76 (m, 1 H) 9.23 - 9.37 (m, 1 H) 9.75 (br s, 1 H) 11.97 (br s, 1 H).

[0787]

[0788] 13-7. N-(2'-chloro-3'-(5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)picolinamido)-2-methyl-[1,1'-biphenyl]-3-yl)-4-(4-hydroxypiperidin-1-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, 화합물 43의 제조

[0789]

[0790]

[0791] A dioxane (5 mL) / H2O (0.5 mL) mixture of N-(3-bromo-2-methyl-phenyl)-4-(4-hydroxy-1-piperidyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide (150 mg, 346.15 μmol, 1 eq), 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (131.64 mg, 519.22 μmol, 1.5 eq), Pd(dppf)Cl2 (25.33 mg, 34.61 μmol, 0.1 eq), and K2CO3 (143.52 mg, 1.04 mmol, 3 eq) was stirred at 90 °C under nitrogen for 12 h. After concentrating the mixture under reduced pressure, the residue was purified by column chromatography (SiO2, DCM: MeOH= 10 / 1) to obtain compound 43-2 (160 mg, 94.3% yield) as a black solid.

[0792]

[0793]

[0794] To a solution of N-[3-(3-amino-2-chloro-phenyl)-2-methyl-phenyl]-4-(4-hydroxy-1-piperidyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide (160 mg, 333.33 μmol, 1 eq) in t-BuOH (10 mL) was added (3R)-1-[(8-chloro-1,7-naphthyridin-3-yl)methyl]pyrrolidin-3-ol (263.72 mg, 1000.00 μmol, 3 eq) and 4 M HCl (in the dioxane (0.1 mL)), and the mixture was stirred in a microwave reactor at 120 °C for 8 h. After concentrating the mixture under reduced pressure, the residue was purified by reversed-phase HPLC (column: Waters X bridge 150 * 25 mm * 5 um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 44%-74% B over 9 min) to obtain compound 43 (56 mg, 23.7% yield) as a yellow solid.

[0795] LCMS m / z 707.4 [M+1] + .

[0796] 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.55 - 1.66 (m, 2 H) 1.75 - 1.85 (m, 2 H) 1.86 - 1.93 (m, 2 H) 2.13 (s, 4 H) 2.17 - 2.22 (m, 1 H) 2.39 - 2.47 (m, 1 H) 2.56 - 2.64 (m, 3 H) 2.85 (br dd, J=9.69, 6.07 Hz, 4 H) 3.60 - 3.67 (m, 1 H) 3.86 - 3.98 (m, 2 H) 4.05 (dd, J=10.57, 5.44 Hz, 1 H) 4.09 - 4.15 (m, 1 H) 4.24 - 4.32 (m, 1 H) 4.36 - 4.42 (m, 1 H) 4.54 - 4.62 (m, 1 H) 4.83 (s, 1 H) 4.88 - 4.91 (m, 3 H) 6.85 (s, 1 H) 6.99 (d, J=7.41 Hz, 1 H) 7.12 (d, J=8.63 Hz, 1 H) 7.22 (d, J=5.88 Hz, 1 H) 7.32 - 7.37 (m, 1 H) 7.43 - 7.48 (m, 1 H) 7.73 (d, J=8.13 Hz, 1 H) 8.16 (d, J=5.88 Hz, 1 H) 8.19 (s, 1 H) 8.92 (d, J=1.88 Hz, 1 H) 9.05 (dd, J=8.25, 1.50 Hz, 1 H).

[0797]

[0798] 13-8. 1-(2-((2'-chloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2-methyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl)piperidine-4-carboxylic acid, 화합물 44의 제조

[0799]

[0800]

[0801] methyl 1-[2-[(3-bromo-2-methyl-phenyl)carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]piperidine-4-carboxylate (150 mg, 315.54 μmol, 1 eq), 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (120.00 mg, 473.31 μmol, 1.5 eq), Pd(dppf)Cl2 (23.09 mg, 31.55 μmol, 0.1 eq), K2CO3 (130.83 mg, 946.62 μmol, 3 eq) of dioxane (5 mL) / H2O (0.5 mL) mixture under nitrogen conditions at 90 °C. The mixture was stirred for 12 hours. After concentration under reduced pressure, the mixture was purified by column chromatography (SiO2, DCM: MeOH = 10 / 1) to obtain compound 44-1 (160 mg, 95.1% yield) as a black solid.

[0802] LCMS m / z 522.2 [M+1] + .

[0803]

[0804]

[0805] To a solution of methyl 1-[2-[[3-(3-amino-2-chloro-phenyl)-2-methyl-phenyl]carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]piperidine-4-carboxylate (160 mg, 306.49 μmol, 1 eq) in t-BuOH (10 mL) was added (3R)-1-[(8-chloro-1,7-naphthyridin-3-yl)methyl]pyrrolidin-3-ol (242.49 mg, 919.47 μmol, 3 eq) and 4 M HCl (in the dioxane (0.1 mL)), and the mixture was stirred in a microwave reactor at 120 °C for 8 h. After concentrating the mixture under reduced pressure, the residue was purified by reversed-phase HPLC (column: Phenomenex Luna C18 150 * 25 mm * 10 um; mobile phase: [water (TFA)-ACN]; gradient: 12% - 42% B over 9 min) to obtain compound 44-2 (220 mg, 95.8% yield) as a pale brown solid.

[0806] LCMS m / z 749.3 [M+1] + .

[0807]

[0808]

[0809] A solution of methyl 1-[2-[[3-[2-chloro-3-[[3-[[(3S)-3-hydroxypyrrolidin-1-yl]methyl]-1,7-naphthyridin-8-yl]amino]phenyl]-2-methyl-phenyl]carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]piperidine-4-carboxylate (220 mg, 293.61 μmol, 1 eq) and LiOH (61.60 mg, 1.47 mmol, 5 eq) in H2O (4 mL) / MeOH (20 mL) was stirred at room temperature for 12 h. After concentrating the mixture under reduced pressure, the residue was purified by reversed-phase HPLC (column: Waters X bridge 150 * 25 mm * 5 um; mobile phase: [water (NH4HCO3) - ACN]; gradient: 22% - 52% B over 9 min) to obtain compound 44 (45 mg, 20.8% yield) as a yellow solid.

[0810] LCMS m / z 735.4 [M+1] + .

[0811] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.67 (br d, J=12.23 Hz, 5 H) 1.81 (br t, J=11.92 Hz, 2 H) 1.86 - 1.92 (m, 1 H) 1.93 - 2.04 (m, 5 H) 2.12 - 2.20 (m, 2 H) 2.26 (br s, 1 H) 2.38 (dd, J=9.66, 3.55 Hz, 1 H) 2.42 - 2.48 (m, 1 H) 2.62 - 2.70 (m, 2 H) 2.71 - 2.79 (m, 2 H) 3.82 (br d, J=9.78 Hz, 2 H) 3.95 (br dd, J=9.72, 5.20 Hz, 1 H) 3.99 - 4.08 (m, 1 H) 4.15 - 4.26 (m, 2 H) 6.64 (s, 1 H) 6.95 (d, J=7.19 Hz, 1 H) 7.06 (d, J=7.46 Hz, 1 H) 7.27 - 7.35 (m, 2 H) 7.49 (t, J=7.89 Hz, 1 H) 7.62 (t, J=6.27 Hz, 1 H) 8.18 (d, J=5.75 Hz, 1 H) 8.24 (s, 1 H) 8.91 (d, J=1.59 Hz, 1 H) 9.09 (d, J=7.91 Hz, 1 H) 9.53 (d, J=3.30 Hz, 1 H) 9.90 (s, 1 H).

[0812]

[0813] [제조예 14]

[0814] 화합물 45 내지 51의 제조

[0815]

[0816] 14-1. 4-(2-(2-((3'-(4-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamido)-2,2'-dimethyl-[1,1'-biphenyl]- 3-yl)carbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic Preparation of acid, compound 45

[0817]

[0818] To a solution of 5-tert-butoxycarbonyl-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridine-2-carboxylic acid (5.08 g, 18.06 mmol, 1 eq) in DMF (50 mL) were added 3-bromo-2-methyl-aniline (3.36 g, 18.06 mmol, 2.23 mL, 1 eq), HATU (10.30 g, 27.09 mmol, 1.5 eq), and DIPEA (4.67 g, 36.12 mmol, 6.29 mL, 2 eq), and the reaction mixture was stirred at room temperature for 12 h. H2O (200 mL) was added to the reaction mixture, and the precipitated solid was filtered to obtain compound 45-3 (3 g, 5.88 mmol, 32.5% yield) as a pale yellow solid.

[0819] LCMS m / z 449.0 [M+1] + .

[0820] 1H NMR (400 MHz, chloroform-d) δ = 9.30 - 9.03 (m, 1H), 7.86 - 7.78 (m, 1H), 7.37 - 7.28 (m, 1H), 7.07 - 6.98 (m, 1H), 4.53 - 4.31 (m, 2H), 3.96 - 3.80 (m, 3H), 3.78 - 3.61 (m, 2H), 2.66 - 2.56 (m, 2H), 2.42 - 2.35 (m, 3H), 1.60 - 1.48 (m, 4H), 1.58 - 1.45 (m, 4H), 1.46 - 1.37 (m, 9H).

[0821]

[0822]

[0823] A 4 M HCl / EtOAc (15 mL) solution of tert-butyl 2-[(3-bromo-2-methyl-phenyl)carbamoyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridine-5-carboxylate (3 g, 6.68 mmol, 1 eq) was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure to obtain compound 45-4 (2.5 g) as a white solid, which was used in the next reaction without further purification.

[0824]

[0825]

[0826] To a solution of N-(3-bromo-2-methyl-phenyl)-1-methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-2-carboxamide (2.5 g, 6.48 mmol, 1 eq, HCl) in MeOH (100 mL) was slowly added dropwise DIEA (1.68 g, 12.96 mmol, 2.26 mL, 2 eq) at room temperature until the pH of the reaction mixture became 8–9. Methyl 4-(2-oxoethyl)norbornane-1-carboxylate (1.40 g, 7.13 mmol, 1.10 eq) was slowly added dropwise at room temperature, and the reaction mixture was stirred at room temperature for 2 h. NaBH3CN (2.04 g, 32.41 mmol, 5 eq) was added to the reaction mixture, and the mixture was stirred at room temperature for 18 h. 1M aq. HCl (300 mL) was added and extracted with ethyl acetate (50 mL * 3). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent: Ethyl acetate / Petroleum ether / TEA = 1:1:0.01 @ 80 mL / min) to obtain compound 45-6 (2.2 g, 4.07 mmol, 62.8% yield) as a white solid.

[0827] LCMS m / z 529.2 [M+1] + .

[0828]

[0829]

[0830] N-[2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (492.70 mg, 1.25 mmol, 1.1 eq), methyl 4-[2-[2-[(3-bromo-2-methyl-phenyl)carbamoyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]norbornane-1-carboxylate (600 mg, 1.13 mmol, 1 eq), Pd(dppf)Cl2 (82.92 mg, 113.32 umol, 0.1 eq), K2CO3 (469.85 mg, 3.40 A mixture of 1,4-dioxane (20 mL) / H2O (5 mL) (3 mmol, 3 eq) was stirred at 100 °C for 24 h under nitrogen conditions. The reaction mixture was filtered and concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 1 to 0 / 1) to obtain compound 45-8 (560 mg, 429.06 μmol, 37.9% yield) as a yellow solid.

[0831] LCMS m / z 718.3 [M+1] + .

[0832]

[0833]

[0834] A mixture of methyl 4-[2-[1-methyl-2-[[2-methyl-3-[2-methyl-3-[(4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carbonyl)amino]phenyl]phenyl]carbamoyl]-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]norbornane-1-carboxylate (98.35 mg, 137.01 umol, 1 eq) and NaBH4 (25.9 mg, 685.05 umol, 5 eq) in MeOH (6 mL) was stirred at room temperature for 6 h. After concentrating the reactant under reduced pressure, the residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (NH4HCO3)-ACN]; B%: 20%-50%, 8 min) to obtain compound 45-9 (76 mg, 77.1% yield) as a white solid.

[0835] LCMS m / z 720.4 [M+1] + .

[0836]

[0837]

[0838] A solution of methyl 4-[2-[1-methyl-2-[[2-methyl-3-[2-methyl-3-[(4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carbonyl)amino]phenyl]phenyl]carbamoyl]-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]norbornane-1-carboxylate (98.35 mg, 137.01 umol, 1 eq) and LiOHㆍH2O (17.25 mg, 411.03 umol, 3 eq) in MeOH (6 mL) / H2O (2 mL) / THF (2 mL) was stirred at room temperature for 6 h. After concentrating the reactant under reduced pressure, the residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (NH4HCO3)-ACN]; B%: 20%-50%, 8 min) to obtain compound 45 (48 mg, 48.6% yield) as a white solid.

[0839] LCMS m / z 706.4 [M+1] + .

[0840] 1H NMR ( 400 MHz, DMSO-d6) δ = 9.72 (s, 1H), 9.52 (s, 1H), 7.72 - 7.65 (m, 1H), 7.61 - 7.56 (m, 1H), 7.28 (t, J = 7.7 Hz, 2H), 6.96 (t, J = 6.6 Hz, 2H), 6.69 (s, 1H), 5.56 (s, 1H), 4.76 (s, 1H), 4.18 - 4.10 (m, 2H), 3.87 (s, 3H), 3.52 - 3.38 (m, 3H), 2.75 (d, J = 5.0 Hz, 2H), 2.70 - 2.63 (m, 3H), 2.40 - 2.27 (m, 1H), 2.18 (d, J = 7.8 Hz, 1H), 2.04 - 1.99 (m, 1H), 1.97 - 1.95 (m, 3H), 1.94 - 1.92 (m, 3H), 1.90 - 1.83 (m, 2H), 1.80 - 1.67 (m, 3H), 1.57 - 1.47 (m, 4H), 1.45 (s, 2H), 1.39 (d, J = 11.1 Hz, 2H).

[0841]

[0842] 14-2. 4-(2-(2-((3'-(4-((2-acetamidoethyl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid, 화합물 46의 제조

[0843]

[0844]

[0845] N-(2-aminoethyl)acetamide (142.28 mg, 1.39 mmol, 132.97 uL, 10 eq), methyl 4-[2-[1-methyl-2-[[2-methyl-3-[2-methyl-3-[(4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carbonyl)a mino]phenyl]phenyl]carbamoyl]-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]norbornane-1-carboxylate 100 mg, 139.30 umol, 1 eq), HOAc (83.65 mg, 1.39 mmol, 80 uL, 10 eq), NaBHCN (43.77 mg, 696.52 umol, 5 eq) in MeOH (6 mL) / DMF (2 mL) / THF (2 mL) and stirred at 60°C for 6 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um; mobile phase: [water (FA)-ACN]; B%: 11%-41%, 10 min) to obtain compound 45-11 (90 mg, 4 80.4% yield) as a white solid.

[0846] LCMS m / z 804.5 [M+1] + .

[0847]

[0848]

[0849] methyl 4-[2-[2-[[3-[3-[[4-(2-acetamidoethylamino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carbonyl]amino]-2-methyl-ph enyl]-2-methyl-phenyl]carbamoyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]norbornane-1-carboxylate A MeOH (6 mL) / THF (2 mL) / H2O (2 mL) mixture of (90 mg, 111.94 umol, 1 eq) and LiOHㆍH2O (14 mg, 335.82 umol, 3 eq) was stirred at 60 °C for 6 hours. After concentrating the reactant under reduced pressure, the residue was purified by prep-HPLC (column: Waters Xbridge C18 150*50mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 18%-48%, 10 min) to obtain compound 46 (42 mg, 47.1% yield) as a white solid.

[0850] LCMS m / z 790.5 [M+1] + .

[0851] 1H NMR (400 MHz, DMSO-d6) δ = 9.72 (s, 1H), 9.50 (s, 1H), 7.84 (br s, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.27 (t, J = 7.8 Hz, 2H), 6.96 (dd, J = 4.3, 6.8 Hz, 2H), 6.73 (s, 1H), 4.14 (s, 2H), 3.87 (s, 4H), 3.44 - 3.40 (m, 3H), 3.15 - 3.10 (m, 2H), 2.75 (d, J = 5.0 Hz, 2H), 2.67 - 2.60 (m, 3H), 2.57 - 2.55 (m, 1H), 2.33 (s, 2H), 2.18 (d, J = 6.7 Hz, 1H), 2.01 (s, 1H), 1.95 (s, 3H), 1.93 (s, 3H), 1.89 - 1.82 (m, 2H), 1.81 (s, 3H), 1.76 - 1.70 (m, 2H), 1.69 - 1.63 (m, 1H), 1.53 (s, 4H), 1.44 (s, 2H), 1.39 (d, J = 11.4 Hz, 2H).

[0852]

[0853] 14-3. 4-(2-(2-((3'-(4-((R)-3-hydroxypyrrolidin-1-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid, 화합물 47의 제조

[0854]

[0855]

[0856] (3R)-pyrrolidin-3-ol (119.36 mg, 1.37 mmol, 113.68 uL, 10 eq), methyl 4-[2-[1-methyl-2-[[2-methyl-3-[2-methyl-3-[(4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carbonyl)a mino]phenyl]phenyl]carbamoyl]-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]norbornane-1-carboxylate (98.35 mg, 137.01 umol, 1 eq), NaBHCN (43.05 mg, 685.06 umol, 5 eq), HOAc (82.3 mg, 1.37 mmol, 78.35 uL, 10 A mixture of MeOH (6 mL) / DMF (2 mL) / THF (2 mL) was stirred at 60 °C for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reversed-phase HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; B%: 10%-40%, 10 min) to obtain compound 45-13 (85 mg, 78.6% yield) as a white solid.

[0857] LCMS m / z 789.5 [M+1] + .

[0858]

[0859]

[0860] 4-[2-[2-[[3-[3-[[4-[(3R)-3-hydroxypyrrolidin-1-yl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carbonyl]amino]-2-methyl-phenyl]-2-methyl-phenyl]carbamoyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]norbornane-1-carboxylate (85 mg, 107.73 umol, 1 eq) and LiOHㆍH2O (13.56 mg, 323.19 mmol, 3 eq) were added to a solution of MeOH (6 mL) / THF (2 mL) / H2O (2 mL) and stirred at 60 °C for 6 h. After concentrating the reactant under reduced pressure, the residue was purified by reversed-phase HPLC (column: Waters Xbridge C18 150*50mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 18%-48%, 10 min) to obtain compound 47 (45 mg, 53.9% yield) as a white solid.

[0861] LCMS m / z 775.8 [M+1] + .

[0862] 1H NMR (400 MHz, DMSO-d6) δ = 9.72 (s, 1H), 9.52 (d, J = 3.5 Hz, 1H), 7.68 (d, J = 8.7 Hz, 1H), 7.58 (s, 1H), 7.28 (t, J = 7.9 Hz, 2H), 6.98 - 6.94 (m, 2H), 6.68 (d, J = 7.6 Hz, 1H), 4.78 - 4.62 (m, 1H), 4.17 (m, 3H), 3.87 (s, 3H), 3.80 (m, J = 5.1 Hz, 1H), 3.44 - 3.40 (m, 2H), 2.81 - 2.71 (m, 3H), 2.71 - 2.62 (m, 4H), 2.60 - 2.53 (m, 4H), 2.33 (s, 1H), 2.28 - 2.18 (m, 1H), 1.95 (s, 3H), 1.94 (s, 3H), 1.91 - 1.83 (m, 5H), 1.78 - 1.68 (m, 2H), 1.52 (m, 5H), 1.44 (s, 2H), 1.41 - 1.34 (m, 2H).

[0863]

[0864] 14-4. 4-(2-(2-((3'-(4-((2-hydroxyethyl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid, 화합물 48의 제조

[0865]

[0866]

[0867] 2-aminoethanol (83.69 mg, 1.37 mmol, 82.86 uL, 10 eq), methyl 4-[2-[1-methyl-2-[[2-methyl-3-[2-methyl-3-[(4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carbonyl)a mino]phenyl]phenyl]carbamoyl]-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]norbornane-1-carboxylate (98.35 mg, 137.01 umol, 1 eq), NaBHCN (43.05 mg, 685.06 umol, 5 eq), HOAc (16.46 mg, 274.02 umol, 15.67 uL, 2 eq) in MeOH (6 mL) / DMF (2 mL) / THF (2 mL) solution and stirred at 60 °C for 6 h. The reaction mixture was concentrated under reduced pressure and purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um; mobile phase: [water (FA)-ACN]; B%: 10%-40%, 10 min) to obtain compound 45-15 (85 mg, 81.3% yield) as a white solid.

[0868] LCMS m / z763.5 [M+1] + .

[0869]

[0870]

[0871] Methyl 4-[2-[2-[[3-[3-[[4-(2-hydroxyethylamino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carbonyl]amino]-2-methyl-phenyl]-2-methyl-phenyl]carbamoyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]norbornane-1-carboxylate (70 mg, 91.75 umol, 1 eq) and LiOHㆍH2O (11.55 mg, 275.25 umol, 3 eq) were added to a solution of MeOH (15 mL) / THF (3 mL) / H2O (3 mL) and stirred at 60°C for 6 h. After concentrating the reactant under reduced pressure, the residue was purified by reversed-phase HPLC (column: Waters Xbridge C18 150*50mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 18%-48%, 10 min) to obtain compound 48 (40 mg, 57.6% yield) as a white solid.

[0872] LCMS m / z 749.6 [M+1] + .

[0873] 1H NMR (400 MHz, DMSO-d6) δ = 9.72 (s, 1H), 9.52 (s, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.28 (t, J = 7.8 Hz, 2H), 6.99 - 6.93 (m, 2H), 6.74 (s, 1H), 4.70 - 4.41 (m, 1H), 4.14 (m, 2H), 3.94 (m, 1H), 3.87 (s, 3H), 3.50 (m, 2H), 3.45 - 3.40 (m, 3H), 2.78 - 2.63 (m, 6H), 2.58 - 2.54 (m, 1H), 2.33 (m, 2H), 2.20 (m, 1H), 2.03 (m, 1H), 1.95 (s, 3H), 1.93 (s, 3H), 1.91 - 1.81 (m, 3H), 1.80 - 1.67 (m, 3H), 1.57 - 1.48 (m, 4H), 1.45 (s, 2H), 1.39 (m, 2H)

[0874]

[0875] 14-5. 4-(2-(2-((2,2'-dimethyl-3'-(4-((((S)-5-oxopyrrolidin-2-yl)methyl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid, 화합물 49의 제조

[0876]

[0877]

[0878] methyl 4-[2-[1-methyl-2-[[2-methyl-3-[2-methyl-3-[(4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carbonyl)a mino]phenyl]phenyl]carbamoyl]-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]norbornane-1-carboxylate (70 mg, 236.82 umol, 1 eq), DIEA (153.03 mg, 1.18 mmol, 206.24 uL) in MeOH (10 mL) / THF (2 mL) mixture of 5-(aminomethyl)pyrrolidin-2-one (135.16 mg, 897.42 umol, 3.79 eq, HCl) Add 5 eq) and leave at room temperature for 15 minutes. The mixture was stirred. NaBH3CN (74.41 mg, 1.18 mmol, 5 eq) and HOAc (142.2 mg, 2.37 mmol, 135.4 uL, 10 eq) were added to the reaction mixture and stirred at 60 °C for 12 h. The mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; B%: 8%-38%, 10 min) to obtain compound 45-17 (100 mg, 51.8% yield) as a white solid.

[0879] LCMS m / z 816.9 [M+1] + .

[0880]

[0881]

[0882] Methyl 4-[2-[1-methyl-2-[[2-methyl-3-[2-methyl-3-[[4-[(5-oxopyrrolidin-2-yl)methylamino]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carbonyl]amino]phenyl]phenyl]carbamoyl]-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]norbornane-1-carboxylate (100 mg, 122.55 umol, 1 eq) and LiOH (8.79 mg, 367.65 umol, 3 eq) were added to a solution of MeOH (10 mL) / H2O (5 mL) and stirred at room temperature for 12 h. After concentrating the reactant under reduced pressure, the residue was purified by prep-HPLC (column: Waters Xbridge C18 150*50mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 15%-45%, 10 min) to obtain compound 49 (60 mg, 60.4% yield) as a white solid.

[0883] LCMS m / z 802.6 [M+1] + .

[0884] 1H NMR (400 MHz, DMSO-d6) δ = 9.72 (s, 1H), 9.51 (s, 1H), 7.68 (d, J = 7.1 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.28 (t, J = 7.8 Hz, 2H), 6.96 (dd, J = 5.0, 6.6 Hz, 2H), 6.77 (d, J = 9.5 Hz, 1H), 4.26 - 4.01 (m, 3H), 3.90 (d, J = 7.6 Hz, 1H), 3.87 (s, 4H), 3.63 - 3.55 (m, 3H), 2.75 (d, J = 5.1 Hz, 2H), 2.68 - 2.58 (m, 4H), 2.22 - 1.98 (m, 5H), 1.95 (s, 3H), 1.93 (s, 3H), 1.91 - 1.80 (m, 3H), 1.79 - 1.64 (m, 4H), 1.58 - 1.48 (m, 4H), 1.47 - 1.32 (m, 4H).

[0885]

[0886] 14-6. 4-(2-(2-((3'-(4-((carboxymethyl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid, 화합물 50의 제조

[0887]

[0888]

[0889] 2-aminoacetic acid 18 (177.77 mg, 2.37 mmol, 10 eq), methyl 4-[2-[1-methyl-2-[[2-methyl-3-[2-methyl-3-[(4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carbonyl)a mino]phenyl]phenyl]carbamoyl]-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]norbornane-1-carboxylate (170 mg, 236.82 umol, 1 eq), NaBH3CN (74.41 mg, 1.18 mmol, 5 eq), and HOAc (142 mg, 2.37 mmol, 135 uL, 10 eq) were added to MeOH (10 mL) / THF (2 mL) solution. The mixture was stirred at 60 °C for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; B%: 10%-40%, 10 min) to obtain compound 45-19 (100 mg, 54.4% yield) as a white solid.

[0890] LCMS m / z 777.6 [M+1] + .

[0891]

[0892]

[0893] 2-[[2-[[3-[3-[[5-[2-(4-methoxycarbonylnorbornan-1-yl)ethyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridine-2-carbonyl]amino]-2-methyl-phenyl]-2-methyl-phenyl]carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]amino]acetic acid (100 mg, 128.71 umol, 1 eq) and LiOHㆍH2O (16.20 mg, 386.14 umol, 3 eq) were added to a solution of MeOH (20 mL) / H2O (5 mL) and stirred at 60 °C for 12 h. After concentrating the reactant under reduced pressure, the residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; B%: 10%-40%, 10 min) to obtain compound 50 (45 mg, 44.5% yield) as a yellow solid.

[0894] LCMS m / z 763.5 [M+1] + .

[0895] 1H NMR (400 MHz, DMSO-d6) δ = 9.72 (s, 1H), 9.54 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.64 - 7.51 (m, 1H), 7.27 (t, J = 7.8 Hz, 2H), 6.96 (dd, J = 4.0, 6.9 Hz, 2H), 6.73 (s, 1H), 4.14 (m, 4H), 4.06 - 3.92 (m, 3H), 3.91 - 3.82 (m, 4H), 3.25 - 3.10 (m, 4H), 2.75 (m, 2H), 2.69 - 2.62 (m, 2H), 2.62 - 2.55 (m, 1H), 2.21 (m, 1H), 2.03 - 1.83 (m, 10H), 1.79 - 1.66 (m, 3H), 1.56 - 1.47 (m, 4H), 1.44 (s, 2H), 1.38 (m, 2H)

[0896]

[0897] 14-7. 4-(2-(2-((3'-(4-((2-carboxypropan-2-yl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid, 화합물 51의 제조

[0898]

[0899]

[0900] methyl 4-[2-[2-[(3-bromo-2-methyl-phenyl)carbamoyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]norbornane-1-carboxylate (200 mg, 377.74 μmol, 1 eq), methyl 2-methyl-2-[[2-[[2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]amino]propanoate (206.26 mg, 415.51 μmol, 1.1 eq), CsF (172.14 mg, 1.13 mmol, 41.83 μL, 3 A mixture of dioxane (8 mL) / H2O (2 mL) of dichloropalladium iron (24.62 mg, 37.77 μmol, 0.1 eq) and ditert-butyl(cyclopentyl)phosphane was stirred under nitrogen at 90 °C for 2 h. The mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC (column: Phenomenex luna C18 150 * 40 mm * 15 μm; mobile phase: [water (TFA)-ACN]; gradient: 20%-50% B over 15 min) to obtain compound 51-2 (172 mg, 52.8% yield) as a white solid.

[0901] LCMS m / z 819.6 [M+1] + .

[0902]

[0903]

[0904] To a solution of methyl 4-[2-[2-[[3-[3-[[4-[(2-methoxy-1,1-dimethyl-2-oxo-ethyl)amino]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carbonyl]amino]-2-methyl-phenyl]-2-methyl-phenyl]carbamoyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]norbornane-1-carboxylate (120 mg, 146.52 μmol, 1 eq) in H2O (3 mL) / MeOH (10 mL) was added LiOH (10.54 mg, 439.56 μmol, 3 eq), and the mixture was stirred at room temperature for 12 h. After concentrating the mixture under reduced pressure, the residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 12%-42% B over 9 min) to obtain compound 51 (82 mg, 67.2% yield) as a white solid.

[0905] LCMS m / z 791.7 [M+1] + .

[0906] 1H NMR (400 MHz, DMSO-d6 ) δ = 9.70 (s, 1H), 9.51 (s, 1H), 7.72 (br d, J = 2.8 Hz, 1H), 7.56 (d, J = 7.5 Hz, 1H), 7.27 (t, J = 7.7 Hz, 2H), 6.95 (dd, J = 4.6, 6.8 Hz, 2H), 6.73 (s, 1H), 4.44 - 4.32 (m, 1H), 4.16 - 4.04 (m, 3H), 3.98 - 3.92 (m, 1H), 3.86 (s, 3H), 3.17 (s, 3H), 2.74 (br d, J = 5.5 Hz, 2H), 2.69 - 2.62 (m, 3H), 2.21 - 2.10 (m, 1H), 2.07 - 1.97 (m, 2H), 1.94 (s, 3H), 1.92 (s, 3H), 1.88 - 1.80 (m, 2H), 1.77 - 1.69 (m, 2H), 1.67 - 1.59 (m, 1H), 1.58 - 1.48 (m, 4H), 1.44 (s, 2H), 1.41 - 1.34 (m, 2H), 1.29 (d, J = 3.4 Hz, 5H).

