Heterocyclic compounds as inhibitors of KRAS G12C

Abstract

The present invention provides heterocyclic compounds and their applications as inhibitors of KRASG12C, particularly compounds of any of formulae I to XI, or stereoisomers, enantiomers, atropisomers, or pharmaceutically acceptable salts thereof, wherein the definitions of each group in the formula are described in detail in the specification. The present invention relates to heterocyclic compounds as inhibitors of KRAS G12C mutants, and compositions containing such compounds that can be used to treat a variety of conditions associated with KRAS G12C, such as cancer.

Description

Technical Field

[0001] The present invention relates to a heterocyclic compound as an inhibitor of the KRAS G12C mutant and a composition containing the compound that can be used to treat various pathological conditions related to KRAS G12C, such as cancer.

Background Art

[0002] The RAS protein is a small membrane-bound guanine nucleotide-binding protein that functions as a molecular switch by cycling between an active GTP-bound conformation and an inactive GDP-bound conformation. The RAS protein has three major isoforms, KRAS, NRAS, and HRAS, and plays an important role in the regulation of cell growth, differentiation, and survival. Hyperactivation mutations of the major RAS isoforms are, due to the most common KRAS mutations in human cancers to date, one of the most common lesions found in cancers. Most of these mutations cause oncogenic transformation and increase the population of active GTP-bound individuals. The most frequent site of oncogenic mutations in KRAS is residue G12, due to the G12C mutation (glycine-12 converted to cysteine) at the residue as one of the frequent mutations. The KRAS G12C mutation is found in ~14% of lung adenocarcinomas, 1% - 4% of pancreatic adenocarcinomas, and colorectal adenocarcinomas, respectively.

Summary of the Invention

Problems to be Solved by the Invention

[0003] Considering the role and frequency of the KRAS G12C mutation in human cancers, there is a strong demand for new treatment methods for cancer patients characterized by the KRAS G12C mutation.

Means for Solving the Problems

[0004] The present invention describes an inhibitor of KRAS G12C. The present invention further describes a formulation containing an inhibitor of KRAS G12C.

[0005] In one embodiment, the present invention features a compound of Formula I, or a pharmaceutically acceptable salt thereof. [Chemical Formula]

[0006] Here, Q is a moiety to which a nucleophile can attach to form a covalent bond, and preferably, exemplary Q structures are shown below.

[0007] [Chemical Formula] X is N, C, CR 3 , or CF. R 3 is H, -CN, or C 1-6 alkyl. -L- is a single bond, a double bond, -NH-, or -N(C 1-6 alkyl)-. R a , R b and R c each is independently H, halogen, substituted or unsubstituted C 1-4 alkyl, substituted or unsubstituted C 1-4 cycloalkyl or cyano. Or, R c can be bonded to a carbon atom of Het-1 to form a bicyclic ring.

[0008] Het-1 is selected from the following bicyclic and tricyclic moieties. [Chemical Formula]

[0009] [Chemical Formula] can also be selected from the following moieties.

[0010] [Chemical Formula] R e and Rd is independently selected from hydrogen and halo. R 1 and R 2 are independently selected from hydrogen, halo, cyano, C 1-6 alkoxy, hydroxy, C(O)NH2, C(O)NHC 1-6 alkyl, C(O)N(C 1-6 alkyl)2, C 1-6 alkylsulfonyl, S(O)2NH2, S(O)2NHC 1-6 alkyl, NHC(O)NH2, NHC(O)NHC 1-6 alkyl, C 1-6 alkyl, NHC(O)OC 1-6 alkyl, C(O)-C 1-6 alkyl, -C(O)C 1-6 alkyl, C 1-6 heteroalkyl, heterocyclyl or heterocyclylalkyl. Alternatively, R 1 and R 2 together with the carbon atoms to which they are attached can form a 3- to 6-membered carbocyclic ring.

[0011] Het-2 is selected from the following heterocyclic moieties.

Chemical Structure

[0012] R 3 and R 6 are each independently H, OH, C 1-6 alkyl, C 3-10 cycloalkyl, C 3-10 heterosilcoalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, NH-C 1-6 alkyl, N(C 1-6 alkyl)2, CN or halo. R 4 is hydrogen, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 2-4 alkenyl, C2-4 is alkynyl, aryl or heteroaryl. R 5 is halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, OH, OR’, N(R’)2, C 2-4 alkenyl, C 2-4 alkynyl, C 0-3 alkylene-C 3-8 cycloalkyl, C 0-3 alkylene-C 3-8 halocycloalkyl, aryl or heteroaryl, C 0-3 alkylene-C 6-14 aryl or C 0-3 alkylene-C 2-14 heteroaryl. Each R’ is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, aryl or heteroaryl. Alternatively, two R’ substituents together with the attached nitrogen atom form a 3-8 membered carbocyclic or 3-8 membered heterocyclic ring containing O, S or NR’. R 7 is C 1-8 alkyl, C 0-3 alkylene-C 6-14 aryl, C 0-3 alkylene-C 2-14 heteroaryl, C 0-3 alkylene-C 3-10 cycloalkyl, C 0-3 alkylene-C 2-10 heterocycloalkyl, C 1-6 alkoxy, O-C 0-3 alkylene-C 6-14 aryl, O-C 0-3 alkylene-C 3-14 heteroaryl, O-C 0-3 alkylene-C 1-10 cycloalkyl, O-C 0-3 alkylene-C 2-14 heterocycloalkyl, NH-C 1-8 alkyl, N(C1-8 (alkyl)2, NH-C 0-3 alkylene-C 6-14 aryl, NH-C 0-3 alkylene-C 2-14 heteroaryl, NH-C 0-3 alkylene-C 1-10 cycloalkyl, NH-C 0-3 alkylene-C 2-14 heterocycloalkyl, halo, -CN or C 1-6 is alkylene-amine. R 8 is H, OH, C 1-6 alkyl, C 1-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 halocycloalkyl, C 1-6 alkoxy, NH-C 1-6 alkyl, N(C 1-6 alkyl)2 or CN. L 1 is a bond, O, S or NR 11 is. L 2 is a bond, -C(O)- or C l-3 is alkylene. R 9 is hydrogen, C 1-8 alkyl, hydroxyC 1-8 alkyl, dihydroxyC 1-8 alkyl, C 1-8 alkyl-NH-C 1-8 alkyl, C 1-8 alkyl-N(C 1-8 alkyl)2, -C l-4 alkylene-NR 11 R 12 is, C 2-10 heterocyclyl, C 2-10 heterocyclylalkyl, C 6-14 aryl, C 2-14 heteroaryl or C 3-14 is heteroarylalkyl, where R 9 is optionally substituted by one or more R 13 s. R 9 -L 1 - may also not exist. R 10 is hydrogen, C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 6-14 aryl, C 7-20 aralkyl or C 3-14 heteroaryl. Here, each of C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 6-14 aryl, C 7-20 aralkyl or C 3-1 heteroaryl may be optionally substituted with one or more R 5 or R 6 . R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently optionally substituted with one or more of the following groups. Halo, cyano, C 1-6 alkoxy, hydroxy, amino, C(O)NH2, C(O)NHC 1-6 alkyl, C(O)NHC 3-6 cycloalkyl, C(O)N(C 1-6 alkyl)2, SC 1-6 alkyl, S(O)C 1-6 alkyl, S(O)2C 1-6 alkyl, SC 3-6 cycloalkyl, S(O)C 3-6 cycloalkyl, S(O)2C 1-6 cycloalkyl, S(O)2NH2, S(O)2NHC 1-6 alkyl, S(O)2NHC 3-6 alkyl, NHC(O)NH2, NHC(O)NHC 1-6 alkyl, NHC(O)NHC 1-6 cycloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, NHC(O)OC 1-6 alkyl, C(O)-C 1-6 cycloalkyl, C(O)C 1-6 alkylamino, C 1-6Heteroalkyl, P(O)(C 1-6 alkyl)2, heterocyclyl or heterocyclylalkyl. R 5 and R 7 The substituents of are linked via a carbon-carbon bond, a carbon-carbon double bond, a carbon-nitrogen bond, an amide bond, an ether bond, an ester bond and a sulfide bond to form a macrocyclic ring. R 11 is H or C 1-3 alkyl. R 12 is independently hydrogen, acyl, C l-8 alkyl, C 1-8 haloalkyl or C 1-8 hydroxyalkyl. R 13 is independently hydrogen, oxo, acyl, hydroxyl, C 1-8 hydroxyalkyl, cyano, halogen, C 1-8 alkyl, aralkyl, C 1-8 haloalkyl, C 1-8 heteroalkyl, C 1-10 cycloalkyl, C 1-10 heterocyclylalkyl, C 1-10 alkoxy, N(C 1-8 alkyl)2, C 1-8 alkyl-N(C 1-8 alkyl)2 or -C l-4 alkylene-NR 11 R 1 wherein C l-8 alkyl may be optionally substituted with one or two substituents selected from R 1 or C 1-8 cycloalkyl.

