Heterocyclic compounds as KRAS G12D inhibitors

Abstract

The present application provides compounds that are inhibitors of KRAS G12D, in particular, the present application provides a compound of the following formula (I), or optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, solvates thereof. The compounds can be used for treating or preventing diseases or disorders associated with the activity or expression of KRAS G12D.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry; specifically, it relates to a novel class of derivatives containing tricyclic heteroaryl groups, their synthesis methods, and their application as a KRAS G12D inhibitor in the preparation of drugs for the treatment of tumors and other related diseases. Background Technology

[0002] KRAS (Kirsten Rat Sarcoma Viral Oncogene Homolog) is a small GTPase belonging to the RAS family. Currently, three RAS genes are known: HRAS, NRAS, and KRAS. RAS proteins play a crucial role in cancer development and progression; RAS mutations are present in 20%-30% of human tumors, with KRAS mutations being the most frequent, commonly found in lung cancer, pancreatic cancer, and colon cancer.

[0003] KRAS protein contains 188 amino acid residues and has multiple functional motifs, including a nucleotide-binding region, transition I and transition II regions, a nucleotide exchange factor (GEF) binding region, a GTPase activator protein (GAP) binding region, and an effector protein binding region. Under normal conditions, KRAS activity is regulated by various upstream signaling factors, such as receptor tyrosine kinases, integrins, and G protein-coupled receptors. KRAS acts as a molecular switch in the cell, switching between GTP and GDP binding states to indicate activation (on) or inactivation (off), transmitting upstream signals to downstream effector proteins. KRAS protein itself has a relatively slow nucleotide exchange rate and weak GTP hydrolysis function. Upon receiving upstream stimuli, with the assistance of guanine nucleotide exchange factors such as SOS1 (Son of Sevenless 1), KRAS protein releases GDP and binds GTP. GTP-bound RAS proteins are in an activated state, recruiting downstream effector proteins and activating signaling pathways such as Raf-MEK-ERK and PI3K-AKT-mTOR, promoting cell growth, proliferation, survival, metabolism, and angiogenesis. When the GTPase activator GAP binds to KRAS, it significantly promotes the GTP hydrolysis function of KRAS, hydrolyzing GTP into GDP. GDP-bound KRAS then becomes inactive, closing the molecular switch. When RAS is mutated, its inherent or GAP-induced GTPase activity is inhibited, keeping RAS in a GTP-bound state with the molecular switch continuously open. This leads to the persistent activation of multiple downstream signaling pathways, resulting in abnormal cell proliferation and growth.

[0004] In pancreatic cancer, up to 90% of patients have KRAS mutations, of which about 40% of point mutations are KRAS G12D mutations. Additionally, KRAS G12D mutations are present in approximately 13.3% of colorectal cancer patients, about 10% of rectal cancer patients, about 4% of non-small cell lung cancer patients, and about 1.7% of small cell lung cancer patients.

[0005] Due to its crucial role in tumorigenesis and its high mutation frequency, KRAS G12D has become a highly attractive anti-tumor target. Currently, there are no effective KRAS G12D inhibitors on the market. Against this backdrop, we have developed a novel class of KRAS G12D inhibitors. Summary of the Invention

[0006] The purpose of this invention is to provide a novel class of KRAS G12D inhibitors.

[0007] In a first aspect, the present invention provides a compound, or an optical isomer thereof, of the structure shown in formula (I), a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, or a solvate:

[0008]

[0009] In formula (I):

[0010] Ar is selected from aryl or heteroaryl; said aryl or heteroaryl group is optionally substituted by one or more groups selected from the group consisting of: halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 Haloalkenyl, C 2-4 alkynyl group, C 2-4 Halogenated alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, C 3-6 Cycloalkyl-O-, 3- to 6-membered heterocyclic-O-, C 3-6 cycloalkyl C 2-4 alkynyl, 3- to 6-membered heterocyclic C 2-4 alkynyl group, C 1-4 Halogenated alkyl C 2-4 acetylenic, NR 2 R 2 CN, SR 2 -OC(O)R k -OP(O)(OR) m )2、-O-CH(R n )-OP(O)(OR m)2; where each R 2 Each can be either hydrogen or C. 1-4 Alkyl; R k Selected from C 1-12 Alkyl groups, wherein the alkyl group is optionally substituted with one or more groups selected from the group consisting of: hydroxyl, C... 1-4 Alkoxy, NR 2 R 2 C(O)OH, C(O)OC 1-2 Alkyl, or CN; R m Selected from hydrogen or C 1-4 Alkyl; R n Selected from hydrogen or C 1-4 Alkyl; the cycloalkyl or heterocyclic group described above may optionally be substituted by one or more groups selected from the group consisting of: halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 Alkyne group, CN, or =M substitution; where M is selected from O or CR. 3 R 4 ;where R 3 and R 4 Each is independently selected from the following group: hydrogen, fluorine, or C. 1-4 alkyl;

[0011] R is selected from 5-12 membered heterocyclic groups, including partially unsaturated or saturated monocyclic or polycyclic heterocyclic groups, wherein the polycyclic heterocyclic groups include spirocyclic, fused-ring, or bridged-ring heterocyclic groups; the heterocyclic group is optionally substituted by one or more groups selected from the group consisting of: halogen, C 1-4 Alkyl, =O, hydroxyl, CN, -CO(O)-CH(R) n )-OC(O)-U; where, R n Selected from hydrogen or C 1-4 Alkyl; U is selected from C 1-18 alkyl;

[0012] Z is selected from chemical bonds, -O-, -S-, and -NR. 5 -、-C(R a )2-、-C≡C-、-CR a =CR a -、-N=、-CR a =; where R 5 Selected from hydrogen or C 1-4 Alkyl; R a Selected from hydrogen, halogen, or C 1-4 alkyl;

[0013] A is selected from chemical bonds, -O-, -S-, and -NR.6 -; where R 6 Selected from hydrogen or C 1-4 alkyl;

[0014] B is selected from -(CR) 7 R 8 ) m -、-(CR 7 R 8 ) m -T-(CR 7 R 8 ) m -; where T is selected from -C≡C-, -CR a =CR a -、C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic group; wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more groups selected from the group consisting of: halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, CN;R 7 and R 8 Each is independently selected from the following group: hydrogen, halogen, or C. 1-4 Alkyl; or R 7 and R 8 Together with the carbon atoms it is attached to, they form C 3-6 cycloalkyl; R a Selected from hydrogen, halogen, or C 1-4 Alkyl group; each m is independently selected from 0, 1, 2, or 3;

[0015] R 1 Selected from C 3-8 Cycloalkyl or 4- to 12-membered heterocyclic groups, wherein the heterocyclic group comprises partially unsaturated or saturated monocyclic or polycyclic heterocyclic groups, and the polycyclic heterocyclic group comprises spirocyclic, fused-ring, or bridged-ring heterocyclic groups; said cycloalkyl or heterocyclic group is optionally substituted by one or more groups selected from the group consisting of: halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy group, -CH2OC(O)NR 9 R 10 CN, SR 2 C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3- to 8-membered heterocyclic, NR h R h 、-(CR 7 R 8 )m -OR h 、-(CR 7 R 8 ) m -NR h R h , or = M replaces; where R 9 and R 10 Each is independently selected from hydrogen or C. 1-4 Alkyl, or R 9 and R 10 Together with the nitrogen atom it is attached to, it forms a 4- to 8-membered heterocyclic group, which contains one or two N atoms and one or more heteroatoms selected from O and S; each R h Each is independently hydrogen, C 1-4 Alkyl, or C 1-4 Halogenated alkyl; M is selected from O or CR 3 R 4 ;where R 2 R 3 R 4 R 7 R 8 The definitions of X and Y are as described above; X and Y are each independently selected from N or CR. 11 Among them, R 11 Selected from hydrogen, halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkynyl group, C 3-6 cycloalkyl, or CN;

[0016] The prerequisite is that when R 1 It does not have the substitution of =M, and M is selected from CR. 3 R 4 At that time, structural fragments Not for

[0017] In this embodiment, each of the above-mentioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is optionally and independently substituted by 1 to 3 substituents independently selected from the group consisting of: halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3- to 8-membered heterocyclic, aryl, heteroaryl, CN, NO2, OR h SR h NR h R h C(O)R tC(O)OR h C(O)NR h R h NR h C(O)R t NR h S(O)2R t , or S(O)2R t The prerequisite is that the resulting chemical structure is stable and meaningful; among them, R t C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic, aryl, or heteroaryl; each R h Each is independently hydrogen, C 1-4 Alkyl, or C 1-4 Halogenated alkyl; or two R h Together with the nitrogen atom attached thereto, they form a 3- to 8-membered heterocyclic group, which contains 1 or 2 N atoms and 0 or 1 heteroatom selected from O or S;

[0018] Unless otherwise specified, the aryl group mentioned above is an aromatic group containing 6-12 carbon atoms; the heteroaryl group is a 5- to 15-membered (preferably 5- to 12-membered) heteroaryl group.

[0019] In another preferred embodiment, when R 1 It does not have the substitution of =M, and M is selected from CR. 3 R 4 At that time, structural fragments for Among them, each R d Each is independently selected from hydrogen and C. 1-4 Alkyl, C 3-6 cycloalkyl; or two R d Together with the same carbon atom it is connected to, they form C 3-6 Cycloalkyl.

[0020] In another preferred embodiment, when R 1 It does not have the substitution of =M, and M is selected from CR. 3 R 4 At that time, structural fragments for

[0021] In another preferred embodiment, when R 1 It does not have the substitution of =M, and M is selected from CR. 3 R 4 At that time, structural fragments for

[0022] In another preferred embodiment, equation (I) is equivalent to equation (II):

[0023]

[0024] In formula (II):

[0025] Ar is selected from aryl or heteroaryl; said aryl or heteroaryl group is optionally substituted by one or more groups selected from the group consisting of: halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 Haloalkenyl, C 2-4 alkynyl group, C 2-4 Halogenated alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, C 3-6 Cycloalkyl-O-, 3- to 6-membered heterocyclic-O-, C 3-6 cycloalkyl C 2-4 alkynyl, 3- to 6-membered heterocyclic C 2-4 alkynyl group, C 1-4 Halogenated alkyl C 2-4 acetylenic, NR 2 R 2 CN, SR 2 -OC(O)R k -OP(O)(OR) m )2、-O-CH(R n )-OP(O)(OR m )2; where each R 2 Each can be either hydrogen or C. 1-4 Alkyl; R k Selected from C 1-12 Alkyl groups, wherein the alkyl group is optionally substituted with one or more groups selected from the group consisting of: hydroxyl, C... 1-4 Alkoxy, NR 2 R 2 C(O)OH, C(O)OC 1-2 Alkyl, or CN; R m Selected from hydrogen, C 1-4 Alkyl; R n Selected from hydrogen or C 1-4 Alkyl; the cycloalkyl or heterocyclic group described above may optionally be substituted by one or more groups selected from the group consisting of: halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4Alkyne group, CN, or =M substitution; where M is selected from O or CR. 3 R 4 ;where R 3 and R 4 Each is independently selected from the following group: hydrogen, fluorine, or C. 1-4 alkyl;

[0026] R is selected from 5-12 membered heterocyclic groups, including partially unsaturated or saturated monocyclic or polycyclic heterocyclic groups, wherein the polycyclic heterocyclic groups include spirocyclic, fused-ring, or bridged-ring heterocyclic groups; the heterocyclic group is optionally substituted by one or more groups selected from the group consisting of: halogen, C 1-4 Alkyl, =O, hydroxyl, CN, -CO(O)-CH(R) n )-OC(O)-U; where, R n Selected from hydrogen or C 1-4 Alkyl; U is selected from C 1-18 alkyl;

[0027] Z is selected from chemical bonds, -O-, -S-, and -NR. 5 -、-C(R a )2-、-C≡C-、-CR a =CR a -、-N=、-CR a =; where R 5 Selected from hydrogen or C 1-4 Alkyl; R a Selected from hydrogen, halogen, or C 1-4 alkyl;

[0028] A is selected from chemical bonds, -O-, -S-, and -NR. 6 -; where R 6 Selected from hydrogen or C 1-4 alkyl;

[0029] B is selected from -(CR) 7 R 8 ) m -、-(CR 7 R 8 ) m -T-(CR 7 R 8 ) m -; where T is selected from -C≡C-, -CR a =CR a -、C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic group; wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more groups selected from the group consisting of: halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxyl, C 1-4 Alkoxy, C 1-4Halogenated alkoxy groups, CN;R 7 and R 8 Each is independently selected from the following group: hydrogen, halogen, or C. 1-4 Alkyl; or R 7 and R 8 Together with the carbon atoms it is attached to, they form C 3-6 cycloalkyl; R a Selected from hydrogen, halogen, or C 1-4 Alkyl group; each m is independently selected from 0, 1, 2, or 3;

[0030] R 1 Selected from C 3-8 Cycloalkyl or 4- to 12-membered heterocyclic groups, wherein the heterocyclic group comprises partially unsaturated or saturated monocyclic or polycyclic heterocyclic groups, and the polycyclic heterocyclic group comprises spirocyclic, fused-ring, or bridged-ring heterocyclic groups; said cycloalkyl or heterocyclic group is optionally substituted by one or more groups selected from the group consisting of: halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy group, -CH2OC(O)NR 9 R 10 CN, SR 2 C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3- to 8-membered heterocyclic, NR h R h 、-(CR 7 R 8 ) m -OR h 、-(CR 7 R 8 ) m -NR h R h , or = M replaces; where R 9 and R 10 Each is independently selected from hydrogen or C. 1-4 Alkyl, or R 9 and R 10 Together with the nitrogen atom it is attached to, it forms a 4- to 8-membered heterocyclic group, which contains one or two N atoms and one or more heteroatoms selected from O and S; each R h Each is independently hydrogen, C 1-4 Alkyl, or C 1-4 Halogenated alkyl; M is selected from O or CR 3 R 4 ;where R 2 R 3 R 4 R7 R 8 The definitions of , and m are as described above;

[0031] R 11 Selected from hydrogen, halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkynyl group, C 3-6 Cycloalkyl, or CN.