[0907]

[0908] [제조예 15]

[0909] 화합물 52 내지 60의 제조

[0910]

[0911] 15-1. 4-(2-(2-((3'-(4-((2-acetamidoethyl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamido)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid, 화합물 52의 제조

[0912] To a DCM (100 mL) solution of 5-tert-butoxycarbonyl-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridine-2-carboxylic acid (3.79 g, 13.47 mmol, 1 eq) and 3-bromo-2-chloro-aniline (5.56 g, 26.93 mmol, 2 eq) were added POCl3 (4.81 g, 40.40 mmol, 2.93 mL, 3 eq) and pyridine (5.33 g, 67.33 mmol, 5.43 mL, 5 eq), and the mixture was stirred at room temperature for 36 h. After concentrating the mixture under reduced pressure, the residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / 1 to 2 / 1) to obtain compound 52-3 (2.28 g, 31.5% yield) as a red solid, which was used in the next reaction without further purification.

[0913] LCMS m / z 471.1 [M+3] + .

[0914]

[0915]

[0916] To a MeOH (80 mL) mixture of N-(3-bromo-2-chloro-phenyl)-1-methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-2-carboxamide (1.03 g, 2.54 mmol, 1 eq, HCl), methyl 4-(2-oxoethyl)norbornane-1-carboxylate (597.27 mg, 3.04 mmol, 1.2 eq) were added NaBH3CN (796.90 mg, 12.68 mmol, 5 eq) and DIEA (393.35 mg, 3.04 mmol, 530.12 μL, 1.2 eq), and the mixture was stirred at 60 °C for 12 h. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 65%-95% B over 15 min) to obtain compound 52-6 (831 mg, 57.8% yield) as a white solid.

[0917] LCMS m / z 551.4 [M+3] + .

[0918]

[0919] To a MeOH (80 mL) mixture of N-(3-bromo-2-chloro-phenyl)-1-methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-2-carboxamide (1.03 g, 2.54 mmol, 1 eq, HCl), methyl 4-(2-oxoethyl)norbornane-1-carboxylate (597.27 mg, 3.04 mmol, 1.2 eq) were added NaBH3CN (796.90 mg, 12.68 mmol, 5 eq) and DIEA (393.35 mg, 3.04 mmol, 530.12 μL, 1.2 eq), and the mixture was stirred at 60 °C for 12 h. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 65%-95% B over 15 min) to obtain compound 52-6 (831 mg, 57.8% yield) as a white solid.

[0920] LCMS m / z 551.4 [M+3] + .

[0921]

[0922]

[0923] methyl 4-[2-[2-[(3-bromo-2-chloro-phenyl)carbamoyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]norbornane-1-carboxylate (300 mg, 545.57 μmol, 1 eq), N-[2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (340.17 mg, 818.35 μmol, 1.5 eq), K2CO3 (226.21 mg, 1.64 mmol, 3 eq), ditert-butyl(cyclopentyl)phosphane;dichloropalladium;iron (53.34 mg, 81.84 μmol, 0.15 eq) of dioxane (80 mL) / H2O (16 mL) mixture was stirred at 90 °C under nitrogen for 12 h. The mixture was concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0–20% Ethyl acetate / Petroleum ether gradient @ 50 mL / min) to obtain compound 52-8 (218 mg, 45.6% yield) as a red solid.

[0924] LCMS m / z 760.4 [M+3] + .

[0925]

[0926]

[0927] methyl 4-[2-[2-[[2-chloro-3-[2-chloro-3-[(4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carbonyl)amino]phen yl]phenyl]carbamoyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]norbornane-1-carboxylate (60 mg, 79.08 μmol, 1 eq), N-(2-aminoethyl)acetamide (80.77 mg, 790.84 μmol, 75.77 μL, 10 eq) in MeOH (10 mL) / DMF (2 mL) solution of NaBH3CN (24.85 mg, 395.42 μmol, 5 eq), AcOH (47.49 mg, 790.84 After adding 45.27 μmol, 10 eq) of the compound, the mixture was stirred at 60 °C for 12 hours. The mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 50%-80% B over 9 min) to obtain compound 52-9 (50 mg, 74.8% yield) as a white solid.

[0928] LCMS m / z 844.5 [M+1] + .

[0929]

[0930]

[0931] To a solution of methyl 4-[2-[2-[[3-[3-[[4-(2-acetamidoethylamino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carbonyl]amino]-2-chloro-phenyl]-2-chloro-phenyl]carbamoyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]norbornane-1-carboxylate (50 mg, 59.18 μmol, 1 eq) in H2O (3 mL) / MeOH (2 mL) / THF (1 mL) was added LiOHㆍH2O (7.45 mg, 177.55 μmol, 3 eq), and the mixture was stirred at room temperature for 12 h. After concentrating the mixture under reduced pressure, the residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 20%-50% B over 9 min) to obtain compound 52 (37 mg, 74.5% yield) as a white solid.

[0932] LCMS m / z 830.5 [M+1] + .

[0933] 1H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 9.53 (s, 1H), 8.37 (dd, J = 1.4, 8.2 Hz, 1H), 8.29 (d, J = 7.8 Hz, 1H), 7.82 (t, J = 5.9 Hz, 1H), 7.48 (t, J = 7.8 Hz, 2H), 7.15 (t, J = 8.1 Hz, 2H), 6.79 (s, 1H), 4.19 - 4.09 (m, 2H), 3.90 (s, 3H), 3.88 - 3.86 (m, 1H), 3.42 - 3.39 (m, 2H), 3.16 - 3.10 (m, 2H), 2.74 (br d, J = 5.4 Hz, 2H), 2.69 - 2.60 (m, 4H), 2.55 - 2.52 (m, 2H), 2.17 (br s, 1H), 2.01 (br d, J = 8.6 Hz, 1H), 1.94 - 1.82 (m, 3H), 1.80 (s, 3H), 1.76 - 1.65 (m, 3H), 1.51 (br s, 4H), 1.42 (s, 2H), 1.37 (br d, J = 11.4 Hz, 2H).

[0934]

[0935] 15-2. 4-(2-(2-((2,2'-dichloro-3'-(4-((2-hydroxyethyl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid, 화합물 53의 제조

[0936]

[0937]

[0938] methyl 4-[2-[2-[[2-chloro-3-[2-chloro-3-[(4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carbonyl)amino]phen yl]phenyl]carbamoyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]norbornane-1-carboxylate (60 mg, 79.08 μmol, 1 eq), NaBH3CN (24.85 mg, 395.42 μmol, 5 eq), AcOH (47.49 mg, 790.84 μmol, After adding 45.27 μL, 10 eq) to the solution, the mixture was stirred at 60 °C for 12 hours. The mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 52%-82% B over 9 min) to obtain compound 52-10 (50 mg, 78.6% yield) as a white solid.

[0939] LCMS m / z 804.6 [M+1] + .

[0940]

[0941]

[0942]

[0943] To a solution of methyl 4-[2-[2-[[2-chloro-3-[2-chloro-3-[[4-(2-hydroxyethylamino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carbonyl]amino]phenyl]phenyl]carbamoyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]norbornane-1-carboxylate (50 mg, 62.21 μmol, 1 eq) in H2O (3 mL) / THF (1 mL) / MeOH (1 mL) was added LiOHㆍH2O (7.83 mg, 186.62 μmol, 3 eq), and the mixture was stirred at room temperature for 3 hours. After concentrating the mixture under reduced pressure, the residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 20%-50% B over 50 min) to obtain compound 53 (38 mg, 47.15 μmol, 75.8% yield) as a white solid.

[0944] LCMS m / z 789.4 [M+1] + .

[0945] 1H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 9.53 (s, 1H), 8.37 (d, J = 8.3 Hz, 1H), 8.29 (d, J = 7.9 Hz, 1H), 7.48 (t, J = 7.9 Hz, 2H), 7.15 (t, J = 8.1 Hz, 2H), 6.78 (s, 1H), 4.63 - 4.41 (m, 1H), 4.19 - 4.10 (m, 2H), 3.90 (s, 4H), 3.47 (br t, J = 5.8 Hz, 2H), 3.42 - 3.39 (m, 2H), 2.74 (br d, J = 5.3 Hz, 2H), 2.67 (br d, J = 3.8 Hz, 4H), 2.57 - 2.52 (m, 2H), 2.33 (br s, 1H), 2.18 (br d, J = 8.0 Hz, 1H), 2.06 - 1.97 (m, 1H), 1.96 - 1.80 (m, 4H), 1.76 - 1.66 (m, 3H), 1.51 (br s, 4H), 1.43 (s, 2H), 1.37 (br d, J = 11.1 Hz, 2H).

[0946]

[0947] 15-3. 4-(2-(2-((2,2'-dichloro-3'-(4-((((S)-5-oxopyrrolidin-2-yl)methyl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid, 화합물 54의 제조

[0948]

[0949]

[0950] methyl 4-[2-[2-[[2-chloro-3-[2-chloro-3-[(4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carbonyl)amino]phen yl]phenyl]carbamoyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]norbornane-1-carboxylate (60 mg, 79.08 μmol, 1 eq), (5S)-5-(aminomethyl)pyrrolidin-2-one (119.10 mg, 790.84 μmol, 10 eq, HCl) in MeOH (10 mL) / DMF (2 mL) solution of DIEA (112.43 mg, 869.92 μmol, 151.52 μmol) μL, 11 eq), NaBHCN (24.85 mg, 395.42 μmol, 5 eq), AcOH (47.49 mg, 790.84 μmol, 45.27 μL, 10 eq) were added and stirred at 60 °C for 12 hours. The mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 52%-82% B over 9 min) to obtain compound 52-11 (50 mg, 73.7% yield) as a white solid.

[0951] LCMS m / z 856.5 [M+1] + .

[0952]

[0953]

[0954] To a solution of methyl 4-[2-[2-[[2-chloro-3-[2-chloro-3-[[4-[[(2S)-5-oxopyrrolidin-2-yl]methylamino]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carbonyl]amino]phenyl]phenyl]carbamoyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]norbornane-1-carboxylate (50 mg, 58.35 μmol, 1 eq) in H2O (3 mL) / THF (1 mL) / MeOH (2 mL) was added LiOHㆍH2O (7.35 mg, 175.06 μmol, 3 eq), and the mixture was stirred at room temperature for 3 hours. After concentrating the mixture under reduced pressure, the residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 22%-52% B over 9 min) to obtain compound 54 (30 mg, 60.3% yield) as a white solid.

[0955] LCMS m / z 844.4 [M+3] + .

[0956] 1H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 9.53 (s, 1H), 8.37 (d, J = 8.4 Hz, 1H), 8.29 (d, J = 8.3 Hz, 1H), 7.69 (d, J = 19.0 Hz, 1H), 7.48 (t, J = 7.7 Hz, 2H), 7.15 (t, J = 8.4 Hz, 2H), 6.83 (d, J = 11.9 Hz, 1H), 4.15 (br d, J = 5.4 Hz, 2H), 3.90 (s, 4H), 3.58 (br s, 1H), 3.42 - 3.40 (m, 2H), 2.74 (br d, J = 4.8 Hz, 2H), 2.68 - 2.57 (m, 5H), 2.24 - 1.96 (m, 6H), 1.94 - 1.81 (m, 3H), 1.77 - 1.61 (m, 5H), 1.51 (br s, 4H), 1.44 - 1.34 (m, 4H).

[0957]

[0958] 15-5. 4-(2-(2-((3'-(4-((carboxymethyl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamido)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid, 화합물 56의 제조

[0959]

[0960]

[0961] methyl 4-[2-[2-[[2-chloro-3-[2-chloro-3-[(4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carbonyl)amino]phen yl]phenyl]carbamoyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]norbornane-1-carboxylate NaBH3CN (40.59 mg, 645.85 μmol, 5 eq), AcOH (77.57 mg, 1.29 mmol, Add 73.94 μL, 10 eq) After stirring, the mixture was stirred at 60 °C for 12 hours. The mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 30%-60% B over 9 min) to obtain compound 52-12 (70 mg, 66.2% yield) as a white solid.

[0962] LCMS m / z 817.2 [M+1] + .

[0963]

[0964]

[0965] To a solution of 2-[[2-[[2-chloro-3-[2-chloro-3-[[5-[2-(4-methoxycarbonylnorbornan-1-yl)ethyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridine-2-carbonyl]amino]phenyl]phenyl]carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]amino]acetic acid (70 mg, 85.60 μmol, 1 eq) in H2O (3 mL) / THF (2 mL) / MeOH (1 mL) was added LiOHㆍH2O (10.78 mg, 256.80 μmol, 3 eq), and the mixture was stirred at room temperature for 3 hours. After concentrating the mixture under reduced pressure, the residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 12%-42% B over 9 min) to obtain compound 56 (61 mg, 86.9% yield) as a white solid.

[0966] LCMS m / z 803.5 [M+1] + .

[0967] 1H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 9.56 (s, 1H), 8.39 - 8.34 (m, 1H), 8.26 (d, J = 8.3 Hz, 1H), 7.48 (t, J = 7.9 Hz, 2H), 7.15 (t, J = 9.2 Hz, 2H), 6.82 (s, 1H), 4.15 (br t, J = 6.1 Hz, 2H), 4.05 (br t, J = 5.9 Hz, 1H), 3.89 (s, 3H), 2.74 (br d, J = 4.8 Hz, 3H), 2.70 - 2.64 (m, 4H), 2.35 - 2.30 (m, 1H), 2.19 (br s, 1H), 2.08 - 2.06 (m, 1H), 2.04 - 1.97 (m, 1H), 1.88 - 1.81 (m, 2H), 1.79 - 1.67 (m, 4H), 1.59 - 1.47 (m, 5H), 1.43 (s, 2H), 1.37 (br d, J = 12.3 Hz, 2H), 1.23 (br s, 2H).

[0968]

[0969] 15-6. (3R)-1-(2-((3'-(5-(2-(4-carboxybicyclo[2.2.1]heptan-1-yl)ethyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl)pyrrolidine-3-carboxylic acid, 화합물 57의 제조

[0970]

[0971]

[0972] methyl 4-[2-[2-[[2-chloro-3-[2-chloro-3-[(4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carbonyl)amino]phenyl ]phenyl]carbamoyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]norbornane-1-carboxylate(70 mg, 92.26 μmol, 1 eq), NaBH3CN (28.99 mg, 461.32 μmol, 5 eq), AcOH (55.40 mg, 922.64 μmol, After adding 52.82 μL, 10 eq) to the solution, the mixture was stirred at 60 °C for 12 hours. The mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 32%-62% B over 9 min) to obtain compound 52-13 (45 mg, 48.9% yield) as a white solid.

[0973] LCMS m / z 857.2 [M+1] + .

[0974]

[0975]

[0976] (3R)-1-[2-[[2-chloro-3-[2-chloro-3-[[5-[2-(4-methoxycarbonylnorbornan-1-yl)ethyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridine-2-carbonyl]amino]phenyl]phenyl]carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]pyrrolidine-3-carboxylic acid (45 mg, 52.46 μmol, 1 eq) in H2O (3 mL) / THF (2 mL) / MeOH (1 mL) was added LiOHㆍH2O (6.60 mg, 157.38 μmol, 3 eq) and stirred at room temperature for 3 hours. After concentrating the mixture under reduced pressure, the residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 12%-42% B over 9 min) to obtain compound 57 (28 mg, 62.6% yield) as a white solid.

[0977] LCMS m / z 844.8 [M+3] + .

[0978] 1H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 9.55 (s, 1H), 8.37 (dd, J = 1.5, 8.3 Hz, 1H), 8.26 (dd, J = 4.5, 8.1 Hz, 1H), 7.48 (t, J = 7.9 Hz, 2H), 7.15 (dd, J = 7.9, 9.3 Hz, 2H), 6.71 (d, J = 4.9 Hz, 1H), 4.25 - 4.04 (m, 3H), 3.89 (s, 3H), 3.81 (br s, 1H), 2.93 - 2.86 (m, 2H), 2.78 - 2.71 (m, 4H), 2.70 - 2.64 (m, 4H), 2.63 - 2.58 (m, 2H), 2.37 - 2.29 (m, 1H), 2.24 (br s, 1H), 1.98 - 1.81 (m, 8H), 1.75 - 1.67 (m, 2H), 1.55 - 1.48 (m, 4H), 1.43 (s, 2H), 1.37 (br d, J = 10.8 Hz, 2H).

[0979]

[0980] 15-7. 4-(2-(2-((2,2'-dichloro-3'-(4-(4-hydroxypiperidin-1-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid, 화합물 58의 제조

[0981]

[0982]

[0983] To a solution of N-(3-bromo-2-chloro-phenyl)-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (2.5 g, 6.78 mmol, 1 eq) in MeOH (25 mL) was added NaBH4 (852.41 mg, 13.56 mmol, 2 eq) at 0 °C, and the mixture was stirred at room temperature for 5 h. Aq. sat'd NH4Cl (120 mL) solution was added to the mixture, and then extracted with EtOAc (120 mL*2). The organic layer was washed with brine (200 mL), dried over Na2SO4, and concentrated under reduced pressure to obtain compound 58-2 (2.62 g, 93.8% yield) as a white solid, which was used in the next reaction without further purification.

[0984] LCMS m / z 372.0 [M+3] + .

[0985]

[0986]

[0987] To a solution of N-(3-bromo-2-chloro-phenyl)-4-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide (2.2 g, 5.94 mmol, 1 eq) in DCM (60 mL) was added SOCl2 (10.59 g, 89.04 mmol, 6.47 mL, 15 eq) at 0 °C, and the mixture was stirred at room temperature for 2 h. After adding H2O (300 mL) solution to the mixture, it was extracted with EtOAc (150 mL*2). The organic layer was washed with brine (300 mL), dried over Na2SO4, concentrated under reduced pressure, and purified by flash silica gel chromatography (Petroleum ether / Ethyl acetate=100 / 1 to 3 / 1) to obtain compound 58-3 (1.42 g, 56.5% yield) as a white solid.

[0988] LCMS m / z 389.8 [M+1] + .

[0989]

[0990]

[0991] To a mixture of N-(3-bromo-2-chloro-phenyl)-4-chloro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide (1.5 g, 3.86 mmol, 1 eq) and piperidin-4-ol (5 mL) were added DIEA (1.49 g, 11.57 mmol, 2.01 mL, 3 eq) and NaI (173.36 mg, 1.16 mmol, 0.3 eq), and the mixture was stirred at 90 °C for 12 h. After cooling the mixture to room temperature, H2O (100 mL) was added, and extracted with ethyl acetate (50 mL * 3). The organic layer was washed with brine (200 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Kromasil Eternity XT 250*80mm*10μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 35%-65% B over 50 min) to obtain compound 58-4 (1.32 g, 71.6% yield) as a white solid.

[0992] LCMS m / z 455.0 [M+3] + .

[0993] 1H NMR (400 MHz, DMSO-d6) δ = 9.64 (br s, 1H), 8.09 (dd, J = 1.4, 8.1 Hz, 1H), 7.58 (dd, J = 1.4, 8.1 Hz, 1H), 7.33 (t, J = 8.1 Hz, 1H), 6.63 (s, 1H), 4.55 (br s, 1H), 4.25 - 4.16 (m, 1H), 4.06 (dt, J = 4.5, 11.9 Hz, 1H), 3.96 (dd, J = 5.3, 10.0 Hz, 1H), 3.52 - 3.39 (m, 1H), 2.77 - 2.69 (m, 1H), 2.68 - 2.61 (m, 1H), 2.45 - 2.34 (m, 1H), 2.26 (br t, J = 9.3 Hz, 1H), 2.20 - 2.10 (m, 1H), 2.01 - 1.84 (m, 2H), 1.76 - 1.62 (m, 3H), 1.49 - 1.31 (m, 2H).

[0994]

[0995]

[0996] N-(3-bromo-2-chloro-phenyl)-4-(4-hydroxy-1-piperidyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide (250 mg, 550.95 μmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (419.72 mg, 1.65 mmol, 3 eq), KOAc (162.21 mg, 1.65 mmol, 3 eq), Dioxane (10 mL) mixture of Pd(dppf)Cl2ㆍCH2Cl2 (44.99 mg, 55.10 μmol, 0.1 eq) was reacted under nitrogen conditions at 90 °C. The mixture was stirred for 2 hours. After filtering the mixture, the filtrate was concentrated under reduced pressure, and the residue was purified by prep-TLC (Dichloromethane: Methanol=10 / 1) to obtain compound 58-5 (236 mg, 59.8% yield) as a white solid.

[0997] LCMS m / z 501.2 [M+1] + .

[0998]

[0999]

[1000] methyl 4-[2-[2-[(3-bromo-2-chloro-phenyl)carbamoyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]norbornane-1-carboxylate (130 mg, 236.41 μmol, 1 eq), N-[2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(4-hydroxy-1-piperidyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide (142.08 mg, 283.69 μmol, 1.2 eq), CsF (107.73 mg, 709.24 μmol, 26.18 μL, 3 eq), A mixture of ditert-butyl(cyclopentyl)phosphane;dichloropalladium iron (15.41 mg, 23.64 μmol, 0.1 eq) and dioxane (8 mL) / H2O (2 mL) was stirred at 90 °C under nitrogen for 2 h. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by prep-HPLC (column: Phenomenex luna C18 150*40mm* 15μm; mobile phase: [water (FA)-ACN]; gradient: 12%-42% B over 15 min) to obtain compound 58-6 (82 mg, 39.0% yield) as a white solid.

[1001] LCMS m / z 843.2 [M+1] + .

[1002]

[1003]

[1004] To a solution of methyl 4-[2-[2-[[2-chloro-3-[2-chloro-3-[[4-(4-hydroxy-1-piperidyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carbonyl]amino]phenyl]phenyl]carbamoyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]norbornane-1-carboxylate (80 mg, 94.80 μmol, 1 eq) in H2O (3 mL) / MeOH (10 mL) was added LiOH (6.80 mg, 284.41 μmol, 3 eq) at 0 °C, and the mixture was stirred at room temperature for 12 h. After concentrating the mixture under reduced pressure, the residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 18%-48% B over 15 min) to obtain compound 58 (42 mg, 50.7% yield) as a white solid.

[1005] LCMS m / z 829.5 [M+1] + .

[1006] 1H NMR (400 MHz, DMSO-d6 ) δ = 9.88 (s, 1H), 9.53 (s, 1H), 8.46 - 8.32 (m, 1H), 8.26 (dd, J = 3.9, 6.8 Hz, 1H), 7.48 (t, J = 7.9 Hz, 2H), 7.14 (t, J = 8.4 Hz, 2H), 6.65 (s, 1H), 4.56 (d, J = 4.0 Hz, 2H), 4.19 (br s, 2H), 4.15 - 4.06 (m, 3H), 3.94 (br d, J = 4.5 Hz, 2H), 3.89 (s, 3H), 3.16 (d, J = 5.3 Hz, 4H), 2.74 (br d, J = 4.4 Hz, 3H), 2.65 (br s, 3H), 2.43 - 2.36 (m, 2H), 2.12 (br s, 2H), 1.96 (br d, J = 14.8 Hz, 2H), 1.85 (br s, 2H), 1.73 - 1.69 (m, 3H), 1.51 (s, 3H), 1.43 (s, 3H), 1.37 (br d, J = 10.8 Hz, 2H).

[1007]

[1008] 15-8. 1-(2-((3'-(5-(2-(4-carboxybicyclo[2.2.1]heptan-1-yl)ethyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl)piperidine-4-carboxylic acid, 화합물 59의 제조

[1009]

[1010]

[1011] To a mixture of N-(3-bromo-2-chloro-phenyl)-4-chloro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide (600 mg, 1.54 mmol, 1 eq) in methyl piperidine-4-carboxylate (662.42 mg, 4.63 mmol, 3 eq) were added DIEA (597.91 mg, 4.63 mmol, 805.81 μL, 3 eq) and NaI (69.34 mg, 462.64 μmol, 0.3 eq) at room temperature, and the mixture was stirred at 50 °C for 12 h. After cooling the mixture to room temperature, H2O (40 mL) was added, and the mixture was extracted with ethyl acetate (40 mL * 3). The organic layer was washed with brine (60 mL), dried over Na2SO4, concentrated under reduced pressure, and the residue was extracted with prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 52%-82% B over 15 min) to obtain compound 59-2 (560 mg, 69.5% yield) as a white solid.

[1012] LCMS m / z 497.1[M+3] + .

[1013]

[1014]

[1015] methyl 4-[2-[(3-bromo-2-chloro-phenyl)carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]cyclohexanecarboxylate (70 mg, 141.47 μmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (53.89 mg, 212.20 μmol, 1.5 eq), KOAc (41.65 mg, 424.41 μmol, 3 eq), dioxane (5 mL) mixture was stirred at 90 °C under nitrogen conditions for 2 hours. After filtering the mixture, the filtrate was concentrated under reduced pressure, and the residue was purified by prep-TLC (Dichloromethane: Methanol=10 / 1) to obtain compound 59-3 (86 mg, 89.7% yield) as a white solid.

[1016] LCMS m / z 543.2 [M+1] + .

[1017]

[1018]

[1019] methyl 4-[2-[2-[(3-bromo-2-chloro-phenyl)carbamoyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]norbornane-1-carboxylate (100 mg, 181.86 μmol, 1 eq), methyl 1-[2-[[2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]piperidine-4-carboxylate (118.47 mg, 218.23 μmol, 1.2 eq), CsF (82.87 mg, 545.57 μmol, 20.14 μL, 3 A mixture of dioxane (8 mL) / H2O (2 mL) of dichloropalladium iron (11.85 mg, 18.19 μmol, 0.1 eq), ditert-butyl(cyclopentyl)phosphane, and dichloropalladium iron (11.85 mg, 18.19 μmol, 0.1 eq) was stirred at 90 °C under nitrogen for 2 h. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by prep-HPLC (column: C18 150Υ30 mm; mobile phase: [water (FA)-ACN]; gradient: 20%-50% B over 7 min) to obtain compound 59-4 (82 mg, 48.3% yield) as a white solid.

[1020] LCMS m / z 887.4[M+1] + .

[1021]

[1022]

[1023] To a solution of methyl 1-[2-[[2-chloro-3-[2-chloro-3-[[5-[2-(4-methoxycarbonylnorbornan-1-yl)ethyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridine-2-carbonyl]amino]phenyl]phenyl]carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]piperidine-4-carboxylate (60 mg, 67.73 μmol, 1 eq) in H2O (3 mL) / MeOH (10 mL) was added LiOH (4.45 mg, 203.19 μmol, 3 eq) at 0 °C, and the mixture was stirred at room temperature for 12 h. After concentrating the mixture under reduced pressure, the residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 15%-45% B over 9 min) to obtain 59 (32 mg, 52.3% yield) as a white solid.

[1024] LCMS m / z 857.4 [M+1] + .

[1025] 1H NMR (400 MHz, DMSO-d6 ) δ = 9.90 (s, 1H), 9.54 (s, 1H), 8.37 (dd, J = 1.2, 8.3 Hz, 1H), 8.30 - 8.24 (m, 1H), 7.49 (t, J = 7.3 Hz, 2H), 7.15 (t, J = 8.4 Hz, 2H), 6.67 (s, 1H), 4.20 (br d, J = 13.0 Hz, 1H), 4.11 - 3.93 (m, 2H), 3.90 (s, 3H), 3.42 - 3.39 (m, 3H), 2.81 - 2.71 (m, 3H), 2.67 (br d, J = 3.9 Hz, 3H), 2.58 - 2.52 (m, 3H), 2.45 - 2.38 (m, 1H), 2.36 - 2.10 (m, 4H), 2.00 - 1.93 (m, 1H), 1.84 (br d, J = 13.1 Hz, 4H), 1.75 - 1.59 (m, 4H), 1.55 - 1.48 (m, 4H), 1.43 (s, 2H), 1.38 (br d, J = 10.4 Hz, 2H).

[1026]

[1027] 15-9. 4-(2-(2-((3'-(4-((2-carboxypropan-2-yl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamido)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid, 화합물 60의 제조

[1028]

[1029]

[1030] DIEA (99.65 mg, 771.06 μmol, 134.30 μL, 3 eq) and NaI (11.56 mg, 77.11 μmol, 0.3 eq) were added to a mixture of N-(3-bromo-2-chloro-phenyl)-4-chloro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide (100 mg, 257.02 μmol, 1 eq) and methyl 2-amino-2-methyl-propanoate (90.33 mg, 771.06 μmol, 3 eq) at room temperature, and the mixture was stirred at 90 °C for 12 h. After cooling the mixture to room temperature, H2O (20 mL) was added, and extracted with ethyl acetate (20 mL * 3). The organic layer was washed with brine (40 mL), dried over Na2SO4, concentrated under reduced pressure, and the residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 52%-82% B over 15 min) to obtain compound 60-2 (83 mg, 61.8% yield) as a white solid.

[1031] 1 H NMR (400 MHz, DMSO-d6) δ = 9.64 (s, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.62 - 7.57 (m, 1H), 7.34 (t, J = 8.0 Hz, 1H), 6.72 - 6.69 (m, 1H), 4.18 - 4.06 (m, 2H), 3.93 - 3.86 (m, 1H), 3.65 (s, 2H), 3.69 - 3.61 (m, 1H), 2.19 - 2.07 (m, 1H), 1.95 (br d, J = 5.4 Hz, 1H), 1.63 - 1.54 (m, 1H), 1.32 (d, J = 4.3 Hz, 6H).

[1032]

[1033]

[1034] methyl 2-[[2-[(3-bromo-2-chloro-phenyl)carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]amino]-2-methyl-propanoate (80 mg, 170.30 μmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (129.74 mg, 510.90 μmol, 3 eq), KOAc (50.14 mg, 510.90 μmol, 3 eq), cyclopentyl(diphenyl)phosphane;dichloromethane;

[1035] A mixture of dichloropalladium iron (13.91 mg, 17.03 μmol, 0.1 eq) and dioxane (8 mL) was stirred at 90 °C under nitrogen for 2 h. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by prep-TLC (Dichloromethane: Methanol=10 / 1) to obtain compound 60-3 (112 mg, 99.2% yield) as a white solid.

[1036] LCMS m / z 517.2 [M+1] + .

[1037]

[1038]

[1039] methyl 4-[2-[2-[(3-bromo-2-chloro-phenyl)carbamoyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]norbornane-1-carboxylate (80 mg, 145.48 μmol, 1 eq), methyl 2-[[2-[[2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]amino]-2-methyl-propanoate (90.23 mg, 174.58 μmol, 1.2 eq), CsF (66.30 mg, 436.45 μmol, 16.11 μL, 3 A mixture of dioxane (8 mL) / H2O (2 mL) of ditert-butyl(cyclopentyl)phosphane;dichloropalladium;iron (9.48 mg, 14.55 μmol, 0.1 eq) and dichloropalladium was stirred at 90 °C under nitrogen for 2 h. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by prep-HPLC (column: C18 150Υ30 mm; mobile phase: [water (FA)-ACN]; gradient: 25%-55% B over 7 min) to obtain compound 60-4 (32 mg, 24.3% yield) as a white solid.

[1040] LCMS m / z 861.2 [M+1] + .