[0013] Each of alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heteroaryl may be substituted with the substituents defined in the definition section of this specification. In the following chemical formula, "alkyl" refers to a straight-chain (sometimes referred to as linear) one.

[0014] In another form, the present invention provides a compound of formula II or a pharmaceutically acceptable salt thereof:

Chemical formula

Chem.

[0015]

Chem.

[0016]

Chem.

[0017]

Chem.

[0018]

Chem.

[0019] In another embodiment, the present invention provides a compound of formula III or a pharmaceutically acceptable salt thereof:

Chem.

[0020] Here, R 3 , R 4 and R 5 are as defined above. Q is selected from the following moieties.

Chemical formula

[0021]

Chemical formula

Chemical formula

[0022]

Chemical formula

[0023]

Chemical formula

[0024] In another form, the present invention features a compound of formula IV or a pharmaceutically acceptable salt thereof:

Chemical formula

[0025] Here, Q and R 7 Are defined as above.

[0026]

Chemical formula

Chemical formula

[0027]

Chemical formula

Chemical formula

[0028] In another aspect, the present invention provides a compound of formula V or a pharmaceutically acceptable salt thereof:

Chemical formula

[0029] wherein, Q and R 7 are defined as above.

[0030]

Chemical formula

Chemical formula

[0031]

Chemical formula

[0032]

Chemical formula

[0033] In another aspect, the present invention provides a compound of formula VI or a pharmaceutically acceptable salt thereof:

Chemical formula

[0034] Here, Q is defined as described above.

[0035] [Chemical formula] is [Chemical formula] as follows.

[0036] Z, Y, R 1 , R 2 , R 3 , R 4 and R 5 are defined as described above. W is N or CR 6 as follows. R 6 is defined as described above. n and m are independently 0, 1, 2, 3, 4 or 5.

[0037] [Chemical formula] can also be selected from the following parts.

[0038] [Chemical formula] R e and R d are independently selected from hydrogen and halo. R a and R b are defined as described above. R 3 , R 4 and R 5 are defined as described above. R 15 is independently branched or linear C 1-6 alkyl, C 1-6 alkenyl, C 3-6 cycloalkyl, C 3-6Heterocyclyl, -SC 1-6 Alkyl, -OC 1-6 Alkyl, -OC 3-6 Is heterocyclyl, -OC3-6-cyclyl, -SC3-6 heterocyclyl, or -SC3-6-cyclyl. R 16 Is -S(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -S(O)2NHC 1-6 Alkyl, -S(O)2N(C 1-6 Alkyl alkyl)2, -P(O)(C 1-6 Is alkyl)2.

[0039] In another form, the present invention provides a compound of formula VII or a pharmaceutically acceptable salt thereof:

Chemical formula

[0040] Here, Q is defined as above.

[0041]

Chemical formula

Chemical formula

[0042] Z, Y, R 1 , R 2 , R 3 And R 4 Are defined as above. W is N or CR 6 Is. R 6 Is defined as above. n and m are independently 0, 1, 2, 3, 4, or 5. R 17 And R 18 Are halogen, branched or linear C 1-6 Alkyl, C 3-6 Cycloalkyl, C3-6 heterosilyl, -SC 1-6 alkyl, -OC 1-6 alkyl, -OC3-6 heterosicyl, -OC3-6-cicyl, -SC3-6 heterosicyl, -SC3-6 cicyl, -S(O)C 1-6 alkyl, -S(O)2C 1-6 alkyl, -S(O)2NHC 1-6 alkyl, -S(O)2N(C 1-6 alkyl)2 and -P(O)(C 1-6 is independently selected from the group consisting of L3 is -(CH2) q C(O)-, -O(CH2) q C(O)-, -NR 19 (CH2) q NR 20 -, -(CH2) q NR 20 -, -O(CH2) q O-, -(CH2) q C(O)NR 19 -, -O(CH2) q C(O)NR 19 -, -S(CH2) q C(O)-, -S(CH2) q C(O)-; -O(CH2) q C(O)NR 19 -, -O(CH2) q CNR 19 -, -S(CH2) q O-, -O(CH2) q S-, -S(CH2) q S-, -NR 19 (CH2) q C(O)N 20 -, -NR 19 (CH2) q C-, -NR 19 (CH2) q O-, -O(O)(CH2) q -, -O(O)(CH2) q -, -O(O)(CH2) q S-, -(CH2) t CH=CH(CH2) r -, -O(CH2) q CH=CH(CH2)r -, -(CH2) q CH=CH(CH2) r O-, -O(CH2) q CH=CH(CH2) r O-, -S(CH2) q CH=CH(CH2) r -, -(CH2) q CH=CH(CH2) r S-, -O(CH2) q CH=CH(CH2) r S-, -S(CH2) q CH=CH(CH2) r O-, -C(CH2) q S(CH2) r -, -C(CH2) q O(CH2) r is independently selected from the group consisting of. q and r are independently selected from 1 to 6. Preferably, q and r are each independently 1, 2, 3, 4, 5 or 6. R 19 and R 20 are independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl.

[0043]

Chemical formula

[0044]

Chemical formula

[0045] In another form, the present invention provides a compound of formula VIIA or a pharmaceutically acceptable salt thereof:

Chemical formula

[0046] Here, [Chemical formula] is [Chemical formula] .