[0032] In another preferred embodiment, the structural segment in formula (I) or formula (II) Selected from the following group groups:

[0033]

[0034] Indicates the connection sites between the above structural segments and other structures in formula (I) or formula (II);

[0035] "*" indicates a chiral center;

[0036] The above groups are optionally surrounded by 0, 1 or 2 R groups. 13 Replace, where R 13 Selected from halogens, C 1-4 Alkyl, =O, hydroxyl, or CN.

[0037] In another preferred embodiment, Ar is selected from the group consisting of phenyl and naphthyl.

[0038] In another preferred embodiment, Ar is selected from the following group:

[0039]

[0040]

[0041] Indicates the connection sites between the above structural segments and other structures in formula (I) or formula (II);

[0042] "*" indicates a chiral center.

[0043] In another preferred embodiment, the structural segment in formula (I) or formula (II) Groups selected from the following group:

[0044]

[0045] "*" indicates a chiral center;

[0046] This indicates the connection point between the above structural segment and other structures in formula (I) or formula (II).

[0047] In another preferred embodiment, equation (I) is equation (IIIa) or equation (IIIb).

[0048]

[0049] "*" indicates a chiral center;

[0050] Among them, Ar, A, B, R 1 R 11 The definition is as described above.

[0051] In another preferred embodiment, equation (I) is equivalent to equation (IV).

[0052]

[0053] Each R d Each is independently selected from hydrogen and C. 1-4 Alkyl, C 3-6 cycloalkyl; or two R d Together with the same carbon atom it is connected to, they form C 3-6 cycloalkyl; and at least two R d Together with the same carbon atom it is connected to, they form C 3-6 cycloalkyl;

[0054] Ar, A, B, R 1 R 11 The definition is as described above.

[0055] In another preferred embodiment, equation (I) is equation (V).

[0056]

[0057] R 1 Selected from C 3-8 Cycloalkyl or 4- to 12-membered heterocyclic groups;

[0058] R 12 Selected from hydrogen, halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, -CH2OC(O)NR 9 R 10 C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic, CN, OR h SR h NR h R h 、-(CR 7 R8 ) m -OR h 、-(CR 7 R 8 ) m -NR h R h ;

[0059] n is selected from 0, 1, or 2;

[0060] Ar, X, Y, R, A, B, R 7 R 8 R 9 R 10 R h The definitions of , and m are as described above.

[0061] In another preferred embodiment, equation (I) is equation (VI).

[0062]

[0063] R is selected from the following group:

[0064]

[0065] Ar is selected from the following group:

[0066]

[0067] "*" indicates a chiral center;

[0068] Indicates the connection sites between the R group and other structures of the compound of formula (VI);

[0069] Indicates the connection sites between the Ar group and other structures of the compound of formula (VI);

[0070] R 13 Selected from halogens, C 1-4 Alkyl, =O, hydroxyl, or CN;

[0071] R 14 and R 15 Each is independently selected from halogens, C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 Haloalkenyl, C 2-4 alkynyl group, C 2-4 Halogenated alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, C 3-6Cycloalkyl-O-, 3- to 6-membered heterocyclic-O-, NR 2 R 2 CN, SR 2 -OC(O)R k -OP(O)(OR) m )2、-O-CH(R n )-OP(O)(OR m )2; where each R 2 Each can be either hydrogen or C. 1-4 Alkyl; R k Selected from C 1-12 Alkyl groups, wherein the alkyl group is optionally substituted with one or more groups selected from the group consisting of: hydroxyl, C... 1-4 Alkoxy, NR 2 R 2 C(O)OH, C(O)OC 1-2 Alkyl, or CN; R m Selected from hydrogen or C 1-4 Alkyl; R n Selected from hydrogen or C 1-4 Alkyl; the cycloalkyl or heterocyclic group described above may optionally be substituted by one or more groups selected from the group consisting of: halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 Alkyne group, CN, or =M substitution; where M is selected from O or CR. 3 R 4 ;where R 3 and R 4 Each is independently selected from the following group: hydrogen, fluorine, or C. 1-4 alkyl;

[0072] k is selected from 0, 1, or 2;

[0073] p is selected from 0, 1, 2, 3, 4, or 5;

[0074] q is selected from 0, 1, 2, 3, or 4;

[0075] R 11 The definition is as described above; R d The definition is as described above.

[0076] In another preferred embodiment, equation (I) is equation (VII).

[0077]

[0078] "*" indicates a chiral center;

[0079] R 13 R 14 R 11 The definitions of k and p are as described above.

[0080] In another preferred embodiment, equation (I) is equation (VIII).

[0081]

[0082] E is selected from chemical bonds, -O-, -S-, and -NR. 5 -、-C≡C-、or-CR a =CR a -;

[0083] R 16 Selected from C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic group; wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more groups selected from the group consisting of: halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 Alkyne group, CN, or =M substitution; where M is selected from O or CR. 3 R 4 ;where R 3 and R 4 Each is independently selected from the following group: hydrogen, fluorine, or C. 1-4 alkyl;

[0084] R, A, B, R 1 R 11 R 5 and R a The definition is as described above; R 15 The definitions of q are as described above.

[0085] In another preferred embodiment, equation (I) is equation (IX).

[0086]

[0087] Among them, Ar, A, B, R 1 R 11 The definition is as described above.

[0088] In another preferred embodiment, equation (I) is equation (X).

[0089]

[0090] Among them, Ar, A, B, R 1 R11 The definition is as described above.

[0091] In another preferred embodiment, in equation (IX) or equation (X)

[0092] Structural fragments Selected from the following group groups:

[0093]

[0094] Ar is selected from the following group:

[0095]

[0096] "*" indicates a chiral center;

[0097] Representing structural fragments Or Ar, the connection site with other structures in formula (IX) or formula (X). In another preferred embodiment, formula (I) is formula (XI).

[0098]

[0099] "*" indicates a chiral center;

[0100] R 11 Selected from hydrogen, halogens, C 1-4 alkyl;

[0101] R 11’ Selected from hydrogen, halogens, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, or CN;

[0102] The definitions of Ar and R are as described above.

[0103] In another preferred embodiment, equation (I) is equation (XII).

[0104]

[0105] "*" indicates a chiral center;

[0106] R 11 and R 11’ The definition is as described above;

[0107] R 13 R 14 The definitions of k and p are as described above.

[0108] In another preferred embodiment, equation (I) is equation (XIII).

[0109]

[0110] "*" indicates a chiral center;

[0111] R 11 Selected from hydrogen, halogens, C 1-4 alkyl;

[0112] X is selected from N or CR 11’ Among them, R 11’ Selected from hydrogen, halogens, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, or CN;

[0113] R 13 Selected from halogens, C 1-4 Alkyl, =O, hydroxyl, or CN;

[0114] R 14 Selected from halogens, C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 Haloalkenyl, C 2-4 alkynyl group, C 2-4 Halogenated alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, C 3-6 Cycloalkyl-O-, 3- to 6-membered heterocyclic-O-, NR 2 R 2 CN, SR 2 Among them, each R 2 Each can be either hydrogen or C. 1-4 alkyl;

[0115] R 14’ Selected from hydrogen, -OC(O)R k -OP(O)(OR) m )2, or -O-CH(R n )-OP(O)(OR m )2; where R k Selected from C 1-12 Alkyl groups, wherein the alkyl group is optionally substituted with one or more groups selected from the group consisting of: hydroxyl, C... 1-4 Alkoxy, NR 2 R 2 C(O)OH, C(O)OC 1-2 Alkyl, or CN; R m Selected from hydrogen or C 1-4 Alkyl; R n Selected from hydrogen or C 1-4 alkyl;

[0116] R 17 Selected from hydrogen or -CO(O)-CH(R) n )-OC(O)-U; where, R n Selected from hydrogen or C 1-4 Alkyl; U is selected from C 1-18 alkyl;

[0117] k is selected from 0, 1, or 2;

[0118] p is selected from 0, 1, 2, 3, or 4.

[0119] In another aspect, the present invention provides a compound with the structure shown in formula (XIV), or an optical isomer thereof, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, or a solvate:

[0120]

[0121] In formula (XIV):

[0122] "*" indicates a chiral center;

[0123] R 11 Selected from hydrogen, halogens, C 1-4 alkyl;

[0124] X is selected from N or CR 11’ Among them, R 11’ Selected from hydrogen, halogens, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, or CN;

[0125] R 18 Selected from halogens, C 1-4 Alkyl, or C 1-4 Alkoxy;

[0126] The definitions of Ar and R are as described above.

[0127] In another preferred embodiment, the compound of formula (I) is selected from the group consisting of:

[0128]

[0129]

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140] In the above structural formula, "*" represents a chiral center, which can be optionally R-configuration, S-configuration, or a mixture of R-configuration and S-configuration; The carbon atoms bonded by the bond can optionally be in the R configuration or S configuration, or optionally in the cis or trans configuration.

[0141] A second aspect of the present invention provides a pharmaceutical composition comprising the compound described in the first aspect of the present invention, or an optical isomer thereof, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate, and a pharmaceutically acceptable carrier.

[0142] A third aspect of the invention provides the use of a compound, or an optical isomer thereof, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, or a solvate, as described in the first aspect of the invention, for the preparation of a pharmaceutical composition for treating a disease, condition, or symptom associated with KRAS G12D activity or expression.

[0143] In another preferred embodiment, the disease, symptom, or condition is selected from the group consisting of: pancreatic cancer, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, colon cancer, colorectal cancer, thyroid cancer, embryonal rhabdomyosarcoma, granulosa cell tumor of the skin, melanoma, liver cancer, rectal cancer, bladder cancer, pharyngeal cancer, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, kidney cancer, skin cancer, lymphoma, gastric cancer, acute myeloid leukemia, myelofibrosis, B-cell lymphoma, monocytic leukemia, splenomegaly with polycythemia, eosinophilic polycythemia syndrome, myeloma, and various solid tumors and hematologic malignancies. Detailed Implementation

[0144] Through long-term and in-depth research, the inventors unexpectedly discovered a novel class of KRAS G12D inhibitors, along with their preparation methods and applications. The compounds of this invention can be applied to the treatment of various diseases related to the activity of these small GTPases. Based on the above findings, the inventors completed this invention.

[0145] the term

[0146] Unless otherwise specified, the word “or” as used in this article has the same meaning as “and / or” (referring to both “or” and “and”).

[0147] Unless otherwise specified, in all compounds of the present invention, each chiral carbon atom (chiral center) may optionally be in the R configuration or the S configuration, or a mixture of the R and S configurations.

[0148] As used herein, the term "alkyl" refers to a straight-chain (i.e., unbranched) or branched saturated hydrocarbon group containing only carbon atoms, either alone or as part of other substituents, or a combination of straight and branched groups. When an alkyl group is preceded by a carbon number definiteness (e.g., C...), it is used to indicate a carbon atom number. 1-10 When ), it refers to the alkyl group containing 1-10 carbon atoms. For example, C 1-8 Alkyl refers to an alkyl group containing 1 to 8 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or similar groups.

[0149] As used herein, the term "alkenyl," whether alone or as part of other substituents, refers to a straight-chain or branched carbon chain group having at least one carbon-carbon double bond. Alkenyl groups can be substituted or unsubstituted. When an alkenyl group is preceded by a carbon number definiteness (e.g., C...), it signifies a carbon chain group. 2-8 When ), it refers to the alkenyl group containing 2-8 carbon atoms. For example, C 2-8 Alkenyl refers to an alkenyl group containing 2-8 carbon atoms, including vinyl, propenyl, 1,2-butenyl, 2,3-butenyl, butadienyl, or similar groups.

[0150] As used herein, the term "alkynyl" refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond, either alone or as part of other substituents. The alkynyl group can be straight-chain or branched, or a combination thereof. When the alkynyl group is preceded by a carbon number limit (e.g., C...), it is considered a alkynyl group. 2-8 When alkynyl is used, it means that the alkynyl group contains 2-8 carbon atoms. For example, the term "C 2-8 "Alynyl" refers to a straight-chain or branched alkynyl group having 2-8 carbon atoms, including ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, sec-butynyl, tert-butynyl, or similar groups.