[1041]

[1042]

[1043] To a solution of methyl 4-[2-[2-[[2-chloro-3-[2-chloro-3-[[4-[(2-methoxy-1,1-dimethyl-2-oxo-ethyl)amino]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carbonyl]amino]phenyl]phenyl]carbamoyl]-1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl]ethyl]norbornane-1-carboxylate (60 mg, 69.78 μmol, 1 eq) in H2O (3 mL) / MeOH (10 mL) was added LiOH (5.01 mg, 209.34 μmol, 3 eq) at 0 °C, and the mixture was stirred at room temperature for 12 h. After concentrating the mixture under reduced pressure, the residue was purified by prep-TLC (Dichloromethane: Methanol=10 / 1) to obtain compound 60 (12 mg, 19.6% yield) as a white solid.

[1044] LCMS m / z 831.3 [M+1] + .

[1045] 1H NMR (400 MHz, DMSO-d6 ) δ = 9.88 (s, 1H), 9.53 (s, 1H), 8.36 (d, J = 7.6 Hz, 1H), 8.27 (d, J = 8.3 Hz, 1H), 7.48 (t, J = 8.3 Hz, 2H), 7.14 (t, J = 8.2 Hz, 2H), 6.79 (s, 1H), 4.14 - 4.07 (m, 2H), 3.92 (br s, 1H), 3.89 (s, 3H), 2.74 (br d, J = 5.1 Hz, 3H), 2.68 - 2.64 (m, 3H), 2.35 - 2.30 (m, 1H), 2.12 (br s, 2H), 2.01 (br s, 2H), 1.88 - 1.77 (m, 3H), 1.76 - 1.66 (m, 3H), 1.65 - 1.58 (m, 1H), 1.56 - 1.45 (m, 5H), 1.42 (s, 2H), 1.39 - 1.34 (m, 2H), 1.28 (d, J = 4.4 Hz, 6H).

[1046]

[1047] [제조예 16]

[1048] 화합물 61 내지 66의 제조

[1049]

[1050] 16-1. (3R)-1-((7-cyano-2-(3'-(4-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid, 화합물 61의 제조

[1051]

[1052]

[1053] To a mixture of 2-(3-bromo-2-methyl-phenyl)-5-formyl-1,3-benzoxazole-7-carbonitrile (8 g, 23.45 mmol, 1 eq) in MeOH (100 mL) were added NaBH3CN (7.37 g, 117.25 mmol, 5 eq), methyl (3R)-pyrrolidine-3-carboxylate (4.54 g, 35.17 mmol, 1.5 eq), and DIPEA (6.06 g, 46.90 mmol, 8.17 mL, 2 eq), and the mixture was stirred at 70 °C for 3 h. The reaction mixture was concentrated under reduced pressure to remove MeOH, and then diluted with H2O (400 mL). After extraction with EA (150 mL X 3), the organic layer was dried over Na2SO4 and concentrated under reduced pressure. Compound 61-3 (8 g, 67.5% yield) was used in the next reaction without further purification.

[1054] LCMS m / z 456.2 [M+2] + .

[1055] 1 H NMR (400 MHz, DMSO-d6) δ = 8.12 - 8.00 (m, 2H), 7.89 - 7.78 (m, 2H), 7.37 (t, J = 7.9 Hz, 1H), 3.80 - 3.64 (m, 3H), 3.04 (br d, J = 9.4 Hz, 1H), 2.75 (s, 3H), 2.73 - 2.54 (m, 2H), 2.31 - 1.67 (m, 2H).

[1056]

[1057]

[1058] methyl (3R)-1-[[2-(3-bromo-2-methyl-phenyl)-7-cyano-1,3-benzoxazol-5-yl]methyl]pyrrolidine-3-carboxylate (520 mg, 1.14 mmol, 1 eq), N-[2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (450.60 mg, 1.14 mmol, 1 eq), K2CO3 (441.17 mg, 3.19 mmol, 2.8 eq), Pd(dppf)Cl2·CH2Cl2 (46.55 mg, 57.00 umol, 0.05 eq) A dioxane (5 mL) / H2O (0.6 mL) mixture was stirred at 90 °C under nitrogen for 2 h. The reaction mixture was diluted with H2O (40 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was washed with brine (60 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Petroleum ether / Ethyl acetate=100 / 1 to 3 / 1) to obtain compound 61-5 (502 mg, 61.6% yield) as a white solid.

[1059] 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.73 (s, 1H), 8.30 - 8.13 (m, 2H), 8.00 (d, J = 0.9 Hz, 1H), 7.69 (d, J = 1.3 Hz,1H), 7.49 (s, 1H), 7.48 - 7.42 (m, 1H), 7.39 - 7.32 (m, 2H), 7.02 (d, J = 6.6 Hz, 1H), 4.52 - 4.43 (m, 2H), 3.78 (s, 2H), 3.71 (s,3H), 3.13 - 3.03 (m, 1H), 2.91 (t, J = 8.8 Hz, 1H), 2.81 - 2.67 (m, 4H), 2.65 - 2.57 (m, 1H), 2.51 (s, 3H), 2.45 (q, J = 6.2 Hz,2H), 2.20 - 2.12 (m, 2H), 2.10 (s, 3H).

[1060]

[1061]

[1062] To a solution of methyl (3R)-1-[[7-cyano-2-[2-methyl-3-[2-methyl-3-[(4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carbonyl)amino]phenyl]phenyl]-1,3-benzoxazol-5-yl]methyl]pyrrolidine-3-carboxylate (450 mg, 700.17 μmol, 1 eq) in MeOH (6 mL) was added NaBH4 (88.00 mg, 1.40 mmol, 2 eq) at 0 °C, and the reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was diluted with H2O (40 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was washed with brine (60 mL), dried over Na2SO4, concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (Petroleum ether / Ethyl acetate=100 / 1 to 1 / 1) to obtain compound 61-11-1 (432 mg, 86.13% yield) as a white solid.

[1063] LCMS m / z 645.3 [M+1] + .

[1064] 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.72 (s, 1H), 8.30 - 8.12 (m, 2H), 8.00 (s, 1H), 7.69 (s, 1H), 7.52 - 7.40 (m, 1H), 7.38 - 7.29 (m, 2H), 6.99 (d, J = 7.5 Hz, 1H), 6.91 (s, 1H), 5.07 - 4.89 (m, 1H), 4.30 - 4.16 (m, 1H), 3.78 (s, 2H), 3.70 (s, 3H), 3.16 - 3.01 (m, 1H), 2.91 (br t, J = 8.5 Hz, 1H), 2.81 - 2.66 (m, 2H), 2.65 - 2.56 (m, 1H), 2.50 (s, 3H), 2.42 - 2.19 (m, 2H), 2.14(br d, J = 7.4 Hz, 2H), 2.08 (s, 3H), 2.03 - 1.91 (m, 2H), 0.00 (s, 2H).

[1065]

[1066]

[1067] To a THF (8 mL) / H2O (8 mL) mixture of methyl (3R)-1-[[7-cyano-2-[3-[3-[(4-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carbonyl)amino]-2-methyl-phenyl]-2-methyl-phenyl]-1,3-benzoxazol-5-yl]methyl]pyrrolidine-3-carboxylate (380 mg, 589.41 μmol, 13.81 μL, 1 eq) was added LiOHㆍH2O (74.19 mg, 1.77 mmol, 3 eq) at 0 °C, and the mixture was stirred at room temperature for 12 h. The pH of the reaction mixture was adjusted to 7 with aq. 1 N HCl solution, and the precipitated solid was filtered. The filtered solid was purified by prep-HPLC (column: Waters Xbridge C18 150*50mm* 10um; mobile phase: [water(NH4HCO3)-ACN]; B%: 18%) to obtain compound 61 (128 mg, yield 95%) as a white solid.

[1068] LCMS m / z 631.3 [M+1] + .

[1069] 1H NMR (400 MHz, DMSO-d6) δ = 9.58 (s, 1H), 8.21 - 8.06 (m, 2H), 7.89 (d, J = 1.1 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.56 (t, J = 7.7 Hz, 1H), 7.41 (d, J = 6.6 Hz, 1H), 7.32 (t, J = 7.8 Hz, 1H), 7.04 (d, J = 7.0 Hz, 1H), 6.70 (s, 1H), 5.68 - 5.45 (m, 1H), 4.77 (br t, J = 5.7 Hz, 1H), 4.18 - 4.10 (m, 2H), 3.76 (br d, J = 7.8 Hz, 2H), 3.04 - 2.89 (m, 2H), 2.81 - 2.63 (m, 3H), 2.61 - 2.56 (m, 2H), 2.43 (s, 3H), 2.25 - 2.12 (m, 1H), 2.10 - 1.97 (m, 3H), 1.95 (s, 3H), 1.80 - 1.66 (m, 1H).

[1070]

[1071] 16-2. (3R)-1-((2-(3'-(4-((2-acetamidoethyl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid, 화합물 62의 제조

[1072]

[1073]

[1074] To a MeOH (3 mL) mixture of methyl (3R)-1-[[7-cyano-2-[2-methyl-3-[2-methyl-3-[(4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carbonyl)amino]phenyl]phenyl]-1,3-benzoxazol-5-yl]methyl]pyrrolidine-3-carboxylate (200 mg, 311.19 μmol, 1 eq) and N-(2-aminoethyl)acetamide (317.83 mg, 3.11 mmol, 297.04 μL, 10 eq) was added DIPEA (40.22 mg, 311.19 μmol, 54.20 μL, 1 eq) at room temperature, and the reaction mixture was stirred at 60 °C for 2 h. NaBH3CN (39.11 mg, 622.37 μmol, 2 eq) was added and stirred at 60 °C for 2 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um; mobile phase: [water(FA)-ACN]; B%: 10%-40%, 10 min) to obtain compound 61-11-2 (126 mg, 52.7% yield) as a white solid.

[1075] 1H NMR (400 MHz, DMSO-d6) δ = 9.56 (d, J = 2.4 Hz, 1H), 8.31 - 8.05 (m, 3H), 7.95 - 7.75 (m, 2H), 7.65 - 7.49 (m, 2H), 7.41(d, J = 7.3 Hz, 1H), 7.32 (t, J = 7.8 Hz, 1H), 7.03 (d, J = 7.4 Hz, 1H), 6.74 (s, 1H), 4.26 - 4.06 (m, 2H), 3.95 - 3.82 (m, 2H),3.76 (s, 2H), 3.61 (s, 5H), 3.20 - 3.11 (m, 3H), 3.06 (br d, J = 1.0 Hz, 2H), 2.82 - 2.72 (m, 1H), 2.70 - 2.61 (m, 3H), 2.59 - 2.53(m, 3H), 2.43 (s, 3H), 2.19 (td, J = 5.8, 7.7 Hz, 1H), 2.09 - 1.96 (m, 3H), 1.95 (s, 3H), 1.81 (s, 3H), 1.74 - 1.62 (m, 1H).

[1076]

[1077]

[1078] To a THF (8 mL) / H2O (4 mL) solution of methyl (3R)-1-[[2-[3-[3-[[4-(2-acetamidoethylamino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carbonyl]amino]-2-methyl-phenyl]-2-methyl-phenyl]-7-cyano-1,3-benzoxazol-5-yl]methyl]pyrrolidine-3-carboxylate (100 mg, 137.20 μmol, 1 eq) was added LiOHㆍH2O (17.27 mg, 411.61 μmol, 3 eq) at 0 °C, and the mixture was stirred at room temperature for 12 h. The pH of the reaction mixture was adjusted to 7 with aq. 1 N HCl solution, and the precipitated solid was filtered. The filtered solid was purified by prep-HPLC (column: Waters Xbridge C18 150*50mm* 10μm; mobile phase: [water(NH4HCO3)-ACN]; B%: 16%-46%, 10 min) to obtain compound 62 (48 mg, 46.4% yield) as a white solid.

[1079] LCMS m / z 715.4 [M+1] + .

[1080] 1H NMR (400 MHz, DMSO-d6) δ = 9.55 (d, J = 2.6 Hz, 1H), 8.21 - 8.08 (m, 2H), 7.88 (s, 1H), 7.83 (t, J = 5.3 Hz, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.55 (t, J = 7.7 Hz, 1H), 7.40 (d, J = 6.8 Hz, 1H), 7.34 - 7.26 (m, 1H), 7.03 (d, J = 7.1 Hz, 1H), 6.73 (s,1H), 4.20 - 4.06 (m, 2H), 3.90 - 3.84 (m, 1H), 3.81 - 3.62 (m, 3H), 3.13 (q, J = 6.3 Hz, 2H), 3.00 - 2.90 (m, 1H), 2.78 - 2.70 (m,1H), 2.69 - 2.60 (m, 3H), 2.56 - 2.53 (m, 2H), 2.42 (s, 3H), 2.18 (s, 1H), 2.04 - 1.96 (m, 3H), 1.95 (s, 3H), 1.80 (s, 3H), 1.67 (dd, J = 2.4, 10.3 Hz, 1H).

[1081]

[1082] 16-3. (3R)-1-((7-cyano-2-(3'-(4-((R)-3-hydroxypyrrolidin-1-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid, 화합물 63의 제조

[1083]

[1084]

[1085] HOAc (1.05 g, 17.48 mmol, 1000 μL, 56.19 eq) was added to a solution of methyl (3R)-1-[[7-cyano-2-[2-methyl-3-[2-methyl-3-[(4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carbonyl)amino]phenyl]phenyl]-1,3-benzoxazol-5-yl]methyl]pyrrolidine-3-carboxylate (200 mg, 311.19 μmol, 1 eq), (3R)-pyrrolidin-3-ol (271.11 mg, 3.11 mmol, 258.20 μL, 10 eq) in MeOH (30 mL) / THF (6 mL) / DMF (2 mL) at room temperature, and the reaction mixture was stirred at 60 °C for 2 h. It was stirred. After adding NaBH3CN (97.78 mg, 1.56 mmol, 5 eq), the reaction mixture was stirred at 60 °C for 2 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um; mobile phase: [water(FA)-ACN]; B%: 8%-50%, 14 min) to obtain compound 61-11-3 (120 mg, 51.3% yield) as a white solid.

[1086] 1H NMR (400 MHz, DMSO-d6) δ = 9.67 (s, 1H), 8.20 - 8.11 (m, 3H), 7.98 - 7.87 (m, 1H), 7.59 - 7.53 (m, 2H), 7.41 (d, J =7.5 Hz, 1H), 7.32 (t, J = 7.8 Hz, 1H), 7.05 (d, J = 7.0 Hz, 1H), 6.52 (s, 1H), 4.44 - 4.13 (m, 4H), 4.00 - 3.73 (m, 2H), 3.62 (s, 4H), 3.20 - 3.04 (m, 3H), 2.67 (d, J = 2.0 Hz, 2H), 2.43 (s, 4H), 2.33 (s, 1H), 2.27 - 2.22 (m, 1H), 2.13 - 1.98 (m, 5H), 1.95 (s, 5H), 1.84 - 1.62 (m, 1H).

[1087]

[1088]

[1089] To a THF (3 mL) / H2O (3 mL) solution of methyl (3R)-1-[[7-cyano-2-[3-[3-[[4-[(3R)-3-hydroxypyrrolidin-1-yl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carbonyl]amino]-2-methyl-phenyl]-2-methyl-phenyl]-1,3-benzoxazol-5-yl]methyl]pyrrolidine-3-carboxylate (120 mg, 168.11 μmol, 1 eq) was added LiOHㆍH2O (21.16 mg, 504.33 μmol, 3 eq) at 0 °C, and the reaction mixture was reacted at room temperature for 12 h. The pH of the reaction mixture was adjusted to 7 with Aq. 1 N HCl solution, and the precipitated solid was filtered. The filtered solid was purified by prep-HPLC (column: Waters Xbridge C18 150*50mm* 10μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 20%-50%, 10 min) to obtain compound 63 (80 mg, 64.6 yield) as a white solid.

[1090] LCMS m / z 730.3 [M+1] + .

[1091] 1H NMR (400 MHz, DMSO-d6) δ = 9.57 (d, J = 3.8 Hz, 1H), 8.19 - 8.08 (m, 2H), 7.88 (d, J = 1.0 Hz, 1H), 7.55 (s, 2H), 7.40 (d, J = 6.9 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.03 (d, J = 7.4 Hz, 1H), 6.68 (d, J = 7.3 Hz, 1H), 4.88 - 4.54 (m, 1H), 4.21 - 4.12 (m, 3H), 3.83 - 3.73 (m, 4H), 2.97 - 2.87 (m, 2H), 2.81 - 2.71 (m, 2H), 2.71 - 2.59 (m, 3H), 2.57 - 2.54 (m, 2H), 2.42 (s, 3H), 2.28 - 2.17 (m, 1H), 2.02 - 1.96 (m, 2H), 1.95 (s, 3H), 1.89 (s, 2H), 1.56 (td, J = 4.1, 8.0 Hz, 1H).

[1092]

[1093] 16-4. (3R)-1-((7-cyano-2-(3'-(4-((2-hydroxyethyl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid, 화합물 64의 제조

[1094]

[1095]

[1096] A mixture of methyl (3R)-1-[[7-cyano-2-[2-methyl-3-[2-methyl-3-[(4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carbonyl)amino]phenyl]phenyl]-1,3-benzoxazol-5-yl]methyl]pyrrolidine-3-carboxylate (200 mg, 311.19 μmol, 1 eq) and 2-aminoethanol (190.08 mg, 3.11 mmol, 188.20 μL, 10 eq) in MeOH (30 mL) / THF (6 mL) / DMF (2 mL) was added HOAc (1.05 g, 17.49 mmol, 1000 μL, 56.19 eq) at room temperature and stirred at 60 °C for 2 h. After adding NaBH3CN (39.11 mg, 622.38 μmol, 2 eq), the reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was concentrated under reduced pressure and purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um; mobile phase: [water (FA)-ACN]; B%: 8%-50%, 14 min) to obtain compound 61-11-4 (132 mg, 55.5% yield) as a white solid.

[1097] 1H NMR (400 MHz, DMSO-d6) δ = 9.60 (d, J = 2.5 Hz, 1H), 8.18 - 8.05 (m, 3H), 7.87 (d, J = 1.0 Hz, 1H), 7.63 - 7.51 (m, 2H), 7.44 - 7.38 (m, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.03 (d, J = 7.0 Hz, 1H), 6.81 (s, 1H), 4.20 - 4.12 (m, 3H), 4.12 - 4.04 (m, 3H), 4.01 - 3.87 (m, 5H), 3.76 (d, J = 2.0 Hz, 5H), 3.60 (s, 3H), 3.53 (t, J = 5.8 Hz, 2H), 3.14 - 2.99 (m, 1H), 2.83 - 2.72 (m, 3H), 2.72 - 2.64 (m, 1H), 2.56 (t, J = 7.3 Hz, 3H), 2.42 (s, 3H), 2.27 - 2.15 (m, 1H), 2.13 - 1.97 (m, 3H), 1.94 (s, 3H), 1.85 -1.72 (m, 1H).

[1098]

[1099]

[1100] To a THF (3 mL) / H2O (3 mL) solution of methyl (3R)-1-[[7-cyano-2-[3-[3-[[4-(2-hydroxyethylamino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carbonyl]amino]-2-methyl-phenyl]-2-methyl-phenyl]-1,3-benzoxazol-5-yl]methyl]pyrrolidine-3-carboxylate (120 mg, 174.47 μmol, 1 eq) was added LiOHㆍH2O (21.96 mg, 523.42 μmol, 3 eq) at 0 °C, and the reaction mixture was stirred at room temperature for 12 h. The pH of the reaction mixture was adjusted to 7 with Aq. 1 N HCl solution, and the precipitated solid was filtered. The filtered solid was purified by prep-HPLC (column: Waters Xbridge C18 150*50mm* 10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 18%-48%, 10 min) to obtain compound 64 (76 mg, 61.4% yield) as a white solid.

[1101] LCMS m / z 674.6 [M+1] + .

[1102] 1H NMR (400 MHz, DMSO-d6) δ = 9.55 (d, J = 2.4 Hz, 1H), 8.21 - 8.08 (m, 2H), 7.87 (d, J = 1.1 Hz, 1H), 7.64 - 7.50 (m, 2H), 7.48 - 7.36 (m, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.03 (d, J = 6.8 Hz, 1H), 6.72 (s, 1H), 4.18 - 4.10 (m, 2H), 3.90 - 3.86 (m, 1H), 3.75 (d, J = 7.6 Hz, 3H), 3.48 (t, J = 5.8 Hz, 4H), 2.98 - 2.89 (m, 1H), 2.76 - 2.65 (m, 4H), 2.58 - 2.53 (m, 2H), 2.42 (s, 3H), 2.24 - 2.13 (m, 1H), 2.04 - 1.96 (m, 3H), 1.95 (s, 3H), 1.76 - 1.62 (m, 1H).

[1103]

[1104] 16-5. (3R)-1-((7-cyano-2-(2,2'-dimethyl-3'-(4-((((S)-5-oxopyrrolidin-2-yl)methyl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid, 화합물 65의 제조

[1105]

[1106]

[1107] methyl (3R)-1-[[7-cyano-2-[2-methyl-3-[2-methyl-3-[(4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carbonyl)amino]phenyl]phenyl]-1,3-benzoxazol-5-yl]methyl]pyrrolidine-3-carboxylate (200 mg, 311.19 μmol, 1 eq), (5S)-5-(aminomethyl)pyrrolidin-2-one (355.21 mg, 3.11 mmol, 297.04 μL, 10 eq) in MeOH (30 mL) / THF (6 mL) / DMF (1 mL) solution of DIPEA (402.18 mg, 3.11 mg) at room temperature. mmol, 542.02 μL, 10 eq) and then 60 °C for 2 h. NaBH3CN (97.78 mg, 1.56 mmol, 5 eq) was added to the reaction mixture and stirred at 60 °C for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um; mobile phase: [water (FA)-ACN]; B%: 8%-38%, 10 min) to obtain compound 61-11-5 (140 mg, 57.6% yield) as a white solid.

[1108] 1H NMR (400 MHz, DMSO-d6) δ = 9.55 (s, 1H), 8.17 - 8.14 (m, 3H), 8.12 (d, J = 1.1 Hz, 1H), 7.88 (d, J = 1.1 Hz, 1H), 7.69 (d, J = 19.6 Hz, 1H), 7.63 - 7.59 (m, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.44 - 7.38 (m, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.03 (d, J = 7.4 Hz, 1H), 6.77 (d, J = 9.6 Hz, 1H), 4.24 - 4.06 (m, 3H), 3.95 - 3.85 (m, 2H), 3.81 - 3.74 (m, 3H), 3.60 (s, 3H), 3.58 (s, 2H), 3.06 (dd, J = 8.3, 9.8 Hz, 1H), 2.79 - 2.65 (m, 3H), 2.62 - 2.53 (m, 4H), 2.42 (s, 3H), 2.20 - 2.08 (m, 3H), 2.07 - 1.97 (m, 3H), 1.95 (s, 4H), 1.77 - 1.62 (m, 2H).

[1109]

[1110]

[1111] To a THF (3 mL) / H2O (1 mL) solution of methyl (3R)-1-[[7-cyano-2-[2-methyl-3-[2-methyl-3-[[4-[[(2S)-5-oxopyrrolidin-2-yl]methylamino]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carbonyl]amino]phenyl]phenyl]-1,3-benzoxazol-5-yl]methyl]pyrrolidine-3-carboxylate (130 mg, 175.47 μmol, 1 eq) was added LiOHㆍH2O (22.09 mg, 526.42 μmol, 3 eq) at 0 °C, and the reaction mixture was stirred at room temperature for 12 h. The pH of the reaction mixture was adjusted to 7 with Aq. 1 N HCl solution, and the precipitated solid was filtered. The filtered solid was purified by prep-HPLC (column: Waters Xbridge C18 150*50mm* 10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 18%-48%, 10 min) to obtain compound 65 (72 mg, 53.6% yield) as a white solid.

[1112] LCMS m / z 727.2 [M+1] + .

[1113] 1H NMR (400 MHz, DMSO-d6) δ = 9.55 (s, 1H), 8.21 - 8.08 (m, 2H), 7.88 (d, J = 1.0 Hz, 1H), 7.69 (d, J = 19.8 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.55 (t, J = 7.7 Hz, 1H), 7.40 (d, J = 6.9 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.03 (d, J = 7.4 Hz, 1H), 6.77 (d, J = 9.8 Hz, 1H), 4.18 - 4.09 (m, 2H), 3.91 - 3.85 (m, 1H), 3.75 (d, J = 7.5 Hz, 3H), 3.58 (s, 3H), 2.94 (d, J = 7.4 Hz, 1H), 2.77 - 2.70 (m, 1H), 2.68 - 2.58 (m, 3H), 2.58 - 2.53 (m, 2H), 2.42 (s, 3H), 2.11 (s, 4H), 2.01 - 1.96 (m, 2H), 1.95 (s,3H), 1.76 - 1.62 (m, 2H).

[1114]

[1115] 16-6. (3R)-1-((2-(3'-(4-((carboxymethyl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid, 화합물 66의 제조

[1116]

[1117]

[1118] A mixture of methyl (3R)-1-[[7-cyano-2-[2-methyl-3-[2-methyl-3-[(4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carbonyl)amino]phenyl]phenyl]-1,3-benzoxazol-5-yl]methyl]pyrrolidine-3-carboxylate (200 mg, 311.19 μmol, 1 eq) and 2-aminoacetic acid (233.60 mg, 3.11 mmol, 297.04 μL, 10 eq) in MeOH (30 mL) / DMF (1 mL) / THF (6 mL) was stirred at 60 °C for 2 h. After adding NaBH3CN (97.78 mg, 1.56 mmol, 5 eq), the mixture was stirred at 60 °C for 2 h. After concentrating the reactant under reduced pressure, the residue was purified by prep-HPLC (column: Phenomenex luna C18 150*40mm* 15μm; mobile phase: [water (FA)-ACN]; B%: 10%-40%, 9 min) to obtain compound 61-11-6 (150 mg, 65.2% yield) as a white solid.

[1119] 1H NMR (400 MHz, DMSO-d6) δ = 9.60 (d, J = 1.4 Hz, 1H), 8.17 - 8.09 (m, 2H), 7.88 (d, J = 1.1 Hz, 1H), 7.64 - 7.50 (m, 2H), 7.31 (t, J = 7.8 Hz, 1H), 7.03 (d, J = 7.0 Hz, 1H), 6.77 (s, 1H), 4.22 - 4.12 (m, 2H), 4.06 (s, 1H), 3.76 (d, J = 1.3 Hz, 2H), 3.60 (s, 3H), 3.33 (s, 5H), 3.13 - 2.97 (m, 2H), 2.80 - 2.64 (m, 4H), 2.61 - 2.54 (m, 4H), 2.43 (s, 3H), 2.25 - 2.15 (m, 1H), 2.08 - 1.97 (m, 3H), 1.95 (s, 3H), 1.85 - 1.69 (m, 1H).

[1120]

[1121]

[1122] To a THF (3 mL) / H2O (1 mL) solution of 2-[[2-[[3-[3-[7-cyano-5-[[(3R)-3-methoxycarbonylpyrrolidin-1-yl]methyl]-1,3-benzoxazol-2-yl]-2-methyl-phenyl]-2-methyl-phenyl]carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]amino]acetic acid (120 mg, 171.00 μmol, 1 eq) was added LiOHㆍH2O (21.53 mg, 513.00 μmol, 3 eq) at 0 °C, and the mixture was stirred at room temperature for 12 h. The pH of the reaction mixture was adjusted to 7 with Aq. 1 N HCl solution, and the precipitated solid was filtered. The filtered solid was purified by prep-HPLC (column: Waters Xbridge C18 150*50mm* 10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 18%-48%, 10 min) to obtain compound 66 (82 mg, 66.24% yield) as a white solid.

[1123] LCMS m / z 688.2 [M+1] + .

[1124] 1H NMR (400 MHz, DMSO-d6) δ = 9.59 (s, 1H), 8.19 - 8.08 (m, 2H), 7.86 (s, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.54 (s, 1H), 7.39 (d, J = 7.4 Hz, 1H), 7.30 (t, J = 7.8 Hz, 1H), 7.02 (d, J = 7.5 Hz, 1H), 6.77 (s, 1H), 4.14 (d, J = 6.1 Hz, 3H), 4.05 (d, J = 5.8 Hz, 3H), 3.74 (d, J = 7.9 Hz, 3H), 3.26 (s, 2H), 2.97 - 2.88 (m, 1H), 2.79 - 2.70 (m, 1H), 2.69 - 2.62 (m, 1H), 2.57 - 2.53 (m, 2H), 2.42 (s, 3H), 2.27 - 2.15 (m, 1H), 2.03 - 1.97 (m, 2H), 1.94 (s, 3H), 1.75 (d, J = 5.6 Hz, 1H).

[1125]

[1126] [Manufacturing Example 17]

[1127] Preparation of compounds 67 to 70

[1128]

[1129] 17-1. (3R)-1-((7-cyano-2-(2,2'-dichloro-3'-(4-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid, compound 67 manufacturing

[1130]

[1131]

[1132] To a solution of compound 67-1 (25 g, 117.81 mmol, 1 eq) in MeCN (200 mL) were added K2CO3 (17.00 g, 123.00 mmol, 1.04 eq) and ethyl 4-bromobutanoate (16.9 mL, 117.92 mmol, 1 eq), and the mixture was stirred at 80 °C for 4 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 67-2 (60.3 g, 74.5% yield) as a white solid.

[1133] LCMS m / z 327.2 [M+1] + .

[1134] 1 H NMR (400 MHz, CDCl3) δ 7.33 (s, 1H), 4.69 (t, J = 6.9 Hz, 2H), 4.42 - 4.32 (m, 4H), 4.10 (q, J = 7.2 Hz, 2H), 2.36 - 2.29 (m, 2H), 2.23 - 2.15 (m, 2H), 1.38 (dt, J = 4.1, 7.1 Hz, 6H), 1.23 (t, J = 7.2 Hz, 3H).

[1135]

[1136]

[1137]

[1138] To a solution of compound 67-2 (30 g, 91.93 mmol, 1 eq) in toluene (280 mL) was slowly added KOtBu (11.35 g, 101.12 mmol, 1.1 eq) at room temperature over 5 minutes. The reaction mixture was stirred at room temperature for 25 minutes and then at 90 °C for 3 hours. EA (600 mL), aq. NH4Cl (700 mL), and aq. 1 M HCl (350 mL) were sequentially added to the reaction mixture, followed by extraction with EA (400 mLХ3). The organic layer was washed with aq. NH4Cl (700 mLХ2), dried over Na2SO4, and concentrated under reduced pressure. The residue was stirred at room temperature for 20 minutes to precipitate a solid. The solid was filtered to obtain compound 67-3 (23.9 g, 92.7% yield) as a white solid.

[1139] LCMS m / z 281.1 [M+1] + .

[1140] 1 H NMR (400 MHz, CDCl3) δ 12.03 (s, 1H), 7.15 (s, 1H), 4.42 (q, J = 7.2 Hz, 2H), 4.35 - 4.29 (m, 4H), 2.91 (t, J = 7.5 Hz, 2H), 1.43 - 1.34 (m, 6H).