[0047] R 1 and R 2 are hydrogen, halo, C 0-6 alkylene-CN, C 0-6 alkyleneNR 19 R 20 , C 1-6 alkoxy, hydroxy, C 0-6 alkylene-C(O)NH2, C 0-6 alkylene-C(O)NHC 1-6 alkyl, C 0-6 alkylene-C(O)N(C 1-6 alkyl)2, C 0-6 alkylene-S(O)2-C 1-6 alkyl, C 0-6 alkylene-S(O)2NH2, C 0-6 alkylene-S(O)2NHC 1-6 alkyl, C 0-6 alkylene-S(O)2N(C 1-6 alkyl)2, C 0-6 alkylene-NHC(O)NH2, C 0-6 alkylene-NHC(O)NHC 1-6 alkyl, C 0-6 alkylene-NR 19 C(O)N(C 1-6 alkyl)2, C 1-6 alkyl, C 0-6 alkylene-NHC-NHC(O)OC 1-6 alkyl, C 0-6 alkylene-C(O)-C 1-6 alkyl, C 1-6 heteroalkyl, C 0-6 alkylene-heterocyclyl or C 0-6It is independently selected from alkylene - heterocyclylalkyl. Or, R 1 and R 2 can form a 3 - to 6 - membered carbon ring together with the carbon atoms to which both are attached. Z and Y are independently N or CR 3 . W is N or CR 6 . W 1 is N or CR 3 . W 2 is N or CR 4 . Z 1 , Z 2 , Z 3 , Z 4 and Z 5 are independently N or CR 18 . R 3 , R 4 and R 6 are independently H, OH, CN or halo, C 1-6 alkyl, C 3-10 cycloalkyl, C 3-10 heteroalkyl, C 3-10 heterocycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, NH - C 1-6 alkyl, N(C 1-6 alkyl)2, C 3-8 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 2-6 heterocyclyl, aryl or heteroaryl. R 17 and R 18 are halogen, CN, branched or linear C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 heterosilyl, - SC 1-6 alkyl, - OC 1-6 alkyl, - OC3 - 6 heterosicyl, - OC3 - 6 sicyl, NH - C 1-6 alkyl, N(C 1-6(alkyl)2, -SC3-6 heterocyclyl, -SC3-6 cyl, -S(O)C 1-6 alkyl, -S(O)2C 1-6 alkyl, -S(O)2NH2, -S(O)2NHC 1-6 alkyl, -S(O)2N(C 1-6 alkyl)2, P(O)(C 1-6 alkyl)2, C 2-6 heterocyclyl, C 6-10 aryl or C 1-5 is independently selected from heteroaryl. L3 is, -(CH2) q , -(CH2) q C(O)-, -O(CH2) q C(O)-, -NR 19 (CH2) q NR 20 -, -(CH2) q NR 20 -, -O(CH2) q O-, -(CH2) q C(O)NR 19 -, -(CH2) q C(S)NR 19 -, -(CH2) q CHCF3NR 19 -, -(CH2) q NR 19 C(O)-, -(CH2) q NR 19 CHCF3-, -C(O)NR 19 (CH2) q -, -CHCF3NR 19 (CH2) q -, -C(S)NR 19 (CH2) q -, -O(CH2) q C(O)NR 19 -, -O(CH2) q C(S)NR 19 -, -S(O) v (CH2) q C(O)-, -O(CH2) q C(O)NR 19 -, -NR 19 C(O)(CH2) q C(O)NR20 -, -C(O)NR 19 (CH2) q C(O)NR 20 -, -C(O)NR 19 (CH2) q NR 20 C(O)-, -NR 19 C(O)(CH2) q NR 20 C(O)-, O(CH2) q CNR 19 -, -S(O) v (CH2) q O-, -O(CH2) q S(O) v -, -S(O) v (CH2) q -, -(CH2) q S(O) v -, -S(O) v (CH2) q S(O) v -, -NR 19 (CH2) q C(O)NR 20 -, -NR 19 (CH2) q -, -NR 19 C(O)(CH2) q -, -NR 19 CHCF3(CH2) q -, -NR 19 (CH2) q O -, -(CH2) r OC(O)(CH2) q -, -OC(O)(CH2) q -, -OC(O)(CH2) q S(O) v -, -(CH2) q CH=CH(CH2) r -, -NR 19 (CH2) q CH=CH(CH2) r -, NR 19 C(O)(CH2) q CH=CH(CH2) r -, -(CH2) q CH=CH(CH2) r C(O)NR20 -, -(CH2) q NR 19 C(O)NR 20 (CH2) r -, -(CH2) q NR 19 C(S)NR 20 (CH2) r -, -(CH2) q NR 19 S(O)2NR 20 (CH2) r -, -(CH2) q S(O) v (CH2) r -, -(CH2) q S(O)2NR 20 (CH2) r -, -(CH2) q NR 19 S(O) v (CH2) r -, -(CH2) q SS(CH2) r -, -(CH2) q S(CH2) r -,-(CH2) q O(CH2) r -, -(CH2) q NR 19 (CH2) r -, -(CH2) q C≡C(CH2) r -, -O(CH2) q CH=CH(CH2) r -, -O(CH2) q CH≡CH(CH2) r -, -(CH2) q CH=CH(CH2) r O-, -(CH2) q CH≡CH(CH2) r O-, -O(CH2) q CH=CH(CH2) r O-, -O(CH2) q CH≡CH(CH2) r O-, -S(O) v (CH2) q CH=CH(CH2) r -, S(O)v (CH2) q CH≡CH(CH2) r -, -(CH2) q CH=CH(CH2) r S(O) v -, (CH2) q CH≡CH(CH2) r S(O) v -, -O(CH2) q CH=CH(CH2) r S(O) v -, -O(CH2) q CH≡CH(CH2) r S(O) v -, -S(O) v (CH2) q CH=CH(CH2) r O-, S(O) v (CH2) q CH≡CH(CH2) r O-, -C(CH2) q S(CH2) r -, -C(CH2) q O(CH2) r -, -C(O)NR 19 S(O)2(CH2) q -, or -(CH2) q S(O)2NR 19 C(O)-; or L3 is L4-L5-L6. L4 and L6 are -(CH2) q -, -O(CH2) q -, -S(CH2) q -, -NR 19 (CH2) q -, -(CH2) q NR 20 -, -(CH2) q O-, -(CH2) q S-, -(CH2) q C(O)-, -C(O)(CH2) q -, -(CH2) q C(O)NR 19 -, -NR 19 (C(O)(CH2) q -, -(CH2) qCH=CH(CH2) r -, -O(CH2) q CH=CH(CH2) r -, -(CH2) q CH=CH(CH2) r O-, -S(CH2) q CH=CH(CH2) r -, -(CH2) q CH=CH(CH2) r S-, -O(CH2) q CH=CH(CH2) r S-, or -S(CH2) q CH=CH(CH2) r is independently selected from. L5 is C 2-6 heterocyclyl, C 6-10 aryl or C 1-9 heteroaryl. Each oxo group of L3, L4, L5 and L6 can independently be replaced by a thiocarbonyl group, -C(S)-, an oxetane group, an imine group or -C(=NR 19 )-. q and r are independently selected from 0 to 10. Preferably, q and r are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. v is 0, 1 or 2. R 19 and R 20 are independently selected from hydrogen, C 1-6 alkyl, C 3-10 heteroalkyl, C 3-10 cycloalkyl, C 6-10 aryl, C 1-5 heteroaryl or C 2-6 heterocyclyl. Or, R 19 and R 20 can also be connected to form a ring. Q is a moiety capable of forming a covalent bond with a nucleophile, and preferably, exemplary structures of Q are shown below.

Chemical formula

[0048]

Chemical formula

[0049]

Chemical formula

[0050] In another form, the present invention provides a compound of formula VIIB or a pharmaceutically acceptable salt thereof:

Chemical formula

[0051] where

Chemical formula

[0052] R 17 , Z, Z 5 , W, W 1 , W 2 and L3 are defined as above. L6 is -(CH2) q -, -(CH2) q C(O)-, -O(CH2) q C(O)-, -NR 19 (CH2) q NR 20 -, -(CH2) q NR20 -, -O(CH2) q O-, -(CH2) q C(O)NR 19 -, -(CH2) q NR 19 C(O)-, -C(O)NR 19 (CH2) q -, -O(CH2) q C(O)NR 19 -, -S(O) v (CH2) q C(O)-, -O(CH2) q C(O)NR 19 -, -NR 19 C(O)(CH2) q C(O)NR 20 -, -C(O)NR 19 (CH2) q C(O)NR 20 -, -C(O)NR 19 (CH2) q NR 20 C(O)-, -NR 19 C(O)(CH2) q NR 20 C(O)-, O(CH2) q CNR 19 -, -S(O) v (CH2) q O-, -O(CH2) q S(O) v -, -S(O) v (CH2) q S(O) v -, -NR 19 (CH2) q C(O)NR 20 -, -NR 19 (CH2) q -, -NR 19 C(O)(CH2) q -, -NR 19 (CH2) q O -, -O(O)(CH2) q -, -O(O)(CH2) q -, -O(O)(CH2) q S(O) v -, -(CH2) q CH=CH(CH2)r -, -NR 19 (CH2) q CH=CH(CH2) r -, NR 19 C(O)(CH2) q CH=CH(CH2) r -, -(CH2) q CH=CH(CH2) r C(O)NR 20 -, -(CH2) q C≡C(CH2) r -, -O(CH2) q CH=CH(CH2) r -, -O(CH2) q CH≡CH(CH2) r -, -(CH2) q CH=CH(CH2) r O-, -(CH2) q CH≡CH(CH2) r O-, -O(CH2) q CH=CH(CH2) r O-, -O(CH2) q CH≡CH(CH2) r O-, -S(O) v (CH2) q CH=CH(CH2) r -, S(O) v (CH2) q CH≡CH(CH2) r -, -(CH2) q CH=CH(CH2) r S(O) v -, (CH2) q CH≡CH(CH2) r S(O) v -, -O(CH2) q CH=CH(CH2) r S(O) v -, -O(CH2) q CH≡CH(CH2) r S(O) v -, -S(O) v (CH2) q CH=CH(CH2) r O-, S(O) v (CH2) qCH≡CH(CH2) r O-, -C(CH2) q S(CH2) r -, And -C(CH2) q O(CH2) r is independently selected from. q and r are independently selected from 0 to 10. Preferably, q and r are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. v is 0, 1 or 2. L3 and L6 can also be absent.

[0053]

Chemical formula

[0054] In another form, the present invention provides a compound of formula VIIC or a pharmaceutically acceptable salt thereof:

Chemical formula

[0055]

Chemical formula

[0056] In another form, the present invention provides a compound of formula VIII or a pharmaceutically acceptable salt thereof:

Chemical formula

[0057] Here, Q, L 1 , L2 , R 9 and R 10 are defined as above.