[0151] As used herein, the term "cycloalkyl" refers to a cyclic group having a saturated or partially saturated monocyclic ring, bicyclic or polycyclic (fused, bridged or spirocyclic) ring. When a cycloalkyl group is preceded by a carbon number determination (e.g., C...), it is used to indicate the presence of a carbon number limit (e.g., C...). 3-10 When ), it refers to the cycloalkyl group containing 3-10 carbon atoms. In some preferred embodiments, the term "C" is used. 3-8"Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or bicyclic alkyl group having 3-8 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, or similar groups. "Spirocycloalkyl" refers to a bicyclic or polycyclic group in which monocyclic rings share a single carbon atom (called a spiro atom). These may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. "Fused cycloalkyl" refers to a fully carbon bicyclic or polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system. One or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. "Bridged cycloalkyl" refers to a fully carbon polycyclic group in which any two rings share two non-directly connected carbon atoms. These may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. All atoms in the cycloalkyl group are carbon atoms. The following are some examples of cycloalkyl groups; the present invention is not limited to the cycloalkyl groups described below.

[0152]

[0153] Unless otherwise stated, the terms used in the specification and claims have the following meanings. "Aryl" refers to a monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, such as phenyl and naphthyl. The aryl ring may be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent group must be on a carbon atom of a ring having a conjugated π-electron system. Aryl groups can be substituted or unsubstituted. Some examples of aryl groups are given below; the invention is not limited to the aryl groups described below.

[0154]

[0155] "Heteroaryl" refers to an aromatic monocyclic or polycyclic group containing one or more heteroatoms (optionally nitrogen, oxygen, and sulfur), or a polycyclic group consisting of a heterocyclic group (containing one or more heteroatoms, optional nitrogen, oxygen, and sulfur) fused with an aryl group, with the linking site located on the aryl group. Heteroaryl groups can be optionally substituted or unsubstituted. Some examples of heteroaryl groups are given below; however, this invention is not limited to the heteroaryl groups described below.

[0156]

[0157] "Heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein one or more ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl. Polycyclic heterocyclic groups refer to heterocyclic groups including spirocyclic, fused-ring, and bridged-ring groups. "Spirocyclic heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in the system shares an atom (called a spiro atom) with other rings in the system, wherein one or more ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. "Fused-ring heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system; one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system, and one or more ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. "Bridged heterocyclic groups" refer to polycyclic heterocyclic groups in which any two rings share two non-directly connected atoms. These may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system, and one or more ring atoms are selected from nitrogen, oxygen, or sulfur, while the remaining ring atoms are carbon. If a saturated ring and an aromatic ring are present simultaneously in the heterocyclic group (for example, a saturated ring and an aromatic ring fused together), the point of attachment to the parent ring must be on the saturated ring. Note: When the point of attachment to the parent ring is on the aromatic ring, it is called a heteroaryl group, not a heterocyclic group. Below are some examples of heterocyclic groups; this invention is not limited to the heterocyclic groups described below.

[0158]

[0159] As used herein, the term "halogen" refers to F, Cl, Br, and I, either alone or as part of other substituents.

[0160] As used herein, the term "substitution" (with or without the "arbitrarily" modified) refers to the substitution of one or more hydrogen atoms on a particular group by a particular substituent. The particular substituent is the substituent described accordingly above, or the substituent appearing in the various embodiments. Unless otherwise specified, an arbitrarily substituted group may have a substituent selected from a particular group at any substituted site of that group, and the substituents may be the same or different at each position. Cyclic substituents, such as heterocyclic groups, may be attached to another ring, such as a cycloalkyl group, thereby forming a spirobicyclic system, i.e., two rings sharing a common carbon atom. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are those that are stable or chemically feasible. The substituents include, for example (but are not limited to): C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-8 Cycloalkyl, 3- to 12-membered heterocyclic groups, aryl, heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C 1-8Aldehyde group, C 2-10 Acyl group, C 2-10 Ester group, amino group.

[0161] For convenience and to conform to common understanding, the terms "arbitrary substitution" or "optional substitution" apply only to sites that can be substituted by substituents, and do not include chemically impossible substitutions.

[0162] As used herein, unless otherwise specified, the term "pharmaceutically acceptable salt" means a salt suitable for contact with the tissues of an object (e.g., a human) without producing undesirable side effects. In some embodiments, a pharmaceutically acceptable salt of a compound of the present invention includes salts of the compounds of the present invention having acidic groups (e.g., potassium, sodium, magnesium, calcium salts) or salts of the compounds of the present invention having basic groups (e.g., sulfates, hydrochlorides, phosphates, nitrates, carbonates).

[0163] use:

[0164] The present invention provides the use of compounds of formula (I), or their deuterated derivatives, their salts, isomers (enantiomers or diastereomers, if present), hydrates, pharmaceutically acceptable carriers or excipients for the inhibition of KRASG12D.

[0165] The compound of this invention can be used as a KRAS G12D inhibitor.

[0166] This invention is a single inhibitor of KRAS G12D, which aims to prevent, alleviate, or cure diseases by regulating the activity of KRAS G12D. The diseases referred to include pancreatic cancer, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, colon cancer, colorectal cancer, thyroid cancer, embryonal rhabdomyosarcoma, granulosa cell tumors of the skin, melanoma, liver cancer, rectal cancer, bladder cancer, pharyngeal cancer, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, kidney cancer, skin cancer, lymphoma, gastric cancer, acute myeloid leukemia, myelofibrosis, B-cell lymphoma, monocytic leukemia, splenomegaly with polycythemia, eosinophilic polycythemia syndrome, multiple myeloma, and various solid tumors and hematologic malignancies.

[0167] The compounds of the present invention and their deuterated derivatives, as well as pharmaceutically acceptable salts or isomers thereof (if present) or hydrates thereof and / or compositions thereof, can be formulated together with pharmaceutically acceptable excipients or carriers to obtain compositions that can be administered in vivo to mammals, such as men, women and animals, for the treatment of conditions, symptoms and diseases. The compositions can be in the form of tablets, pills, suspensions, solutions, emulsions, capsules, aerosols, sterile injections, sterile powders, etc. In some embodiments, pharmaceutically acceptable excipients include microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate, mannitol, hydroxypropyl-β-cyclodextrin, β-cyclodextrin (added), glycine, disintegrants (such as starch, croscarmellose sodium, complex silicates and high molecular weight polyethylene glycol), granulation binders (such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic), and lubricants (such as magnesium stearate, glycerin and talc). In a preferred embodiment, the pharmaceutical composition is in a dosage form suitable for oral administration, including but not limited to tablets, solutions, suspensions, capsules, granules, and powders. The amount of the compound or pharmaceutical composition of the present invention administered to the patient is not fixed and is usually given at a pharmaceutically effective dose. Simultaneously, the actual amount of compound administered can be determined by the physician based on the actual situation, including the condition being treated, the chosen route of administration, the actual compound administered, and the patient's individual condition. The dosage of the compound of the present invention depends on the specific purpose of treatment, the route of administration, the patient's condition, and the physician's judgment. The proportion or concentration of the compound of the present invention in the pharmaceutical composition depends on various factors, including dosage, physicochemical properties, and route of administration.

[0168] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions.

[0169] General synthetic methods for compounds

[0170] Abbreviations and Chemical Reagents

[0171] Ac = Acetyl group

[0172] Boc = tert-Butoxycarbonyl

[0173] t-BuOK = Potassium tert-butoxide

[0174] Catacxium-A-Pd-G3 = [n-Butyl di(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II)

[0175] m-CPBA = 3-chloroperoxybenzoic acid

[0176] DAST = diethylaminosulfur trifluoride

[0177] DCM = dichloromethane

[0178] 1,4-dioxane=1,4-dioxane

[0179] DIPEA or DIEA = N,N-diisopropylethylamine

[0180] DIBAL-H = Diisobutylaluminum hydride

[0181] DMAP = 4-Dimethylaminopyridine

[0182] DMF = N,N-dimethylformamide

[0183] DMSO = dimethyl sulfoxide

[0184] EtOAc or EA = ethyl acetate

[0185] HATU = N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea)

[0186] LiHMDS = Lithium dibis(trimethylsilylamine)

[0187] Me = methyl

[0188] NMP = N-methylpyrrolidone

[0189] MOM = methoxymethyl

[0190] Ph = phenyl

[0191] Py = pyridine

[0192] i-PrOH = Isopropanol

[0193] TBAF = Tetra-n-Butylammonium Fluoride

[0194] TIPS = Triisopropylsilyl

[0195] TEA = Triethylamine

[0196] Tf = trifluoromethanesulfonyl group

[0197] TFA = Trifluoroacetic acid

[0198] THF = Tetrahydrofuran

[0199] TMS = Trimethylsilyl

[0200] TsOH = p-Toluenesulfonic acid

[0201] The compounds of the present invention, formulas (IA), (IB), and (IC), can be prepared by the following methods:

[0202] Reaction 1:

[0203]

[0204] Compound (Ia) undergoes a substitution reaction in an inert solvent under basic conditions to give intermediate (Ib). Intermediate (Ib) undergoes a substitution reaction in an inert solvent under basic conditions to give intermediate (Ic). Next, intermediate (Ic) reacts with compound (IA-3) to give intermediate (Id). Then, the target compound is obtained through one or two deprotection reactions.

[0205] The definitions of Z and R in the above reaction formula are the same as those stated above.

[0206] Reaction 2:

[0207]

[0208] Compound (Ia) reacts with compound (IB-1) in an inert solvent to give intermediate (If). Intermediate (If) undergoes a substitution reaction in an inert solvent under basic conditions to give intermediate (Ig). Intermediate (Ig) selectively reduces the exocyclic double bond to intermediate (Ih). Intermediate (Ih) reacts with compound (IB-2) in an inert solvent to give intermediate (Ii). Finally, the target compound is obtained through one or two deprotection reactions.

[0209] Reaction 3:

[0210]

[0211] Compound (Ia) undergoes a substitution reaction in an inert solvent under basic conditions to give intermediate (Ik). Intermediate (Ik) undergoes a substitution reaction under basic conditions to give intermediate (Il). Intermediate (Il) reacts with compound (IC-2) in an inert solvent to give intermediate (Im), which is then subjected to a deprotection reaction to obtain the target compound.

[0212] In the above reaction formula, R b and R c The definition is the same as the description of the substituent on Ar above.

[0213] Reaction 4:

[0214]

[0215] Compounds (VIIa) and (VIIb) react in an inert solvent under basic conditions to give compound (VIIc), which is then reduced to give compound (VIId). Compounds (Ia) and (VIIe) undergo a substitution reaction to give intermediate (VIIf). Intermediate (VIIf) and compound (VIId) undergo a substitution reaction under basic conditions to give intermediate (VIIg). Intermediate (VIIg) reacts with compound (VIIh) in an inert solvent to give intermediate (VIIi), which is then deprotected to give the target compound. The target compound with a single chiral configuration can be obtained by using the R or S isomer of compound (VIIa) in the first step of the reaction, ultimately yielding the target compound with R or S chirality; alternatively, intermediate (VIIi) can be resolved by chiral resolution followed by removal of the protecting group to obtain the target compound with R or S chirality; or the target compound with R or S chirality can be obtained by chiral resolution of the racemic mixture of compound (VII-A).

[0216] In the above reaction formula, R 13 R 14 The definitions of , k, and p are the same as those in the statement of power claim 9.

[0217] In the above formulas, the definitions of each group are as described above. The reagents and conditions for each step can be those conventionally used in this type of preparation method in the art. After the compound structure of this invention is disclosed, the above selections can be made by those skilled in the art based on their knowledge.

[0218] Pharmaceutical Compositions and Administration

[0219] Because the compounds of the present invention have excellent inhibitory activity against KRAS G12D, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat, prevent and alleviate diseases related to KRAS G12D activity or expression levels.

[0220] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 5-200 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0221] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0222] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0223] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0224] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0225] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0226] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0227] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0228] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0229] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0230] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0231] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 5–500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skill of a skilled physician.

[0232] The main advantages of this invention include:

[0233] 1. A compound as shown in Formula I is provided.

[0234] 2. A novel KRAS G12D inhibitor is provided, as well as its preparation and application, wherein the inhibitor can inhibit the activity of KRAS G12D at extremely low concentrations.

[0235] 3. A class of pharmaceutical compositions for treating diseases associated with KRAS G12D activity is provided.

[0236] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0237] Example

[0238] Example 1: Preparation of Compound 1

[0239]

[0240] Compound 1a was synthesized according to the method described in patent WO2021041671. Compound 1a (60 mg, 0.24 mmol) and N,N-diisopropylethylamine (215 mg, 1.66 mmol) were dissolved in dichloromethane (3 mL). The mixture was stirred at -40 °C while compound 1b (50 mg, 0.24 mmol) was added. The reaction mixture was stirred at -40 °C for 1 hour. After the reaction was complete, water was added. The mixture was extracted with dichloromethane (3 × 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:ethyl acetate = 5:1) to give a yellow solid product 1c (90 mg, yield 88%). MS m / z 428.3 [M+H] + .

[0241] Compound 1d was obtained commercially. Compound 1c (60 mg, 0.14 mmol), compound 1d (34 mg, 0.21 mmol), and N,N-diisopropylethylamine (54 mg, 0.42 mmol) were sequentially dissolved in 1,4-dioxane (1.5 mL), and the reaction mixture was stirred overnight at 90 °C. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 25:1) to give a yellow oily product 1e (42 mg, yield 54%). MS m / z 551.5 [M+H] + .