[1141]

[1142]

[1143] A mixture of compound 67-3 (23.9 g, 85.27 mmol, 1 eq), HCl (306.00 g, 3.11 mol, 300 mL, 36.42 eq) and H2O (150 mL) was stirred at 100 °C for 6 h under nitrogen conditions. The reaction mixture was concentrated under reduced pressure, and MeCN (30 mL) was added to the residue, which was stirred at room temperature for 20 min to precipitate a solid. The solid was filtered to obtain compound 67-4 (12.9 g, 83.9% yield) as a white solid.

[1144] 1 H NMR (400 MHz, DMSO-d6) δ 13.02 (br s, 1H), 7.13 (s, 1H), 4.43 - 4.38 (m, 2H), 2.71 - 2.66 (m, 2H), 2.34 - 2.27 (m, 2H).

[1145]

[1146]

[1147] A dioxane (100 mL) mixture of compound 67-1A (10 g, 48.43 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (14.76 g, 58.12 mmol, 1.2 eq), potassium acetate (7.13 g, 72.65 mmol, 1.5 eq), tricyclohexylphosphane (2.72 g, 9.69 mmol, 3.14 mL, 0.2 eq) and Pd2(dba)3 (4.44 g, 4.84 mmol, 0.1 eq) was stirred at 120°C under nitrogen for 4 h. The reaction mixture was filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 1 / 1) to obtain compound 67-5A (14.7 g, 89.78% yield) as a yellow solid.

[1148] LCMS m / z 254.1 [M+1] + .

[1149] 1 H NMR (400 MHz, CDCl3) δ 7.64 - 7.61 (m, 1H), 7.06 (s, 1H), 6.83 (dd, J = 2.5, 6.9 Hz, 1H), 4.71 - 3.49 (m, 2H), 1.37 (s, 12H).

[1150]

[1151]

[1152] A mixture of compound 67-5A (7.8 g, 23.07 mmol, 75% purity, 1 eq), compound 67-4 (4.20 g, 23.30 mmol, 1.01 eq), HATU (10.53 g, 27.69 mmol, 1.2 eq), and DIEA (11.93 g, 92.30 mmol, 16.08 mL, 4 eq) in DCM (150 mL) was stirred at room temperature under nitrogen for 18 h. The reaction mixture was diluted with DCM (200 mL) and washed with water (150 mL Х 4). The organic layer was washed with brine (200 mL Х 2), dried over Na2SO4, concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 0 / 1) to obtain compound 67-11 (4.86 g, 40.5% yield) as a white solid.

[1153] LCMS m / z 416.0 [M+1] + .

[1154] 1 H NMR (400 MHz, CDCl3) δ 9.47 (s, 1H), 8.65 (dd, J = 1.6, 8.2 Hz, 1H), 7.49 - 7.42 (m, 2H), 7.31 (t, J = 7.7 Hz, 1H), 4.52 - 4.45 (m, 2H), 2.79 - 2.72 (m, 2H), 2.49 - 2.41 (m, 2H), 1.39 (s, 12H).

[1155]

[1156]

[1157] To a dioxane (15 mL) / H2O (1.5 mL) mixture of compounds 67-10 (1 g, 2.11 mmol, 1 eq) and 67-11 (1.14 g, 2.74 mmol, 1.3 eq), K3PO4 (894.25 mg, 4.21 mmol, 2 eq) and Pd-118 (137.29 mg, 210.64 umol, 0.1 eq) were added, and the reaction mixture was stirred at 80°C under nitrogen for 18 h. The reaction mixture was diluted with H2O (30 mL) and extracted with EA (50 mL Х3). The organic layer was washed with brine (50 mL X2), dried over Na2SO4, concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=3 / 1 to 0 / 1) to obtain compound 67-12 (500 mg, 30.9% yield) as a pale yellow solid.

[1158] LCMS m / z 683.3 [M+1] + .

[1159] 1 H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.25 - 8.20 (m, 1H), 8.17 (s, 1H), 8.11 (dd, J = 1.4, 8.1 Hz, 1H), 7.94 (d, J = 1.2 Hz, 1H), 7.76 - 7.66 (m, 2H), 7.54 (t, J = 7.9 Hz, 1H), 7.32 - 7.26 (m, 2H), 4.51 - 4.44 (m, 2H), 3.82 - 3.72 (m, 2H), 3.13 - 3.02 (m, 1H), 2.76 - 2.66 (m, 4H), 2.58 - 2.53 (m, 2H), 2.38 - 2.29 (m, 3H), 1.99 (s, 3H), 1.22 - 1.12 (m, 2H).

[1160]

[1161]

[1162] A mixture of MeOH (2 mL) / THF (2 mL) / DMF (1 mL) containing compound 67-12 (100 mg, 146.30 umol, 1 eq), (5S)-5-(aminomethyl)pyrrolidin-2-one (83.50 mg, 731.49 umol, 5 eq), and AcOH (175.70 mg, 2.93 mmol, 167.34 uL, 20 eq) was stirred at 60 °C for 30 min, then NaBH3CN (275.80 mg, 4.39 mmol, 30 eq) was added and stirred at 60 °C for 16 h. H2O (1 mL) was added to the reaction mixture, and the residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water (NH4HCO3)-ACN]; B%: 45%-75%, 11 min) to obtain compounds 67-12-1 (67 mg, 66.0% yield) and 67-12-4 (23 mg, 19.9% ​​yield), respectively, as white solids.

[1163]

[1164]

[1165] (Compound 67-12-1)

[1166] LCMS m / z 685.3 [M+1] + .

[1167] 1H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 8.33 - 8.16 (m, 3H), 7.94 (d, J = 1.2 Hz, 1H), 7.76 - 7.66 (m, 2H), 7.52 (t, J = 7.9 Hz, 1H), 7.24 (dd, J = 1.3, 7.6 Hz, 1H), 6.75 (s, 1H), 5.61 (d, J = 5.5 Hz, 1H), 4.77 (br d, J = 6.3 Hz, 1H), 4.19 - 4.11 (m, 2H), 3.77 (d, J = 2.9 Hz, 2H), 3.60 (s, 3H), 3.10 - 3.04 (m, 1H), 2.80 - 2.71 (m, 2H), 2.70 - 2.65 (m, 3H), 2.20 - 2.11 (m, 1H), 2.04 - 1.95 (m, 3H), 1.77 - 1.69 (m, 1H).

[1168]

[1169]

[1170]

[1171] (화합물 67-12-4)

[1172] LCMS m / z 783.3 [M+1] + .

[1173] 1H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.33 - 8.14 (m, 3H), 7.94 (d, J = 1.2 Hz, 1H), 7.76 - 7.65 (m, 3H), 7.52 (t, J = 7.9 Hz, 1H), 7.24 (dd, J = 1.4, 7.6 Hz, 1H), 6.84 (d, J = 11.9 Hz, 1H), 4.23 - 4.09 (m, 2H), 3.95 - 3.83 (m, 1H), 3.77 (d, J = 2.9 Hz, 2H), 3.60 (s, 4H), 3.10 - 3.02 (m, 1H), 2.74 (br d, J = 8.5 Hz, 1H), 2.70 - 2.65 (m, 3H), 2.19 - 1.86 (m, 9H), 1.75 - 1.64 (m, 2H).

[1174]

[1175]

[1176] A solution of compound 67-12-1 (67 mg, 97.73 μmol, 1 eq) and LiOHㆍH2O (8.93 mg, 212.88 μmol, 2.18 eq) in THF (2 mL) / H2O (0.4 mL) was stirred at room temperature for 2 h. The pH range of the reaction mixture was adjusted to 6-7 with aq. 1 N HCl solution, and the residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water (NH4HCO3)-ACN]; B%: 23%-53%, 11 min) to obtain compound 67 (48 mg, 71.7% yield) as a white solid.

[1177] LCMS m / z 671.3 [M+1] + .

[1178] 1H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 8.29 (d, J = 8.1 Hz, 1H), 8.22 (dd, J = 1.9, 7.6 Hz, 1H), 8.17 (s, 1H), 7.94 (d, J = 1.2 Hz, 1H), 7.76 - 7.66 (m, 2H), 7.52 (t, J = 7.9 Hz, 1H), 7.28 - 7.21 (m, 1H), 6.75 (s, 1H), 5.60 (br s, 1H), 4.77 (br s, 1H), 4.17 - 4.11 (m, 2H), 3.76 (br d, J = 8.6 Hz, 2H), 2.98 - 2.88 (m, 2H), 2.77 - 2.63 (m, 3H), 2.20 - 2.12 (m, 1H), 2.03 - 1.90 (m, 4H), 1.77 - 1.68 (m, 1H).

[1179]

[1180] 17-2. (3R)-1-((7-cyano-2-(2,2'-dichloro-3'-(4-((((S)-5-oxopyrrolidin-2-yl)methyl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid, 화합물 68의 제조

[1181]

[1182]

[1183] LiOHㆍH2O (5.48 mg, 130.49 μmol, 2 eq) was added to a THF (4 mL) / H2O (1 mL) solution of compound 67-12-4 (51 mg, 65.24 μmol, 1 eq) and stirred at room temperature for 2 hours. The pH range of the reaction mixture was adjusted to 6-7 with aq. 1 N HCl solution, and the mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25mm*5 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 28%-58%, 11 min) to obtain compound 68 (50 mg, 98.3% yield) as a white solid.

[1184] LCMS m / z 769.3 [M+1] + .

[1185] 1 H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.30 (br d, J = 8.1 Hz, 1H), 8.22 (dd, J = 1.5, 7.6 Hz, 1H), 8.17 (s, 1H), 7.94 (s, 1H), 7.76 - 7.64 (m, 3H), 7.52 (t, J = 8.0 Hz, 1H), 7.24 (br d, J = 7.4 Hz, 1H), 6.84 (d, J = 11.9 Hz, 1H), 4.15 (br d, J = 5.2 Hz, 2H), 3.88 (td, J = 6.2, 12.5 Hz, 1H), 3.80 - 3.71 (m, 2H), 3.58 (br d, J = 2.0 Hz, 2H), 2.96 - 2.90 (m, 1H), 2.71 (br d, J = 8.3 Hz, 1H), 2.65 (br dd, J = 5.8, 14.5 Hz, 2H), 2.59 (br d, J = 6.1 Hz, 1H), 2.54 (br d, J = 3.8 Hz, 2H), 2.21 - 1.89 (m, 9H), 1.74 - 1.64 (m, 2H).

[1186]

[1187] 17-3. (3R)-1-((2-(3'-(4-((2-acetamidoethyl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxami do)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-7-cyanobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic Preparation of acid, compound 69

[1188]

[1189]

[1190] A MeOH (2 mL) / THF (2 mL) / DMF (1 mL) mixture of compound 67-12 (120 mg, 175.56 umol, 1 eq), N-(2-aminoethyl)acetamide (89.65 mg, 877.78 umol, 83.79 uL, 5 eq), and AcOH (210.85 mg, 3.51 mmol, 200.81 uL, 20 eq) was stirred at 60°C for 30 min, then NaBH3CN (330.97 mg, 5.27 mmol, 30 eq) was added and stirred at 60°C for 16 h. H2O (1 mL) was added to the reaction mixture, and the residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water (NH4HCO3)-ACN]; B%: 45%-75%, 11 min) to obtain compound 67-12-2 (89 mg, 65.8% yield) as a white solid.

[1191] LCMS m / z 771.3 [M+1] + .

[1192] 1H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.34 - 8.27 (m, 1H), 8.22 (dd, J = 1.8, 7.6 Hz, 1H), 8.17 (s, 1H), 7.94 (d, J = 0.8 Hz, 1H), 7.84 (br t, J = 5.2 Hz, 1H), 7.76 - 7.67 (m, 2H), 7.52 (t, J = 7.9 Hz, 1H), 7.24 (dd, J = 1.3, 7.6 Hz, 1H), 6.79 (s, 1H), 4.20 - 4.09 (m, 2H), 3.88 (br t, J = 6.1 Hz, 1H), 3.77 (d, J = 2.7 Hz, 2H), 3.60 (s, 3H), 3.21 - 3.01 (m, 4H), 2.82 - 2.71 (m, 2H), 2.68 - 2.66 (m, 2H), 2.62 (br s, 2H), 2.28 - 2.13 (m, 2H), 2.06 - 1.90 (m, 4H), 1.80 (s, 3H), 1.72 - 1.62 (m, 1H).

[1193]

[1194]

[1195] LiOHㆍH2O (9.70 mg, 231.27 μmol, 2 eq) was added to a THF (4 mL) / H2O (1 mL) solution of compound 67-12-2 (89 mg, 115.63 μmol, 1 eq) and stirred at room temperature for 2 hours. The pH range of the reaction mixture was adjusted to 6-7 with aq. 1 N HCl solution, and the mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (column: Welch Xtimate C18 150*25mm*5 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 23%-53%, 11 min) to obtain compound 69 (80 mg, 89.4% yield) as a white solid.

[1196] LCMS m / z 757.3 [M+1] + .

[1197] 1 H NMR (400 MHz, DMSO-d6) δ 9.56 (s, 1H), 8.30 (dd, J = 1.2, 8.2 Hz, 1H), 8.22 (dd, J = 1.8, 7.6 Hz, 1H), 8.17 (s, 1H), 7.94 (d, J = 1.1 Hz, 1H), 7.83 (br t, J = 5.2 Hz, 1H), 7.75 - 7.65 (m, 2H), 7.52 (t, J = 7.9 Hz, 1H), 7.24 (dd, J = 1.4, 7.6 Hz, 1H), 6.79 (s, 1H), 4.19 - 4.11 (m, 2H), 3.88 (br t, J = 5.9 Hz, 1H), 3.76 (br d, J = 8.5 Hz, 2H), 3.13 (br d, J = 6.2 Hz, 2H), 3.01 - 2.89 (m, 2H), 2.72 (br d, J = 8.3 Hz, 1H), 2.70 - 2.59 (m, 4H), 2.55 (br s, 1H), 2.22 - 2.14 (m, 1H), 2.03 - 1.90 (m, 4H), 1.80 (s, 3H), 1.71 - 1.62 (m, 1H).

[1198]

[1199] 17-4. (3R)-1-((7-cyano-2-(2,2'-dichloro-3'-(4-((2-hydroxyethyl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamido)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid, 화합물 70의 제조

[1200]

[1201]

[1202] A MeOH (2 mL) / THF (2 mL) / DMF (1 mL) mixture of compound 67-12 (120 mg, 175.56 umol, 1 eq), 2-aminoethanol (53.62 mg, 877.78 umol, 53.09 uL, 5 eq), and AcOH (210.84 mg, 3.51 mmol, 200.80 uL, 20 eq) was stirred at 60°C for 30 min, then NaBH3CN (330.96 mg, 5.27 mmol, 30 eq) was added and stirred at 60°C for 16 h. H2O (1 mL) was added to the reaction mixture, and the residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water (NH4HCO3)-ACN]; B%: 45%-75%, 11 min) to obtain compound 67-12-3 (71 mg, 54.9% yield) as a white solid.

[1203] LCMS m / z 730.3 [M+1] + .

[1204] 1 H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.32 - 8.16 (m, 3H), 7.94 (s, 1H), 7.78 - 7.65 (m, 2H), 7.52 (br t, J = 7.9 Hz, 1H), 7.24 (br d, J = 7.0 Hz, 1H), 6.78 (s, 1H), 4.52 (br t, J = 5.3 Hz, 1H), 4.15 (br s, 2H), 3.89 (br t, J = 5.8 Hz, 1H), 3.77 (br d, J = 2.1 Hz, 2H), 3.60 (s, 4H), 3.52 - 3.44 (m, 4H), 3.09 - 3.03 (m, 1H), 2.74 (br d, J = 8.6 Hz, 2H), 2.23 - 2.12 (m, 2H), 2.07 - 1.85 (m, 5H), 1.75 - 1.63 (m, 1H).

[1205]

[1206]

[1207] To a THF (4 mL) / H2O (1 mL) solution of compound 67-12-3 (71 mg, 97.44 μmol, 1 eq) was added LiOHㆍH2O (8.18 mg, 194.89 μmol, 2 eq) and stirred at room temperature for 2 hours. The pH range of the reaction mixture was adjusted to 6-7 with aq. 1 N HCl solution, and the mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water (NH4HCO3)-ACN]; B%: 18%-48%, 11 min) to obtain compound 70 (50 mg, 71.30% yield) as a white solid.

[1208] LCMS m / z 716.5 [M+1] + .

[1209] 1 H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.30 (d, J = 7.5 Hz, 1H), 8.22 (dd, J = 1.8, 7.6 Hz, 1H), 8.17 (s, 1H), 7.94 (d, J = 1.0 Hz, 1H), 7.76 - 7.64 (m, 2H), 7.52 (t, J = 8.0 Hz, 1H), 7.24 (dd, J = 1.3, 7.5 Hz, 1H), 6.78 (s, 1H), 4.64 - 4.38 (m, 1H), 4.18 - 4.11 (m, 2H), 3.89 (br t, J = 6.1 Hz, 1H), 3.76 (br d, J = 8.5 Hz, 2H), 3.50 - 3.45 (m, 5H), 2.97 - 2.92 (m, 1H), 2.75 - 2.65 (m, 4H), 2.57 (br d, J = 1.4 Hz, 1H), 2.22 - 2.14 (m, 1H), 2.05 - 1.90 (m, 4H), 1.74 - 1.65 (m, 1H).

[1210]

[1211] [Manufacturing Example 18]

[1212] Preparation of compounds 71 ​​to 80

[1213]

[1214] 18-1. Preparation of 4-hydroxy-N-(3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, compound 71

[1215]

[1216]

[1217] To a solution of 5-bromopyridine-2-carboxylic acid (10 g, 49.50 mmol, 1 eq) in MeOH (79.18 g, 2.47 mol, 100.00 mL, 49.92 eq) was added c-H2SO4 (9.20 g, 93.80 mmol, 5.00 mL, 1.89 eq) and stirred at 70 °C for 2 hours. Water (600 mL) was added to the mixture and extracted with EtOAc (600 mL*2). The organic layer was washed with brine (600 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Petroleum ether / Ethyl acetate=100 / 1 to 1 / 1) to obtain compound 71-2 (10.2 g, 85.8% yield) as a white solid.

[1218] 1H NMR (400 MHz, DMSO-d6) δ = 8.86 (d, J = 1.9 Hz, 1H), 8.27 (dd, J = 2.4, 8.4 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 3.89 (s, 3H).

[1219]

[1220]

[1221] A mixture of methyl 5-bromopicolinate (9.8 g, 45.36 mmol, 1 eq), potassium trifluoro(vinyl)boranuide (6.08 g, 45.36 mmol, 1 eq), K3PO4 (28.89 g, 136.09 mmol, 3 eq), and Pd(dppf)Cl2 (1.85 g, 2.27 mmol, 0.05 eq) in dioxane (100 mL) was stirred at 100 °C for 2 hours under nitrogen conditions. Water (600 mL) was added to the mixture, and then extracted with EtOAc (600 mL*2). The organic layer was washed with brine (600 mL), dried over Na2SO4, concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (Petroleum ether / Ethyl acetate=100 / 1 to 1 / 1) to obtain compound 71-3 (6.2 g, 75.8% yield).

[1222] 1 H NMR (400 MHz, DMSO-d6) δ = 8.78 (d, J = 1.9 Hz, 1H), 8.12 - 8.06 (m, 1H), 8.04 - 7.96 (m, 1H), 6.85 (dd, J = 11.1, 17.8 Hz, 1H), 6.13 (d, J) = 17.6 Hz, 1H), 5.54 (d, J = 11.1 Hz, 1H), 3.87 (s, 3H).

[1223]

[1224]

[1225] t-BuOK (6.88 g, 61.28 mmol, 2 eq) was added to a THF (80 mL) solution of methyl 5-vinylpyridine-2-carboxylate (5 g, 30.64 mmol, 1 eq) and 3-bromo-2-methyl-aniline (5.70 g, 30.64 mmol, 3.78 mL, 1 eq) at -20 °C, and the mixture was stirred at 20 °C for 2 hours. Water (1000 mL) was added to Mitxture, and the organic layer was extracted with ethyl acetate (500 mL x 3). The organic layer was washed with brine (600 mL), dried over Na2SO4, concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (Petroleum ether / Ethyl acetate=100 / 1 to 1 / 1) to obtain compound 71-5 (6.8 g, 55.9% yield) as a white solid.

[1226] 1 H NMR (400 MHz, DMSO-d6) δ = 10.45 (s, 1H), 8.82 (d, J = 1.6 Hz, 1H), 8.33 - 8.17 (m, 1H), 8.15 - 8.06 (m, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.19 (t, J = 8.0 Hz, 1H), 6.90 (dd, J = 11.0, 17.8 Hz, 1H), 6.16 (d, J = 17.8 Hz, 1H), 5.56 (d, J = 11.1 Hz, 1H), 2.34 (s, 3H).

[1227]

[1228]

[1229] N-(3-bromo-2-methyl-phenyl)-5-vinyl-pyridine-2-carboxamide (1.8 g, 5.68 mmol, 1 eq) was bubbled with ozone for 30 min in MeOH (20 mL), then PPh3 (2.98 g, 11.35 mmol, 2 eq) was added, and the mixture was stirred at room temperature for 2 h. Water (40 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic layer was washed with brine (60 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Petroleum ether / Ethyl acetate=100 / 1 to 3 / 1) to give compound 71-6 (92 mg, 54.8% yield) as a white solid.

[1230] LCMS m / z 318.9 [M+1] + .

[1231]

[1232]

[1233] A THF (15 mL) / MeOH (15 mL) solution of N-(3-bromo-2-methyl-phenyl)-5-formyl-pyridine-2-carboxamide (1.6 g, 5.01 mmol, 1 eq), 2-aminoethanol (612.45 mg, 10.03 mmol, 606.39 μL, 2 eq), and HOAc (361.27 mg, 6.02 mmol, 344.07 μL, 1.2 eq) was stirred at 70 °C for 2 h. NaBH3CN (472.57 mg, 7.52 mmol, 1.5 eq) was added to the mixture, and the mixture was stirred at 70 °C for 2 h. Water (40 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic layer was washed with brine (60 mL), dried over Na2SO4, concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (Petroleum ether / Ethyl acetate=100 / 1 to 1 / 1) to obtain compound 71-7 (1.78 g, 87.7% yield) as a white solid.

[1234] 1 H NMR (400 MHz, DMSO-d6) δ = 10.48 (s, 1H), 8.69 (d, J = 1.3 Hz, 1H), 8.23 ​​(s, 1H), 8.16 - 8.07 (m, 1H), 8.03 (d, J = 1.9 Hz, 1H), 7.73 - 7.60 (m, 1H), 7.49 (d, J = 7.5 Hz, 1H), 7.34 - 7.10 (m, 1H), 5.53 - 5.50 (m, 1H), 3.90 (s, 2H), 3.50 (t, J = 5.8 Hz, 2H), 2.62 (t, J = 5.8 Hz, 2H), 2.34 (s, 3H).

[1235]

[1236]

[1237] N-(3-bromo-2-methyl-phenyl)-5-[(2-hydroxyethylamino)methyl]pyridine-2-carboxamide (500 mg, 1.37 mmol, 1 eq), N-[2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (813.88 mg, 2.06 mmol, 1.5 eq), K2CO3 (531.23 mg, 3.84 mmol, 2.8 eq), Pd(dppf)Cl2 (56.05 mg, 68.64 umol, 0.05 eq) dioxane (15 mL) / H2O (4 mL) mixture under nitrogen conditions at 90 °C. The mixture was stirred for 2 hours. Water (40 mL) was added to the mixture, and extracted with ethyl acetate (30 mL x 3). The organic layer was washed with brine (60 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Dichloromethane: Methanol = 100 / 1 to 10 / 1) to obtain compound 71-9 (330 mg, 39.1% yield) as a white solid.

[1238] 1H NMR (400 MHz, DMSO-d6) δ = 10.34 (s, 1H), 9.87 (s, 1H), 8.68 (s, 1H), 8.20 - 8.13 (m, 1H), 8.03 (d, J = 1.5 Hz, 1H), 7.87 (d, J = 7.7 Hz, 1H), 7.49 (s, 1H), 7.34 - 7.23 (m, 3H), 7.05 - 6.96 (m, 2H), 4.53 - 4.40 (m, 3H), 3.88 (s, 2H), 3.48 (t, J = 5.7 Hz, 4H), 2.76 - 2.65 (m, 3H), 2.60 (t, J = 5.8 Hz, 2H), 2.38 - 2.30 (m, 4H), 2.01 (s, 4H), 1.94 (s, 3H).

[1239]

[1240]

[1241] To a solution of N-[3-[3-[[5-[(2-hydroxyethylamino)methyl]pyridine-2-carbonyl]amino]-2-methyl-phenyl]-2-methyl-phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (50 mg, 90.48 μmol, 1 eq) in MeOH (3 mL) was added NaBH4 (6.85 mg, 180.96 μmol, 2 eq) at 0 °C, and the mixture was stirred at 25 °C for 2 h. The pH of the mixture was adjusted to aq. After adjusting to 7 with 1N HCl solution, the precipitated solid was filtered and purified by prep-HPLC (column: Waters Xbridge C18 150*50mm* 10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 20%-50%, 10 min) to obtain compound 71 (21 mg, 39.7% yield) as a white solid.

[1242] LCMS m / z 555.1 [M+1] +.

[1243] 1 H NMR (400 MHz, DMSO-d6) δ = 10.33 (s, 1H), 9.53 (s, 1H), 8.67 (s, 1H), 8.13 (d, J = 7.9 Hz, 1H), 8.01 (br d, J = 7.5 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.30 (td, J = 7.8, 15.5 Hz, 2H), 6.97 (d, J = 7.4 Hz, 2H), 6.69 (s, 1H), 5.57 (d, J = 5.4 Hz, 1H), 4.76 (d, J = 5.8 Hz, 1H), 4.51 (s, 1H), 4.20 - 4.07 (m, 2H), 3.85 (s, 2H), 3.48 (d, J = 4.6 Hz, 2H), 2.56 (d, J = 8.9 Hz, 2H), 2.20 - 2.10 (m, 1H), 2.01 (s, 3H), 1.94 (s, 3H), 1.76 - 1.67 (m, 1H).

[1244]

[1245] 18-2. 4-((2-acetamidoethyl)amino)-N-(3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, 화합물 72의 제조

[1246]

[1247]

[1248] To a solution of N-[3-[3-[[5-[(2-hydroxyethylamino)methyl]pyridine-2-carbonyl]amino]-2-methyl-phenyl]-2-methyl-phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (50 mg, 90.48 μmol, 1 eq) and N-(2-aminoethyl)acetamide (92.41 mg, 904.78 umol, 86.36 μL, 10 eq) in MeOH (3 mL) was added HOAc (217.33 mg, 3.62 mmol, 206.99 μL, 40 eq), and the mixture was stirred at room temperature for 2 h. After adding NaBH3CN (11.37 mg, 180.96 μmol, 2 eq) to the mixture, the mixture was stirred at 60 °C for 10 hours. The mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC (column: Waters Xbridge C18 150*50mm* 10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 20%-50%, 10 min) to obtain compound 72 (32 mg, 52.6% yield) as a white solid.

[1249] LCMS m / z 639.3 [M+1] + .

[1250] 1H NMR (400 MHz, DMSO-d6) δ = 10.32 (s, 1H), 9.52 (d, J = 2.0 Hz, 1H), 8.67 (d, J = 1.4 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 8.06 - 7.98 (m, 1H), 7.94 - 7.78 (m, 2H), 7.57 (d, J = 7.9 Hz, 1H), 7.29 (td, J = 7.8, 15.6 Hz, 2H), 6.97 (d, J = 7.5 Hz, 2H), 6.72 (s, 1H), 4.64 - 4.50 (m, 1H), 4.40 (t, J = 5.1 Hz, 1H), 4.19 - 4.06 (m, 2H), 3.84 (s, 3H), 3.13 (q, J = 6.3 Hz, 2H), 2.68 - 2.62 (m, 2H), 2.57 (s, 2H), 2.28 - 2.12 (m, 2H), 2.00 (s, 3H), 1.94 (s, 3H), 1.80 (s, 3H), 1.72 - 1.56 (m, 1H), 1.05 (t, J = 7.0 Hz, 4H).

[1251]

[1252] 18-3. N-(3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-4-((R)-3-hydroxypyrrolidin-1-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, 화합물 73의 제조

[1253]

[1254]

[1255] HOAc (305.27 mg, 5.08 mmol, 290.74 μL, 56.19 eq) was added to a solution of N-[3-[3-[[5-[(2-hydroxyethylamino)methyl]pyridine-2-carbonyl]amino]-2-methyl-phenyl]-2-methyl-phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (50 mg, 90.48 μmol, 1 eq) and (R)-pyrrolidin-3-ol (78.82 mg, 904.78 μmol, 75.07 μL, 10 eq) in MeOH (30 mL) at room temperature, and the mixture was stirred at room temperature for 2 hours. After adding NaBH3CN (28.43 mg, 452.39 μmol, 5 eq) to the mixture, the mixture was stirred at 60 °C for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um; mobile phase: [water (FA)-ACN]; B%: 8%-50%, 14 min) to obtain compound 73 (31 mg, 52.1% yield) as a white solid.

[1256] LCMS m / z 624.7 [M+1] + .

[1257] 1H NMR (400 MHz, DMSO-d6) δ = 10.33 (s, 1H), 9.53 (d, J = 3.0 Hz, 1H), 8.67 (d, J = 1.1 Hz, 1H), 8.13 (d, J = 8.0 Hz, 1H), 8.02 (d, J = 1.8 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.57 (dd, J = 2.9, 7.9 Hz, 1H), 7.29 (td, J = 7.8, 15.8 Hz, 2H), 6.97 (d, J = 7.5 Hz, 2H), 6.67 (d, J = 7.1 Hz, 1H), 4.71 (t, J = 4.9 Hz, 1H), 4.52 (t, J = 5.1 Hz, 1H), 4.23 - 4.09 (m, 3H), 3.85 (s, 2H), 3.81 - 3.72 (m, 1H), 3.48 (q, J = 5.5 Hz, 2H), 2.95 - 2.74 (m, 2H), 2.73 - 2.64 (m, 1H), 2.62 - 2.53 (m, 3H), 2.28 - 2.18 (m, 1H), 2.01 (s, 3H), 1.94 (s, 4H), 1.89 (s, 2H), 1.56 (d, J = 3.4 Hz, 1H).