[0058]

Chem.

[0059]

Chem.

[0060]

Chem.

[0061]

Chem.

[0062] In another embodiment, the present invention provides a compound of formula IX or a pharmaceutically acceptable salt thereof:

Chem.

[0063] wherein

Chem.

[0064]

Chem.

[0065]

Chem.

[0066]

Chem.

[0067] In another embodiment, the present invention provides a compound of formula X or a pharmaceutically acceptable salt thereof:

Chem.

[0068] Here,

Chem.

[0069]

Chem.

[0070] Or

Chemical formula

[0071]

Chemical formula

[0072] In another embodiment, the present invention provides a compound of formula XI or a pharmaceutically acceptable salt thereof:

Chemical formula

[0073] Here,

Chemical formula

[0074]

Chemical formula

[0075]

Chemical formula

[0076]

Chemical formula

[0077] In some embodiments, the present invention also includes stereoisomers, enantiomers, atropisomers or pharmaceutically acceptable salts of any of the compounds of Formula I to Formula XI above.

[0078] In some embodiments, the compounds of Formula I to Formula XI are selected from stereoisomers, enantiomers, atropisomers or pharmaceutically acceptable salts thereof.

[0079] In some embodiments, the compounds of Formula I to Formula XI, or stereoisomers, enantiomers or atropisomers thereof, or pharmaceutically acceptable salts thereof, are selected from the following compounds:

[0080]

Chemical formula

[0081]

Chemical formula

[0082]

Chemical formula

[0083]

Chem.

[0084]

Chem.

[0085]

Chem.

[0086]

Chem.

[0087]

Chem.

[0088]

Chem.

[0089]

Chem.

[0090]

Chem.

[0091]

Chem.

[0092]

Chem.

[0093]

Chem.

[0094]

Chem.

[0095]

Chem.

[0096]

Chem.

[0097]

Chem.

[0098]

Chem.

[0099]

Chem.

[0100]

Chem.

[0101]

Chem.

[0102]

Chem.

[0103]

Chem.

[0104]

Chem.

[0105]

Chem.

[0106] In another aspect, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound disclosed herein, or a pharmaceutically acceptable carrier.

[0107] In another aspect, the present invention provides a method for treating a disease mediated by a KRAS G12C mutant. Preferably, the method comprises administering to a subject a therapeutically effective amount of a compound disclosed herein.

[0108] Preferably, the disease mediated by the KRAS G12C mutant is cancer, more preferably pancreatic cancer, colorectal cancer, hepatocellular carcinoma, breast cancer, ovarian cancer, lung cancer, liver cancer, sarcoma, and / or any other form of cancer.

[0109] In another aspect, the present invention provides a method for treating a disease mediated by a KRAS G12C mutant. The method comprises administering to a subject a therapeutically effective amount of a compound disclosed herein. In another aspect, the present invention is characterized by a method for treating any one of diseases exemplified by pancreatic cancer, colorectal cancer, hepatocellular carcinoma, breast cancer, ovarian cancer, lung cancer, liver cancer, sarcoma, etc. by administering to a subject a therapeutically effective amount of a compound disclosed herein.

[0110] In another aspect, the present invention provides the use of a compound disclosed herein, or a pharmaceutically acceptable salt thereof for treating or preventing a disease mediated by a KRAS G12C mutant.

[0111] The present invention includes all possible combinations of the embodiments described above and below.

Advantages of the Invention

[0112] It should be understood that each of the above technical features of the invention and the technical features described specifically (such as examples) can be combined with each other within the scope of the present invention to constitute new or preferred technical solutions.

Modes for Carrying Out the Invention

[0113] Definitions The term "alkyl", unless otherwise specified, refers to a straight-chain (i.e., unbranched) or branched-chain, cyclic hydrocarbon group, or a combination thereof, having the specified number of carbon atoms (i.e., C 1-10 refers to 1 to 10 carbons), which can be fully saturated, mono- or poly-unsaturated, and includes divalent and polyvalent groups, either by itself or as part of another substituent. Examples of saturated hydrocarbon groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, and homologs and isomers such as n-pentyl, n-hexyl, n-heptyl, and n-octyl. Unsaturated alkyl groups have one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers. An alkyl group limited to a hydrocarbon group is called "homoalkyl". The alkyl is optionally substituted with one or more halogen atoms.

[0114] The term "alkyl halide" refers to an alkyl as defined above in which one or more hydrogen atoms have been replaced by halogen atoms.

[0115] The term "alkylene" refers to a divalent group derived from an alkyl, exemplified by but not limited to -CH2CH2CH2CH2-, -CH2CH=CHCH2-, -CH2C≡CCH2-, -CH2CH2CH(CH2CH2CH3)CH2-, either by itself or as part of another substituent. Typically, an alkyl (or alkylene) group has from 1 to 24 carbon atoms, preferably 10 or fewer carbon atoms in the present invention. "Lower alkyl" or "lower alkylene" is a shorter-chain alkyl or alkylene group generally having 8 or fewer carbon atoms. The alkylene is optionally substituted with one or more halogen atoms.

[0116] The term "alkynyl" refers to a carbon chain that can be linear, branched, or a combination thereof and contains at least one carbon-carbon triple bond. Examples of alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl, and the like. The alkynyl is optionally substituted with one or more halogen atoms.

[0117] The term "cycloalkyl" refers to a monocyclic or bicyclic saturated carbon ring each having from 3 to 10 carbon atoms. The "condensed analog" of cycloalkyl refers to a monocyclic ring fused to an aryl or heteroaryl group where the point of attachment is in the non-aromatic portion. Examples of cyclopropyl and its condensed analogs include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl, and the like. The cycloalkyl is optionally substituted with one or more halogen atoms.

[0118] The term "alkoxy" refers to a straight-chain or branched alkoxy group having the specified number of carbon atoms. For example, C 1-6 Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, and the like.

[0119] Unless otherwise specified, the term "heteroalkyl" refers to a stable straight-chain or branched-chain, cyclic hydrocarbon group, or a combination thereof, consisting of at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si and S, which may optionally oxidize nitrogen, phosphorus and sulfur atoms and may optionally quaternize nitrogen heteroatoms, as itself or as part of another substituent. The heteroatoms O, N, P, S and Si are replaced at any internal position of the heteroalkyl group or at the position where the alkyl group is attached to the rest of the molecule. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH2-CH3 and -CN. For example, up to two or three heteroatoms are consecutive, such as in -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. Similarly, the term "heteroalkylene" refers to a divalent group derived from heteroalkyl, exemplified by, but not limited to, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-, as itself or as part of another substituent. For heteroalkylene groups, the heteroatoms can also occupy either or both of the chain ends (e.g., alkyleneoxo, alkylenedioxo, alkylenamino, alkylenediamino). Further, for alkylene and heteroalkylene linking groups, the direction in which the formula of the linking group is written does not indicate the orientation of the linking group. For example, the formula -C(O)OR' represents both -C(O)OR'- and -R'OC(O)-. As described above, the heteroalkyl groups used herein include groups attached to the rest of the molecule via heteroatoms exemplified by -C(O)R', -C(O)NR', -NR'R", -OR', -SR', and / or -SO2R'.When listing "heteroalkyl" and then listing specific heteroalkyl groups exemplified by -NR'R", it may be understood that the terms heteroalkyl and -NR'R" are not unnecessary or mutually exclusive. Rather, the specific heteroalkyl groups are listed to make it clearer. Thus, the term "heteroalkyl" should not be construed herein to exclude specific heteroalkyl groups exemplified by -NR'R".

[0120] The term "cycloalkoxy" refers to cycloalkyl as defined above bonded to an oxygen atom, exemplified by cyclopropyloxy.

[0121] The term "halogenated alkoxy" refers to alkoxy as defined above in which one or more hydrogen atoms are replaced by halogen atoms.

[0122] The term "aryl" refers to a monocyclic or bicyclic aromatic ring containing only carbon atoms. The "fused analog" of aryl refers to an aryl group fused to a monocyclic cycloalkyl or monocyclic heterosilyl group where the point of attachment is in the aromatic moiety. Examples of aryl and its fused analogs include phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl, 2,3-dihydrobenzofuranyl, dihydrobenzopyranyl, 1,4-benzodioxanyl, etc.