[0242] Compound 1f was synthesized according to the method described in patent WO2021041671. Compound 1e (42 mg, 0.08 mmol), compound 1f (43 mg, 0.13 mmol), and methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (5.5 mg, 0.008 mmol) were added to a reaction flask, and the mixture was purged with nitrogen three times. Then, tetrahydrofuran (1.5 mL) and potassium phosphate aqueous solution (1.5 M, 0.15 mL) were added. The reaction mixture was stirred at 60 °C for 2 hours under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature and water was added. The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 25:1) to give 1 g (33 mg, yield 60%) of a yellow oily product. MS m / z 721.8 [M+H] + .

[0243] 1 g (29 mg, 0.04 mmol) of the compound was dissolved in 3 mL of dichloromethane, and then 0.5 mL of trifluoroacetic acid was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude product was then dissolved in methanol, and the pH was adjusted to approximately 7 by adding an appropriate amount of ammonia. The mixture was then concentrated under reduced pressure again. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1, 2% ammonia) to give a pale yellow solid product 1 (13.6 mg, yield 59%). 1 H NMR (500MHz, CD3OD) δ9.13 (s, 1H), 7.60 (d, J = 7.8Hz, 1H), 7.42-7.37 (m, 1H), 7.34 (t, J = 2.2 Hz,1H),7.18-7.15(m,1H),6.94-6.88(m,1H),5.65-5.49(m,1H),4.75-4.66(m,2H),4.39- 4.34(m,2H),4.20(s,2H),4.05-3.83(m,3H),3.57-3.43(m,3H),2.76-2.65(m,1H),2.65-2 .54(m,1H),2.47-2.41(m,1H),2.38-2.29(m,2H),2.22-2.14(m,1H),1.09-1.02(m,4H)ppm. MS m / z 577.6[M+H] + .

[0244] Example 2: Preparation of Compound 2

[0245]

[0246] Compounds 2a and 1f were synthesized according to the method described in patent WO2021041671. Compound 2a (22 mg, 0.04 mmol), compound 1f (27 mg, 0.08 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (3 mg, 0.004 mmol), and potassium phosphate aqueous solution (1.5 M, 0.08 mL) were sequentially dissolved in 1,4-dioxane (1 mL). The reaction mixture was bubbled under nitrogen for 1 minute. The reaction mixture was stirred at 100°C for 2 hours in a sealed tube. After the reaction was complete, the mixture was cooled to room temperature and water was added. The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 25:1) to give a yellow solid product 2b (27 mg, yield 94%). MS m / z 721.9 [M+H] + .

[0247] Compound 2b (25 mg, 0.03 mmol) was dissolved in dichloromethane (2 mL), and then 85% m-chloroperoxybenzoic acid (8 mg, 0.04 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 8:1) to give a pale yellow solid product 2c (11 mg, yield 43%). MS m / z 737.9 [M+H] + .

[0248] Compound 2c (10 mg, 0.01 mmol) was dissolved in acetonitrile (1.5 mL), and then a 4M solution of 1,4-dioxane (0.2 mL) containing hydrogen chloride was added. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was then dissolved in methanol, and the pH was adjusted to approximately 7 by adding a suitable amount of ammonia. The mixture was then concentrated under reduced pressure again. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1, 2% ammonia) to give a pale yellow solid product 2 (5.3 mg, yield 66%). 1H NMR(500MHz,CD3OD)δ9.07(s,1H),7.60(d,J=8.0Hz,1H),7.42-7.36(m,1H),7.33(t,J=2.2Hz,1H ),7.16(d,J=1.5Hz,1H),6.91(dd,J=13.1,7.6Hz,1H),5.72-5.53(m,1H),5.00(d,J=11.7Hz,1H) ,4.80-4.72(m,2H),4.53(d,J=11.8Hz,1H),4.19-3.99(m,3H),3.93(s,2H),3.84-3.79(m,2H),3 .75-3.68(m,1H),3.13-3.00(m,1H),2.50-2.35(m,2H),2.29-2.21(m,3H),2.01-1.91(m,4H)ppm. MSm / z 593.7[M+H] + .

[0249] Example 3: Preparation of Compound 3

[0250]

[0251] Compound 3a (10 g, 70 mmol) was dissolved in a mixed solution of dichloromethane (30 mL) and acetonitrile (30 mL). The reaction solution was cooled to 0 °C, and N,N-diisopropylethylamine (9.50 g, 84 mmol) and bromomethyl methyl ether (8.75 g, 70 mmol) were added sequentially, with stirring continued for 2 hours. After most of the starting material was converted, the solvent was removed by vacuum concentration, ethyl acetate was added, and the system was adjusted to weakly acidic pH with 1 N HCl solution. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 75:25) to give compound 3b (600 mg, yield 4.6%). 1 H NMR (500MHz, CD3OD) δ6.91 (t, J = 1.6 Hz, 1H), 6.72 (d, J = 1.6 Hz, 2H), 4.97 (s, 2H), 3.34 (s, 3H) ppm.

[0252] Compound 3b (640 mg, 3.4 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of a dichloromethane solution containing pyridine (200 mg) (1 mL) and compound 3c (1.24 g, 3.4 mmol). The reaction was carried out at room temperature for 2 hours. After most of the starting material was converted, the system was adjusted to weakly acidic by adding 1 N HCl solution, followed by washing with a small amount of saturated sodium bisulfite solution. The aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 85:15) to give compound 3d (420 mg, 45%). 1 H NMR (500MHz, CDCl3) δ7.16 (d, J = 2.8 Hz, 1H), 7.06 (d, J = 2.8 Hz, 1H), 5.58 (brs, 1H), 5.08 (s, 2H), 3.47 (s, 3H) ppm.

[0253] Compound 3d (250 mg, 0.93 mmol) was dissolved in DMF (2 mL), and cesium carbonate (630 mg, 1.9 mmol) and bromocyclobutane (630 mg, 4.7 mmol) were added sequentially. The reaction was carried out at 80 °C for 16 hours. The reaction was quenched with water, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 90:10) to give compound 3e (220 mg). 1 H NMR(500MHz, CDCl3)δ7.16(d,J=2.9Hz,1H),7.04(d,J=2.9Hz,1H),5.10(s,2H), 4.53-4.47(m,1H),3.47(s,3H),2.43-2.22(m,4H),1.73(m,1H),1.44(m,1H)ppm.

[0254] Compound 3e (15 mg, 0.046 mmol), Pd(dppf)Cl2·CH2Cl2 (4 mg, 0.005 mmol), bis-pinacolborate (24 mg, 0.093 mmol), and potassium acetate (15 mg, 0.138 mmol) were dissolved in 1,4-dioxane (1 mL) and reacted at 100 °C for 4 hours under nitrogen protection. After most of the starting material was converted, the reaction was quenched with water, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 95:5) to give compound 3f (5 mg, 45% yield). 1H NMR(500MHz, CDCl3) δ7.09(d,J=3.0Hz,1H),6.92(d,J=3.0Hz,1H),5.12(s,2H ),4.13–4.04(m,1H),3.47(s,3H),2.03-1.93(m,4H),1.35-1.15(m,14H)ppm.

[0255] Compound 3g was synthesized according to the method described in patent WO2021041671. Compound 3f (34 mg, 0.061 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (5 mg, 0.0061 mmol), and compound 3g (32 mg, 0.086 mmol) were dissolved in tetrahydrofuran (2 mL) under nitrogen protection. Potassium phosphate (1.5 M, 0.5 mL) was added, and the mixture was heated to 60 °C for 3 hours under nitrogen protection. After most of the starting material was converted, the reaction was quenched with water. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol = 95:5) to give compound 3h (31 mg, yield 37%). MS m / z 757.5 [M+H] + .

[0256] Compound 3h (15 mg, 0.02 mmol) was dissolved in acetonitrile (1 mL), and a 1,4-dioxane solution of hydrogen chloride (6 M, 1 mL) was added. The mixture was stirred at room temperature for 30 minutes. After complete conversion of the starting material, the solvent was evaporated under reduced pressure, and the pH was adjusted to alkaline by adding 2 drops of ammonia. The solution was diluted with dichloromethane, dried over anhydrous sodium sulfate, and purified by preparative thin-layer chromatography to obtain the target product compound 3 (7 mg, yield 57%). 1 H NMR(500MHz,CD3OD)δ9.05(s,1H),6.97(d,J=2.9Hz,1H),6.79(d,J=2.9Hz,1H),5.38-5.27( m,1H),4.60(t,J=12.0Hz,2H),4.29(dd,J=34.1,10.6Hz,2H),4.16-4.06(m,1H),3.74-3.66( m,3H),3.35(d,J=14.1Hz,1H),3.30-3.22(m,3H),3.04(td,J=9.7,5.8Hz,1H),2.40-2.13(m ,3H),2.07–2.00(m,2H),1.88(m,4H),1.80-1.69(m,3H),1.41(m,2H),1.29-1.19(m,2H)ppm.

[0257] Example 4: Preparation of compounds 4, 4S, and 4R

[0258]

[0259] Compound 4b was synthesized using the method described in the literature (European Journal of Organic Chemistry, 2015, vol. 2015, #4, pp. 871-875). Potassium tert-butoxide (851 mg, 7.58 mmol) was dissolved in DMF (10 mL), cooled to -50 °C under a nitrogen atmosphere, and a DMF solution of compound 4a (890 mg, 4.21 mmol, racemic) and compound 4b (733 mg, 3.79 mmol) in 5 mL was added dropwise. The reaction mixture was slowly heated to room temperature and stirred for 0.5 hours. The reaction solution was quenched with saturated ammonium chloride aqueous solution (5 mL), then concentrated hydrochloric acid (3 mL) was added, and the mixture was stirred at room temperature for 1 hour. Water (30 mL) was added, and the mixture was extracted three times with ethyl acetate (30 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain a pale yellow oily compound 4c (188 mg, 18%). 1 H NMR (500MHz, CDCl3) δ4.39-4.33(m,1H),4.23(q,J=7.1Hz,2H),3.78-3.72(m,1H),3.16-3.11(m,1H),2.85-2. 76(m,1H),2.66-2.60(m,1H),2.53-2.46(m,1H),2.43-2.36(m,1H),2.19-2.11(m,1H),1.29(t,J=7.1Hz,3H). MS m / z 246.3[M+H] +

[0260] Lithium aluminum hydride (58 mg, 0.77 mmol) was dissolved in tetrahydrofuran (1 mL). A tetrahydrofuran solution of compound 4c (188 mg, 0.77 mmol) in 2 mL was added under an ice bath and nitrogen atmosphere. The reaction mixture was heated and stirred at 65 °C for 3 hours. Water (0.06 mL), 15% sodium hydroxide (0.06 mL), and water (0.18 mL) were added sequentially under an ice bath. The mixture was stirred at room temperature for 15 minutes, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography to obtain a pale yellow oily compound 4d (38 mg, 26%).

[0261] Compound 4e was synthesized according to the method described in patent WO2021041671. Compound 4e (80 mg, 0.19 mmol) and compound 4d (38 mg, 0.20 mmol) were dissolved in dioxane (1 mL), and then diisopropylethylamine (72 mg, 0.56 mmol) was added. The reaction mixture was heated and stirred at 90 °C for 24 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain a white solid compound 4f (33 mg, 30%). MS m / z 581.5, 583.4 [M+H] + .

[0262] Compound 4g was synthesized according to the method described in patent WO2021041671. Compound 4f (29 mg, 0.05 mmol), compound 4g (33 mg, 0.10 mmol), potassium phosphate (32 mg, 0.15 mmol), and methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (4 mg, 0.005 mmol) were dissolved in a 1,4-dioxane / water mixture (0.5 mL / 0.1 mL). The reaction mixture was heated and stirred at 90 °C for 2 hours under a nitrogen atmosphere. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a white solid, compound 4h (27 mg, 72%). MS m / z 751.5 [M+H] + .

[0263] Compound 4h (27 mg, 0.36 mmol) was dissolved in acetonitrile (0.5 mL), and 1,4-dioxane (0.2 mL) of 4M hydrogen chloride was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the pH was adjusted to 7-8 with ammonia. It was then concentrated under reduced pressure again. The crude product was purified by preparative thin-layer chromatography to obtain a white solid compound 4 (13 mg, 60%, racemic). 1H NMR(500MHz,CD3OD)δ9.04(s,1H),7.59(d,J=8.3Hz,1H),7.41-7.36(m,1H),7.33(brs,1H),7.1 6(d,J=1.7Hz,1H),6.91(dd,J=13.0,7.6Hz,1H),4.71-4.64(m,2H),4.35(dd,J=43.8,10.8Hz,2H ),3.87-3.72(m,5H),3.46(d,J=14.1Hz,1H),3.20-3.14(m,1H),2.81(d,J=15.8Hz,1H),2.76-2 .71(m,1H),2.53(d,J=16.0Hz,1H),2.18-2.09(m,1H),2.04-1.97(m,1H),1.96-1.83(m,6H)ppm. 19 F NMR (471MHz, CD3OD) δ-92.24--93.42(m),-115.68--115.86(m),-140.74(d,J=2.7Hz)ppm. MS m / z 607.7[M+H] + Compound 4 (racemic mixture) was resolved by chiral column chromatography to give compounds 4S and 4R.