[1258]

[1259] 18-4. N-(3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-4-((R)-3-hydroxypyrrolidin-1-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, 화합물 74의 제조

[1260]

[1261]

[1262] To a solution of N-[3-[3-[[5-[(2-hydroxyethylamino)methyl]pyridine-2-carbonyl]amino]-2-methyl-phenyl]-2-methyl-phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (50 mg, 90.48 μmol, 1 eq) and 2-aminoethanol (55.27 mg, 904.78 μmol, 54.72 μL, 10 eq) in MeOH (5 mL) was added HOAc (305.28 mg, 5.08 mmol, 290.75 μL, 56.19 eq), and the mixture was stirred at 60 °C for 2 h. After adding NaBH3CN (11.37 mg, 180.96 μmol, 2 eq), the mixture was stirred at 60 °C for 2 hours, concentrated under reduced pressure, and the residue was purified by prep-HPLC (column: Waters Xbridge C18 150*50mm* 10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 20%-50%, 10 min) to obtain compound 74 (30 mg, 52.7% yield) as a yellow solid.

[1263] LCMS m / z 598.1 [M+1] + .

[1264] 1H NMR (400 MHz, DMSO-d6) δ = 10.33 (s, 1H), 9.52 (s, 1H), 8.67 (d, J = 1.3 Hz, 1H), 8.13 (d, J = 7.9 Hz, 1H), 8.01 (dd, J = 1.9, 7.9 Hz, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.30 (td, J = 7.8, 15.8 Hz, 2H), 6.98 (d, J = 7.5 Hz, 2H), 6.72 (s, 1H), 4.53 (d, J = 5.4 Hz, 2H), 4.21 - 4.05 (m, 2H), 3.94 - 3.77 (m, 3H), 3.48 (q, J = 5.5 Hz, 5H), 2.72 - 2.65 (m, 2H), 2.58 (t, J = 5.8 Hz, 2H), 2.24 - 2.15 (m, 1H), 2.01 (s, 3H), 1.94 (s, 3H), 1.76 - 1.61 (m, 1H).

[1265]

[1266] 18-5. N-(3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-4-(((5-oxopyrrolidin-2-yl)methyl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, 화합물 75의 제조

[1267]

[1268]

[1269] N-[3-[3-[[5-[(2-hydroxyethylamino)methyl]pyridine-2-carbonyl]amino]-2-methyl-phenyl]-2-methyl-phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (100 mg, 180.96 μmol, 1 eq), (5S)-5-(aminomethyl)pyrrolidin-2-one (206.55 mg, 1.81 mmol, 297.04 μL, 10 eq) and DIPEA (233.87 mg, 1.81 mmol, 315.18 μL, 10 eq) in MeOH (5 mL) in HOAc (217.33 mg, 3.62 μL, 10 eq). mmol, 206.99 μL, 20 eq) at 25 °C. The mixture was stirred for 2 hours. NaBH3CN (56.86 mg, 904.78 μmol, 5 eq) was added to the mixture, the mixture was stirred at 60 °C for 2 hours, concentrated under reduced pressure, and the residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 20%-50%, 10 min) to obtain compound 75 (22 mg, 17.7% yield) as a white solid.

[1270] LCMS m / z 651.7 [M+1] + .

[1271] 1H NMR (400 MHz, DMSO-d6) δ = 10.33 (s, 1H), 9.52 (br s, 1H), 8.68 (s, 1H), 8.14 (br d, J = 7.8 Hz, 1H), 8.03 (br d, J = 8.3 Hz, 1H), 7.86 (br d, J = 8.3 Hz, 1H), 7.69 (br d, J = 19.4 Hz, 1H), 7.57 (br d, J = 7.8 Hz, 1H), 7.33 - 7.21 (m, 2H), 6.97 (br d, J = 7.6 Hz, 2H), 6.76 (d, J = 9.3 Hz, 1H), 4.67 - 4.51 (m, 1H), 4.13 (br d, J = 4.0 Hz, 3H), 3.89 (s, 4H), 2.63 - 2.57 (m, 4H), 2.11 (br s, 5H), 2.00 (s, 3H), 1.94 (s, 3H), 1.75 - 1.64 (m, 2H), 1.23 (br s, 2H).

[1272]

[1273] 18-6. 2-((2-((3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl)amino)acetic acid, 화합물 76의 제조

[1274]

[1275]

[1276] To a solution of N-[3-[3-[[5-[(2-hydroxyethylamino)methyl]pyridine-2-carbonyl]amino]-2-methyl-phenyl]-2-methyl-phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (100 mg, 180.96 μmol, 1 eq) and 2-aminoacetic acid (135.84 mg, 1.81 mmol, 297.04 μL, 10 eq) in MeOH (5 mL) was added HOAc (217.33 mg, 3.62 mmol, 206.99 μL, 20 eq), and the mixture was stirred at 60 °C for 2 h. NaBH3CN (56.86 mg, 904.78 μmol, 5 eq) was added to the mixture, stirred at 60 °C for 10 hours, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5um; mobile phase: [water (NH4HCO3)-ACN]; B%: 10%-40%, 10 min) to obtain compound 76 (32 mg, 27.4% yield) as a white solid.

[1277] LCMS m / z 612.6 [M+1] + .

[1278] 1H NMR (400 MHz, DMSO-d6) δ = 10.33 (s, 1H), 9.56 (s, 1H), 8.68 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 8.02 (dd, J = 1.5, 8.0 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.56 (br d, J = 7.9 Hz, 1H), 7.29 (td, J = 7.8, 15.8 Hz, 2H), 6.97 (br d, J = 7.6 Hz, 2H), 6.77 (s, 1H), 4.14 (br t, J = 6.0 Hz, 2H), 4.08 - 4.02 (m, 1H), 3.88 (s, 2H), 3.49 - 3.47 (m, 4H), 3.28 (s, 2H), 2.60 (t, J = 5.8 Hz, 2H), 2.30 - 2.12 (m, 1H), 2.01 (s, 3H), 1.94 (s, 3H), 1.86 - 1.63 (m, 1H).

[1279]

[1280] 18-7. (3R)-1-(2-((3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl)pyrrolidine-3-carboxylic acid, 화합물 77의 제조

[1281]

[1282]

[1283] To a DMF (15 mL) solution of N-[3-[3-[[5-[(2-hydroxyethylamino)methyl]pyridine-2-carbonyl]amino]-2-methyl-phenyl]-2-methyl-phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (220 mg, 398.10 μmol, 1 eq) and (3R)-pyrrolidine-3-carboxylic acid (320.83 mg, 2.79 mmol, 7 eq) was added HOAc (239.06 mg, 3.98 mmol, 227.89 μL, 10 eq), and the mixture was stirred at 60 °C for 2 h. NaBH3CN (125.08 mg, 1.99 mmol, 5 eq) was added to the mixture, stirred at 60 °C for 2 hours, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 10%-40% B over 9 min) to obtain compound 77 (62 mg, 22.7% yield) as a white solid.

[1284] LCMS m / z 652.5 [M+1] + .

[1285] 1H NMR (400 MHz, DMSO-d6) δ = 10.34 (s, 1H), 9.55 (br s, 1H), 8.68 (s, 1H), 8.14 (d, J = 8.0 Hz, 1H), 8.03 (br d, J = 8.0 Hz, 1H), 7.88 (br d, J = 8.0 Hz, 1H), 7.58 (br dd, J = 3.3, 7.8 Hz, 1H), 7.40 - 7.20 (m, 2H), 6.98 (br d, J = 7.4 Hz, 2H), 6.67 (d, J = 4.3 Hz, 1H), 4.31 - 4.04 (m, 3H), 3.87 (s, 2H), 3.81 (br s, 2H), 3.49 (br t, J = 5.7 Hz, 3H), 2.95 - 2.82 (m, 2H), 2.78 - 2.67 (m, 2H), 2.65 - 2.55 (m, 3H), 2.25 (br s, 1H), 2.02 (s, 3H), 1.95 (s, 6H).

[1286]

[1287] 18-8. N-(3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-4-(4-hydroxypiperidin-1-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, 화합물 78의 제조

[1288]

[1289]

[1290] To a solution of N-(3-bromo-2-methyl-phenyl)-5-formyl-pyridine-2-carboxamide (1 g, 3.13 mmol, 1 eq) in MeOH (20 mL) were added 2-aminoethanol (1.91 g, 31.33 mmol, 1.89 mL, 10 eq), NaBH3CN (984.48 mg, 15.67 mmol, 5 eq), and AcOH (940.77 mg, 15.67 mmol, 896.83 μL, 5 eq), and the mixture was stirred at room temperature for 12 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by reversed-phase HPLC (column: Waters X bridge 150 * 25 mm * 5 um; mobile phase: [water (NH4HCO3) - ACN]; radient: 14% - 44% B over 9 min) to obtain compound 78-1 (473 mg, 38.5% yield) as a white solid.

[1291] LCMS m / z 363.06 [M+3] + .

[1292] 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.12 (br s, 2 H) 2.51 (s, 3 H) 2.87 (t, J=5.07 Hz, 2 H) 3.66 - 3.81 (m, 2 H) 3.98 (s, 2 H) 7.14 (t, J=8.07 Hz, 1 H) 7.41 (d, J=8.00 Hz, 1 H) 7.93 (br d, J=7.63 Hz, 1 H) 8.12 - 8.24 (m, 1 H) 8.27 (d, J=7.88 Hz, 1 H) 8.62 (s, 1 H) 10.10 (br s, 1 H).

[1293]

[1294]

[1295] 4-(4-hydroxy-1-piperidyl)-N-[2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide (100 mg, 208.16 μmol, 1 eq), N-(3-bromo-2-methyl-phenyl)-5-[(2-hydroxyethylamino)methyl]pyridine-2-carboxamide (75.82 mg, 208.16 μmol, 1 eq), ditert-butyl(cyclopentyl)phosphane;dichloropalladium iron (13.57 mg, 20.82 μmol, 0.1 eq), K2CO3 (86.31 mg, 624.47 μmol, 3 eq) of dioxane (2.5 mL) / H2O (0.5 mL) mitxure was stirred at 90 °C under nitrogen for 4 h. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by reversed-phase HPLC (column: Waters X bridge 150 * 25 mm * 5 um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 25% - 55% B over 9 min) to obtain compound 78 (17 mg, 12.7% yield) as a yellow solid.

[1296] LCMS m / z 637.84 [M+1] + .

[1297] 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.54 - 1.66 (m, 2 H) 1.77 - 1.85 (m, 1 H) 1.86 - 1.94 (m, 3 H) 2.06 (s, 3 H) 2.12 (s, 4 H) 2.21 - 2.29 (m, 1 H) 2.38 - 2.47 (m, 1 H) 2.53 - 2.61 (m, 1 H) 2.76 - 2.90 (m, 5 H) 3.63 (dt, J=8.82, 4.47 Hz, 1 H) 3.70 - 3.74 (m, 2 H) 3.96 - 4.01 (m, 2 H) 4.02 - 4.15 (m, 3 H) 4.23 - 4.32 (m, 1 H) 6.84 (s, 1 H) 7.07 (dd, J=7.88, 3.63 Hz, 3 H) 7.34 (q, J=8.30 Hz, 3 H) 7.67 (d, J=7.63 Hz, 1 H) 7.93 (d, J=7.63 Hz, 1 H) 8.03 - 8.08 (m, 1 H) 8.21 - 8.25 (m, 1 H) 8.72 (br d, J=1.38 Hz, 1 H).

[1298]

[1299]

[1300] 18-9. 1-(2-((3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl)piperidine-4-carboxylic acid, 화합물 79의 제조

[1301]

[1302]

[1303] methyl 1-[2-[[2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]piperidine-4-carboxylate (100 mg, 191.41 μmol, 1 eq), N-(3-bromo-2-methyl-phenyl)-5-[(2-hydroxyethylamino)methyl]pyridine-2-carboxamide (69.72 mg, 191.41 μmol, 1 eq), ditert-butyl(cyclopentyl)phosphane;dichloropalladium iron (12.47 mg, 19.14 μmol, 0.1 eq) and K2CO3 (79.36 mg, 574.23 μmol, 3 eq) A mixture of dioxane (2.5 mL) / H2O (0.5 mL) was stirred at 90 °C under nitrogen for 6 hours. The mixture was concentrated under reduced pressure, purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / 1), and further purified by reversed-phase HPLC (column: Phenomenex Luna C18 150 * 25 mm * 10 um; mobile phase: [water (TFA)-ACN]; gradient: 13%-43% B over 9 min) to obtain compound 79-1 (100 mg, 67.6% yield) as a white solid.

[1304] LCMS m / z 680.6 [M+1] + .

[1305]

[1306]

[1307] methyl 1-[2-[[3-[3-[[5-[(2-hydroxyethylamino)methyl]pyridine-2-carbonyl]amino]-2-methyl-phenyl]-2-methyl-phenyl]carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]piperidine-4-carboxylate (100 mg, A H2O (4 mL) / MeOH (20 mL) mixture of 147.10 μmol, 1.49 μL, 1 eq) and LiOH (30.86 mg, 735.50 μmol, 5 eq) was stirred at room temperature for 12 hours. After concentrating the mixture under reduced pressure, the residue was purified by reversed-phase HPLC (column: Phenomenex Luna C18 150 * 25 mm * 10 um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 15%- 45% B over 10 min) to obtain compound 79 (52 mg, 52.5% yield) as a yellow solid.

[1308] LCMS m / z 666.4 [M+1] + .

[1309] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 - 1.73 (m, 4 H) 1.79 - 1.91 (m, 3 H) 1.96 (s, 3 H) 2.03 (s, 3 H) 2.12 - 2.36 (m, 5 H) 2.59 - 2.61 (m, 2 H) 2.67 - 2.74 (m, 2 H) 2.77 - 2.85 (m, 1 H) 3.47 - 3.50 (m, 2 H) 3.87 (s, 2 H) 3.97 (br dd, J=10.51, 4.28 Hz, 1 H) 4.05 - 4.11 (m, 1 H) 4.18 - 4.24 (m, 1 H) 4.49 - 4.56 (m, 1 H) 6.64 (s, 1 H) 6.99 (d, J=7.58 Hz, 2 H) 7.31 (dt, J=15.98, 7.84 Hz, 2 H) 7.58 (t, J=6.48 Hz, 1 H) 7.89 (d, J=7.58 Hz, 1 H) 8.01 - 8.05 (m, 1 H) 8.15 (d, J=7.95 Hz, 1 H) 8.69 (s, 1 H) 9.55 (d, J=5.75 Hz, 1 H) 10.34 (s, 1 H).

[1310]

[1311] 18-10. 2-((2-((3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl)amino)-2-methylpropanoic acid, 화합물 80의 제조

[1312]

[1313]

[1314] N-(3-bromo-2-methyl-phenyl)-5-[(2-hydroxyethylamino)methyl]pyridine-2-carboxamide 71-7 (121.07 mg, 332.39 μmol, 1.1 eq), methyl 2-methyl-2-[[2-[[2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]amino]propanoate (150 mg, 302.17 μmol, 1 eq), CsF (91.80 mg, 604.34 μmol, 22.31 μL, 2 eq), ditert-butyl(cyclopentyl)phosphane;dichloropalladium;iron (19.69 A mixture of dioxane (5 mL) / H2O (1 mL) (mg, 30.22 μmol, 0.1 eq) was stirred at 80 °C for 4 h under N2 conditions. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, DCM: MeOH = 0:1) to obtain compound 80-1 (100 mg, 38.9% yield) as a yellow solid.

[1315] LCMS m / z 654.4 [M+1] + .

[1316]

[1317]

[1318] To a THF (20 mL) / H2O (10 mL) solution of methyl 2-[[2-[[3-[3-[[5-[(2-hydroxyethylamino)methyl]pyridine-2-carbonyl]amino]-2-methyl-phenyl]-2-methyl-phenyl]carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]amino]-2-methyl-propanoate 80-1 (100 mg, 152.96 μmol, 1 eq) was added LiOH·H2O (19.26 mg, 458.88 μmol, 3 eq), and the mixture was stirred at room temperature for 12 h. The mixture was concentrated under reduced pressure and purified by reversed-phase HPLC ((0.1% NH3ㆍH2O condition) column: Phenomenex Luna C18 150 * 25 mm * 10 um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 12%-42% B over 10 min) to obtain compound 80 (17 mg, 17.2% yield) as a white solid.

[1319] LCMS m / z 640.4 [M+1] + .

[1320] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.29 (d, J=3.75 Hz, 6 H) 1.59 - 1.69 (m, 1 H) 1.94 (s, 4 H) 2.02 (s, 4 H) 2.08 (s, 3 H) 2.11 - 2.18 (m, 1 H) 2.55 - 2.62 (m, 3 H) 3.86 (s, 3 H) 3.90 - 3.96 (m, 2 H) 4.08 - 4.14 (m, 2 H) 6.75 (s, 1 H) 6.98 (d, J=7.50 Hz, 2 H) 7.25 - 7.35 (m, 2 H) 7.58 (d, J=7.88 Hz, 1 H) 7.88 (d, J=8.13 Hz, 1 H) 7.98 - 8.06 (m, 1 H) 8.14 (d, J=7.88 Hz, 1 H) 8.68 (s, 1 H) 9.52 (s, 1 H) 10.28 - 10.38 (m, 1 H)

[1321]

[1322] [Manufacturing Example 19]

[1323] Preparation of compounds 81 to 90

[1324]

[1325] 19-1. Preparation of N-(2,2'-dichloro-3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-[1,1'-biphenyl]-3-yl)-4-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, compound 81

[1326]

[1327]

[1328] To a mixture of potassium trifluoro(vinyl)boranuide (20.00 g, 149.28 mmol, 1.29 eq) and dioxane (400 mL) / H2O (80 mL) were added Pd(dppf)Cl2 (8.5 g, 11.62 mmol, 0.1 eq) and Na2CO3 (37 g, 349.09 mmol, 3.02 eq), and the mixture was stirred at 90 °C under nitrogen for 18 h. The mixture was filtered, and the filtrate was diluted with H2O (200 mL) and extracted with EA (300 mL x 2). The organic layer was washed with brine (200 mL x 3), dried over Na2SO4, concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (Eluent of 0–30% Ethyl acetate / Petroleum) to obtain compound 81-2 (16.4 g, 86.8% yield) as a yellow liquid.

[1329] LCMS m / z 163.8 [M+1] + .

[1330] 1 H NMR (400MHz, Choroform-d) δ 8.72 (d, J =2.0 Hz, 1H), 8.10 (d, J =8.0 Hz, 1H), 7.86 (dd, J =2.1, 8.2 Hz, 1H), 6.76 (dd, J =10.9, 17.7 Hz, 1H), 5.95 (d, J =17.6 Hz, 1H), 5.53 (d, J =11.0 Hz, 1H), 4.00 (s, 3H).

[1331]

[1332]

[1333] LiHMDS (1 M, 36.77 mL, 2 eq) was added to a THF (100 mL) solution of compound 81-2 (3 g, 18.39 mmol, 1 eq) and compound 81-3 (4.5 g, 21.80 mmol, 1.19 eq) at 0°C, and the mixture was stirred at room temperature for 16 h. Aq. saturated NH4Cl solution (100 mL) and H2O (50 mL) were added sequentially to the mixture, and then extracted with EA (100 mL x 2). The organic layer was separated into aq. After washing with saturated NaCl solution (200 mL x 2), drying with Na2SO4, and concentration under reduced pressure, the residue was separated by flash silica gel chromatography (Eluent of 0~30% Ethyl acetate / Petroleum), and then triturated with petroleum ether / EA (10:1, 80 mL) to obtain compound 81-4 (4.8 g, 77.3% yield) as a white solid.

[1334] LCMS (m / z 338.7 [M+1] + .

[1335] 1 H NMR (400MHz, DMSO-d6) δ 10.68 (s, 1H), 8.86 (d, J =1.5 Hz, 1H), 8.41 - 8.32 (m, 1H), 8.25 - 8.19 (m, 1H), 8.19 - 8.12 (m, 1H), 7.60 (dd, J =1.0, 8.0 Hz, 1H), 7.37 (t, J =8.2 Hz, 1H), 6.90 (dd, J =11.0, 17.8 Hz, 1H), 6.19 (d, J =17.6 Hz, 1H), 5.58 (d, J =11.0 Hz, 1H).

[1336]

[1337]

[1338] Compound 81-4 (3.8 g, 11.26 mmol, 1 eq) was cooled to 0°C in a THF (90 mL) / H2O (45 mL) mixture, and dipotassium dioxide (dioxo) osmium dihydrate (24.88 mg, 67.54 μmol, 0.006 eq) and NaIO4 (7.22 g, 33.77 mmol, 1.87 mL, 3 eq) were slowly added. The mixture was stirred at room temperature for 2 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 81-5 (4.4 g, 89% yield) as a white solid, which was used in the next reaction without further purification.

[1339] 1 H NMR (400MHz, DMSO-d6) δ 10.76 (s, 1H), 10.26 - 10.17 (m, 1H), 9.22 (d, J =1.5 Hz, 1H), 8.52 (dd, J=2.0, 8.0 Hz, 1H), 8.36 (d, J =8.0 Hz, 1H), 8.26 (dd, J =1.2, 8.2 Hz, 1H), 7.63 (dd, J =1.2, 8.1 Hz, 1H), 7.38 (t, J =8.2 Hz, 1H).

[1340]

[1341]

[1342] To a solution of compound 81-5 (2.9 g, 8.54 mmol, 1 eq) and 2-aminoethanol (725.00 mg, 11.87 mmol, 717.82 uL, 1.39 eq) in DMF (80 mL) was added HOAc (1.22 g, 20.28 mmol, 1.16 mL, 2.38 eq) and stirred at 60 °C for 30 min. To the mixture was added NaBH3CN (1.9 g, 30.24 mmol, 3.54 eq) and stirred at 60 °C for 3 h. The mixture was diluted with H2O (200 mL), washed with aq. saturated NaHCO3 solution to pH 8, and extracted with EA (200 mL x 2). The organic layer was dried over Na2SO4, concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (Eluent of 0–20% MeOH / DCM) to obtain compound 81-6 (1.4 g, 39.8% yield) as a yellow solid.

[1343] LCMS m / z 396.0 [M+1] + .

[1344] 1 H NMR (400MHz, DMSO-d6) δ 10.72 (s, 1H), 8.71 (d, J =1.4 Hz, 1H), 8.37 (dd, J =1.3, 8.2 Hz, 1H), 8.16 (d, J =8.0 Hz, 1H), 8.06 (dd, J =2.0, 8.0 Hz, 1H), 7.61 (dd, J =1.4, 8.1 Hz, 1H), 7.38 (t, J =8.2 Hz, 1H), 4.53 (br s, 1H), 3.88 (s, 2H), 3.54 - 3.46 (m, 2H), 2.60 (t, J =5.8 Hz, 2H).

[1345]

[1346]

[1347] To a dioxane (20 mL) / H2O (4 mL) mixture of compound 81-6 (500 mg, 1.30 mmol, 1 eq) and compound 81-7 (800.00 mg, 1.92 mmol, 1.48 eq), K3PO4 (850 mg, 4.00 mmol, 3.08 eq), diitert-butyl(cyclopentyl)phosphane;dichloropalladium iron (83.33 mg, 127.86 umol, 9.84e-2 eq) was added, and the mixture was stirred at 70°C under nitrogen for 5 hours. The mixture was diluted with H2O (50 mL) and extracted with EA (50 mL x 2). The organic layer was separated into aq. Washing with saturated NaCl solution (50 mL x 3), drying with Na2SO4, and concentrating under reduced pressure, the residue was purified by flash silica gel chromatography (Eluent of 0~20% DCM / MeOH) to obtain compounds 81-8 (450 mg, 55.4% yield) and 81 (209.5 mg, 68.5% yield) as yellow and white solids, respectively.

[1348]

[1349]

[1350] LCMS 594.9 m / z [M+1] + .

[1351] 1H NMR (400MHz, DMSO-d6) δ 10.73 (s, 1H), 9.83 (s, 1H), 8.70 (s, 1H), 8.53 (d, J =8.0 Hz, 1H), 8.19 (d, J =8.0 Hz, 1H), 8.11 (d, J =8.0 Hz, 1H), 8.06 (br d, J =8.0 Hz, 1H), 7.53 (td, J =8.0, 11.0 Hz, 2H), 7.30 (s, 1H), 7.24 (d, J =7.5 Hz, 1H), 7.19 (d, J =7.4 Hz, 1H), 4.49 (td, J =5.7, 13.4 Hz, 3H), 3.86 (s, 2H), 3.48 (q, J =5.6 Hz, 2H), 2.72 (t, J =6.3 Hz, 2H), 2.68 (s, 1H), 2.58 (t, J =5.8 Hz, 2H), 2.38 - 2.31 (m, 3H).

[1352]

[1353]

[1354] LCMS 594.9m / z [M+1] + .

[1355] 1H NMR (400MHz, DMSO-d6) δ 10.73 (s, 1H), 9.56 (s, 1H), 8.70 (s, 1H), 8.53 (br d, J =8.0 Hz, 1H), 8.35 - 8.27 (m, 1H), 8.19 (d, J =8.0 Hz, 1H), 8.06 (br d, J =7.8 Hz, 1H), 7.52 (td, J =7.8, 15.4 Hz, 2H), 7.18 (br d, J =7.5 Hz, 2H), 6.75 (s, 1H), 5.61 (br d, J =5.0 Hz, 1H), 4.77 (br d, J =5.3 Hz, 1H), 4.56 - 4.45 (m, 1H), 4.15 (br s, 2H), 3.86 (s, 2H), 3.53 - 3.43 (m, 2H), 2.58 (br t, J=5.8 Hz, 3H), 2.20 - 2.14 (m, 1H), 2.16 (br s, 1H), 2.06 - 1.99 (m, 1H), 1.93 (br d, J =6.5 Hz, 1H), 2.08 - 1.87 (m, 1H), 1.78 - 1.71 (m, 1H).

[1356]

[1357] 19-2. 4-((2-acetamidoethyl)amino)-N-(2,2'-dichloro-3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-[1,1'-biphenyl]-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, 화합물 82의 제조

[1358]

[1359]

[1360] A mixture of MeOH (4 mL) / THF (4 mL) / DMF (2 mL) containing compound 81-8 (200 mg, 337.01 μmol, 1 eq), compound 81-9 (200.00 mg, 1.96 mmol, 186.92 uL, 5.81 eq), and AcOH (210.00 mg, 3.50 mmol, 200.00 uL, 10.38 eq) was stirred at 60 °C for 30 min, and then NaBH3CN (120.00 mg, 1.91 mmol, 5.67 eq) was added. The mixture was stirred at 60 °C for 18 h. The mixture was diluted with H2O (25 mL) and extracted with EA (50 mL x 2). The organic layer was filtered and filtered with aq. Washed with saturated NaCl solution (50 mL x 3), dried over Na2SO4, concentrated under reduced pressure, the residue was purified by prep-HPLC (column: Phenomenex C18 80*40mm*3um; mobile phase: [water (NH4HCO3)-ACN]; B%: 36%-66%, 8 min) to obtain compound 82 (105.65 mg, 44.3% yield) as a white solid.

[1361] LCMS 681.3 m / z [M+1] + .

[1362] 1H NMR (400MHz, DMSO-d6) δ 10.73 (s, 1H), 9.55 (s, 1H), 8.70 (s, 1H), 8.54 (br d, J =8.0 Hz, 1H), 8.35 - 8.28 (m, 1H), 8.19 (d, J =7.8 Hz, 1H), 8.06 (br d, J =7.8 Hz, 1H), 7.84 (br s, 1H), 7.52 (td, J =7.9, 15.5 Hz, 2H), 7.19 (br d, J =7.5 Hz, 2H), 6.80 (s, 1H), 4.50 (br t, J =5.3 Hz, 1H), 4.21 - 4.10 (m, 2H), 3.92 - 3.85 (m, 3H), 3.48 (q, J =5.4 Hz, 2H), 3.14 (q, J =6.2 Hz, 2H), 2.64 (br t, J =6.4 Hz, 2H), 2.58 (br t, J =5.8 Hz, 3H), 2.19 (br d, J =8.0 Hz, 1H), 2.32 (br d, J =15.6 Hz, 1H), 2.00 (br d, J =4.8 Hz, 1H), 1.91 (br d, J =7.0 Hz, 1H), 1.81 (s, 3H), 1.72 - 1.62 (m, 1H).

[1363]

[1364] 19-3. N-(2,2'-dichloro-3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-[1,1'-biphenyl]-3-yl)-4-((2-hydroxyethyl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, 화합물 83의 제조

[1365]

[1366]

[1367] A solution of compound 81-8 (150 mg, 252.76 μmol, 1 eq), 2-aminoethanol (60.00 mg, 982.29 μmol, 59.41 μL, 3.89 eq), and AcOH (157.50 mg, 2.62 mmol, 150.00 μL, 10.38 eq) in MeOH (3 mL) / THF (3 mL) / DMF (1.5 mL) was stirred at 60 °C for 30 min. NaBH3CN (90.00 mg, 1.43 mmol, 5.67 eq) was added to the reaction mixture, and the mixture was stirred at 60 °C for 18 h. The reaction mixture was diluted with H2O (25 mL) and extracted with EA (20 mL x 2). The organic layer was filtered and washed with aq. Washed with saturated NaCl solution (50 mL x 3), dried over Na2SO4, concentrated under reduced pressure, the residue was purified by prep-HPLC (column: Phenomenex C18 80*40mm*3um; mobile phase: [water (NH4HCO3)-ACN]; B%: 36%-66%, 8 min) to obtain compound 83 (34.94 mg, 21.4% yield) as a white solid.

[1368] LCMS 640.3 m / z [M+1] + .

[1369] 1H NMR (400MHz, DMSO-d6) δ 10.73 (s, 1H), 9.55 (s, 1H), 8.71 (s, 1H), 8.58 - 8.49 (m, 1H), 8.35 - 8.27 (m, 1H), 8.19 (d, J =8.0 Hz, 1H), 8.09 - 8.02 (m, 1H), 7.52 (td, J =8.0, 16.1 Hz, 2H), 7.19 (br d, J =7.5 Hz, 2H), 6.79 (s, 1H), 4.51 (q, J =5.5 Hz, 2H), 4.20 - 4.11 (m, 2H), 3.89 (br d, J =6.3 Hz, 1H), 3.86 (s, 2H), 3.48 (q, J =5.7 Hz, 4H), 2.68 (br d, J =2.0 Hz, 2H), 2.58 (br t, J =5.8 Hz, 3H), 2.18 (br s, 1H), 2.24 - 2.11 (m, 1H), 2.03 (br d, J =7.3 Hz, 1H), 1.91 (br s, 1H), 1.69 (br d, J =11.3 Hz, 1H).

[1370]

[1371] 19-4. N-(2,2'-dichloro-3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-[1,1'-biphenyl]-3-yl)-4-((((S)-5-oxopyrrolidin-3-yl)methyl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, 화합물 84의 제조

[1372]

[1373]

[1374] To a DMF (3 mL) mixture of compound 81-8 (120 mg, 202.20 μmol, 1 eq), (5S)-5-(aminomethyl)pyrrolidin-2-one (180.00 mg, 1.20 mmol, 5.91 eq, HCl), and AcOH (126.00 mg, 2.10 mmol, 120.00 uL, 10.38 eq) was added NaBH3CN (72.00 mg, 1.15 mmol, 5.67 eq), and the mixture was stirred at 60 °C for 18 h. The reaction mixture was diluted with H2O (25 mL) and extracted with EA (20 mL x 2). The organic layer was filtered and filtered with aq. Washed with saturated NaCl solution (50 mL x 3), dried over Na2SO4, concentrated under reduced pressure, the residue was purified by prep-HPLC (column: Phenomenex C18 80*40mm*3um; mobile phase: [water (NH4HCO3)-ACN]; B%: 34%-64%, 8 min) to obtain compound 84 (43.8 mg, 30.9% yield) as a white solid.