[0123] The term "heteroaryl" refers to a monocyclic or bicyclic aromatic ring having 5 to 6 atoms per ring and containing at least one (1, 2 or 3) heteroatom selected from N, O and S. The "condensed analog" of heteroaryl refers to a heteroaryl group condensed to a monocyclic cycloalkyl group or a monocyclic heterocyclyl group where the point of attachment is in the aromatic moiety. Examples of heteroaryl include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, benzoinyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyridazinyl, furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl, etc.

[0124] The alkyl group, the aryl group and the heteroaryl group mentioned in the definition are unsubstituted or substituted by at least one substituent selected from groups consisting of substituents.

[0125] The substituents are selected from the group consisting of a halogen atom, a hydroxyl group, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, a haloalkoxy group having 1 to 4 carbon atoms, a cyano group, an alkynyl group having 2 to 6 carbon atoms, an alkanoyl group having 1 to 5 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a heteroaryl group, an aryl group, an aralkoxy group having 7 to 10 carbon atoms, and an arylcarbonyl group. Two adjacent x groups are optionally combined to form an alkylene or alkenylene chain having 3 or 4 carbon atoms, an alkenyl group having 2 to 5 carbon atoms, an alkylthio group having 1 to 4 carbon atoms, an aminosulfinyl group, an aminosulfonyl group, a hydroxy group, -SF5, a hydroxyalkyl group having 1 to 4 carbon atoms, a nitro group, an amino group, a carboxy group, an alkoxycarbonyl group having 2 to 5 carbon atoms, an alkoxyalkyl group having 1 to 4 carbon atoms, an alkylsulfonyl group having 1 to 4 carbon atoms, an alkanoylamino group having 1 to 4 carbon atoms, an alkanoyl(alkyl)amino group having 1 to 6 carbon atoms in both the alkanoyl and alkyl moieties, an alkanoylaminoalkyl group having 1 to 6 carbon atoms in both the alkanoyl and each alkyl moiety, an alkanoyl(alkyl)aminoalkyl group having 1 to 6 carbon atoms in both the alkanoyl and each alkyl moiety, an alkylsulfonylamino group having 1 to 4 carbon atoms, a mono- or dialkylaminocarbonyl group having 1 to 6 carbon atoms, a mono- or dialkylaminosulfinyl group having 1 to 6 carbon atoms, a mono- or dialkylaminosulfonyl group having 1 to 6 carbon atoms, an aminoalkyl group having 1 to 4 carbon atoms, a mono- or dialkylamino group having 1 to 6 carbon atoms, a mono- or dialkylaminoalkyl group having 1 to 6 carbon atoms in each alkyl moiety, an aralkyl group having 7 to 10 carbon atoms, a heteroarylalkyl group having 1 to 4 carbon atoms in the alkyl moiety, a heteroarylalkoxy group having 1 to 4 carbon atoms in the alkoxy moiety, and an alkylsulfonylamino group having 1 to 4 carbon atoms.

[0126] The term "heterocyclyl" refers to a monocyclic or bicyclic saturated ring having 3 to 10 atoms, each ring having a point of attachment that can be carbon or nitrogen and containing at least one heteroatom selected from N, S, and O. A "condensed analog" of heterocyclyl refers to a monocyclic heterocyclic ring fused to an aryl or heteroaryl group where the point of attachment is in the non-aromatic portion. Examples of "heterocyclyl" and its condensed analogs include pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, 2,3-dihydrofuro(2,3-b)pyridyl, benzoxazinyl, tetrahydrohydroquinolinyl, tetrahydroisoquinolinyl, dihydroindolyl, and the like. This term also includes a partially unsaturated monocyclic ring that is not aromatic, exemplified by 2- or 4-pyridone linked via nitrogen or N-substituted-(1H,3H)-pyrimidine-2,4-dione (N-substituted uracil).

[0127] The term "halo" or "halogen", unless otherwise specified, refers to a fluorine, chlorine, bromine, or iodine atom, either alone or as part of another substituent. Further, terms such as "haloalkyl" or "halogenated alkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C1-C4)alkyl" is meant to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0128] A "prodrug" refers to a drug that is converted into the parent drug in vivo. Depending on the situation, prodrugs can be very useful because in some cases they are easier to administer than the parent drug. They may be, for example, biologically available by oral administration, while the parent is not. Prodrugs can also improve the solubility of the pharmaceutical composition compared to the parent drug. Examples of prodrugs can be any of the compounds of formula I without limitation. The compound is administered as an ester ("prodrug") to facilitate transport across the cell membrane where water solubility adversely affects mobility, but then, when the compound enters the cell where water solubility is beneficial to the active form, it is metabolically hydrolyzed to a carboxylic acid. Further examples of prodrugs can be short peptides (polyamino acids) linked to acid groups that metabolize the peptide to expose the active moiety.

[0129] Optical isomers - Diastereomers - Atropisomers - Geometric isomers - Tautomers: Any of the compounds from formula I to formula XI may contain one or more asymmetric centers / obstructed rotations around a single bond and can thus occur as racemates and racemic mixtures, single enantiomers, single atropisomers, diastereomer mixtures and individual diastereomers. The present invention is meant to be understood as encompassing all the isomeric forms of the compounds from formula I to formula XI.

[0130] Some of the compounds described herein contain olefinic double bonds and, unless otherwise specified, are meant to include both the E and Z geometric isomers.

[0131] Some of the compounds from formula I to formula XI may contain one or more cyclic ring systems and can thus exist as cis and trans isomers. The present invention is meant to include all such cis and trans isomers.

[0132] Some of the compounds described herein may exist with different bonding points of hydrogen, known as tautomers. Such examples can be a ketone and its enol form known as keto-enol tautomers. Individual tautomers and mixtures thereof are included in the compounds from Formula I to Formula XI.

[0133] The compounds from Formula I to Formula XI can be separated into diastereomeric pairs by HPLC or fractional crystallization from a suitable solvent such as MeOH or EtOAcM or a mixture thereof. The obtained enantiomeric pairs can be separated into individual stereoisomers by the use of an optically active amine or acid as a resolving agent, or by conventional means such as on a chiral HPLC column. Alternatively, any enantiomer of the compounds from Formula I to Formula XI can be obtained by stereospecific synthesis using optically pure starting materials or reagents of known constitution. Stable isotope-labeled analogs: One or more protons in the compounds from Formula I to Formula XI can be replaced by deuterium atoms, thus providing deuterated analogs that can improve pharmacological activity.

[0134] Salts and formulations: The compounds described herein may be useful as free bases or salts.

[0135] The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include those containing aluminum, ammonium, calcium, copper, ferric, iron, lithium, magnesium, manganese salts, manganese, potassium, sodium, zinc, and the like. Particularly preferred are ammonium salts, calcium salts, magnesium salts, potassium salts, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins exemplified by arginine, betaine, caffeine, choline, N,N'-dibenzyl-ethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperazine, glucamine, glucosamine, histidine, hydramine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine.

[0136] When the compounds of the present invention are alkaline, the salts can be prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids. Such acids include acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and the like. Particularly preferred are citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid.

[0137] As used herein, it may be understood to include pharmaceutically acceptable salts for the compounds of Formula I.

[0138] Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with a water or oil-based medium such as peanut oil, liquid paraffin or olive oil.

[0139] An aqueous suspension contains the active substance mixed with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and gum arabic. Dispersing or wetting agents may be natural phospholipids such as lecithin, condensation products of alkylene oxides and fatty acids such as polyoxyethylene stearate, condensation products of ethylene oxide and long-chain aliphatic alcohols such as heptadecaethyleneoxycetanol, condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides such as polyethylene sorbitan monooleate. The aqueous suspension may also contain one or more preservatives such as ethyl, n-propyl or p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents such as sucrose, saccharin or aspartame.

[0140] An oily suspension may be formulated by suspending the active ingredient in a vegetable oil such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspension may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. The above sweetening and flavoring agents may be added to provide a palatable oral formulation. The composition may be preserved by the addition of an antioxidant such as ascorbic acid.

[0141] Dispersible powders and granules suitable for the preparation of aqueous suspensions by the addition of water provide an active ingredient mixed with a dispersant or wetting agent, a suspending agent and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are exemplified by the foregoing. Additional excipients may also be present, such as sweeteners, flavorings and colorants.