[0264] Example 5: Preparation of Compound 5

[0265]

[0266] The synthesis of compound 5d follows the same method as that used for the synthesis of compound 1g.

[0267] Compound 5d (19 mg, 0.026 mmol) was dissolved in acetonitrile (2 mL), and then a 4M solution of 1,4-dioxane (0.2 mL) containing hydrogen chloride was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude product was then dissolved in methanol, and the pH was adjusted to approximately 7 by adding a suitable amount of ammonia. The mixture was then concentrated under reduced pressure again. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1, 2% ammonia) to give a pale yellow solid product 5 (13.8 mg, 90% yield). 1HNMR(500MHz,CD3OD)δ8.94(s,1H),7.59(d,J=8.0Hz,1H),7.41-7.35(m,1H),7.32(t,J=2.1Hz,1H),7.14(d,J=2.3Hz,1H),6.94-6 .87(m,1H),5.38-5.21(m,1H),4.68-4.55(m,2H),4.35-4.16(m,4H),3.29-3.14(m,4H),3.06-2.97(m,4H),2.37-1.85(m,10H)ppm. MS m / z 591.5[M+H] + .

[0268] Example 6: Preparation of Compound 6

[0269]

[0270] Compound 6 was synthesized using the same method as compound 1, yielding a yellow solid compound 6 (9.32 mg). 1 H NMR(500MHz,CD3OD)δ9.18(s,1H),7.59(d,J=7.8Hz,1H),7.41-7.35(m,1H),7.32(t ,J=2.2Hz,1H),7.14(d,J=2.4Hz,1H),6.93-6.88(m,1H),5.37-5.24(m,1H),4.48-4 .44(m,1H),4.35-4.23(m,2H),3.87-3.80(m,2H),3.29-3.15(m,3H),3.05-2.96(m, 1H),2.37-2.17(m,8H),2.14-2.05(m,3H),2.03-1.95(m,2H),1.93-1.83(m,1H)ppm. MS m / z 591.7[M+H] + .

[0271] Example 7: Preparation of Compound 7

[0272]

[0273] Compound 7 was synthesized using the same method as compound 1, yielding a white solid compound 7 (4.19 mg). 1H NMR (500MHz, CD3OD) δ9.16 (s, 1H), 7.59 (d, J = 8.3Hz, 1H), 7.42-7.36 (m, 1H), 7.33 (t, J=2.0Hz,1H),7.16(d,J=2.3Hz,1H),6.94-6.88(m,1H),5.41-5.24(m,1H),5.22-5.10 (m,1H),4.32(dd,J=31.5,10.6Hz,2H),4.00-3.91(m,2H),3.46(s,3H),3.37-3.32(m ,1H)3.28-3.20(m,2H),3.11-3.00(m,1H),2.68-2.56(m,2H),2.39-1.83(m,12H)ppm. MS m / z605.6[M+H] + .

[0274] Example 8: Preparation of Compound 8

[0275]

[0276] The synthesis of compound 8c follows the same method as that used for compound 1e.

[0277] Compound 8c (30 mg, 0.05 mmol), compound 1f (25 mg, 0.07 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (8 mg, 0.01 mmol), and cesium carbonate (52 mg, 0.16 mmol) were dissolved in a 1,4-dioxane / water mixture (1.2 / 0.4 mL). The reaction mixture was bubbled under nitrogen for 1 minute. The reaction mixture was stirred overnight at 90 °C in a sealed tube. After the reaction was complete, the mixture was cooled to room temperature and water was added. The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to give a colorless oily compound 8d (9 mg, yield 23%). MS m / z 735.9 [M+H] + .

[0278] Following the same synthetic method as compound 5, compound 8 (2.91 mg) was obtained as a white solid. 1H NMR (500MHz, CD3OD) δ9.16 (s, 1H), 7.59 (d, J = 8.3Hz, 1H), 7.42-7.36 (m, 1H), 7.33 (t, J = 2.1Hz ,1H),7.16(d,J=2.4Hz,1H),6.95-6.89(m,1H),5.39-5.24(m,1H),4.87-4.78(m,2H),4.37-4 .25(m,2H),3.89-3.77(m,2H),3.36-3.32(m,2H),3.29-3.20(m,3H),3.18-3.12(m,2H),3.06 -3.00(m,1H),2.38-2.28(m,1H),2.27-2.07(m,6H),2.04-1.97(m,2H),1.95-1.85(m,1H)ppm. MS m / z591.6[M+H] + .

[0279] Example 9: Preparation of Compound 9

[0280]

[0281] Compound 9a was synthesized according to the method described in patent WO2021041671. Compound 9b was synthesized according to the method described for compound 8d.

[0282] Compound 9b (14 mg, 0.015 mmol) was dissolved in acetonitrile (2 mL), and then a 4M solution of 1,4-dioxane (4 M hydrogen chloride) (0.3 mL) was added. The reaction mixture was stirred at 0 °C for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure to give a yellow solid product 9c (19 mg, 100% yield). MS m / z 753.8 [M+H] + .

[0283] Compound 9c (19 mg, 0.025 mmol) was dissolved in DMF (0.5 mL), and cesium fluoride (38.2 mg, 0.25 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give a yellow solid, compound 9 (4.02 mg). 1H NMR(500MHz,CD3OD)δ9.11(s,1H),7.82(d,J=7.6Hz,1H),7.50(d,J=6.1Hz,1H),7.41-7.3 7(m,1H),7.33(d,J=2.5Hz,1H),7.15(d,J=2.5Hz,1H),5.39-5.23(m,1H),4.85-4.75(m,2 H),4.36-4.23(m,2H),3.88-3.77(m,2H),3.36-3.33(m,1H),3.29-3.20(m,4H),3.18-3.1 0(m,2H),3.07-2.99(m,2H),2.37-2.20(m,2H),2.16-1.96(m,7H),1.94-1.86(m,1H)ppm. MS m / z 597.6[M+H] + .

[0284] Example 10: Preparation of compounds 10, 10S, and 10R

[0285]

[0286] Compound 4f (18 mg, 0.03 mmol), compound 9a (30 mg, 0.06 mmol), potassium phosphate (19 mg, 0.09 mmol), and methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (2.1 mg, 0.003 mmol) were added to a reaction flask, and the mixture was purged with nitrogen three times. Then, 1,4-dioxane (0.5 mL) and water (0.1 mL) were added. The reaction mixture was stirred at 100 °C for 2 hours under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature and water was added. The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 25:1) to give a yellow oily product 10a (21 mg, 75% yield). MS m / z 913.9 [M+H] + .

[0287] Compound 10a (21 mg, 0.02 mmol) was dissolved in acetonitrile (1 mL), followed by the addition of a 0.3 mL solution of 1,4-dioxane in 4 M hydrogen chloride. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solution was concentrated under reduced pressure to give a yellow solid product 10b (18 mg, 100% yield). MS m / z 768.8 [M+H] + .

[0288] Compound 10b (18 mg, 0.02 mmol) was dissolved in DMF (0.5 mL), and cesium fluoride (30 mg, 0.20 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give a yellow solid compound 10 (5 mg, racemic). 1 H NMR (500MHz, CD3OD) δ9.00(s,1H),7.83-7.79(m,1H),7.50(dd,J=7.1,1.1Hz,1H),7.40-7.37(m,1H),7.32(d,J=2.5Hz,1H),7.15(d,J=2.5 Hz,1H),4.69-4.55(m,2H),4.38-4.25(m,2H),3.83-3.77(m,1H),3.76-3.63(m,4H),3.47-3.41(m,1H),3.19-3.12(m,1H),3.0 2(s,1H),2.82-2.77(m,1H),2.74-2.67(m,1H),2.55-2.48(m,1H),2.1-2.09(m,1H),2.04-1.96(m,1H),1.94-1.79(m,6H)ppm. MS m / z 613.7[M+H] + Compound 10 (racemic mixture) was resolved by chiral column chromatography to give compounds 10S and 10R.

[0289] Example 11: Preparation of compounds 11, 11S, and 11R

[0290]

[0291] Following the method of Example 4, compounds 11, 11S, and 11R were prepared by reacting compound 4f with 11a (synthesized according to the method in patent WO2021041671).

[0292] Example 12: Preparation of compounds 12, 12S, and 12R

[0293]

[0294] Compound 12a was prepared according to the method described in patent WO2021041671.

[0295] Compound 4f (16 mg, 0.03 mmol), compound 12a (27 mg, 0.06 mmol), potassium phosphate (19 mg, 0.09 mmol), and methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (2.1 mg, 0.003 mmol) were added to a reaction flask, and the mixture was purged with nitrogen three times. Then, 1,4-dioxane (0.5 mL) and water (0.1 mL) were added. The reaction mixture was stirred at 100 °C for 2 hours under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature and water was added. The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 25:1) to give a yellow oily product 12b (19 mg, 70% yield). MS m / z 871.9 [M+H] + .

[0296] Compound 12b (19 mg, 0.02 mmol) was dissolved in acetonitrile (1 mL), and then a 4 M solution of 1,4-dioxane (0.3 mL) of hydrogen chloride was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure to give a yellow solid product 12c (17 mg, 100% yield). MS m / z 771.8 [M+H] + .

[0297] The compound 12c (17 mg) obtained in the previous step was dissolved in DMF (0.5 mL), and then cesium fluoride (33 mg, 0.22 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give a white solid compound 12 (5 mg, racemic). 1H NMR (500MHz, CD3OD) δ9.02 (s, 1H), 8.12-8.09 (m, 2H), 7.68-7.62 (m, 2H), 7.44 (t, J = 8. 5Hz,1H),4.65-4.58(m,2H),4.38-4.25(m,2H),3.83-3.77(m,1H),3.75-3.63(m,4H),3 .45-3.40(m,2H),3.17-3.10(m,1H),2.83-2.76(m,1H),2.71-2.67(m,1H),2.54-2.48( m,1H),2.14-2.09(m,1H),2.03-1.95(m,1H),1.94-1.84(m,4H),1.83-1.78(m,2H)ppm. MS m / z 615.6[M+H] + Compound 12 (racemic mixture) was resolved by chiral column chromatography to give compounds 12S and 12R.

[0298] Example 13: Preparation of compounds 13, 13S, and 13R

[0299]

[0300] Compound 13a was prepared according to the method described in patent WO2021041671.

[0301] Compound 4f (31 mg, 0.05 mmol), compound 13a (22 mg, 0.08 mmol), potassium phosphate (32 mg, 0.15 mmol), and methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (3.5 mg, 0.005 mmol) were added to a reaction flask, and the mixture was purged with nitrogen three times. Then, 1,4-dioxane (0.5 mL) and water (0.1 mL) were added. The reaction mixture was stirred at 60 °C for 1 hour under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature and water was added. The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 25:1) to give a yellow oily product 13b (5.2 mg, yield 14%). MS m / z 691.7 [M+H] + .

[0302] Compound 13b (5.2 mg, 0.007 mmol) was dissolved in acetonitrile (1 mL), followed by the addition of a 4M solution of 1,4-dioxane (0.2 mL) containing hydrogen chloride. The reaction mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to give a white solid product 13 (4.1 mg, 92% yield, racemic). LC-MS: MS m / z 591.6 [M+H] + The purity was 100% (254 nm). Compound 13 (racemic mixture) was resolved by chiral column chromatography to give compounds 13S and 13R.

[0303] Example 14: Preparation of compounds 14, 14S, and 14R

[0304]

[0305] Compound 14a was prepared according to the method described in patent WO2021041671.

[0306] Compound 4f (16 mg, 0.03 mmol), compound 14a (15 mg, 0.05 mmol), potassium phosphate (19 mg, 0.09 mmol), and methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (2.1 mg, 0.003 mmol) were added to a reaction flask, and the mixture was purged with nitrogen three times. Then, 1,4-dioxane (0.5 mL) and water (0.1 mL) were added. The reaction mixture was stirred at 100 °C for 2 hours under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature and water was added. The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 25:1) to give a yellow oily product 14b (12 mg, yield 60%). MS m / z 719.8 [M+H] + .

[0307] Compound 14b (12 mg, 0.017 mmol) was dissolved in acetonitrile (1 mL), and then a 1,4-dioxane solution of hydrogen chloride (4 M, 0.3 mL) was added. The reaction mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to give a white solid product 14 (7 mg, 70% yield, racemic). 1H NMR(500MHz,CD3OD)δ9.07(s,1H),8.05(dd,J=8.1,1.1Hz,1H),7.92(dd,J=9.0,6.0Hz,1H),7.57-7.52(m,1 H),7.46(d,J=6.9Hz,1H),7.36(t,J=9.4Hz,1H),4.67-4.59(m,2H),4.39-4.27(m,2H),3.83-3.77(m,1H),3 .76-3.66(m,4H),3.45-3.40(m,1H),3.17-3.12(m,1H),2.83-2.77(m,1H),2.73-2.67(m,1H),2.59-2.49(m ,2H),2.30-2.21(m,1H),2.16-2.10(m,1H),2.04-1.96(m,1H),1.94-1.77(m,6H),0.82(t,J=7.4Hz,3H)ppm. MS m / z619.7[M+H] + Compound 14 (racemic mixture) was resolved by chiral column chromatography to give compounds 14S and 14R.