[1375] LCMS 692.8 m / z [M+1] + .

[1376] 1H NMR (400MHz, DMSO-d6) δ 10.73 (s, 1H), 9.55 (s, 1H), 8.70 (s, 1H), 8.53 (d, J =6.8 Hz, 1H), 8.34 - 8.27 (m, 1H), 8.19 (d, J =8.0 Hz, 1H), 8.11 - 8.02 (m, 1H), 7.70 (br d, J =18.8 Hz, 1H), 7.52 (td, J =7.9, 15.5 Hz, 2H), 7.19 (br d, J =7.5 Hz, 2H), 6.84 (d, J =11.8 Hz, 1H), 4.50 (t, J =5.4 Hz, 1H), 4.21 - 4.10 (m, 2H), 3.86 (s, 3H), 3.58 (br s, 1H), 3.48 (q, J =5.6 Hz, 2H), 2.68 (br s, 1H), 2.62 - 2.55 (m, 4H), 2.22 - 1.98 (m, 6H), 1.91 (br d, J =7.0 Hz, 1H), 1.77 - 1.65 (m, 2H).

[1377]

[1378] 19-5. N-(2,2'-dichloro-3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-[1,1'-biphenyl]-3-yl)-4-((R)-3-hydroxypyrrolidin-1-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, 화합물 85의 제조

[1379]

[1380]

[1381] A DMF (6 mL) mixture of compound 81-8 (250 mg, 421.26 μmol, 1 eq), (3R)-pyrrolidin-3-ol (250.01 mg, 2.87 mmol, 238.10 μL, 6.81 eq), and AcOH (262.50 mg, 4.37 mmol, 250 μL, 10.38 eq) was stirred at 60°C for 30 min. NaBH3CN (150.00 mg, 2.39 mmol, 5.67 eq) was added to the reaction mixture, and the mixture was stirred at 60°C for 18 h. The mixture was diluted with H2O (20 mL), adjusted to pH 8 with aq. saturated NaHCO3 solution, and extracted with EA (50 mL x 2). The organic layer was dried over Na2SO4, concentrated under reduced pressure, and the residue was purified by prep-HPLC (column: Phenomenex C18 80*40mm*3um; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; B%: 36%-66%, 8 min) to obtain compound 85 (82.65 mg, 28.7% yield) as a white solid.

[1382] LCMS 664.4 m / z [M+1] + .

[1383] 1H NMR (400MHz, DMSO-d6) δ 10.73 (s, 1H), 9.56 (s, 1H), 8.71 (s, 1H), 8.53 (br d, J =8.0 Hz, 1H), 8.28 (br d, J =7.5 Hz, 1H), 8.19 (d, J =8.0 Hz, 1H), 8.07 (br d, J =7.5 Hz, 1H), 7.52 (td, J =7.7, 15.9 Hz, 2H), 7.19 (br d, J =7.5 Hz, 2H), 6.74 (d, J =8.5 Hz, 1H), 4.76 - 4.67 (m, 1H), 4.53 (br s, 1H), 4.18 (br s, 3H), 3.88 (s, 2H), 3.81 (br s, 1H), 3.48 (br d, J =5.3 Hz, 1H), 2.92 - 2.87 (m, 1H), 2.78 (br dd, J =6.4, 14.2 Hz, 2H), 2.71 (br d, J =7.5 Hz, 1H), 2.59 (br t, J =5.8 Hz, 3H), 2.44 (br d, J =6.5 Hz, 1H), 2.24 (br s, 1H), 1.96 (br s, 1H), 1.89 (br s, 3H), 1.57 (br s, 1H).

[1384]

[1385] 19-6. (3R)-1-(2-((2,2'-dichloro-3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl)pyrrolidine-3-carboxylic acid, 화합물 86의 제조

[1386]

[1387]

[1388] A solution of compound 81-8 (250 mg, 421.26 μmol, 1 eq), (3R)-pyrrolidine-3-carboxylic acid (250.01 mg, 2.17 mmol, 5.15 eq), and AcOH (262.51 mg, 4.37 mmol, 250.01 uL, 10.38 eq) in DMF (6 mL) was stirred at 60°C for 30 min. NaBH3CN (150.00 mg, 2.39 mmol, 5.67 eq) was added to the reaction mixture, and the mixture was stirred at 60°C for 30 min. The reaction mixture was diluted with H2O (25 mL) and extracted with EA (20 mL x 2). The organic layer was filtered and washed with aq. Washing with saturated NaCl solution (50 mL x 3), drying with Na2SO4, and concentrating under reduced pressure, the residue was purified by flash silica gel chromatography (Eluent of 0~40% MeOH / EA) to obtain compound 81-9 (110 mg, 35.1% yield) as a white solid.

[1389] LCMS 706.4 m / z [M+1] + .

[1390]

[1391]

[1392] LiOHㆍH2O (50 mg, 2.09 mmol, 13.41 eq) was added to a THF (2 mL) / H2O (0.5 mL) mixture of compound 81-9 (110 mg, 155.67 μmol, 1 eq) and stirred at room temperature for 5 h. The mixture was adjusted to pH 7 with aq. 1 N HCl solution, concentrated under reduced pressure, and the residue was purified by prep-HPLC (column: Phenomenex C18 80*40mm*3 μm; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; B%: 17%-47%, 8 min) to obtain compound 86 (41.11 mg, 37.99 yield) as a white solid.

[1393] LCMS 692.4 m / z [M+1] + .

[1394] 1 H NMR (400MHz, DMSO-d6) δ 10.72 (s, 1H), 9.56 (s, 1H), 8.69 (s, 1H), 8.52 (d, J =8.0 Hz, 1H), 8.28 (br s, 1H), 8.18 (d, J =8.0 Hz, 1H), 8.05 (d, J =7.5 Hz, 1H), 7.51 (td, J =8.0, 15.7 Hz, 2H), 7.18 (d, J =7.5 Hz, 2H), 6.72 (d, J =4.5 Hz, 1H), 4.49 (br s, 1H), 4.17 (br d, J =10.8 Hz, 2H), 3.87 - 3.79 (m, 3H), 3.47 (br t, J =5.4 Hz, 2H), 2.90 (br s, 2H), 2.86 - 2.77 (m, 1H), 2.72 (br s, 2H), 2.62 - 2.54 (m, 3H), 2.24 (br s, 1H), 2.00 - 1.86 (m, 5H).

[1395]

[1396] 19-7. N-(2,2'-dichloro-3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-[1,1'-biphenyl]-3-yl)-4-(4-hydroxypiperidin-1-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, 화합물 87의 제조

[1397]

[1398]

[1399] N-(3-bromo-2-chloro-phenyl)-5-[(2-hydroxyethylamino)methyl]pyridine-2-carboxamide (69.82 mg, 181.52 μmol, 1 eq), N-[2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(4-hydroxy-1-piperidyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide (100 mg, 199.67 μmol, 1.1 eq), of ditert-butyl(cyclopentyl)phosphane;dichloropalladium iron (11.83 mg, 18.15 μmol, 0.1 eq), K2CO3 (75.26 mg, 544.56 μmol, 3 eq) A mixture of dioxane (5 mL) and H2O (1 mL) was stirred at 90 °C under nitrogen for 12 h. The mixture was concentrated under reduced pressure and purified by reversed-phase HPLC (column: Waters Xbridge 150 * 25 mm * 5 um; mobile phase: [water (NH4HCO3) - ACN]; gradient: 32% - 62% B over 9 min) to obtain compound 87 (26 mg, 20.9% yield) as a white solid.

[1400] LCMS m / z 678.3 [M+1] + .

[1401] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.30 - 1.51 (m, 2 H) 1.61 - 1.80 (m, 3 H) 1.82 - 2.02 (m, 2 H) 2.10 - 2.45 (m, 4 H) 2.58 (t, J=5.75 Hz, 2 H) 2.62 - 2.79 (m, 2 H) 3.48 (q, J=5.71 Hz, 3 H) 3.86 (s, 2 H) 3.97 (br dd, J=9.76, 5.13 Hz, 1 H) 4.01 - 4.12 (m, 1 H) 4.16 - 4.25 (m, 1 H) 4.47 - 4.61 (m, 2 H) 6.66 (s, 1 H) 7.19 (d, J=7.50 Hz, 2 H) 7.52 (dt, J=15.54, 7.93 Hz, 2 H) 8.06 (dd, J=8.00, 2.00 Hz, 1 H) 8.19 (d, J=8.00 Hz, 1 H) 8.28 (ddd, J=8.16, 4.53, 1.44 Hz, 1 H) 8.53 (dd, J=8.32, 1.44 Hz, 1 H) 8.70 (d, J=1.38 Hz, 1 H) 9.55 (d, J=1.63 Hz, 1 H) 10.73 (s, 1 H).

[1402]

[1403] 19-8. 2-((2-((2,2'-dichloro-3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl)amino)acetic acid, 화합물 89의 제조

[1404]

[1405]

[1406] A solution of compound 81-8 (500 mg, 842.52 μmol, 1 eq), methyl 2-aminoacetate; hydrochloride (400 mg, 3.19 mmol, 3.78 eq), and AcOH (525.01 mg, 8.75 mmol, 500.01 uL, 10.38 eq) in DMF (6 mL) was stirred at 60°C for 30 min. NaBH3CN (300.00 mg, 4.78 mmol, 5.67 eq) was added to the reaction mixture, and the mixture was stirred at 60°C for 18 h. The reaction mixture was diluted with H2O (25 mL) and extracted with EA (20 mL x 2). The organic layer was filtered and washed with aq. Washing with saturated NaCl solution (50 mL x 3), drying with Na2SO4, and concentrating under reduced pressure, the residue was purified by flash silica gel chromatography (Eluent of 0–30% DCM / MeOH) to obtain compound 81-10 (160 mg, 13.3% yield) as a brown solid.

[1407] LCMS 666.4 m / z [M+1] + .

[1408]

[1409]

[1410] LiOHㆍH2O (70 mg, 2.92 mmol, 10.82 eq) was added to a THF (4 mL) / H2O (1 mL) solution of compound 81-10 (180 mg, 270.05 μmol, 1 eq) and stirred at room temperature for 5 hours. The mixture was adjusted to pH 7 with aq. 1 N HCl solution and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex C18 80*40mm*3 μm; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; B%: 16%-46%, 8 min) to obtain compound 89 (53.19 mg, 30.1% yield) as a white solid.

[1411] LCMS 652.3 m / z [M+1] + .

[1412] 1 H NMR (400MHz, DMSO-d6) δ 10.73 (s, 1H), 9.57 (s, 1H), 8.70 (s, 1H), 8.53 (d, J =8.0 Hz, 1H), 8.27 (d, J =8.0 Hz, 1H), 8.19 (d, J =7.8 Hz, 1H), 8.06 (br d, J =8.0 Hz, 1H), 7.51 (td, J =8.0, 15.7 Hz, 2H), 7.18 (d, J =7.8 Hz, 2H), 6.82 (s, 1H), 4.15 (br t, J =6.0 Hz, 2H), 4.03 (br t, J =5.4 Hz, 1H), 3.87 (s, 2H), 3.49 - 3.46 (m, 6H), 3.30 (s, 2H), 2.58 (t, J =5.8 Hz, 2H), 2.18 (br s, 1H), 2.00 (br s, 1H), 1.90 (br d, J =4.3 Hz, 1H), 1.74 (br s, 1H).

[1413]

[1414] 19-9. 1-(2-((2,2'-dichloro-3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl)piperidine-4-carboxylic acid, 화합물 88의 제조

[1415]

[1416]

[1417] To a THF (80 mL) solution of N-(3-bromo-2-chloro-phenyl)-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (7 g, 18.99 mmol, 1 eq) was added NaBH4 (3.59 g, 94.95 mmol, 5 eq) at 0 °C, and the mixture was stirred at room temperature for 16 h. Aq. 4 M HCl (50 mL) was added to the mixture, and the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 1 to 0 / 1) to obtain compound 88-1 (2.5 g, 33.3% yield) as a yellow solid.

[1418] LCMS m / z 368.99 [M+3] + .

[1419] 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.66 - 1.77 (m, 2 H) 2.11 - 2.21 (m, 2 H) 4.13 - 4.18 (m, 2 H) 5.49 - 5.54 (m, 1 H) 6.72 (s, 1 H) 6.69 - 6.79 (m, 1 H) 7.32 (t, J=8.13 Hz, 1 H) 7.58 (dd, J=8.07, 1.19 Hz, 1 H) 8.11 (d, J=7.68 Hz, 1 H) 9.63 (s, 1 H).

[1420]

[1421]

[1422] To a solution of N-(3-bromo-2-chloro-phenyl)-4-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide (2.5 g, 6.75 mmol, 1 eq) in DCM (30 mL) was added SOCl2 (4.01 g, 33.73 mmol, 2.45 mL, 5 eq) at 0 °C and stirred at room temperature for 12 h. To the mixture was added aq. sat'd NH4Cl (200 mL) and extracted with EtOAc (200 mL*2). The organic layer was washed with brine (200 mL), dried over Na2SO4, and concentrated under reduced pressure to give compound 88-2 (2.2 g, 79.6% yield) as a yellow solid, which was used in the next reaction without further purification.

[1423] LCMS m / z 386.95 [M+3] + .

[1424] 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.10 - 2.20 (m, 2 H) 2.28 - 2.37 (m, 2 H) 4.03 (q, J=7.13 Hz, 1 H) 4.37 (dt, J=13.04, 4.61 Hz, 1 H) 5.67 (t, J=4.13 Hz, 1 H) 6.84 (s, 1 H) 7.33 (t, J=8.07 Hz, 1 H) 7.61 (dd, J=8.07, 1.31 Hz, 1 H) 8.01 (dd, J=8.19, 1.19 Hz, 1 H) 9.73 (s, 1 H).

[1425]

[1426]

[1427] To a solution of N-(3-bromo-2-chloro-phenyl)-4-chloro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide (1 g, 2.57 mmol, 1 eq) and methyl piperidine-4-carboxylate (1.10 g, 7.71 mmol, 3 eq), DIEA (996.54 mg, 7.71 mmol, 1.34 mL, 3 eq) and NaI (115.58 mg, 771.06 μmol, 0.3 eq) were added, and the mixture was stirred at 40 °C for 12 h. Methanol (40 mL) was added to the mixture to dissolve the precipitated solid, and H2O (500 mL) was added to precipitate the solid. The precipitated solid was filtered to obtain compound 88-4 (1.2 g, 60.2% yield) as a yellow solid, which was used in the next reaction without further purification.

[1428] LCMS m / z 494.07 [M+3] + .

[1429]

[1430]

[1431] methyl 1-[2-[(3-bromo-2-chloro-phenyl)carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]piperidine-4-carboxylate (300 mg, 605.09 μmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (460.96 mg, 1.82 mmol, 3 eq), AcOK (178.15 mg, 1.82 mmol, 3 eq), Pd(dppf)Cl2 (44.27 mg, 60.51 μmol, 0.1 eq) of dioxane (4 mL) mixture under nitrogen conditions at 90 °C for 12 hours. The mixture was concentrated under reduced pressure and purified by prep-TLC (SiO2, DCM: MeOH = 10:1) to obtain compound 88-5 (500 mg, 91.3% yield) as a yellow solid.

[1432] LCMS m / z 542.25 [M+1] + .

[1433]

[1434]

[1435] methyl 1-[2-[[2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]piperidine-4-carboxylate (359.88 mg, 662.93 μmol, 1.5 eq), N-(3-bromo-2-chloro-phenyl)-5-[(2-hydroxyethylamino)methyl]pyridine-2-carboxamide (170 mg, 441.95 μmol, 1 eq), dietert-butyl(cyclopentyl)phosphane;dichloropalladium;iron (28.80 mg, 44.20 μmol, 0.1 eq), K2CO3 (183.24 mg, 1.33 mmol, 3 A mixture of dioxane (5 mL) / H2O (1 mL) was stirred at 90 °C under nitrogen for 12 h. The mixture was concentrated under reduced pressure and purified by prep-TLC (SiO2, DCM: MeOH = 0:1) to obtain compound 88-6 (200 mg, 44.5% yield) as a white solid.

[1436] LCMS m / z 719.24 [M+1] + .

[1437]

[1438]

[1439] To a H2O (4 mL) / MeOH (4 mL) mixture of methyl 1-[2-[[2-chloro-3-[2-chloro-3-[[5-[(2-hydroxyethylamino)methyl]pyridine-2-carbonyl]amino]phenyl]phenyl]carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]piperidine-4-carboxylate (200 mg, 277.53 μmol, 1 eq) was added LiOHㆍH2O (34.94 mg, 832.59 μmol, 3 eq), and the mixture was stirred at room temperature for 3 hours. After concentrating the mixture under reduced pressure, the residue was purified by reversed-phase HPLC (column: Waters Xbridge Prep OBD C18 150 * 40 mm * 10 um; mobile phase: [water (NH4HCO3) - ACN]; gradient: 5% - 35% B over 15 min) to obtain compound 88 (22 mg, 11.0% yield) as a white solid.

[1440] LCMS m / z 705.22 [M+3] + .

[1441] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.47 - 1.72 (m, 3 H) 1.80 (br t, J=11.63 Hz, 2 H) 1.88 - 2.00 (m, 2 H) 2.07 - 2.30 (m, 3 H) 2.38 - 2.47 (m, 1 H) 2.59 (br s, 2 H) 2.66 (br d, J=10.51 Hz, 1 H) 2.78 (br d, J=10.13 Hz, 1 H) 3.48 (br t, J=5.57 Hz, 2 H) 3.91 - 4.08 (m, 3 H) 4.19 (br d, J=11.38 Hz, 2 H) 4.49 (br s, 3 H) 6.66 (s, 1 H) 7.17 (br d, J=7.50 Hz, 2 H) 7.43 - 7.57 (m, 2 H) 8.05 (br d, J=7.63 Hz, 1 H) 8.18 (d, J=8.00 Hz, 1 H) 8.28 (br dd, J=7.07, 4.32 Hz, 1 H) 8.53 (d, J=7.50 Hz, 1 H) 8.69 (s, 1 H) 9.53 (s, 1 H) 10.72 (s, 1 H).

[1442]

[1443] 19-10. 2-((2-((2,2'-dichloro-3'-(5-(((2-hydroxyethyl)amino)methyl)picolinamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl)amino)-2-methylpropanoic acid, 화합물 90의 제조

[1444]

[1445]

[1446] N-(3-bromo-2-chloro-phenyl)-5-[(2-hydroxyethylamino)methyl]pyridine-2-carboxamide (110 mg, 285.97 μmol, 1 eq), methyl 2-[[2-[[2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]amino]-2-methyl-propanoate (162.58 mg, 314.57 μmol, 1.1 eq), dietert-butyl(cyclopentyl)phosphane;dichloropalladium iron (18.64 mg, 28.60 μmol, 0.1 eq), K2CO3 (118.57 mg, 857.91 μmol, A mixture of dioxane (5 mL) / H2O (1 mL) (3 eq) was stirred at 90 °C under nitrogen for 12 h. The mixture was concentrated under reduced pressure, and the residue was purified by prep-TLC (SiO2, Ethyl acetate: Methanol = 3:1) to obtain compound 90-2 (200 mg, 80.5% yield) as a white solid.

[1447] LCMS m / z 694.2 [M+1] + .

[1448]

[1449]

[1450] To a solution of methyl 2-[[2-[[2-chloro-3-[2-chloro-3-[[5-[(2-hydroxyethylamino)methyl]pyridine-2-carbonyl]amino]phenyl]phenyl]carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]amino]-2-methyl-propanoate (200 mg, 287.93 μmol, 1 eq) in H2O (3 mL) / MeOH (3 mL) was added LiOHㆍH2O (36.25 mg, 863.80 μmol, 3 eq), and the mixture was stirred at room temperature for 12 hours. After concentrating the mixture under reduced pressure, the residue was purified by reversed-phase HPLC (column: Waters Xbridge 150 * 25 mm * 5 um; mobile phase: [water (NH4HCO3) - ACN]; gradient: 15% - 45% B over 9 min) to obtain compound 90 (70 mg, 35.3% yield) as a white solid.

[1451] LCMS m / z 680.3 [M+3] + .

[1452] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.29 (d, J=3.75 Hz, 7 H) 1.58 - 1.69 (m, 1 H) 1.85 - 2.19 (m, 4 H) 2.59 (t, J=5.82 Hz, 2 H) 3.87 (s, 2 H) 3.91 - 3.97 (m, 1 H) 4.07 - 4.17 (m, 2 H) 6.80 (s, 1 H) 7.18 (dt, J=7.63, 1.75 Hz, 2 H) 7.52 (dt, J=15.70, 7.91 Hz, 2 H) 8.06 (dd, J=8.00, 2.00 Hz, 1 H) 8.19 (d, J=8.00 Hz, 1 H) 8.27 - 8.32 (m, 1 H) 8.53 (dd, J=8.25, 1.38 Hz, 1 H) 8.70 (d, J=1.38 Hz, 1 H) 9.54 (s, 1 H) 10.73 (s, 1 H).

[1453]

[1454] [Manufacturing Example 20]

[1455] Preparation of compounds 91 to 99

[1456]

[1457] 20-1. Preparation of 4-((2-hydroxyethyl)amino)-N-(3'-(5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)picolinamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, compound 91

[1458]

[1459]

[1460] A mixture of methyl 5-bromopicolinate (15 g, 69.43 mmol, 1 eq), potassium trifluoro(vinyl)boranuide (18.60 g, 138.87 mmol, 2 eq), K3PO4 (44.22 g, 208.30 mmol, 3 eq), and Pd(dppf)Cl2 (2.84 g, 3.47 mmol, 0.05 eq) in dioxane (150 mL) was stirred at 100 °C for 2 h under nitrogen conditions. The mixture was diluted with H2O (400 mL) and extracted with EtOAc (200 mL*3). The organic layer was washed with brine (400 mL), dried over Na2SO4, concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (Petroleum ether / Ethyl acetate=100 / 1 to 3 / 1) to obtain compound 91-2 (10.2 g, 81.0% yield) as a yellow liquid.

[1461] LCMS m / z 164.1 [M+1] + .

[1462] 1 H NMR (400 MHz, CHLOROFORM-d) δ = 8.64 (d, J = 2.0 Hz, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.78 (dd, J = 2.3, 8.1 Hz, 1H), 6.68 (dd, J = 11.0, 17.6 Hz, 1H), 5.88 (d, J = 17.6 Hz, 1H), 5.44 (d, J = 11.0 Hz, 1H), 3.92 (s, 3H).

[1463]

[1464]

[1465] To a solution of methyl 5-vinylpyridine-2-carboxylate (9.2 g, 56.38 mmol, 1 eq) and 3-bromo-2-methyl-aniline (10.49 g, 56.38 mmol, 6.95 mL, 1 eq) in THF (150 mL) was added LiHMDS (1 M, 112.76 mL, 2 eq) at 0 °C, and the mixture was stirred at 25 °C for 2 hours. The mixture was diluted with H2O (200 mL) and extracted with EtOAc (200 mL*3). The organic layer was washed with brine (600 mL), dried over Na2SO4, concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (Petroleum ether / Ethyl acetate 100 / 1 to 3 / 1) to obtain compound 91-4 (11.2 g, 56.3% yield) as a colorless liquid.

[1466] LCMS m / z 317.0 [M+1] + .

[1467] 1 H NMR (400 MHz, DMSO-d6) δ = 10.46 (s, 1H), 8.81 (d, J = 1.8 Hz, 1H), 8.21 - 7.97 (m, 2H), 7.69 (d, J = 7.8 Hz, 1H), 7.48 (d, J = 7.3 Hz, 1H), 7.18 (t, J = 8.1 Hz, 1H), 6.89 (dd, J = 11.1, 17.8 Hz, 1H), 6.80 - 6.71 (m, 1H), 6.16 (d, J = 17.8 Hz, 1H), 5.55 (d, J = 11.3 Hz, 1H), 2.34 (s, 3H)

[1468]

[1469]

[1470] To a dioxane (80 mL) / H2O (5 mL) mixture of N-(3-bromo-2-methyl-phenyl)-5-vinyl-pyridine-2-carboxamide (3 g, 9.46 mmol, 1 eq) and 6-dimethylpyridine (2.03 g, 18.92 mmol, 2.20 mL, 2 eq) was slowly added dipotassium dioxido(dioxo)osmium dihydrate (697.00 mg, 1.89 mmol, 0.2 eq) and sodium periodate (8.09 g, 37.83 mmol, 2.10 mL, 4 eq) at room temperature over 30 minutes, and the mixture was stirred at room temperature for 12 hours. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (10 mL*3). The organic layer was washed with brine (20 mL), dried over Na2SO4, concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (Petroleum ether / Ethyl acetate=100 / 1 to 3 / 1) to obtain compound 91-5 (1.5 g, 47.2% yield) as a white solid.

[1471] LCMS m / z 319.0 [M+1] + .

[1472] 1 H NMR (400 MHz, DMSO-d6) δ = 10.65 (s, 1H), 10.23 (s, 1H), 9.33 - 9.09 (m, 1H), 8.49 (dd, J = 2.0, 8.0 Hz, 1H), 8.32 (d, J = 8.0 Hz, 1H), 7.67 - 7.47 (m, 2H), 7.20 (t, J = 8.0 Hz, 1H), 2.33 (s, 3H).

[1473]

[1474]

[1475] To a solution of N-(3-bromo-2-methyl-phenyl)-5-formyl-pyridine-2-carboxamide (1.5 g, 4.70 mmol, 1 eq) and (3R)-pyrrolidin-3-ol (409.46 mg, 4.70 mmol, 389.96 μL, 1 eq) in MeOH (60 mL) / THF (10 mL) was added HOAc (15.86 g, 264.08 mmol, 15.10 mL, 56.19 eq), and the mixture was stirred at 50 °C for 30 min. NaBH3CN (1.48 g, 23.50 mmol, 5 eq) was added to the mixture, and the mixture was stirred at 50 °C for 2 h. After concentrating the mixture under reduced pressure, the residue was purified by prep-HPLC (column: Phenomenex luna C18 (250*70mm, 10 μm); mobile phase: [water(FA)-ACN]; B%: 10%-40%, 20 min) to obtain compound 91-7 (1.2 g, 58.8% yield) as a white solid.

[1476] LCMS m / z 392.0 [M+2] + .

[1477]

[1478]

[1479] N-(3-bromo-2-methyl-phenyl)-5-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]pyridine-2-carboxamide (800 mg, 2.05 mmol, 1 eq), N-[2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (1.22 g, 3.07 mmol, 1.5 eq), K2CO3 (793.27 mg, 5.74 mmol, 2.8 eq), Pd(dppf)Cl2 (83.70 mg, 102.49 μmol, 0.05 eq) dioxane (10 mL) / H2O (1 mL) mixture The mixture was stirred at 90 °C under nitrogen conditions for 2 hours. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (10 mL*3). The organic layer was washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Dichloromethane: Methanol=100 / 1 to 5 / 1) to obtain compound 91-9 (1.02 g, 60.3% yield) as a white solid.

[1480] LCMS m / z 579.1 [M+2] + .

[1481]

[1482]

[1483] A solution of N-[3-[3-[[5-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]pyridine-2-carbonyl]amino]-2-methyl-phenyl]-2-methyl-phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (200 mg, 345.63 μmol, 1 eq), 2-aminoethanol (211.12 mg, 3.46 mmol, 209.03 μL, 10 eq), and HOAc (207.55 mg, 3.46 mmol, 197.67 μL, 10 eq) in MeOH (10 mL) / THF (10 mL) was stirred at 60 °C for 2 h. After adding NaBH3CN (65.16 mg, 1.04 mmol, 3 eq) to the mixture, the mixture was stirred at 60 °C for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5μm; mobile phase: [water (ammonia hydroxide v / v)-ACN]; B%: 20%-50%, 9 min) to obtain compound 91 (32 mg, 14.1% yield) as a white solid.

[1484] LCMS m / z 624.4 [M+1] + .

[1485] 1H NMR (400 MHz, DMSO-d6) δ = 10.32 (br s, 1H), 9.51 (br s, 1H), 8.64 (br s, 1H), 8.14 (br d, J = 8.1 Hz, 1H), 7.98 (br d, J = 7.8 Hz, 1H), 7.87 (br d, J = 7.8 Hz, 1H), 7.58 (br d, J = 8.0 Hz, 1H), 7.30 (td, J = 7.6, 15.6 Hz, 2H), 6.98 (br d, J = 7.4 Hz, 2H), 6.71 (s, 1H), 4.72 (br d, J = 3.0 Hz, 1H), 4.51 (br s, 1H), 4.28 - 4.08 (m, 3H), 3.88 (br s, 1H), 3.71 (br d, J = 10.9 Hz, 2H), 3.48 (br d, J = 5.1 Hz, 2H), 2.76 - 2.61 (m, 4H), 2.42 - 2.30 (m, 2H), 2.27 - 2.07 (m, 2H), 2.01 (br s, 3H), 1.94 (br s, 3H), 1.76 - 1.52 (m, 2H).

[1486]

[1487] 20-2. 4-((R)-3-hydroxypyrrolidin-1-yl)-N-(3'-(5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)picolinamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, 화합물 92의 제조

[1488]

[1489]

[1490] A solution of N-[3-[3-[[5-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]pyridine-2-carbonyl]amino]-2-methyl-phenyl]-2-methyl-phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (200 mg, 345.63 μmol, 1 eq), (3R)-pyrrolidin-3-ol (301.11 mg, 3.46 mmol, 286.77 μL, 10 eq), and HOAc (207.55 mg, 3.46 mmol, 197.67 μL, 10 eq) in MeOH (10 mL) / THF (10 mL) was stirred at 60 °C for 2 h. After adding NaBH3CN (65.16 mg, 1.04 mmol, 3 eq) to the mixture, the mixture was stirred at 60 °C for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5μm; mobile phase: [water(NH4HCO3)-ACN]; B%: 24%-54%, 9 min) to obtain compound 92 (21 mg, 8.88% yield) as a white solid.

[1491] LCMS m / z 650.4 [M+1] + .