[0142] The pharmaceutical compositions of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin, or a mixture thereof. Suitable emulsifying agents may be naturally occurring phosphatides such as soy, lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, or condensation products of said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavorings.

[0143] Syrups and elixirs can be formulated with sweeteners such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain thickening agents, preservatives, flavorings and colorants. The pharmaceutical composition can be in the form of a sterile injectable aqueous or oily suspension. This suspension can be formed according to known techniques by using the appropriate dispersants or wetting agents and suspending agents described above. Sterile injectable preparations can also be suspensions in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol, or sterile injectable solutions. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any type of fixed oil containing synthetic monoglycerides or diglycerides can be used. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0144] The compounds of the present invention can also be administered intranasally or by inhalation. The mode of administration typically uses dry powder from a dry powder inhaler (alone, for example, a dry mixture with lactose, or mixed component particles mixed with a phospholipid such as phosphatidylcholine, for example), or with or without the use of a suitable propellant such as 1,1,1,2 - tetrafluoroethane or 1,1,1,2,3,3,3 - heptafluoropropane, and utilizes an aerosol spray from a pressurized container, pump, spray, nebulizer (preferably, nebulizer I that generates fine mist by utilizing electrohydrodynamic force) or inhaler. For intranasal use, the powder can contain a bioadhesive such as chitosan or cyclodextrin as an example.

[0145] The pressurized container, pump, spray, nebulizer or inhaler contains a solution or suspension of the compound of the present invention containing a suitable alternative for the dispersion, solubilization or extended release of ethanol, aqueous ethanol or an active propellant as a solvent, and any surfactant such as sorbitan trioleate, oleic acid or oligolactic acid.

[0146] Before using the dry powder or suspension formulation, the formulation is micronized to a size suitable for delivery by inhalation (usually less than 5 microns).

[0147] This can be achieved by any suitable grinding method such as spiral jet mill, fluidized bed jet mill, supercritical fluid treatment to form nanoparticles, high - pressure homogenization or spray drying.

[0148] Capsules (for example, made of gelatin or HPMC), blisters and cartridges applied to the inhaler are formulated to include a powder mixture of the compound of the present invention, a suitable powder base such as lactose or starch, and a performance modifier such as l - leucine, mannitol or magnesium stearate. Lactose can be anhydrous or monohydrate. Preferably, it appears in the latter form. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

[0149] Suitable solution formulations for use in nebulizers that generate fine mists using electrohydrodynamics may contain from 10 to 20 mg of the compounds of the present invention per actuation on a logarithmic basis, and the actuation volume may vary from 11 to 1001. Typical formulations may contain compounds of propylene glycol, sterile water, ethanol, and sodium chloride from Formula I to Formula XI. Alternative solvents that can be used in place of propylene glycol include glycerol and polyethylene glycol.

[0150] Suitable flavoring agents such as menthol and levomenthol, or sweetening agents such as saccharin or sodium saccharin can be added to the formulations of the present invention for inhalation / intranasal administration.

[0151] Formulations for inhalation / intranasal administration can be formulated, for example, using poly(DL-lactic-co-glycolic acid (PGLA)) to provide immediate release and / or sustained release.

[0152] In the case of dry powder inhalers and aerosols, the dosing unit is determined by a valve that supplies a fixed dose. Units according to the present invention are typically set to administer a fixed dose or "puff" containing from 1 mg to 10 mg of the compounds from Formula I to XI. The total daily dose typically falls within the range of 1 mg to 10 mg. This range can be administered as a single dose or, more commonly, divided into daily doses.

[0153] The compounds from Formula I to XI can also be administered in the form of suppositories for rectal administration of drugs. The composition can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature and liquid at rectal temperature and thus melts in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycol.

[0154] For topical use, creams, ointments, jellies, solutions or suspensions containing the compounds from Formula I to XI are used. (For the purposes of this application, topical application shall include mouthwashes and gargles.)

[0155] To treat the above-mentioned disease, a dosage level of about 0.01 mg to about 140 mg / kg body weight per day, or a dosage level of about 0.5 mg to about 7 g per patient per day can be adopted. For example, this disease can be effectively treated by administering about 0.01 - 50 mg of the compound per kilogram of body weight per day, or about 0.5 mg - about 3.5 g, preferably 2.5 mg - 1 g of the compound per patient per day.

[0156] The amount of the active ingredient that can be combined with the carrier material to produce a single dosage form can vary depending on the treated host and the specific mode of administration. For example, a formulation intended for oral administration to humans can contain 0.5 mg - 5 g of the active agent mixed with a suitable and convenient amount of the carrier material that can vary from about 5% to about 95% of the total composition. Dosage unit forms can generally contain about 1 mg - about 500 mg of the active ingredient, taking about 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg as examples.

[0157] However, it is understood that the specific dosage level for a particular patient depends on various factors including age, body weight, general health, gender, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the specific disease being treated.

[0158] Indications The compounds of the present invention can be used to treat diseases having the KRAS G12C variant. The disease is any form of cancer.

[0159] Combination therapy and targeted therapy The KRAS G12C inhibitors disclosed in this specification can be administered in combination with other cancer treatments. For example, the inhibitor can be administered in combination with other therapeutic agents such as surgical treatment, radiation, or antibodies, other kinase inhibitors, targeted therapies, inhibitors of the MAP kinase signaling pathway, or chemotherapeutic agents. The inhibitor can also be administered in combination with RNAi therapy, antisense therapy, or immunotherapy. The KRAS G12C inhibitors described in this specification can be combined with one, two, or more other therapeutic agents. In the examples outlined below, it is understood that the "second therapeutic agent" also includes a plurality of therapeutic agents other than the KRAS G12C inhibitor. For example, the compounds disclosed in this specification can be combined with agents such as sorafenib, a PD-1 antibody, or a PD-L1 antibody. The KRAS G12C inhibitors described in this specification can be administered together with one, two, or more other therapeutic agents.

[0160] Synthesis The compounds of the present invention can be prepared according to the following synthetic concept.

[0161] Scheme 1

Chemical formula

[0162] Scheme 2

Chemical formula

[0163] Scheme 3

Chemical formula

[0164] Scheme 4

Chemical formula

[0165] Scheme 5

Chem.

[0166] Scheme 6

Chem.

[0167] Scheme 7

Chem.

[0168] Scheme 8

Chem.

[0169] Scheme 9

Chem.

[0170] Scheme 10

Chem.

[0171] Evaluation of Biological Activity 3D Proliferation Assay: NCI-H358 (H358, KRAS G12C) and LS513 (KRAS G12D) cancer cell lines were obtained from ATCC (American Type Culture Collection, VA). Cells were cultured in 96-well round-bottom plates (CORNING INC, NY) with RPMI-1640 medium containing 10% FBS. Compounds (11-point dilutions) and DMSO were added to the wells and cultured with the cells at 37 o °C for 4 days. Next, cell viability was determined by CellTiter-Glo (Promega, WI). The IC 50 values of the compounds were calculated relative to DMSO-treated cells (A: IC 50<0.1 μM; B: IC between 0.1 μM and 1 μM 50 ; C: IC between 1 μM and 10 μM 50 ; D: >10 μM; ND: Not determined) and was determined as the concentration at which 50% inhibition of cell viability was compared.

[0172] Phospho-ERK (pERK) assay: 16 hours before compound treatment, NCI-H358 cells were seeded in 96-well plates (Greiner) of RPMI-1640 containing 10% FBS. Serial dilutions of the compound were made and added to the wells, followed by incubation at 37 °C for 3 hours. After treatment, the cells were fixed with 3.7% formaldehyde (VWR) at RT for 20 minutes, followed by permeabilization with ice-cold methanol at -20 °C for 20 minutes. Next, the methanol was removed and replaced with Intercept (PBS) Blocking Buffer (LiCOR)(registered trademark) supplemented with 0.05% Tween-20, and the cells were incubated at room temperature for 1 hour with gentle shaking. Next, the blocking buffer was replaced with a blocking buffer containing pERK1 / 2 antibody (Cell Signaling), and the cells were incubated at 4 °C overnight with gentle shaking. The well plates were washed 5 times with 1x PBS + 0.1% Tween-20. Next, a blocking buffer containing LiCOR IRDye 680RD secondary antibody (LiCOR) was added, and the cells were incubated at room temperature for 1 hour with gentle shaking. After washing 5 times with 1x PBS + 0.1% Tween-20, the well plates were read using a CLARIOstar plate reader (BMG LABTECH GmbH). IC 50 values were DMSO-treated cells (A: IC 50 <0.1 μM; B: IC between 0.1 μM and 1 μM 50 ; C: IC between 1 μM and 10 μM 50 ; D: >10 μM; ND: Not determined) and was determined as the concentration at which 50% inhibition of the fluorescence signal was compared.