[0308] Example 15: Preparation of Compound 15

[0309]

[0310] Compound 15 was synthesized using the same method as compound 1, yielding a white solid compound 15 (8.5 mg). 1 HNMR(500MHz,CD3OD)δ9.03(s,1H),7.59(d,J=8.4Hz,1H),7.44-7.34(m,1H),7.34 -7.30(m,1H),7.18-7.14(m,1H),6.93-6.89(m,1H),5.39-5.24(m,1H),4.64-4.55( m,2H),4.34-4.25(m,2H),3.36-3.33(m,1H),3.29-3.22(m,3H),3.10-2.98(m,4H), 2.40-2.12(m,3H),2.06-1.96(m,2H),1.95-1.86(m,1H),1.20(d,J=5.0Hz,6H)ppm. MS m / z 579.7[M+H] + .

[0311] Example 16: Preparation of Compound 16

[0312]

[0313] Compound 16 was synthesized using the same method as compound 1, yielding a white solid compound 16 (5.86 mg). 1 HNMR(500MHz,CD3OD)δ9.12(s,1H),7.59(d,J=8.2Hz,1H),7.42-7.35(m,1H),7.34- 7.31(m,1H),7.17(s,1H),6.92(dd,J=13.1,7.6Hz,1H),5.40-5.20(m,1H),4.38-4. 23(m,2H),3.35-3.32(m,3H),3.29-3.16(m,4H),3.10-3.00(m,3H),2.39-2.10(m,3 H),2.05-1.96(m,2H),1.96-1.82(m,1H),1.23-1.17(m,2H),1.09-1.00(m,2H)ppm. MS m / z 577.6[M+H] + .

[0314] Example 17: Preparation of Compound 17

[0315]

[0316] Compound 17 was synthesized using the same method as compound 1, yielding a white solid compound 17 (9.96 mg). 1 HNMR(500MHz,CD3OD)δ9.07(s,1H),7.59(d,J=8.2Hz,1H),7.42-7.36(m,1H),7.34-7.31(m,1H) ,7.17(d,J=2.4Hz,1H),6.92(dd,J=13.1,7.6Hz,1H),5.43-5.23(m,1H),4.38-4.25(m,2H),4.07 -4.01(m,2H),3.96-3.86(m,2H),3.38-3.33(m,1H),3.28-3.23(m,2H),3.17-3.12(m,2H),3.09- 3.02(m,1H),2.42-2.11(m,3H),2.07-1.97(m,2H),1.96-1.86(m,1H),1.26(d,J=4.3Hz,6H)ppm. MS m / z 579.6[M+H] + .

[0317] Example 18: Preparation of compounds 18, 18S, and 18R

[0318]

[0319] Compound 4f (16 mg, 0.03 mmol), compound 18a (24 mg, 0.06 mmol), potassium phosphate (19 mg, 0.09 mmol), and methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (2.1 mg, 0.003 mmol) were added to a reaction flask, and the mixture was purged with nitrogen three times. Then, 1,4-dioxane (0.5 mL) and water (0.1 mL) were added. The reaction mixture was stirred at 100 °C for 2 hours under nitrogen protection. After cooling to room temperature, water was added. The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 25:1) to give a yellow oily product 18b (15 mg, yield 64%). MS m / z 853.9 [M+H] + .

[0320] Compound 18b (15 mg, 0.02 mmol) was dissolved in acetonitrile (1 mL), followed by the addition of a 1,4-dioxane solution of hydrogen chloride (4 M, 0.3 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give a yellow solid product 18c (13 mg, 100% yield). MS m / z 753.7 [M+H] + .

[0321] The compound 18c (13 mg) obtained in the previous step was dissolved in DMF (0.5 mL), and then cesium fluoride (26 mg, 0.17 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give a yellow solid compound 18 (5 mg, yield 54%, racemic). 1HNMR(500MHz,CD3OD)δ9.02(s,1H),8.10(dd,J=8.3,1.2Hz,1H),8.08-8.04(dd,J=8.3,1.2Hz,1H),7.74(dd, J=7.2,1.2Hz,1H),7.69-7.65(m,1H),7.59(dd,J=7.1,1.2Hz,1H),7.55-7.50(m,1H),4.71-4.59(m,2H),4.41 -4.35(m,1H),4.31-4.26(m,1H),3.85-3.73(m,5H),3.49-3.43(m,1H),3.20-3.15(m,1H),3.10(s,1H),2.83 -2.78(m,1H),2.76-2.69(m,1H),2.56-2.49(m,1H),2.16-2.10(m,1H),2.04-1.97(m,1H),1.97-1.84(m,6H). MS m / z597.6[M+H] + Compound 18 (racemic mixture) was resolved by chiral column chromatography to yield compounds 18S and 18R.

[0322] Example 19: Preparation of compounds 19, 19S, and 19R

[0323]

[0324] Compound 1a (150 mg, 0.59 mmol) and diisopropylethylamine (384 mg, 2.97 mmol) were dissolved in dichloromethane (3 mL) and stirred at -40 °C. Then, a dichloromethane (1 mL) dilution of compound 19a (126 mg, 0.59 mmol) was slowly added dropwise. The reaction mixture was stirred at -40 °C for 30 minutes. After dilution with water, the mixture was extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:ethyl acetate = 5:1) to give a yellow solid product 19b (142 mg, 56%). MS m / z 428.3 [M+H]+.

[0325] Compound 19b (97 mg, 0.23 mmol) and compound 4d (43 mg, 0.23 mmol) were dissolved in dioxane (1 mL), and then diisopropylethylamine (89 mg, 0.69 mmol) was added. The reaction mixture was heated and stirred at 90 °C for 48 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the mixture was purified by silica gel column chromatography to obtain a white solid compound 19c (40 mg, 30%). MS m / z 581.5, 583.4 [M+H] +.

[0326] Compound 19c (17 mg, 0.03 mmol), compound 9a (29 mg, 0.06 mmol), potassium phosphate (19 mg, 0.09 mmol), and methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (2.1 mg, 0.003 mmol) were added to a reaction flask, and the mixture was purged with nitrogen three times. Then, 1,4-dioxane (0.5 mL) and water (0.1 mL) were added. The reaction mixture was stirred at 100 °C for 2 hours under nitrogen protection. After cooling to room temperature, water was added. The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 25:1) to give a yellow oily product 19d (19 mg, yield 71%). MS m / z 913.8 [M+H] + .

[0327] Compound 19d (19 mg, 0.02 mmol) was dissolved in acetonitrile (1 mL), followed by the addition of a 1,4-dioxane solution of hydrogen chloride (4 M, 0.3 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give a yellow solid product 19e (16 mg, 100% yield). MS m / z 768.8 [M+H] + .

[0328] The compound 19e (16 mg) obtained in the previous step was dissolved in DMF (0.5 mL), and then cesium fluoride (30 mg, 0.20 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give a yellow solid compound 19 (5 mg, 39% yield, racemic). 1HNMR(500MHz,CD3OD)δ9.04(s,1H),7.82(dd,J=8.0,0.8Hz,1H),7.51(dd,J=7.1,1.1Hz,1H),7.41-7.37 (m,1H),7.32(d,J=2.5Hz,1H),7.16(d,J=2.5Hz,1H),5.19-5.05(m,2H),4.37-4.24(m,2H),3.82-3.79(m ,1H),3.47-3.42(m,1H),3.28-3.19(m,2H),3.18-3.12(m,1H),3.08(s,1H),2.98-2.92(m,2H),2.84-2.7 8(m,1H),2.74-2.69(m,1H),2.56-2.48(m,1H),2.16-2.10(m,4H),2.05-1.94(m,2H),1.95-1.86(m,2H). MS m / z 613.7[M+H] + Compound 19 (racemic mixture) was resolved by chiral column chromatography to yield compounds 19S and 19R.

[0329] Example 20: Preparation of Compound 20, Compound 20S, and Compound 20R

[0330]

[0331] Compound 4f (307 mg, 0.53 mmol), compound 20a (406 mg, 0.79 mmol, synthesized or purchased according to the method in patent WO2021041671), potassium phosphate (337 mg, 1.59 mmol), and methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (38 mg, 0.05 mmol) were added to a reaction flask, and the mixture was purged with nitrogen three times. Then, 1,4-dioxane (5 mL) and water (1 mL) were added. The reaction mixture was stirred at 100 °C for 2 hours under nitrogen protection. After cooling to room temperature, water was added. The mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 25:1) to give a yellow oily product 20b (486 mg, yield 99%). MS m / z 931.9 [M+H] + .

[0332] Compound 20b (486 mg, 0.52 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of a 1,4-dioxane solution of hydrogen chloride (4 M, 3 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solution was concentrated under reduced pressure to give a yellow solid product 20c (411 mg, 100% yield). MS m / z 787.7 [M+H] + .

[0333] The compound 20c (411 mg, 0.52 mmol) obtained in the previous step was dissolved in DMF (10 mL), and then cesium fluoride (790 mg, 5.20 mmol) was added. The reaction mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give a yellow solid compound 20 (174 mg, yield 53%). Compound 20 was resolved by HPLC using a chiral column (CHIRALPAK AD-H, ADH0CE-XG136, 0.46 cm ID × 25 cm L; Hexane / EtOH / DEA = 60 / 40 / 0.1 (V / V / V); 1.0 mL / min) to obtain the first isomer, compound 20-P1 (rt = 4.93 min, 41 mg), and the second isomer, compound 20-P2 (rt = 6.18 min, 43 mg).

[0334] Compounds 20-P1 and 20-P2: one is compound 20S, and the other is compound 20R.

[0335] Compound 20-P1: 1 H NMR (500MHz, CD3OD) δ9.02 (s, 1H), 7.86 (dd, J = 9.1, 5.7Hz, 1H), 7.35 (d, J = 2.5Hz, 1H),7.32(t,J=8.9Hz,1H),7.20(d,J=2.5Hz,1H),4.73-4.61(m,2H),4.42-4.25( m,2H),3.90-3.75(m,5H),3.47(d,J=14.0Hz,1H),3.36(s,1H),3.21-3.15(m,1H) ,2.84-2.71(m,2H),2.58-2.50(m,1H),2.18-2.08(m,1H),2.06-1.85(m,7H)ppm. MS m / z631.2[M+H] + .

[0336] Compound 20-P2: 1H NMR(500MHz,CD3OD)δ9.01(s,1H),7.85(dd,J=9.1,5.7Hz,1H),7.34(d,J=2.5Hz, 1H),7.32(t,J=9.0Hz,1H),7.20(d,J=2.5Hz,1H),4.71-4.59(m,2H),4.43-4.23( m,2H),3.87-3.72(m,5H),3.45(d,J=14.0Hz,1H),3.35(s,1H),3.19-3.13(m,1H) ,2.85-2.69(m,2H),2.56-2.47(m,1H),2.16-2.07(m,1H),2.05-1.83(m,7H)ppm. MS m / z631.2[M+H] + .

[0337] Example 21: Preparation of Compound 21

[0338]

[0339] Compound 19b (150 mg, 0.35 mmol) and compound 1d (84 mg, 0.53 mmol) were dissolved in 1,4-dioxane (2 mL), and N,N-diisopropylethylamine (137 mg, 1.05 mmol) was added. The reaction mixture was heated and stirred at 90 °C for 18 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain a white solid compound 21b (120 mg, 62%). MS m / z 551.2, 553.2 [M+H] + .

[0340] Compound 21b (38 mg, 0.07 mmol), compound 20a (53 mg, 0.10 mmol), potassium phosphate (44 mg, 0.21 mmol), and methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (4.2 mg, 0.007 mmol) were added to a reaction flask, and the mixture was purged with nitrogen three times. Then, 1,4-dioxane (0.5 mL) and water (0.1 mL) were added. The reaction mixture was stirred at 100 °C for 2 hours under nitrogen protection. The reaction mixture was cooled to room temperature and water was added. The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 25:1) to give a yellow oily product 21c (60 mg, yield 96%). MSm / z 901.5 [M+H] + .

[0341] Compound 21c (60 mg, 0.07 mmol) was dissolved in acetonitrile (1 mL), followed by the addition of a 1,4-dioxane solution of hydrogen chloride (4 M, 0.3 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solution was concentrated under reduced pressure to give a yellow solid product 21d (50 mg, 100% yield). MS m / z 757.5 [M+H] + .

[0342] Compound 21d (52 mg, 0.07 mmol) was dissolved in N,N-dimethylformamide (1 mL), and then cesium fluoride (96 mg, 0.7 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 25:1) to give a pale yellow solid product 21 (18 mg, yield 48%). 1 H NMR (500MHz, CD3OD) δ9.04 (s, 1H), 7.86 (dd, J = 9.2, 5.7Hz, 1H), 7.35 (d, J = 2.5Hz, 1H), 7.32 (t, J = 8. 9Hz,1H),7.21(d,J=2.5Hz,1H),5.31(d,J=54.1Hz,1H),5.12(d,J=25.4Hz,2H),4.37-4.17(m,2H), 3.41(d,J=7.2Hz,1H),3.27-3.24(m,2H),3.23-3.20(m,2H),3.20-3.17(m,1H),3.06-3.00(m,1H), 2.97-2.91(m,2H),2.37-2.21(m,2H),2.15-2.09(m,5H),2.05-1.96(m,2H),1.93-1.86(m,1H)ppm. MS m / z 601.1[M+H] + .