[1492] 1H NMR (400 MHz, DMSO-d6) δ = 10.32 (s, 1H), 9.53 (br s, 1H), 8.64 (s, 1H), 8.14 (br d, J = 8.0 Hz, 1H), 7.98 (br d, J = 8.1Hz, 1H), 7.87 (br d, J = 8.0 Hz, 1H), 7.58 (br d, J = 7.6 Hz, 1H), 7.30 (td, J = 7.7, 15.7 Hz, 2H), 6.98 (br d, J = 7.4 Hz, 2H),6.67 (br d, J = 7.1 Hz, 1H), 4.87 - 4.55 (m, 2H), 4.30 - 4.08 (m, 4H), 3.84 - 3.61 (m, 3H), 2.72 (br s, 2H), 2.68 - 2.58 (m, 2H), 2.46 - 2.39 (m, 2H), 2.39 - 2.14 (m, 3H), 2.01 (s, 3H), 1.94 (s, 3H), 1.89 (br s, 2H), 1.56 (br d, J = 3.1 Hz, 2H).

[1493] 20-3. N-(3'-(5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)picolinamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-4-((((S)-5-oxopyrrolidin-2-yl)methyl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, 화합물 93의 제조

[1494]

[1495]

[1496] A mixture of N-[3-[3-[[5-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]pyridine-2-carbonyl]amino]-2-methyl-phenyl]-2-methyl-phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (200 mg, 345.63 umol, 1 eq), (5S)-5-(aminomethyl)pyrrolidin-2-one (394.52 mg, 3.46 mmol, 297.04 μL, 10 eq), and DIPEA (446.69 mg, 3.46 mmol, 602.00 μL, 10 eq) in MeOH (5 mL) / THF (1 mL) solution. HOAc (415.10 mg, 6.91 mmol, After adding 395.33 μL, 20 eq) to the mixture, the mixture was stirred at 60 °C for 2 hours. After adding NaBH3CN (108.60 mg, 1.73 mmol, 5 eq) to the mixture, the mixture was stirred at 60 °C for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5μm; mobile phase: [water (ammonia hydroxide v / v)-ACN]; B%: 20%-50%, 9 min) to obtain compound 93 (18 mg, 7.31% yield) as a white solid.

[1497] LCMS m / z 678.4 [M+1] + .

[1498] 1H NMR (400 MHz, DMSO-d6) δ = 10.32 (s, 1H), 9.51 (br s, 1H), 8.64 (br s, 1H), 8.13 (br t, J = 6.8 Hz, 1H), 7.98 (br d, J = 7.6 Hz, 1H), 7.86 (br t, J = 8.4 Hz, 1H), 7.76 - 7.48 (m, 2H), 7.36 - 7.20 (m, 3H), 7.19 - 7.04 (m, 1H), 6.98 (br d, J = 7.1 Hz, 2H), 6.76 (br d, J = 9.5 Hz, 1H), 4.72 (br d, J = 2.8 Hz, 1H), 4.23 - 4.08 (m, 3H), 3.95 - 3.82 (m, 1H), 3.71 (br d, J = 10.9 Hz, 2H), 3.58 (br s, 1H), 2.78 - 2.67 (m, 2H), 2.62 (br d, J = 6.5 Hz, 2H), 2.44 (br d, J = 6.5 Hz, 2H), 2.37 - 2.27 (m, 4H), 2.11 (br s, 2H), 2.01 (br s, 3H), 1.94 (br s, 3H), 1.76 - 1.63 (m, 2H), 1.56 (br s, 1H).

[1499]

[1500] 20-4. 4-((2-acetamidoethyl)amino)-N-(3'-(5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)picolinamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, 화합물 94의 제조

[1501]

[1502]

[1503] N-[3-[3-[[5-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]pyridine-2-carbonyl]amino]-2-methyl-phenyl]-2-methyl-phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (200 mg, 345.63 μmol, 1 eq) and N-(2-aminoethyl)acetamide (353.00 mg, 3.46 mmol, 329.91 μL, 10 eq), HOAc (207.56 mg, 3.46 mmol, 197.67 μL, 10 eq) in MeOH (20 mL) in NaBHCN (43.44 mg, 691.25 μL). μmol, 2 eq) at 60 °C. The mixture was stirred for 2 hours. After concentrating the mixture under reduced pressure, the residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5μm; mobile phase: [water (ammonia hydroxide v / v)-ACN]; B%: 20%-50%, 9 min) to obtain compound 94 (22 mg, 9.10% yield) as a white solid.

[1504] LCMS m / z 665.6 [M+1] + .

[1505] 1H NMR (400 MHz, DMSO-d6) δ = 10.32 (br s, 1H), 9.51 (br s, 1H), 8.64 (br s, 1H), 8.14 (br d, J = 7.5 Hz, 1H), 7.98 (br d, J = 7.3 Hz, 1H), 7.92 - 7.75 (m, 2H), 7.58 (br d, J = 7.3 Hz, 1H), 7.42 - 7.18 (m, 2H), 6.98 (br d, J = 7.3 Hz, 2H), 6.72 (s, 1H), 4.71 (br d, J = 3.6 Hz, 1H), 4.31 - 4.06 (m, 3H), 3.94 - 3.81 (m, 1H), 3.71 (br d, J = 11.1 Hz, 2H), 3.13 (br d, J = 5.4 Hz, 2H), 2.73 - 2.58 (m, 5H), 2.34 (br d, J = 9.6 Hz, 2H), 2.26 - 2.10 (m, 2H), 2.01 (br s, 4H), 1.94 (br s, 3H), 1.80 (s, 3H), 1.71 - 1.51 (m, 2H).

[1506]

[1507] 20-5. 2-((2-((3'-(5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)picolinamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl)amino)acetic acid, 화합물 95의 제조

[1508]

[1509] To a solution of N-[3-[3-[[5-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]pyridine-2-carbonyl]amino]-2-methyl-phenyl]-2-methyl-phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (200 mg, 345.63 μmol, 1 eq) and 2-aminoacetic acid (259.45 mg, 3.46 mmol, 297.04 μL, 10 eq) in MeOH (5 mL) / THF (1 mL) was added HOAc (415.10 mg, 6.91 mmol, 395.33 μL, 20 eq), and the mixture was stirred at 60 °C for 2 h. After adding NaBH3CN (108.60 mg, 1.73 mmol, 5 eq) to the mixture, the mixture was stirred at 60 °C for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5μm; mobile phase: [water(NH4HCO3)-ACN]; B%: 13%-43%, 9 min) to obtain compound 95 (31 mg, 13.3% yield) as a white solid.

[1510] LCMS m / z 638.4 [M+1] + .

[1511] 1H NMR (400 MHz, DMSO-d6) δ = 10.33 (s, 1H), 9.56 (s, 1H), 8.64 (s, 1H), 8.14 (d, J = 7.9 Hz, 1H), 7.98 (dd, J = 1.7, 8.1 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.56 (br d, J = 8.0 Hz, 1H), 7.30 (td, J = 7.8, 15.4 Hz, 2H), 6.98 (br d, J = 7.5 Hz, 2H), 6.77 (s, 1H), 4.25 - 4.05 (m, 4H), 3.71 (br d, J = 10.9 Hz, 4H), 2.78 - 2.58 (m, 3H), 2.46 - 2.30 (m, 3H), 2.25 - 2.14 (m, 1H), 2.01 (s, 3H), 1.94 (s, 3H), 1.84 - 1.69 (m, 1H), 1.56 (br dd, J = 4.6, 8.3 Hz, 1H), 1.05 (t, J = 7.0 Hz, 1H).

[1512]

[1513] 20-6. (3R)-1-(2-((3'-(5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)picolinamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl)pyrrolidine-3-carboxylic acid, 화합물 96의 제조

[1514]

[1515]

[1516] N-[3-[3-[[5-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]pyridine-2-carbonyl]amino]-2-methyl-phenyl]-2-methyl-phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (200 mg, 345.63 μmol, 1 eq), NaBH3CN (217.20 mg, 3.46 mmol, 10 eq), AcOH (207.56 mg, 3.46 mmol, 197.86 μL, 10 eq) at 60 °C. The mixture was stirred for 12 hours. After concentrating the mixture under reduced pressure, the residue was purified by reversed-phase HPLC (column: Waters Xbridge 150*25 mm* 5 um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 14%-44% B over 9 min) to obtain compound 96 (50 mg, 21.1% yield) as a white solid.

[1517] LCMS m / z 678.6 [M+1] + .

[1518] 1H NMR (400 MHz, DMSO-d6) δ = 10.32 (s, 1H), 9.54 (br d, J = 2.8 Hz, 1H), 8.65 (s, 1H), 8.14 (d, J = 7.9 Hz, 1H), 7.98 (dd, J = 2.1, 7.9 Hz, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.57 (dd, J = 3.2, 7.4 Hz, 1H), 7.34 - 7.25 (m, 2H), 6.98 (d, J = 7.1 Hz, 2H), 6.66 (d, J = 4.3 Hz, 1H), 4.24 - 4.12 (m, 3H), 3.81 - 3.66 (m, 3H), 3.32 (br s, 6H), 2.94 - 2.84 (m, 2H), 2.74 - 2.67 (m, 3H), 2.63 - 2.58 (m, 2H), 2.48 - 2.39 (m, 2H), 2.34 (br dd, J = 3.8, 9.6 Hz, 1H), 2.25 (br s, 1H), 2.01 (s, 3H), 1.94 (s, 4H), 1.61 - 1.52 (m, 1H).

[1519]

[1520] 20-7. N-(2,2'-dichloro-3'-((3-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-[1,1'-biphenyl]-3-yl)-4-(4-hydroxypiperidin-1-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, 화합물 97의 제조

[1521]

[1522]

[1523] To a solution of N-(3-bromo-2-methyl-phenyl)-5-formyl-pyridine-2-carboxamide (1 g, 3.13 mmol, 1 eq) in MeOH (20 mL) were added (3R)-pyrrolidin-3-ol (2.73 g, 31.33 mmol, 2.60 mL, 10 eq), NaBH3CN (984.48 mg, 15.67 mmol, 5 eq), and AcOH (940.77 mg, 15.67 mmol, 896.83 μL, 5 eq), and the mixture was stirred at room temperature for 12 h. The mixture was concentrated under reduced pressure and purified by reversed-phase HPLC (column: Waters X bridge 150 * 25 mm * 5 um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 14%-44% B over 9 min) to obtain compound 97-1 (740 mg, 54.4% yield) as a white solid.

[1524] LCMS m / z 389.07 [M+1] + .

[1525]

[1526]

[1527] A mixture of N-(3-bromo-2-methylphenyl)-4-chloro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide (2 g, 5.43 mmol, 1 eq), piperidin-4-ol (548.73 mg, 5.43 mmol, 1 eq), DIEA (2.10 g, 16.28 mmol, 2.83 mL, 3 eq), and NaI (243.95 mg, 1.63 mmol, 0.3 eq) was stirred at 90 °C for 12 h. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by reversed-phase HPLC (column: Phenomenex luna C18 (250 * 70 mm, 10 um); mobile phase: [water (NH4HCO3)-ACN]; gradient: 30%-60% B over 20 min) to obtain compound 97-2 (1.66 g, 69.9% yield) as a yellow solid.

[1528] LCMS m / z 432.12 [M+1] + .

[1529]

[1530]

[1531] A dioxane (4 mL) mixture of N-(3-bromo-2-methyl-phenyl)-4-(4-hydroxy-1-piperidyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide (200 mg, 461.53 μmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (351.60 mg, 1.38 mmol, 3 eq), AcOK (135.88 mg, 1.38 mmol, 3 eq), and Pd(dppf)Cl2 (33.77 mg, 46.15 μmol, 0.1 eq) was stirred at 90 °C under nitrogen for 12 h. After concentrating the mixture under reduced pressure, the residue was purified by column chromatography (SiO2, Ethyl acetate: Methanol=10 / 1) to obtain compound 97-3 (120 mg, 48.7% yield) as a black liquid.

[1532] LCMS m / z 480.29 [M+1] + .

[1533] 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36 (s, 12 H) 1.49 - 1.66 (m, 4 H) 1.71 - 2.01 (m, 5 H) 2.10 (br s, 1 H) 2.25 (br s, 1 H) 2.40 (br s, 1 H) 2.56 (s, 3 H) 2.89 (s, 2 H) 3.95 (br s, 1 H) 4.06 (br s, 1 H) 4.23 (br s, 1 H) 6.86 (br s, 1 H) 7.19 - 7.25 (m, 1 H) 7.59 (d, J=7.38 Hz, 1 H) 8.17 (br d, J=8.00 Hz, 1 H) 8.67 (br s, 1 H).

[1534]

[1535]

[1536] 4-(4-hydroxy-1-piperidyl)-N-[2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide (80 mg, 166.53 μmol, 1 eq), N-(3-bromo-2-methyl-phenyl)-5-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]pyridine-2-carboxamide (64.99 mg, 166.53 μmol, 1 eq), ditert-butyl(cyclopentyl)phosphane;dichloropalladium iron (10.85 mg, 16.65 μmol, 0.1 eq), K2CO3 (69.05 mg, 499.58 A mixture of dioxane (2.5 mL) / H2O (0.5 mL) (μmol, 3 eq) was stirred at 90 °C under nitrogen for 2 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by reversed-phase HPLC (column: Waters X bridge 150 * 25 mm * 5 um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 28%-58% B over 9 min) to obtain compound 97 (23 mg, 20.8% yield) as a yellow solid.

[1537] LCMS m / z 663.35 [M+1] + .

[1538] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.31 - 1.48 (m, 2 H) 1.52 - 1.61 (m, 1 H) 1.65 - 1.80 (m, 3 H) 1.82 - 1.91 (m, 1 H) 1.95 (s, 3 H) 2.01 - 2.03 (m, 3 H) 2.11 - 2.20 (m, 1 H) 2.11 - 2.20 (m, 1 H) 2.28 (td, J=9.44, 1.25 Hz, 1 H) 2.35 (dd, J=9.57, 3.69 Hz, 1 H) 2.33 - 2.37 (m, 1 H) 2.38 - 2.47 (m, 2 H) 2.38 - 2.47 (m, 1 H) 2.60 - 2.76 (m, 4 H) 3.42 - 3.52 (m, 1 H) 3.66 - 3.78 (m, 2 H) 3.93 - 3.99 (m, 1 H) 4.00 - 4.09 (m, 1 H) 4.20 (br dd, J=8.19, 3.69 Hz, 2 H) 4.55 (d, J=4.13 Hz, 1 H) 4.72 (d, J=4.50 Hz, 1 H) 6.62 (s, 1 H) 6.99 (d, J=7.63 Hz, 2 H) 7.31 (dt, J=16.13, 7.82 Hz, 2 H) 7.55 - 7.60 (m, 1 H) 7.87 (d, J=8.25 Hz, 1 H) 7.97 - 8.01 (m, 1 H) 8.15 (d, J=8.00 Hz, 1 H) 8.65 (s, 1 H) 9.43 - 9.59 (m, 1 H) 10.31 - 10.35 (m, 1 H)

[1539]

[1540] 20-8. 1-(2-((3'-(5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)picolinamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl)piperidine-4-carboxylic acid, 화합물 98의 제조

[1541]

[1542]

[1543] To a THF (20 mL) solution of N-(3-bromo-2-methyl-phenyl)-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (10 g, 28.72 mmol, 1 eq) was added NaBH4 (3.26 g, 86.16 mmol, 3 eq), and the mixture was stirred at room temperature for 16 h. The mixture was added aq. sat'd NH4Cl (200 mL) solution, and extracted with EtOAc (200 mL * 2). The organic layer was washed with brine (200 mL), dried over Na2SO4, and concentrated under reduced pressure to give compound 98-2 (9 g, 78.7% yield), which was used in the next reaction without further purification.

[1544] LCMS m / z 352.1 [M+3] + .

[1545]

[1546]

[1547] To a solution of N-(3-bromo-2-methyl-phenyl)-4-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide (4.6 g, 13.13 mmol, 1 eq) in DCM (30 mL) was added SOCl2 (7.81 g, 65.67 mmol, 4.77 mL, 5 eq), and the mixture was stirred at room temperature for 12 h. The mixture was added aq. sat'd NH4Cl (200 mL) and extracted with EtOAc (200 mL * 2). The organic layer was washed with brine (200 mL), dried over Na2SO4, and concentrated under reduced pressure to give compound 98-3 (9 g, 78.7% yield), which was used in the next reaction without further purification.

[1548] LCMS m / z 369.7 [M+3]+ .

[1549]

[1550]

[1551] To N-(3-bromo-2-methylphenyl)-4-chloro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide (2 g, 5.43 mmol, 1 eq) were added methyl piperidine-4-carboxylate (2.33 g, 16.28 mmol, 3 eq), DIEA (2.10 g, 16.28 mmol, 2.83 mL, 3 eq), and NaI (243.95 mg, 1.63 mmol, 0.3 eq), and the mixture was stirred at 40 °C for 12 h. The mixture was concentrated under reduced pressure and purified by reversed-phase HPLC (column: Phenomenex luna C18 (250 * 70mm, 10 um); mobile phase: [water (NH4HCO3)-ACN]; gradient: 50% - 80% B over 21 min) to obtain compound 98-4 (1.73 g, 66.4% yield) as a yellow solid.

[1552] LCMS m / z 477.2 [M+3] + .

[1553]

[1554]

[1555] methyl 1-[2-[(3-bromo-2-methyl-phenyl)carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]piperidine-4-carboxylate (200 mg, 420.72 μmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (320.51 mg, 1.26 mmol, 3 eq), AcOK (123.87 mg, 1.26 mmol, 3 eq), Pd(dppf)Cl2 (30.78) mg, 42.07 μmol, 0.1 eq) of dioxane (4 mL) mixture under nitrogen conditions at 90 °C for 12 hours. The mixture was stirred for a while. After concentrating the mixture under reduced pressure, the residue was purified by column chromatography (SiO2, Ethyl acetate: Methanol=10 / 1) to obtain compound 98-5 (215 mg, 89.99 yield) as a black liquid.

[1556] LCMS m / z 522.3 [M+1] + .

[1557] 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36 (s, 12 H) 1.93 (br s, 7 H) 2.29 - 2.42 (m, 2 H) 2.56 (s, 3 H) 3.71 (d, J=5.63 Hz, 4 H) 3.92 (br s, 1 H) 4.23 (br s, 2 H) 6.85 (br s, 1 H) 7.21 - 7.25 (m, 1 H) 7.59 (d, J=7.38 Hz, 1 H) 8.11 - 8.21 (m, 1 H) 8.62 - 8.71 (m, 1 H).

[1558]

[1559]

[1560] methyl 1-[2-[[2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]piperidine-4-carboxylate (100 mg, 191.41 μmol, 1.25 eq), N-(3-bromo-2-methyl-phenyl)-5-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]pyridine-2-carboxamide (59.76 mg, 153.13 μmol, 1 eq), ditert-butyl(cyclopentyl)phosphane;dichloropalladium iron (9.98 mg, 15.31 μmol, 0.1 eq), K2CO3 (63.49 mg, A mixture of H2O (3 mL) / dioxane (15 mL) (459.38 μmol, 3 eq) was stirred at 90 °C for 12 h. The mixture was concentrated under reduced pressure and purified by reversed-phase HPLC (column: Waters X bridge Prep OBD C18 150 * 40 mm * 10 um; mobile phase: [water (NH4HCO3) - ACN]; B: 20%, isocratic elution mode) to obtain compound 98-6 (100 mg, 74.0% yield) as a black solid.

[1561] LCMS m / z 706.5 [M+1] + .

[1562]

[1563]

[1564] A mixture of methyl 1-[2-[[3-[3-[[5-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]pyridine-2-carbonyl]amino]-2-methyl-phenyl]-2-methyl-phenyl]carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]piperidine-4-carboxylate (100 mg, 141.67 μmol, 1 eq) and LiOH (29.72 mg, 708.37 μmol, 5 eq) in H2O (4 mL) / MeOH (20 mL) was stirred at room temperature for 12 h. After concentrating the mixture under reduced pressure, the residue was purified by reversed-phase HPLC (column: Phenomenex Luna C18 150 * 25 mm * 10 um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 18%- 48% B over 10 min) to obtain compound 98 (60 mg, 60.60 yield) as a yellow solid.

[1565] LCMS m / z 692.6 [M+1] + .

[1566] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44 - 1.62 (m, 3 H) 1.63 - 1.74 (m, 1 H) 1.77 - 1.86 (m, 2 H) 1.94 (s, 3 H) 2.01 (s, 3 H) 2.10 - 2.30 (m, 3 H) 2.34 (dd, J=9.66, 3.42 Hz, 1 H) 2.39 - 2.48 (m, 2 H) 2.57 - 2.65 (m, 2 H) 2.70 (br dd, J=9.47, 6.17 Hz, 3 H) 2.75 - 2.85 (m, 1 H) 3.62 - 3.78 (m, 3 H) 3.96 (br dd, J=9.54, 5.13 Hz, 1 H) 4.02 - 4.09 (m, 1 H) 4.19 (br d, J=7.21 Hz, 2 H) 4.66 - 4.78 (m, 1 H) 6.62 (s, 1 H) 6.98 (d, J=7.34 Hz, 2 H) 7.29 (dt, J=15.86, 7.78 Hz, 2 H) 7.56 (t, J=7.03 Hz, 1 H) 7.86 (d, J=8.19 Hz, 1 H) 7.98 (dd, J=8.01, 1.89 Hz, 1 H) 8.14 (d, J=8.07 Hz, 1 H) 8.64 (d, J=1.34 Hz, 1 H) 9.53 (d, J=5.62 Hz, 1 H) 10.33 (s, 1 H).

[1567] 20-9. 2-((2-((3'-(5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)picolinamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl)amino)-2-methylpropanoic acid, 화합물 99의 제조

[1568]

[1569]

[1570] N-(3-bromo-2-methyl-phenyl)-5-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]pyridine-2-carboxamide (130 mg, 333.10 μmol, 1 eq), methyl 2-methyl-2-[[2-[[2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]amino]propanoate (181.89 mg, 366.41 μmol, 1.1 eq), CsF (101.20 mg, 666.20 μmol, 24.59 μL, 2 eq), ditert-butyl(cyclopentyl)phosphane;dichloropalladium iron (21.71 mg, 33.31 μmol, 0.1 eq) of dioxane (5 mL) / H2O (1 mL) mixture was stirred at 80 °C under nitrogen for 4 h. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by prep-TLC (SiO2, Ethyl acetate: Methanol = 10:1) to obtain compound 99-1 (170 mg, 49.5% yield) as a brown solid.

[1571] LCMS m / z 680.4 [M+1] + .

[1572]

[1573]

[1574] To a solution of methyl 2-[[2-[[3-[3-[[5-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]pyridine-2-carbonyl]amino]-2-methyl-phenyl]-2-methyl-phenyl]carbamoyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl]amino]-2-methyl-propanoate (170 mg, 250.07 μmol, 1 eq) in THF (30 mL) / H2O (15 mL) was added LiOH (17.94 mg, 750.21 μmol, 3 eq), and the mixture was stirred at room temperature for 12 h. After concentrating the mixture under reduced pressure, the residue was purified by reversed-phase HPLC ((0.1% NH3ㆍH2O condition) column: Phenomenex Luna C18 150 * 25 mm * 10 um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 14%-44% B over 10 min) to obtain compound 99 (75 mg, 44.6% yield) as a white solid.

[1575] LCMS m / z 666.7 [M+1] + .

[1576] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.29 (d, J=3.38 Hz, 6 H) 1.52 - 1.60 (m, 1 H) 1.61 - 1.68 (m, 1 H) 1.94 (s, 3 H) 2.01 (s, 3 H) 2.14 (br dd, J=13.38, 5.75 Hz, 1 H) 2.35 (dd, J=9.63, 3.50 Hz, 1 H) 2.40 - 2.48 (m, 2 H) 2.59 - 2.65 (m, 1 H) 2.70 (dd, J=9.57, 6.19 Hz, 1 H) 3.66 - 3.78 (m, 4H) 3.93 (br dd, J=7.44, 5.19 Hz, 1 H) 4.08 - 4.14 (m, 2 H) 4.17 - 4.24 (m, 1 H) 4.63 - 4.82 (m, 1 H) 6.74 (s, 1 H) 6.97 (d, J=7.50 Hz, 2 H) 7.29 (dt, J=15.79, 7.80 Hz, 2 H) 7.57 (d, J=7.75 Hz, 1 H) 7.87 (d, J=7.75 Hz, 1 H) 7.98 (dd, J=8.00, 2.00 Hz, 1 H) 8.14 (d, J=8.13 Hz, 1 H) H) 8.64 (d, J=1.38 Hz, 1 H) 9.51 (s, 1 H) 10.32 (s, 1 H)

[1577]

[1578] [Manufacturing Example 21]

[1579] Preparation of compounds 100 to 108

[1580]

[1581] 21-1. Preparation of N-(2,2'-dichloro-3'-(5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)picolinamido)-[1,1'-biphenyl]-3-yl)-4-((2-hydroxyethyl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, Compound 100

[1582]

[1583] A solution of compound 100-5 (2 g, 5.89 mmol, 1 eq), (3R)-pyrrolidin-3-ol (800 mg, 9.18 mmol, 761.90 uL, 1.56 eq), and AcOH (1.05 g, 17.49 mmol, 1 mL, 2.97 eq) in DMF (30 mL) was stirred at 60 °C for 30 min. NaBH3CN (1.5 g, 23.87 mmol, 4.05 eq) was added to the mixture, stirred at 60 °C for 30 min, and then diluted with H2O (50 mL). The mixture was adjusted to pH 8 with aq. saturated NaHCO3 solution and extracted with EA (50 mL x 2). The organic layer was dried over Na2SO4, concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (Eluent of 0–100% Ethyl acetate / Petroleum) to obtain compound 100-6 (1.2 g, 47.3% yield) as a yellow solid, which was used in the next reaction without further purification.

[1584] LCMS m / z 411.7 [M+1] + .

[1585] 1H NMR ( 400MHz, DMSO-d6) δ 10.72 (s, 1H), 8.68 (d, J =1.4 Hz, 1H), 8.37 (dd, J =1.3, 8.2 Hz, 1H), 8.17 (d, J =8.0 Hz, 1H), 8.02 (dd, J =2.0, 8.0 Hz, 1H), 7.61 (dd, J =1.4, 8.0 Hz, 1H), 7.38 (t, J =8.2 Hz, 1H), 4.73 (d, J =4.5 Hz, 1H), 4.26 - 4.17 (m, 1H), 3.82 - 3.65 (m, 2H), 2.75 - 2.67 (m, 1H), 2.63 (q, J =7.8 Hz, 1H), 2.45 (dt, J =5.7, 8.3 Hz, 1H), 2.35 (dd, J =3.6, 9.6 Hz, 1H), 2.08 - 1.95 (m, 1H), 1.62 - 1.51 (m, 1H), 1.62 - 1.51 (m, 1H).

[1586]

[1587]

[1588] Compound 100-6 (500 mg, 1.22 mmol, 1 eq), N-[2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridine-2-carboxamide (750.00 mg, 1.80 mmol, 1.48 eq) was added to a dioxane (10 mL) / H2O (2 mL) mixture, and K3PO4 (750.00 mg, 3.53 mmol, 2.90 eq), ditert-butyl(cyclopentyl)phosphane;dichloropalladium;iron (84.29 mg, 129.34 umol, 1.06e-1 eq) were added and stirred at 70°C under nitrogen for 5 h. The mixture was filtered, the filtrate was diluted with H2O (50 mL), and extracted with EA (50 mL x 2). The organic layer was washed with brine (50 mL x 3), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Eluent of 0–100% Ethyl acetate / Petroleum, 0–30% MeOH / EA) to obtain compound 100-7 (600 mg, 72.20% yield) as a yellow solid.

[1589] LCMS m / z 620.9[M+1] + .

[1590] 1H NMR (400MHz, DMSO-d6) δ 10.73 (s, 1H), 9.83 (s, 1H), 8.68 (s, 1H), 8.53 (dd, J =1.3, 8.3 Hz, 1H), 8.20 (d, J =8.0 Hz, 1H), 8.11 (dd, J =1.2, 8.1 Hz, 1H), 8.03 (dd, J =1.7, 8.0 Hz, 1H), 7.53 (td, J =7.9, 11.1 Hz, 2H), 7.30 (s, 1H), 7.27 - 7.15 (m, 2H), 4.74 (d, J =4.5 Hz, 1H), 4.48 (t, J =5.8 Hz, 2H), 4.27 - 4.17 (m, 1H), 3.80 - 3.62 (m, 2H), 2.76 - 2.68 (m, 3H), 2.62 (q, J =7.9 Hz, 1H), 2.48 - 2.41 (m, 1H), 2.39 - 2.31 (m, 3H), 2.07 - 1.96 (m, 1H), 1.63 - 1.48 (m, 1H).

[1591]

[1592]

[1593] A solution of compound 100-7 (190 mg, 306.70 umol, 1 eq), 2-aminoethanol (150 mg, 2.46 mmol, 148.51 uL, 8.01 eq), and AcOH (210.00 mg, 3.50 mmol, 200 uL, 11.40 eq) in DMF (3 mL) was stirred at 60°C for 30 min, then NaBH3CN (120 mg, 1.91 mmol, 6.23 eq) was added and the mixture was stirred at 60°C for 18 h. The mixture was diluted with H2O (20 mL), adjusted to pH 8 with aq. saturated NaHCO3 solution, and extracted with EA (50 mL x 2). The organic layer was dried over Na2SO4, concentrated under reduced pressure, and the residue was purified by prep-HPLC (column: Phenomenex C18 80*40mm*3um; mobile phase: [water (NH3H2O ​​+ NH4HCO3)-ACN]; B%: 34%-64%, 8 min) to obtain compound 100 (55.03 mg, 26.7% yield) as a white solid.

[1594] LCMS m / z 664.4 [M+1] + .

[1595] 1H NMR (400MHz, DMSO-d6) δ 10.73 (s, 1H), 9.83 (s, 1H), 8.68 (s, 1H), 8.53 (dd, J =1.3, 8.3 Hz, 1H), 8.20 (d, J =8.0 Hz, 1H), 8.11 (dd, J =1.2, 8.1 Hz, 1H), 8.03 (dd, J =1.7, 8.0 Hz, 1H), 7.53 (td, J =7.9, 11.1 Hz, 2H), 7.30 (s, 1H), 7.27 - 7.15 (m, 2H), 4.74 (d, J =4.5 Hz, 1H), 4.48 (t, J =5.8 Hz, 2H), 4.27 - 4.17 (m, 1H), 3.80 - 3.62 (m, 2H), 2.76 - 2.68 (m, 3H), 2.62 (q, J =7.9 Hz, 1H), 2.48 - 2.41 (m, 1H), 2.39 - 2.31 (m, 3H), 2.07 - 1.96 (m, 1H), 1.63 - 1.48 (m, 1H).