[0173]

Table 1

[0174] The following abbreviations have the designated meanings. CIP refers to 2-chloro-1,3-dimethylimidazolinium hexafluorophosphate. EA refers to ethyl acetate. DBU refers to 1,8-diazabicyclo[5.4.0]undec-7-ene. DIBAL refers to diisobutylaluminum hydride. DIPEA refers to diisopropylethylamine. DMAP refers to N,N-dimethylaminopyridine. DME refers to 1,2-dimethoxyethane. DMF refers to N,N-dimethylformamide. dmpe refers to 1,2-bis(dimethylphosphino)ethane. DMSO refers to dimethyl sulfoxide. dppb refers to 1,4-bis(diphenylphosphino)butane. dppe refers to 1,2-bis(diphenylphosphino)ethane. dppf refers to 1,1'-bis(diphenylphosphino)ferrocene. dppm refers to 1,1'-bis(diphenylphosphino)methane. DIAD refers to diisopropyl azodicarboxylate. EDCI refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. HATU refers to 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate. HMPA refers to hexamethylphosphoramide. IPA refers to isopropyl alcohol. LDA refers to lithium diisopropylamide. LHMDS refers to lithium bis(hexamethyldisilylamide). LAH refers to lithium aluminum hydride. NCS refers to N-chlorosuccinimide. PE refers to petroleum ether. PyBOP refers to benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate. TDA refers to tris(2-(2-methoxyethoxy)ethyl)amine. DCM refers to dichloromethane. TEA refers to triethylamine. TFA refers to trifluoroacetic acid. THF refers to tetrahydrofuran. NCS refers to N-chlorosuccinimide. NMM refers to N-methylmorpholine. NMP refers to N-methylpyrrolidine. NMM refers to N-methylmorpholine. NMI refers to N-methylimidazole. PPh3 refers to triphenylphosphine. RT or rt refers to room temperature. STAB refers to sodium triacetoxyborate.TCFH refers to chloro-N,N,N’,N’-tetramethylformamidinium hexafluorophosphate. T3P refers to propylphosphonic anhydride.

[0175] HPLC-MS analysis was performed on a Waters HPLC 2790 using a Waters micromass ZQ 4000 (model MAA050) as the mass detector and a Waters 2487 UV as the detector. The column used was a Phenomemex OOB-4605-E0 (5u-XB-C18-100A, 50 x 4.6 mm). The mobile phase consisted of eluent A (water, 0.05% TFA) and eluent B (CH3CN, 0.05% TFA), and elution proceeded at 1 mL / min. The initial conditions were 90% A for 1 minute, then linearly decreased from 90% A to 10% A within 5 minutes, and decreased from 10% A to 90% A within 1 minute. The total run time was 7 minutes.

Example

[0176] Rather than limiting the scope, the present invention will be more readily understood by reference to the following examples described for the purpose of illustrating the invention.

[0177] Example 1 (S)-2 4 -(4-acryloyl-2-methylpiperazin-1-yl)-2 6 , 3 6 -difluoro-1 2 -isopropyl-2 1 , 2 2 -dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidin-1(3,4)-pyridin-3(1,2)-benzena-cyclohepta-fan-2 2 ,5-dione.

Chemical formula

[0178] Step 1 tert-butyl (E)-3-(3-amino-2-isopropylpyridin-4-yl) acrylate [Chemical formula]

[0179] To a solution of 4-iodo-2-isopropylpyridin-3-amine (690 mg, 2.63 mmol), tert-butyl acrylate (505 mg, 3.95 mmol), tritolylphosphine (79 mg, 0.26 mmol), and TEA (399 mg, 3.95 mmol) stirred in DMF (10 ml) was added Pd(OAc)₂ (58 mg, 0.26 mmol) under Ar. The resulting mixture was stirred at 100 °C for 3 h to obtain a black suspension. Next, water (20 mL) and EtOAc (50 mL) were added. The organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc = 1:1) to obtain 600 mg of the title product as a yellow solid. MS (ES+): 262.8[M+1] + .

[0180] Step 2 tert-Butyl 3-(3-amino-2-isopropylpyridin-4-yl)propanoate [Chemical formula]

[0181] To a solution of tert-butyl (E)-3-(3-amino-2-isopropylpyridin-4-yl)acrylate (600 mg, 2.3 mmol) stirred in MeOH (10 ml) was added 10% Pd / C (100 mg) at room temperature. The reaction vessel was purged with H₂ three times, and the resulting mixture was stirred at 30 °C for 16 h. Next, the mixture was filtered, and the filtrate was concentrated to obtain the title product as a yellow oil. MS (ES+): 264.8[M+1] + .

[0182] Step 3 tert-Butyl 3-(3-(3-(2,6-dichloro-5-fluoronicotinoyl)ureido)-2-isopropylpyridin-4-yl)propanoate

Chem.

[0183] Oxalyl chloride (192 mg, 1.49 mmol) was added to a solution of 2,6-dichloro-5-fluoronicotinamide (157 mg, 0.754 mmol) stirred in THF (5 ml) at room temperature under Ar. The resulting mixture was stirred at 80 °C for 1 h, and then the solvent was removed under reduced pressure. Next, the residue was diluted with 5 ml of THF and added dropwise to a stirred solution of the product of Step 2 (100 mg, 0.378 mmol) at 0 °C. After stirring at 0 °C for 1 h, the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was further purified by Prep-TLC (PE:EtOAc = 1:1) to give 168 mg of the title product as a white solid. MS (ES+): 499.0 [M+1] + .

[0184] Step 4 tert-Butyl 3-(3-(7-chloro-6-fluoro-4-hydroxy-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-isopropylpyridin-4-yl)propanoate

Chem.

[0185] To a solution of the product of Step 3 (791 mg, 1.58 mmol) stirred in THF (12 ml) was added KHMDS (1.0 M) (3.5 ml, 3.49 mmol) in Ar at room temperature. After stirring at room temperature for 1 hour, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 671 mg of the pure product as a white solid. MS (ES+): 463.0 [M+1] + 。

[0186] Step 5 tert-Butyl 3-(3-(7-(2-amino-6-fluorophenyl)-6-fluoro-4-hydroxy-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-isopropylpyridin-4-yl)propanoate

Chemical formula

[0187] To a solution of the product of Step 4 (210 mg, 0.453 mmol), 3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (215 mg, 0.907 mmol), and KOAc (134 mg, 1.36 mmol) stirred in dioxane (6 ml) and H2O (2 drops) was added Pd(dppf)Cl2.DCM (37 mg, 0.045 mmol) in Ar at room temperature. After stirring at 80 °C for 1.5 hours to obtain a blank solution, the reaction mixture was treated with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc = 1:2) to give 229 mg of the title product as a white solid. MS (ES+): 537.8 [M+1] + 。

[0188] Step 6 3-(3-(7-(2-Amino-6-fluorophenyl)-6-fluoro-4-hydroxy-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-isopropylpyridin-4-yl)propanoic acid [Chem.]

[0189] To a solution of the product of Step 5 (229 mg, 0.426 mmol) stirred in DCM (3 ml) was added TFA (1 ml) with Ar at room temperature. After stirring at 25 °C for 3 h, the reaction mixture was concentrated to dryness to afford 360 mg of the title product as a yellow oil. MS (ES+): 482.0 [M+1] + .

[0190] Step 7 2 6 ,3 6 -difluoro-2 4 -hydroxy-1 2 -isopropyl-2 1 ,2 2 -dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidin-1(3,4)-pyridin-3(1,2)-benzeneazacycloheptafan-2 2 ,5-dione [Chem.]