[0343] Example 22: Preparation of compound 22

[0344]

[0345] Compound 1e (25 mg, 0.05 mmol), compound 20a (35 mg, 0.07 mmol), potassium phosphate (32 mg, 0.15 mmol), and methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (3 mg, 0.005 mmol) were added to a reaction flask, and the mixture was purged with nitrogen three times. Then, 1,4-dioxane (0.5 mL) and water (0.1 mL) were added. The reaction mixture was stirred at 100 °C for 2 hours under nitrogen protection. The reaction mixture was cooled to room temperature and water was added. The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 25:1) to give a yellow oily product 22a (21 mg, yield 51%). MS m / z 902.5 [M+H] + .

[0346] Compound 22a (22 mg, 0.02 mmol) was dissolved in acetonitrile (1 mL), followed by the addition of a 1,4-dioxane solution of hydrogen chloride (4 M, 0.1 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure to give a yellow solid product 22b (19 mg, 100% yield). MS m / z 757.5 [M+H] + .

[0347] Compound 21b (20 mg, 0.02 mmol) was dissolved in N,N-dimethylformamide (1 mL), followed by the addition of cesium fluoride (38 mg, 0.2 mmol). The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 25:1) to give a pale yellow solid product 22 (8 mg, yield 53%). MS m / z 601.2 [M+H] + . 1H NMR (500MHz, CD3OD) δ8.98 (s, 1H), 7.87-7.84 (m, 1H), 7.35 (d, J = 2.5Hz, 1H), 7.32 (t, J = 9.0Hz, 1H), 7.21 (d, J = 2.5 Hz,1H),5.31(d,J=53.9Hz,1H),4.35-4.18(m,2H),4.14-4.10(m,2H),3.98(s,2H),3.38(d,J=7.3Hz,1H),3.30-3.23(m,2H),3.13 (t,J=5.1Hz,2H),3.06-2.99(m,1H),2.36-2.21(m,2H),2.17-2.10(m,1H),2.05-1.96(m,2H),1.95-1.85(m,1H),0.70(s,4H)ppm.

[0348] Example 23: Preparation of compound 23

[0349]

[0350] Compound 19c (135 mg, 0.23 mmol), compound 20a (179 mg, 0.35 mmol), potassium phosphate (146 mg, 0.69 mmol), and methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (17 mg, 0.02 mmol) were added to a reaction flask, and the mixture was purged with nitrogen three times. Then, 1,4-dioxane (2.5 mL) and water (0.5 mL) were added. The reaction mixture was stirred at 100 °C for 2 hours under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature and water was added. The mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 25:1) to give a yellow oily product 23a (120 mg, yield 55%). MS m / z 931.4 [M+H] + .

[0351] Compound 23a (120 mg, 0.13 mmol) was dissolved in acetonitrile (4 mL), followed by the addition of a 1,4-dioxane solution of hydrogen chloride (4 M, 1.0 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure to give a yellow solid product 23b (101 mg, 100% yield). MS m / z 787.7 [M+H] + .

[0352] Compound 23b (101 mg, 0.13 mmol) obtained in the previous step was dissolved in N,N-dimethylformamide (2 mL), and then cesium fluoride (195 mg, 1.28 mmol) was added. The reaction mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give a yellow solid compound 23 (48 mg, yield 59%, racemic). 1 H NMR(500MHz,CD3OD)δ9.05(s,1H),7.86(dd,J=9.0,5.7Hz,1H),7.35(d,J=2.5Hz,1H),7.32(t, J=9.0Hz,1H),7.22(d,J=2.5Hz,1H),5.19-5.06(m,2H),4.42-4.25(m,2H),3.88-3.80(m,1H), 3.50-3.43(m,1H),3.41(s,1H),3.30-3.22(m,2H),3.21-3.15(m,1H),3.04-2.95(m,2H),2.84 -2.78(m,1H),2.77-2.70(m,1H),2.58-2.49(m,1H),2.20-2.07(m,4H),2.07-1.86(m,4H)ppm. MS m / z 631.1[M+H] + Compound 23 (racemic mixture) was resolved by chiral column chromatography to yield compounds 23S and 23R.

[0353] Example 24: Preparation of compound 24

[0354]

[0355] Compound 4d (100 mg, 0.53 mmol) and compound 1c (204 mg, 0.48 mmol) were dissolved in 1,4-dioxane (1.5 mL), and N,N-diisopropylethylamine (190 mg, 1.47 mmol) was added. The reaction mixture was heated and stirred at 90 °C for 48 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain a white solid compound 24a (127 mg, 41%). 1H NMR(500MHz,CD3OD)δ8.84(s,1H),4.33(dd,J=42.2,10.9Hz,2H),4.14-4.09(m,2 H),3.95(s,2H),3.89-3.82(m,1H),3.77-3.72(m,2H),3.54-3.48(m,1H),3.24-3 .17(m,1H),2.83-2.74(m,2H),2.58-2.51(m,1H),2.19-2.09(m,1H),2.07-1.99( m,1H),1.97-1.89(m,2H),1.48(s,9H),1.06-1.02(m,2H),0.93-0.89(m,2H)ppm. MS m / z 581.5,583.4[M+H] + .

[0356] Compound 24a (127 mg, 0.22 mmol), compound 20a (168 mg, 0.33 mmol), potassium phosphate (140 mg, 0.66 mmol), and methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (16 mg, 0.02 mmol) were added to a reaction flask, and the mixture was purged with nitrogen three times. Then, 1,4-dioxane (2.5 mL) and water (0.5 mL) were added. The reaction mixture was stirred at 100 °C for 2 hours under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature and water was added. The mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 25:1) to give a yellow oily product 24b (117 mg, yield 57%). MS m / z 931.4 [M+H] + .

[0357] Compound 24b (117 mg, 0.12 mmol) was dissolved in acetonitrile (4 mL), followed by the addition of a 1,4-dioxane solution of hydrogen chloride (4 M, 1 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solution was concentrated under reduced pressure to give a yellow solid product 24c (99 mg, 100% yield). MS m / z 787.6 [M+H] + .

[0358] The compound 24c (99 mg, 0.12 mmol) obtained in the previous step was dissolved in N,N-dimethylformamide (2 mL), and then cesium fluoride (191 mg, 1.26 mmol) was added. The reaction mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give a yellow solid compound 24 (57 mg, 72% yield, racemic). 1 H NMR(500MHz,CD3OD)δ 8.98(s,1H),7.85(dd,J=9.0,5.5Hz,1H),7.35(d,J=2.5Hz,1H),7.32(t,J=9.0Hz,1H),7.22 (d,J=2.5Hz,1H),4.39-4.24(m,2H),4.16-4.07(m,2H),3.98(s,2H),3.86-3.78(m,1H),3.5 0-3.43(m,1H),3.39(s,1H),3.21-3.09(m,3H),2.84-2.77(m,1H),2.77-2.69(m,1H),2.57- 2.48(m,1H),2.17-2.07(m,1H),2.06-1.96(m,1H),1.96-1.86(m,2H),0.75-0.65(m,4H)ppm. MS m / z 631.1[M+H] + Compound 24 (racemic mixture) was resolved by chiral column chromatography to yield compounds 24S and 24R.

[0359] Example 25: Preparation of Compound 25

[0360]

[0361] Compound 20 (34 mg, 0.05 mmol) and N,N-diisopropylethylamine (19 mg, 0.15 mmol) were dissolved in dichloromethane (2 mL), cooled to -40 °C, and a dichloromethane solution (1 mL) of compound 25a (13 mg, 0.05 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 0.5 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give a white solid compound 25 (12 mg, yield 26%). 1H NMR(500MHz,CD3OD)δ9.05(s,1H),7.86(dd,J=9.0,5.7Hz,1H),7.36(d,J=2.5Hz,1H),7.32(t,J=9.0Hz,1H),7.2 0(d,J=2.5Hz,1H),5.83(s,2H),4.76-4.63(m,2H),4.59-4.41(m,4H),4.08-4.01(m,1H),3.84-3.65(m,3H),3.4 2-3.35(m,1H),3.34(s,1H),3.00-2.94(m,1H),2.93-2.87(m,1H),2.69-2.62(m,1H),2.39(t,J=7.3Hz,2H),2.2 6-2.19(m,1H),2.14-1.96(m,5H),1.89-1.83(m,2H),1.67-1.59(m,2H),1.38-1.26(m,12H),0.91-0.85(m,3H). MS m / z 859.3[M+H] + Compound 25 (racemic mixture) can be chirally resolved to give compounds 25S and 25R.

[0362] Example 26: Preparation of Compound 26

[0363]

[0364] Compound 25 (6 mg, 0.007 mmol) and N,N-diisopropylethylamine (3 mg, 0.02 mmol) were dissolved in dichloromethane (1 mL), cooled to -40 °C, and a dichloromethane solution of decanyl chloride (2 mg, 0.01 mmol) (1 mL) was added dropwise. The reaction mixture was stirred at room temperature for 0.5 hours, water was added, and the mixture was extracted with dichloromethane (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give compound 26 (4 mg, yield 56%) as a white solid. 1H NMR (500MHz, CD3OD) δ9.06(s,1H),8.09(dd,J=9.0,5.7Hz,1H),7.88(d,J=2.4Hz,1H),7.48(t,J=9.0Hz,1H),7.44(d,J=2.4Hz,1H),5.83 (s,2H),4.74-4.63(m,2H),4.58-4.47(m,3H),4.47-4.41(m,1H),4.09-4.01(m,1H),3.84-3.73(m,2H),3.72-3.65(m,1H),3.45(s,1H), 3.42-3.37(m,1H),2.99-2.93(m,1H),2.93-2.86(m,1H),2.69-2.62(m,3H),2.39(t,J=7.3Hz,2H),2.26-2.20(m,1H),2.14-2.07(m,1H) ,2.06-1.97(m,4H),1.89-1.83(m,2H),1.80-1.73(m,2H),1.66-1.59(m,2H),1.48-1.41(m,2H),1.38-1.23(m,22H),0.92-0.83(m,6H). MS m / z 1013.4[M+H] + Compound 26 (racemic mixture) can be chirally resolved to give compounds 26S and 26R.

[0365] Example 27: Preparation of Compound 27

[0366]

[0367] Compound 20b (100 mg, 0.11 mmol) was dissolved in dichloromethane (3 mL), and a solution of 1,4-dioxane hydrogen chloride (4 M, 0.1 mL) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give compound 27a (67 mg, yield 71%). MS m / z 887.1 [M+H] + .

[0368] Compound 27a (13 mg, 0.015 mmol) and N,N-diisopropylethylamine (6 mg, 0.05 mmol) were dissolved in dichloromethane (2 mL), and the mixture was cooled to -40 °C. Decanoyl chloride (4 mg, 0.02 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 0.5 h, water was added, and the mixture was extracted with dichloromethane (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow solid, compound 27b (16 mg, 100% yield). MS m / z 1041.4 [M+H] + .

[0369] Compound 27b (16 mg, 0.015 mmol) was dissolved in acetonitrile (2 mL), and a solution of 1,4-dioxane hydrogen chloride (4 M, 0.5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours, and then concentrated under reduced pressure to give a yellow solid product 27c (14 mg, 100% yield). MS m / z 941.4 [M+H] + .

[0370] Compound 27c (14 mg, 0.015 mmol) obtained in the previous step was dissolved in N,N-dimethylformamide (1 mL), and then cesium fluoride (23 mg, 0.15 mmol) was added. The reaction mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give a yellow solid compound 27 (3 mg, yield 26%). MS m / z 785.3 [M+H] + . 1H NMR(500MHz,CD3OD)δ9.04(s,1H),8.09(dd,J=9.0,5.7Hz,1H),7.88(d,J=2.4Hz,1H),7.48(t,J=9.0Hz,1H),7 .44(d,J=2.4Hz,1H),4.75-4.65(m,2H),4.45-4.39(m,1H),4.34-4.27(m,1H),3.94-3.74(m,5H),3.47(t,J=12 0.5Hz, 2H), 3.19(dd, J=11.0, 6.9Hz, 1H), 2.84-2.79(m, 1H), 2.76(d, J=8.4Hz, 1H), 2.65(t, J=7.4Hz, 2H), 2.58-2.52(m, 1H), 2.18-2.10(m, 1H), 2.09-1.85(m, 7H), 1.80-1.73(m, 2H), 1.45-1.23(m, 12H), 0.91-0.86(m, 3H). Compound 27 (racemic mixture) can be chirally resolved to give compounds 27S and 27R.

[0371] Example 28: Preparation of compound 28

[0372]

[0373] Compound 27a (11 mg, 0.012 mmol) and N,N-diisopropylethylamine (6 mg, 0.05 mmol) were dissolved in dichloromethane (2 mL), and the mixture was cooled to -40 °C. Acetyl chloride (2 mg, 0.02 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 0.5 h, water was added, and the mixture was extracted with dichloromethane (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow solid, compound 28a (11 mg, 100% yield). MS m / z 929.6 [M+H] + .