[1596]

[1597] 21-2. N-(2,2'-dichloro-3'-(5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)picolinamido)-[1,1'-biphenyl]-3-yl)-4-((R)-3-hydroxypyrrolidin-1-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, 화합물 101의 제조

[1598]

[1599]

[1600] A solution of compound 100-7 (150 mg, 242.13 μmol, 1 eq), (3R)-pyrrolidin-3-ol (150 mg, 1.72 mmol, 142.86 μL, 7.11 eq), and AcOH (157.50 mg, 2.62 mmol, 150 μL, 10.83 eq) in DMF (3 mL) was stirred at 60°C for 30 min, then NaBH3CN (100 mg, 1.59 mmol, 6.57 eq) was added, and the mixture was stirred at 60°C for 18 h. The mixture was diluted with H2O (20 mL), adjusted to pH 8 with aq. saturated NaHCO3 solution, and extracted with EA (50 mL x 2). The organic layer was dried over Na2SO4, concentrated under reduced pressure, and the residue was purified by prep-HPLC (column: Phenomenex C18 80*40mm*3um; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; B%: 40%-70%, 8 min) to obtain compound 101 (91.19 mg, 54.4% yield) as a white solid.

[1601] LCMS m / z 690.4[M+1] + .

[1602] 1H NMR (400MHz, DMSO-d6) δ 10.72 (s, 1H), 9.56 (s, 1H), 8.68 (s, 1H), 8.52 (dd, J =1.3, 8.3 Hz, 1H), 8.32 - 8.25 (m, 1H), 8.20 (d, J =8.0 Hz, 1H), 8.03 (dd, J =1.9, 8.2 Hz, 1H), 7.52 (td, J =8.0, 15.9 Hz, 2H), 7.19 (br d, J =7.5 Hz, 2H), 6.74 (d, J =8.8 Hz, 1H), 4.76 - 4.67 (m, 2H), 4.25 - 4.13 (m, 4H), 3.81 (br d, J =4.3 Hz, 1H), 3.78 - 3.66 (m, 2H), 2.94 - 2.67 (m, 3H), 2.66 - 2.52 (m, 2H), 2.49 - 2.30 (m, 3H), 2.23 (br s, 1H), 2.06 - 1.83 (m, 5H), 1.62 - 1.50 (m, 2H)

[1603]

[1604] 21-3. N-(2,2'-dichloro-3'-(5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)picolinamido)-[1,1'-biphenyl]-3-yl)-4-((((S)-5-oxopyrrolidin-2-yl)methyl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, 화합물 102의 제조

[1605]

[1606]

[1607] A solution of compound 100-7 (150 mg, 242.13 μmol, 1 eq), (5S)-5-(aminomethyl) pyrrolidin-2-one (200 mg, 1.33 mmol, 5.48 eq, HCl), and AcOH (157.50 mg, 2.62 mmol, 150.00 uL, 10.83 eq) in DMF (3 mL) was stirred at 60 °C for 30 min, then NaBH3CN (100 mg, 1.59 mmol, 6.57 eq) was added, and the mixture was stirred at 60 °C for 18 h. The mixture was diluted with H2O (20 mL), adjusted to pH 8 with aq. saturated NaHCO3 solution, and extracted with EA (50 mL x 2). The organic layer was dried over Na2SO4, concentrated under reduced pressure, and the residue was purified by prep-HPLC (column: Phenomenex C18 80*40mm*3um; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; B%: 37%-67%, 8 min) to obtain compound 102 (72.37 mg, 41.65% yield) as a white solid.

[1608] LCMS m / z 917.4 [M+1] + .

[1609] 1H NMR (400MHz, DMSO-d6) δ 10.72 (s, 1H), 9.55 (s, 1H), 8.68 (s, 1H), 8.56 - 8.48 (m, 1H), 8.30 (d, J =7.8 Hz, 1H), 8.20 (d, J =8.0 Hz, 1H), 8.03 (d, J =7.8 Hz, 1H), 7.70 (d, J =18.3 Hz, 1H), 7.52 (td, J =7.8, 15.7 Hz, 2H), 7.19 (br d, J =7.8 Hz, 2H), 6.84 (d, J =11.8 Hz, 1H), 4.73 (d, J =4.8 Hz, 1H), 4.26 - 4.12 (m, 3H), 3.88 (br s, 1H), 3.78 - 3.66 (m, 2H), 3.58 (br s, 1H), 2.75 - 2.55 (m, 5H), 2.49 - 2.39 (m, 1H), 2.35 (dd, J =3.5, 9.8 Hz, 1H), 2.21 - 2.07 (m, 4H), 2.02 (td, J =7.0, 13.7 Hz, 2H), 1.97 - 1.86 (m, 1H), 1.78 - 1.63 (m, 2H), 1.57 (br s, 1H).

[1610]

[1611] 21-4. 4-((2-acetamidoethyl)amino)-N-(2,2'-dichloro-3'-(5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)picolinamido)-[1,1'-biphenyl]-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide, 화합물 103의 제조

[1612]

[1613]

[1614] A solution of compound 100-7 (150 mg, 242.13 μmol, 1 eq), N-(2-aminoethyl) acetamide (150 mg, 1.47 mmol, 140.19 uL, 6.07 eq), and AcOH (157.50 mg, 2.62 mmol, 150.00 uL, 10.83 eq) in DMF (3 mL) was stirred at 60 °C for 30 min, then NaBH3CN (100 mg, 1.59 mmol, 6.57 eq) was added, and the mixture was stirred at 60 °C for 18 h. The mixture was diluted with H2O (20 mL), adjusted to pH 8 with aq. saturated NaHCO3 solution, and extracted with EA (50 mL x 2). The organic layer was dried over Na2SO4, concentrated under reduced pressure, and the residue was purified by prep-HPLC (column: Phenomenex C18 80*40mm*3um; mobile phase: [water (NH3H2O ​​+ NH4HCO3)-ACN]; B%: 36%-66%, 8 min) to obtain compound 103 (91.47 mg, 53.5% yield) as a white solid.

[1615] LCMS m / z 707.3[M+1] + .

[1616] 1H NMR (400MHz, DMSO-d6) δ 10.72 (s, 1H), 9.54 (s, 1H), 8.67 (s, 1H), 8.52 (d, J =8.3 Hz, 1H), 8.30 (d, J =8.0 Hz, 1H), 8.19 (d, J =7.8 Hz, 1H), 8.03 (br d, J =7.8 Hz, 1H), 7.83 (br s, 1H), 7.52 (td, J =8.0, 15.9 Hz, 2H), 7.18 (br d, J =7.8 Hz, 2H), 6.79 (s, 1H), 4.72 (d, J =4.5 Hz, 1H), 4.25 - 4.09 (m, 3H), 3.88 (br s, 1H), 3.79 - 3.63 (m, 2H), 3.18 - 3.09 (m, 2H), 2.74 - 2.58 (m, 4H), 2.47 - 2.40 (m, 1H), 2.34 (dd, J =3.3, 9.5 Hz, 1H), 2.47 - 2.30 (m, 1H), 2.17 (br s, 2H), 2.00 (br dd, J =6.9, 12.7 Hz, 2H), 1.92 (br s, 1H), 1.81 (s, 3H), 1.66 (br d, J =10.5 Hz, 1H), 1.55 (br d, J =4.5 Hz, 1H).

[1617]

[1618] 21-5. 2-((2-((2,2'-dichloro-3'-(5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)picolinamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl)amino)acetic acid, 화합물 104의 제조

[1619]

[1620]

[1621] Compound 100-7 (150 mg, 242.13 umol, 1 eq), methyl 2-aminoacetate; A solution of hydrochloride (150 mg, 1.19 mmol, 4.93 eq) and AcOH (157.50 mg, 2.62 mmol, 150.00 uL, 10.83 eq) in DMF (3 mL) was stirred at 60 °C for 30 min, then NaBH3CN (100.00 mg, 1.59 mmol, 6.57 eq) was added, and the mixture was stirred at 60 °C for 18 h. The mixture was diluted with H2O (20 mL), adjusted to pH 8 with aq. saturated NaHCO3 solution, and extracted with EA (50 mL x 2). The organic layer was dried over Na2SO4, concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (eluent of 0–40% MeOH / EA) to give compound 100-8 (150 mg, 63.8% yield) as a yellow solid.

[1622] LCMS m / z 692.4 [M+1] + .

[1623]

[1624]

[1625] LiOH H2O (70 mg, 2.92 mmol, 13.50 eq) was added to a THF (2 mL) / H2O (0.5 mL) solution of compound 100-8 (150 mg, 216.58 μmol, 1 eq) and stirred at room temperature for 5 h. The mixture was adjusted to pH 7 with aq. 1 N HCl solution, concentrated under reduced pressure, and purified by prep-HPLC (column: Phenomenex C18 80*40mm*3 μm; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; B%: 27%-57%, 8 min) to give compound 104 (61.69 mg, 40.1% yield) as a white solid.

[1626] LCMS m / z 678.3[M+1] + .

[1627] 1 H NMR (400MHz, DMSO-d6) δ 10.72 (s, 1H), 9.57 (s, 1H), 8.68 (s, 1H), 8.53 (d, J =8.3 Hz, 1H), 8.28 (d, J =8.3 Hz, 1H), 8.20 (d, J =8.0 Hz, 1H), 8.03 (dd, J =1.8, 8.0 Hz, 1H), 7.52 (td, J=7.9, 15.6 Hz, 2H), 7.19 (d, J =7.5 Hz, 2H), 6.82 (s, 1H), 4.27 - 4.11 (m, 4H), 4.04 (br t, J =5.6 Hz, 1H), 3.78 - 3.65 (m, 2H), 3.30 (s, 3H), 2.70 (dd, J =6.1, 9.7 Hz, 1H), 2.62 (q, J =7.7 Hz, 1H), 2.49 - 2.41 (m, 1H), 2.35 (dd, J =3.6, 9.7 Hz, 1H), 2.20 (br dd, J =5.6, 13.4 Hz, 1H), 2.01 (br dd, J =6.9, 12.9 Hz, 2H), 1.91 (br dd, J =6.5, 13.8 Hz, 1H), 1.80 - 1.68 (m, 1H), 1.62 - 1.50 (m, 1H).

[1628]

[1629] 21-6. (3R)-1-(2-((2,2'-dichloro-3'-(5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)picolinamido)-[1,1'-biphenyl]-3-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-yl)pyrrolidine-3-carboxylic acid, 화합물 105의 제조

[1630]

[1631]

[1632]

[1633] To a solution of compound 100-7 (50 mg, 80.71 μmol, 1 eq), (3R)-pyrrolidine-3-carboxylic acid (92.92 mg, 807.11 μmol, 10 eq) in MeOH (2 mL) / DMF (1 mL) were added NaBH3CN (50.72 mg, 807.11 μmol, 10 eq), AcOH (48.47 mg, 807.11 μmol, 46.20 μL, 10 eq), and stirred at 60 °C for 18 h. After concentrating the mixture under reduced pressure, the residue was purified by reversed-phase HPLC (column: Waters Xbridge 150*25 mm* 5 um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 18%-48% B over 9 min) to obtain compound 105 (5 mg, 8.36% yield) as a white solid.

[1634] LCMS m / z 718.2 [M+1] + .

[1635] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.53 - 1.63 (m, 1 H) 1.86 - 2.02 (m, 6 H) 2.32 - 2.38 (m, 2 H) 2.58 - 2.65 (m, 2 H) 2.66 - 2.76 (m, 3 H) 2.88 - 2.98 (m, 2 H) 3.18 (s, 2 H) 3.67 - 3.79 (m, 2 H) 3.83 (br s, 1 H) 4.14 - 4.24 (m, 3 H) 4.62 - 4.83 (m, 1 H) 6.73 (d, J =4.63 Hz, 1 H) 7.19 (br d, J =7...

Claims

1. A compound of the following chemical formula 1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above formula, X1 and X2 are each independently hydrogen, halo, haloalkyl, cyano, alkyl, alkenyl, alkynyl, -N(Ra)2, -ORa, -SRa, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein Ra is each independently hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, Y1 and Y2 are each independently a single bond, or alkyl, alkenyl, alkynyl, -ORb-, -N(Rb)-, -C(=O)Rb-, -C(=O)N(Rb)-, -C(=S)N(Rb)-, -N(Rb)C(=O)-, -N(Rb)S(=O)-, -N(Rb)S(=O)(=NH)-, -CH=C(Rb)-, -N(Rb)CH(OH)-, or -N(Rb)S(=O)2-, wherein Rb is each independently hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. Z1 and Z2 are each independently hydrogen, halo, cyano, alkyl, alkenyl, alkynyl, -C(=O)Rc, -C(=O)N(Rc)(Rd), -C(=O)ORc, -N(Rc)(Rd), -N(Rc)C(=O)Rd, -NH(Rc)C(=O)Rd, -NH(Rc)NHC(=O)Rd, -N(Rc)S(=O)Rd, -N(Rc)S(=O)2Rd, -NO2, -ORc, -OC(=O)Rc, -SRc, -S(=O)Rc, -S(=O)N(Rc)(Rd), -S(=O)2Rc, -S(=O)2N(Rc)(Rd), cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein Rc and Rd is each independently hydrogen, hydroxy, -COOH, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, The above alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl may be substituted or unsubstituted.

2. In paragraph 1, X1 and X2 are each independently hydrogen, halo, C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 It is alkynyl, Y1 and Y2 are each independently a single bond, or C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, -ORb-, -N(Rb)-, -C(=O)Rb-, -C(=O)N(Rb)-, -N(Rb)C(=O)-, -N(Rb)S(=O)-, -N(Rb)S(=O)(=NH)-, -CH=C(Rb)-, -N(Rb)CH(OH)- or -N(Rb)S(=O)2-, wherein Rb is each independently hydrogen, halo, C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 It's alkynyl Z1 and Z2 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 alkynyl, -C(=O)N(Rc)(Rd), -C(=O)ORc, -N(Rc)(Rd), -N(Rc)C(=O)Rd, -N(Rc)S(=O)Rd, -N(Rc)S(=O)2Rd, -NO2, -ORc, -OC(=O)Rc, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein Rc and Rd are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, A compound of formula 1 or a pharmaceutically acceptable salt thereof, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl may be substituted or unsubstituted.

3. In paragraph 2, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl, Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, -N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo, C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 It is alkynyl, Z1 and Z2 are each independently hydrogen; aryl; heterocycloalkyl substituted with 1 to 3 heteroatoms selected from the group consisting of N, O or S; or heteroaryl substituted with 1 to 3 heteroatoms selected from the group consisting of N, O or S, The above aryl, heterocycloalkyl, or heteroaryl is halo, -OH, -CN, -C 1-6 Alkyl, -OC 1-6 Alkyl, haloalkyl, -C 1-6 Alkyl-OH, -C 1-6 Alkyl-COOH, -C 1-6 Alkyl-NH-C 1-6 Alkyl-COOH, -C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-COOH, -C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-C(=O)-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-OH, -NH-C 1-6 Alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -NH-C 1-6 Alkyl-OH, -N(C 1-6 Alkyl-OH)(C 1-6 Alkyl-OH), -N(C 1-6 Alkyl-COOH)(C 1-6 Alkyl-COOH), -NH-C 1-6 Alkyl-(C 1-6 Alkyl-OH)2, -NH-C 1-6 Alkyl-COOH, -NH-C 1-6 Alkyl-NH-C(=O)C 1-6 Alkyl, -NH-C 1-6 Alkyl-C(=O)-OC 1-6 Alkyl, -NH-C 1-6 Alkyl-OC 1-6 Alkyl, -NH-C 1-6 Alkyl-NH-SO2-C 1-6 Alkyl, heterocycloalkyl, -C 1-6 Alkyl-heterocycloalkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-heterocycloalkyl, -C 1-6 Alkyl-bicycloalkyl-COOH, -NH-heterocycloalkyl, -NH-C 1-6 Alkyl-heterocycloalkyl and -NH-cycloalkyl-OC 1-6 which may be substituted or unsubstituted with one or more substituents selected from the group consisting of alkyl, At this time, the heterocycloalkyl and cycloalkyl are halo, =O, -OH, COOH, -C 1-6 Alkyl-OH, and -C(=O)C 1-6 A compound of formula 1 or a pharmaceutically acceptable salt thereof, characterized in that it can be substituted or unsubstituted with one or more substituents selected from the group consisting of alkyl.

4. In paragraph 3, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl, Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, -N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl, Z1 and Z2 are each independently hydrogen, or And, R1 to R17 are each independently hydrogen, halo, -OH, -CN, -C 1-6 Alkyl, -OC 1-6 Alkyl, haloalkyl, -C 1-6 Alkyl-OH, -C 1-6 Alkyl-COOH, -C 1-6 Alkyl-NH-C 1-6 Alkyl-COOH, -C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-COOH, -C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-C(=O)-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-OH, -NH-C 1-6 Alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -NH-C 1-6 Alkyl-OH, -N(C 1-6 Alkyl-OH)(C 1-6 Alkyl-OH), -N(C 1-6 Alkyl-COOH)(C 1-6 Alkyl-COOH), -NH-C 1-6 Alkyl-(C 1-6 Alkyl-OH)2, -NH-C 1-6 Alkyl-COOH, -NH-C 1-6 Alkyl-NH-C(=O)C 1-6 Alkyl, -NH-C 1-6 Alkyl-C(=O)-OC 1-6 Alkyl, -NH-C 1-6 Alkyl-OC 1-6 Alkyl, -NH-C 1-6 Alkyl-NH-SO2-C 1-6 Alkyl, heterocycloalkyl, -C 1-6 Alkyl-heterocycloalkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-heterocycloalkyl, -C 1-6 Alkyl-bicycloalkyl-COOH, -NH-heterocycloalkyl, -NH-C 1-6 Alkyl-heterocycloalkyl, or -NH-cycloalkyl-OC 1-6 It is alkyl, The above heterocycloalkyl and cycloalkyl are halo, =O, -OH, COOH, -C 1-6 Alkyl-OH, and -C(=O)C 1-6 A compound of formula 1 or a pharmaceutically acceptable salt thereof, characterized in that it can be substituted or unsubstituted with one or more substituents selected from the group consisting of alkyl.

5. In paragraph 4, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl, Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, -N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl, Z1 and Z2 are each independently hydrogen, or And, R1a to R1c, R2a to R2d, R3a to R3b, R4 to R6, R7a to R7b and R8 to R17 are each independently hydrogen, halo, -OH, -CN, -C 1-6 Alkyl, haloalkyl, -C 1-6 Alkyl-OH, -C 1-6 Alkyl-COOH, -C 1-6 Alkyl-NH-C 1-6 Alkyl-COOH, -C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-C(=O)-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-OH, -NH-C 1-6 Alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -NH-C 1-6 Alkyl-OH, -N(C 1-6 Alkyl-OH)(C 1-6 Alkyl-OH), -NH-C 1-6 Alkyl-(C 1-6 Alkyl-OH)2, -NH-C 1-6 Alkyl-COOH, -NH-C 1-6 Alkyl-NH-C(=O)C 1-6 Alkyl, -NH-C 1-6 Alkyl-C(=O)-OC 1-6 Alkyl, -NH-C 1-6 Alkyl-OC 1-6 Alkyl, -NH-C 1-6 Alkyl-NH-SO2-C 1-6 Alkyl, heterocycloalkyl, -C 1-6 Alkyl-heterocycloalkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-heterocycloalkyl, -C 1-6 Alkyl-bicycloalkyl-COOH, -NH-heterocycloalkyl, -NH-C 1-6 Alkyl-heterocycloalkyl, or -NH-cycloalkyl-OC 1-6 It is alkyl, The above heterocycloalkyl is pyrrolidine or azetidine, which may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, =O, -OH and -COOH, The above cycloalkyl is =O, -OH, COOH, -C 1-6 Alkyl-OH, and -C(=O)C 1-6 A compound of formula 1 or a pharmaceutically acceptable salt thereof, characterized in that it can be substituted or unsubstituted with one or more substituents selected from the group consisting of alkyl.

6. In paragraph 5, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl, Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, -N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl, Z1 or Z2 When, The above R1a, R1b and R1c are each independently hydrogen, halo, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-heterocycloalkyl, -C 1-6 Alkyl-heterocycloalkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-COOH, -C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-C(=O)-C 1-6 Alkyl or -C 1-6 Alkyl-NH-C 1-6 Alkyl-OH, A compound of formula 1 or a pharmaceutically acceptable salt thereof, characterized in that the heterocycloalkyl is pyrrolidine which may be substituted or unsubstituted with one or more substituents selected from the group consisting of =O, -OH and COOH.

7. In paragraph 5, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl, Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, -N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl, Z1 or Z2 When, The above R1a and R1c are each independently hydrogen, halo, -C 1-6 Alkyl, or -OC 1-6 It is alkyl, R1b is hydrogen, halo, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-heterocycloalkyl, -C 1-6 Alkyl-heterocycloalkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-COOH, -C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-C(=O)-C 1-6 Alkyl or -C 1-6 Alkyl-NH-C 1-6 Alkyl-OH, The above heterocycloalkyl is , or A compound of formula 1 or a pharmaceutically acceptable salt thereof, characterized in that:

8. In paragraph 5, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl, Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, -N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl, Z1 or Z2 is , , or A compound of formula 1 or a pharmaceutically acceptable salt thereof, characterized in that 9. In paragraph 5, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl, Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, -N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl, Z1 or Z2 When, The above R2a, R2b, R2c and R2d are each independently hydrogen, halo, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 1-6 Alkyl-heterocycloalkyl or -C 1-6 Alkyl-NH-C 1-6 Alkyl-OH, A compound of formula 1 or a pharmaceutically acceptable salt thereof, wherein the heterocycloalkyl is pyrrolidine, which may be substituted or unsubstituted with OH.

10. In paragraph 5, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl, Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, -N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl, Z1 or Z2 When, The above R2a, R2b, R2c and R2d are each independently hydrogen, halo, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 1-6 Alkyl-heterocycloalkyl or -C 1-6 Alkyl-NH-C 1-6 Alkyl-OH, The above heterocycloalkyl is A compound of formula 1 or a pharmaceutically acceptable salt thereof, characterized in that:

11. In paragraph 5, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl, Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, -N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl, Z1 or Z2 is or A compound of formula 1 or a pharmaceutically acceptable salt thereof, characterized in that:

12. In paragraph 5, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl, Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, -N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl, Z1 or Z2 When, The above R3a and R3b are each independently hydrogen, -OC 1-6 Alkyl or -C 1-6 Alkyl-NH-C 1-6 Alkyl-heterocycloalkyl, A compound of formula 1 or a pharmaceutically acceptable salt thereof, characterized in that the heterocycloalkyl is pyrrolidine which may be substituted or unsubstituted with =O.

13. In paragraph 5, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl, Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, -N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl, Z1 or Z2 When, The above R3a and R3b are each independently hydrogen, -OC 1-6 Alkyl or -C 1-6 Alkyl-NH-C 1-6 Alkyl-heterocycloalkyl, The above heterocycloalkyl is A compound of formula 1 or a pharmaceutically acceptable salt thereof, characterized in that:

14. In paragraph 5, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl, Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, -N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl, Z1 or Z2 is A compound of formula 1 or a pharmaceutically acceptable salt thereof, characterized in that:

15. In paragraph 5, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl, Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, -N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl, Z1 or Z2 When, The above R4 is hydrogen or -C 1-6 Alkyl-heterocycloalkyl, A compound of formula 1 or a pharmaceutically acceptable salt thereof, wherein the heterocycloalkyl is pyrrolidine or azetidine, which may be unsubstituted or substituted with -OH or halo.

16. In paragraph 5, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl, Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, -N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl, Z1 or Z2 When, The above R4 is hydrogen or -C 1-6 It may be at least one selected from the group consisting of alkyl-heterocycloalkyl, The above heterocycloalkyl is or A compound of formula 1 or a pharmaceutically acceptable salt thereof, characterized in that:

17. In paragraph 5, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl, Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, -N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl, Z1 or Z2 is or A compound of formula 1 or a pharmaceutically acceptable salt thereof, characterized in that:

18. In paragraph 5, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl, Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, -N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl, Z1 or Z2 When, The above R5 is hydrogen, -C 1-6 is alkyl or haloalkyl, R6 is hydrogen or -C 1-6 Alkyl-heterocycloalkyl, A compound of formula 1 or a pharmaceutically acceptable salt thereof, wherein the heterocycloalkyl is pyrrolidine or azetidine, which may be unsubstituted or substituted with -OH or halo.

19. In paragraph 5, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl, Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, -N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl, Z1 or Z2 When, The above R5 is hydrogen, -C 1-6 is alkyl or haloalkyl, R6 is hydrogen or -C 1-6 Alkyl-heterocycloalkyl, The above heterocycloalkyl is or A compound of formula 1 or a pharmaceutically acceptable salt thereof, characterized in that:

20. In paragraph 5, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl, Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, -N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl, Z1 or Z2 is or A compound of formula 1 or a pharmaceutically acceptable salt thereof, characterized in that:

21. In paragraph 5, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl, Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, -N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl, Z1 or Z2 When, The above R7a and R7b are each independently hydrogen, -CN or -C 1-6 Alkyl-heterocycloalkyl, A compound of formula 1 or a pharmaceutically acceptable salt thereof, wherein the heterocycloalkyl is pyrrolidine, which may be substituted or unsubstituted with -COOH.

22. In paragraph 5, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl, Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, -N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl, Z1 or Z2 is A compound of formula 1 or a pharmaceutically acceptable salt thereof, characterized in that:

23. In paragraph 5, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl, Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, -N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl, Z1 or Z2 When, The above R8 and R9 are each independently hydrogen, -C 1-6 Alkyl or - C 1-6 A compound of formula 1, characterized in that it is alkyl-bicycloalkyl-COOH, or a pharmaceutically acceptable salt thereof.

24. In paragraph 5, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl, Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, -N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl, Z1 or Z2 is A compound of formula 1 or a pharmaceutically acceptable salt thereof, characterized in that:

25. In paragraph 5, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl, Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, -N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl, Z1 or Z2 When, The above R10 is hydrogen, halo, -OH, -C 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -NH-C 1-6 Alkyl-NH-C(=O)C 1-6 Alkyl, -NH-C 1-6 Alkyl-C(=O)-OC 1-6 Alkyl, -NH-C 1-6 Alkyl-OC 1-6 Alkyl, -OC 1-6 Alkyl, heterocycloalkyl, -NH-heterocycloalkyl, -NH-C 1-6 Alkyl-heterocycloalkyl, -NH-cycloalkyl, -NH-C 1-6 Alkyl-COOH, -NH-C 1-6 Alkyl-OH, -N(C 1-6 Alkyl-OH)(C 1-6 Alkyl-OH), -NH-C 1-6 Alkyl-(C 1-6 Alkyl-OH)2 or NH-C 1-6 Alkyl-NH-SO2-C 1-6 It is alkyl, The above heterocycloalkyl and cycloalkyl are =O, -OH, COOH, -C 1-6 Alkyl-OH, and -C(=O)C 1-6 A compound of formula 1 or a pharmaceutically acceptable salt thereof, characterized in that it can be substituted or unsubstituted with one or more substituents selected from the group consisting of alkyl.

26. In paragraph 5, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl, Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, -N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl, Z1 or Z2 When, The above R10 is hydrogen, -OH, -C 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -NH-C 1-6 Alkyl-NH-C(=O)C 1-6 Alkyl, -NH-C 1-6 Alkyl-C(=O)-OC 1-6 Alkyl, -NH-C 1-6 Alkyl-OC 1-6 Alkyl, heterocycloalkyl, -NH-heterocycloalkyl, -NH-C 1-6 Alkyl-heterocycloalkyl, -NH-cycloalkyl, -NH-C 1-6 Alkyl-COOH, -NH-C 1-6 Alkyl-OH, -N(C 1-6 Alkyl-OH)(C 1-6 Alkyl-OH), -NH-C 1-6 Alkyl-(C 1-6 Alkyl-OH)2 or NH-C 1-6 Alkyl-NH-SO2-C 1-6 It is alkyl, The above heterocycloalkyl and cycloalkyl are or A compound of formula 1 or a pharmaceutically acceptable salt thereof, characterized in that:

27. In paragraph 5, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl, Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, -N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl, Z1 or Z2 When, The above R11 is hydrogen, halo or -C 1-6 A compound of formula 1, characterized in that it is alkyl, or a pharmaceutically acceptable salt thereof.

28. In paragraph 5, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl, Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, -N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl, Z1 or Z2 A compound of formula 1 or a pharmaceutically acceptable salt thereof, characterized in that:

29. In paragraph 5, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl, Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, -N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl, Z1 or Z2 When, The above R12 is -C, which may be substituted or unsubstituted with hydrogen or halo. 1-6 A compound of formula 1, characterized in that it is alkyl, or a pharmaceutically acceptable salt thereof.

30. In paragraph 5, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl, Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, -N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl, Z1 or Z2 or A compound of formula 1 or a pharmaceutically acceptable salt thereof, characterized in that:

31. In paragraph 5, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl, Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, -N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl, Z1 or Z2 When, At this time, the above R13 is hydrogen, or -C 1-6 A compound of formula 1, characterized in that it is alkyl, or a pharmaceutically acceptable salt thereof.

32. In paragraph 5, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl, Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, -N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl, Z1 or Z2 A compound of formula 1 or a pharmaceutically acceptable salt thereof, characterized in that:

33. In paragraph 5, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl, Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, -N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl, Z1 or Z2 When, At this time, the above R14 is hydrogen, -C 1-6 Alkyl or -NH(C 1-6 A compound of formula 1, characterized in that it is alkyl)COOH, or a pharmaceutically acceptable salt thereof.

34. In paragraph 5, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl, Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, -N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl, Z1 or Z2 A compound of formula 1 or a pharmaceutically acceptable salt thereof, characterized in that:

35. In paragraph 5, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl, Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, -N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl, Z1 or Z2 When, At this time, the above R15 is hydrogen, -C 1-6 Alkyl or -C 1-6 A compound of formula 1, characterized in that it is alkyl-OH, or a pharmaceutically acceptable salt thereof.

36. In paragraph 5, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl, Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, -N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl, Z1 or Z2 A compound of formula 1 or a pharmaceutically acceptable salt thereof, characterized in that:

37. In paragraph 5, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl, Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, -N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl, Z1 or Z2 When, At this time, the above R16 is hydrogen, -C 1-6 Alkyl, -C 1-6 Alkyl-OH or -C 1-6 A compound of formula 1, characterized in that it is alkyl-COOH, or a pharmaceutically acceptable salt thereof.

38. In paragraph 5, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl, Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, -N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl, Z1 or Z2 or A compound of formula 1 or a pharmaceutically acceptable salt thereof, characterized in that:

39. In paragraph 5, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl, Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, -N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl, Z1 or Z2 When, At this time, the above R17 is hydrogen or -C 1-6 A compound of formula 1, characterized in that it is alkyl, or a pharmaceutically acceptable salt thereof.

40. In paragraph 5, X1 and X2 are each independently hydrogen, halo or C 1-6 It is alkyl, Y1 and Y2 are each independently a single bond, -N(Rb)-, N(Rb)C(=O)-, -N(Rb)CH(OH)- or -CH=C(Rb)-, wherein Rb is each independently hydrogen, halo or C 1-6 It is alkyl, Z1 or Z2 A compound of formula 1 or a pharmaceutically acceptable salt thereof, characterized in that:

41. A compound selected from the group consisting of the following compounds or a pharmaceutically acceptable salt thereof:

42. A composition for treating or preventing cancer, characterized by comprising a compound of any one of claims 1 to 41 or a pharmaceutically acceptable salt thereof.

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