[0374] Compound 28a (11 mg, 0.012 mmol) was dissolved in acetonitrile (2 mL), and a solution of 1,4-dioxane hydrogen chloride (4 M, 0.5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours, and then concentrated under reduced pressure to give a yellow solid product 28b (10 mg, 100% yield). MS m / z 829.5 [M+H] + .

[0375] Compound 28b (10 mg, 0.012 mmol) obtained in the previous step was dissolved in N,N-dimethylformamide (1 mL), followed by the addition of cesium fluoride (18 mg, 0.12 mmol). The reaction mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give a yellow solid, compound 28 (2 mg, 25% yield). MS m / z 673.1 [M+H] + Compound 28 (racemic mixture) can be chirally resolved to give compounds 28S and 28R.

[0376] Example 29: Preparation of compound 29

[0377]

[0378] Compound 27a (39 mg, 0.04 mmol) was dissolved in N,N-dimethylformamide (1 mL), followed by the addition of cesium fluoride (67 mg, 0.44 mmol). The reaction mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give a yellow solid, compound 29a (23 mg, 73% yield). MS m / z 731.3 [M+H] + .

[0379] Compound 29a (10 mg, 0.014 mmol) and N,N-diisopropylethylamine (6 mg, 0.05 mmol) were dissolved in acetonitrile (2 mL), and phosphorus oxychloride (3 mg, 0.02 mmol) was added dropwise under ice bath conditions. The reaction mixture was stirred under ice bath conditions for 10 minutes, and then saturated sodium bicarbonate aqueous solution (0.5 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with ethyl acetate after adding water. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 29b (10 mg, 91% yield) as a yellow solid. MS m / z 811.3 [M+H] + .

[0380] Compound 29b (10 mg, 0.012 mmol) was dissolved in acetonitrile (2 mL), and a 1,4-dioxane solution of hydrogen chloride (4 M, 0.5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain a yellow solid compound 29 (4 mg, yield 45%). MS m / z 711.1 [M+H] +Compound 29 (4 mg, 0.005 mmol) was dissolved in acetonitrile (1 mL), and an aqueous solution of sodium hydroxide (0.4 mg, 0.01 mmol) (0.5 mL) was added. The reaction mixture was lyophilized to give a yellow solid, the disodium salt of compound 29, 29-Na (4 mg, 100% yield). MS m / z 711.1 [M+H] + Compound 29 (racemic mixture) can be chirally resolved to give compounds 29S and 29R.

[0381] Example 30: Preparation of compound 30

[0382]

[0383] Compound 30a (100 mg, 0.20 mmol, synthesized using the method described in patent WO2022002102), compound 4d (56 mg, 0.30 mmol), cesium carbonate (193 mg, 0.60 mmol), and triethylenediamine (22 mg, 0.20 mmol) were dissolved in a mixed solution of N,N-dimethylformamide (0.5 mL) and tetrahydrofuran (0.5 mL) and stirred at room temperature for 3 hours. Water was added to the reaction mixture. The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to give a yellow oily product 30b (70 mg, yield 54%). MS m / z 658.0 & 660.0 [M+H] + .

[0384] Compound 30b (35 mg, 0.05 mmol), compound 20a (41 mg, 0.08 mmol), potassium phosphate (34 mg, 0.15 mmol), and methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (3 mg, 0.005 mmol) were added to a reaction flask, and the mixture was purged with nitrogen three times. Then, 1,4-dioxane (0.5 mL) and water (0.1 mL) were added. The reaction mixture was stirred at 100 °C for 2 hours under nitrogen protection. The reaction mixture was cooled to room temperature and water was added. The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 25:1) to give a yellow oily product 30c (30 mg, yield 56%). MSm / z 964.5&965.5[M+H] + .

[0385] Compound 30c (30 mg, 0.03 mmol) was dissolved in acetonitrile (1 mL), followed by the addition of a 1,4-dioxane solution of hydrogen chloride (4 M, 0.1 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solution was concentrated under reduced pressure to give a yellow solid product 30d (26 mg, 100% yield). MS m / z 820.3 & 822.3 [M+H] + .

[0386] Compound 30d (26 mg, 0.03 mmol) was dissolved in N,N-dimethylformamide (1 mL), and then cesium fluoride (45 mg, 0.3 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 25:1) to give a pale yellow solid product 30 (4 mg, yield 20%). 1 H NMR(500MHz,MeOD-d4)δ7.84(dd,J=9.2,5.9Hz,1H),7.82(br,J=4.8Hz,1H),7.34-7.27(m,2H),7.03(d,J=2.1Hz,1H),4.52(dd,J= 34.3,13.0Hz,2H),4.39-4.32(m,1H),4.30-4.24(m,1H),3.92-3.80(m,3H),3.77-3.63(m,2H),3.47(d,J=14.1Hz,1H),3.26(s, 1H),3.22-3.15(m,1H),2.81(d,J=15.7Hz,1H),2.78-2.70(m,1H),2.53(d,J=16.2Hz,1H),2.17-2.10(m,1H),2.05-1.89(m,7H). MS m / z 664.1&666.1[M+H] + Compound 30 (racemic mixture) can be chirally resolved to give compounds 30S and 30R.

[0387] Example 31: 3D Cell Proliferation Inhibition Experiment

[0388] Compound activity was expressed as inhibition of cell proliferation in AGS (human gastric cancer cell line, KRAS G12D mutation), GP2D (human colon cancer cell line, KRAS G12D mutation), HPAC (human pancreatic cancer cell line, KRAS G12D mutation), and AsPC1 (human pancreatic cancer cell line, KRAS G12D mutation) 3D cells using the Cell Titer-Glo (CTG) method. The compound was dissolved in DMSO to prepare a 10 mM stock solution, which was then diluted appropriately with culture medium. The supernatant was removed, the cells were washed once with DPBS, 2 mL of trypsin was added, and the cells were incubated at 37°C for a short time until they detached from the culture dish. 5 mL of fresh culture medium was added to resuspend the cells, and the cells were centrifuged at 1000 rpm for 5 minutes at room temperature. The supernatant was removed, and the cells were resuspended in 5 mL of fresh culture medium and cultured using Countess. TM II. Cell count. 200 nmol of the compound was added to each well of an Ultra-low attachment 384-well plate using an Echo 550 microplate, followed by 40 μL of cells. After incubation at 37°C and 5% CO2 for seven days, CTG was added, and signals were recorded using Envision. The inhibition rate was calculated using the following formula: Inhibition% = (Ave_H - Sample) / (Ave_H - Ave_L) x 100%. Where Ave_H represents the average reading of the DMSO wells, Sample represents the average reading of the compound wells, and Ave_L represents the average reading of the 10 μM positive control group. The concentration logarithmic value was used as the X-axis, and the percentage inhibition rate as the Y-axis. A dose-response curve was fitted using the log(inhibitor) vs. response-variable slope function of GraphPad Prism 5 to determine the IC50 of each compound on cell proliferation inhibition. 50 Value or inhibition rate. The activities of some representative compounds are shown in Table 1.

[0389] Table 1. Inhibitory activity against 3D cell proliferation

[0390]

[0391] Example 32: Experiment combining KRAS G12D and SOS1

[0392] The positive control and test compound (10 mM stock solution) were serially diluted 3-fold with 100% DMSO. 2 μL of the diluted compound was transferred to 18 μL of diluent and mixed thoroughly. Then, 2 μL of the diluted compound was added to each well of a 384-well plate, with each sample repeated twice. The 384-well plate was centrifuged at 1000 rpm. 4 μL of KRAS G12D>P mixture was added to each well, followed by 4 μL of LOS1, and incubated for 15 minutes. Then, 10 μL of Tag-Tb and Tag-XL665 were added, and the plate was incubated at 4°C for 3 hours. HTRF (665 nM and 615 nM values) signals were read using BMG. The concentration log value was used as the X-axis, and 665 nM / 615 nM as the Y-axis, with the formula Y = Bottom + (Top - Bottom) / (1 + 10^(LogIC)). 50 -X)*HillSlope)) fitted dose-response curves to obtain the IC50 values ​​of each compound on enzyme activity. 50 Values. The activities of some representative compounds are shown in Table 2.

[0393] Table 2. KRAS G12D & SOS1 binding inhibitory activity

[0394] 10 <15 20 <15 21 <15 22 <15 28 <30 30 <60

[0395] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound with the structure shown in formula (VI) below, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof: R is selected from the following group: Ar can be one of the following groups: " "Indicates the chiral center; " " indicates the connection site between the R group and other structures of the compound of formula (VI); " " indicates the connection site between the Ar group and other structures of the compound of formula (VI); R 13 Selected from halogens, C 1-4 Alkyl, =O, hydroxyl, CN; R 14 Each is independently selected from halogens, C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 Haloalkenyl, C 2-4 alkynyl group, C 2-4 Halogenated alkynyl, NR 2 R 2 CN, SR 2 -OC(O)R k -OP(O)(OR) m )2、-O- CH(R n )-OP(O)(OR m )2; where, R 2 Each can be either hydrogen or C. 1-4 Alkyl; R k Selected from C 1-12 Alkyl, wherein C 1-12 Alkyl groups are optionally substituted with one or more groups selected from the group consisting of: hydroxyl, C 1-4 Alkoxy, NR 2 R 2 C(O)OH, C(O)OC 1-2 Alkyl, CN; R m Selected from hydrogen or C 1-4 Alkyl; R n Selected from hydrogen or C 1-4 alkyl; k is selected from 0, 1, or 2; p is selected from 0, 1, 2, 3, 4, 5; R 11 Selected from hydrogen, halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkynyl group, C 3-6 Cycloalkyl, CN.

2. The compound of claim 1, or its optical isomer, or its pharmaceutically acceptable salt, characterized in that, In formula (VI), R is selected from the following group: " " indicates the connection point between the above structural segment and other structures in equation (VI); R 13 The definition of k is as described in claim 1.

3. The compound of claim 1, or its optical isomer, or its pharmaceutically acceptable salt, characterized in that, Ar is selected from the following group: " “” indicates the connection point between the above structural segment and other structures in equation (VI).

4. The compound of claim 1, or its optical isomer or its pharmaceutically acceptable salt, characterized in that, Structural fragments Selected from the following group: " "Indicates the chiral center; " “” indicates the connection point between the above structural segment and other structures in equation (VI).

5. The compound of claim 1, or its optical isomer, or its pharmaceutically acceptable salt, characterized in that, Equation (VI) is equivalent to Equation (VII). " "Indicates the chiral center; R 13 R 14 R 11 The definitions of k and p are as described in claim 1.

6. The compound of claim 1, or its optical isomer or its pharmaceutically acceptable salt, characterized in that, Equation (VI) is equivalent to Equation (IX). Among them, Ar and R 11 The definition is as described in claim 1; structural fragment Selected from the following group groups: Ar is selected from the following group: " "Indicates structural fragments" Or the connection site between Ar and other structures in formula (IX).

7. The compound of claim 1, or its optical isomer or its pharmaceutically acceptable salt, characterized in that, Equation (VI) is equivalent to Equation (X). Among them, Ar and R 11 The definition is as described in claim 1; structural fragment Selected from the following group groups: Ar is selected from the following group: " "Indicates structural fragments" Or the connection site between Ar and other structures in formula (X).

8. The compound of claim 1, or its optical isomer or its pharmaceutically acceptable salt, characterized in that, The pharmaceutically acceptable salts are selected from the group consisting of: potassium salts, sodium salts, magnesium salts, calcium salts, sulfates, hydrochlorides, phosphates, sulfonates, or carbonates.

9. A compound of formula (XII) or an optical isomer thereof or a pharmaceutically acceptable salt thereof. " "Indicates the chiral center; R 11’ Selected from hydrogen, halogens, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, CN; R 11 R 13 R 14 The definitions of k and p are as described in claim 1.

10. A compound selected from the group consisting of the following: an optical isomer thereof or a pharmaceutically acceptable salt thereof: In the above structural formula, " "Indicates the chiral center." 11. A compound selected from the group consisting of: an optical isomer thereof or a pharmaceutically acceptable salt thereof:

12. A pharmaceutical composition, characterized in that, It comprises the compound or optical isomer thereof or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 11, and a pharmaceutically acceptable carrier thereof.

13. Use of a compound of any one of claims 1 to 11, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that, Used to prepare pharmaceutical compositions for treating diseases related to the activity or expression level of KRAS G12D.

14. The use as described in claim 13, characterized in that, The diseases mentioned are selected from the following group: pancreatic cancer, non-small cell lung cancer, small cell lung cancer, colorectal cancer, thyroid cancer, embryonal rhabdomyosarcoma, liver cancer, bladder cancer, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, kidney cancer, skin cancer, lymphoma, gastric cancer, acute myeloid leukemia, myelofibrosis, splenomegaly with polycythemia, eosinophilic polycythemia syndrome, and myeloma.

15. The use as described in claim 13, characterized in that, The diseases mentioned are selected from the following group: squamous cell carcinoma of the lung, colon cancer, granular cell tumor of the skin, melanoma, rectal cancer, pharyngeal cancer, B-cell lymphoma, and monocytic leukemia.

Images