[0191] To a solution of the product of Step 6 (360 mg, 0.74 mmol) and NMI (920 mg, 14.5 mmol) stirred in DMF (20 ml) was added TCFH (628 mg, 3.74 mmol) with Ar at room temperature. The resulting mixture was stirred at 25 °C for 1 h, then quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (DCM:MeOH = 10:1) to afford 160 mg of the title product as a yellow solid. MS (ES+): 463.8 [M+1] +

[0192] Step 8 tert-butyl (S)-4-(2 6 ,3 6 -difluoro-1 2-Isopropyl-2 2 ,5-dioxo-2 1 ,2 2 -dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidine-1(3,4)-pyridina-3(1,2)-benzacycloheptafan-2 4 -yl)-3-methylpiperazine-1-carboxylate [Chemical formula]

[0193] POCl3 (318 mg, 2.06 mmol) was added to a solution of the product of Step 8 (160 mg, 0.344 mmol) and DIPEA (446 mg, 3.44 mmol) stirred in CH3CN (3 ml) at room temperature under Ar. The resulting mixture was stirred at 80 °C for 1 hour and then concentrated to dryness. The residue was dissolved in 3 ml of DMF, and the resulting solution was treated with DIPEA (244 mg, 1.9 mmol) and tert-butyl (S)-3-methylpiperazine-1-carboxylate (140 mg, 0.68 mmol) at room temperature under Ar. After stirring at 25 °C for 2 hours, the reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by Prep-TLC (EtOAc:MeOH = 15:1) to give 33 mg of the title product as a yellow solid. MS (ES+): 646.0[M+1] + .

[0194] Step 9 (S)-2 4 -(4-acryloyl-2-methylpiperazin-1-yl)-2 6 ,3 6 -difluoro-1 2 -isopropyl-2 1 ,2 2 -dihydro-4-aza-2(1,7)-pyrido [2,3-d]pyrimidine-1(3,4)-pyridina-3(1,2)-benzacycloheptafan-2 2 ,5-dione [Chemical formula]

[0195] To a solution of the product of Step 8 (30 mg, 0.046 mmol) that had been stirred in DCM (2 ml) was added TFA (0.5 ml) with Ar at room temperature. After stirring at 25 °C for 1 h, the mixture was concentrated to dryness and diluted with 2 ml of DCM. The resulting solution was treated with DIPEA (24 mg, 0.186 mmol) and acryloyl chloride (5 mg, 0.046 mmol) with Ar at room temperature. The resulting mixture was stirred at 25 °C for 0.5 h, the reaction was quenched with water, and then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by Prep-TLC (EtOAc:MeOH = 15:1) to give 5.5 mg of the title product as a yellow solid. MS (ES+): 600.0[M+1] + 。

[0196] 1 1H NMR spectrum: (400 MHz, CD3OD) δ 8.43 (d, 1H), 8.24 - 8.21 (m, 1H), 7.42 - 7.33 (m, 2H), 7.00 - 6.96 (m, 2H), 6.92 - 6.90 (m, 1H), 6.2 (d, 1H), 5.72 (d, 1H), 5.22 (m, 1H), 3.98 (m, 3H), 3.52 - 3.51 (m, 1H), 2.9 (m, 1H), 2.74 - 2.67 (m, 2H), 2.35 (m, 1H), 2.14 - 2.06 (m, 1H), 1.9 (m, 1H), 1.3 - 1.1 (m, 6H), 0.36 - 0.25 (m, 2H).

[0197] Example 2 (S)-2 4 -(4 - acryloyl - 2 - methylpiperazin - 1 - yl)-2 6 ,3 6 -difluoro - 1 2 -isopropyl - 2 1 ,2 2-Dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidine-1(3,4)-pyridina-3(1,2)-benzacycloheptafan-2 2 -one

Chem.

[0198] Step 1 2 6 ,3 6 -difluoro-2 4 -hydroxy-1 2 -isopropyl-2 1 ,2 2 -dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidine-1(3,4)- pyridina-3(1,2)-benzacycloheptafan-2 2 -one

Chem.

[0199] To a solution of the product of Step 7 of Example 1 (6.7 g, 14.5 mmol) being stirred in DME (140 ml) was added borane-methyl sulfide complex at 0 °C under Ar. The reaction mixture was stirred at 45 °C for 2 h and then quenched with MeOH at 0 °C. After stirring for 2 h, water was added and the reaction mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (EA:PE = 4:1) to give 3.5 g of the pure product. MS (ES+): 450.0 [M+1] + .

[0200] Step 2 tert-butyl (S)-4-(2 6 ,3 6 -difluoro-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidine-1(3,4)-pyridina-3(1,2)-benzacycloheptafan-24 -(Il)-3-Methylpiperazine-1-carboxylate

Chemical formula

[0201] POCl3 (4.09 g, 26.7 mmol) was added to a solution of the product of step 1 (2 g, 4.3 mmol) and DIPEA (5.74 g, 44.5 mmol) stirred in CH3CN (20 ml) at rt under Ar. The mixture was stirred at 80 °C for 0.5 h and then concentrated to dryness. The residue was dissolved in 20 ml of DMF, and the resulting solution was treated at 0 °C with DIPEA (2.87 g, 22.3 mmol) and tert-butyl (S)-3-methylpiperazine-1-carboxylate (1.78 g, 8.9 mmol). After stirring at 0 for 5 min, the reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc:MeOH = 15:1) to give 1.54 g of the title product as a yellow solid. MS (ES+): 632.0 [M+1] + 。

[0202] Step 3 (S)-2 4 -(4-Acryloyl-2-methylpiperazin-1-yl)-2 6 ,3 6 -Difluoro-1 2 -Isopropyl-2 1 ,2 2 -Dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidin-1(3,4)-pyridina-3(1,2)-benzena cycloheptafan-2 2 -One

Chemical formula

[0203] To a solution of the product of Step 2 (2 g, 3.17 mmol) being stirred in DCM (20 ml) was added TFA (20 ml) at rt under Ar. The resulting mixture was stirred at room temperature for 0.5 h and then concentrated to dryness. The residue was dissolved in 40 ml of DCM and the resulting solution was treated at 0 °C with (4.1 g, 31.7 mmol) and acryloyl chloride (240 mg, 2.69 mmol) at 0 °C. After stirring at 0 °C for 5 min, the reaction was completed, the reaction was quenched with water and then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (EtOAc:MeOH = 15:1) to give 1.38 g of the title product as a yellow solid. MS (ES+): 586.0 [M+1] +

[0204] 1 1H NMR spectrum: (400 MHz, CDCl3) δ 8.62 (d, 1H), 7.85 (dd, 1H), 7.25 - 7.21 (m, 2H), 6.59 - 6.40 (m, 3H), 5.84 (d, 1H), 5.36 (m, 1H), 4.8 - 3.2 (m, 7H), 3.32 (d, 1H), 3.1 - 2.79 (m, 3H), 2.38 - 2.0 (m, 3H), 1.63 - 1.52 (m, 3H), 1.47 - 1.25 (m, 5H), 1.03 - 0.78 (d, 3H).

[0205] Example 2A & 2B Separation of Example 2: Example 2 was separated using Daicel CHIRALPAK® IA 250*20 mm, 5μm at room temperature with an eluent of Hex:EtOH = 60:40 at 15 mL / min and a UV detector at 214 nm. Example 2A: Retention time: 4.6 min, MS (ESI, m / e): 586 [M+1] + .

[0206] 11H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J = 5.0 Hz, 1H), 8.25 (d, J = 9.6 Hz, 1H), 7.39 - 7.22 (m, 2H), 6.87 (m, 1H), 6.69 (d, J = 8.2 Hz, 1H), 6.62 - 6.53 (t, 1H), 6.21 (d, J = 16.5 Hz, 1H), 5.78 (d, J = 10.7 Hz, 1H), 4.84 (m, 2H), 4.51 (d, J = 13.9 Hz, 1H), 4.33 - 3.98 (m, 3H), 3.57 (m, 2H), 3.31 - 3.11 (m, 2H), 2.80 (m, 2H), 2.42 (m, 1H), 2.20 (m, 1H), 2.04 - 1.84 (m, 1H), 1.43 - 1.20 (m, 3H), 1.08 (d, J = 6.4 Hz, 3H), 0.88 (d, J = 6.7 Hz, 3H). Example 2B: Retention time: 5.7 min, MS (ESI, m / e): 586 [M+1] + .

[0207] 1 1H NMR (400 MHz, DMSO-d6) δ 8.47 (m, 2H), 7.38 - 7.22 (m, 2H), 6.89 (m, 1H), 6.69 (d, J = 8.2 Hz, 1H), 6.63 - 6.51 (t, 1H), 6.23 (m, 1H), 5.78 (d, J = 10.3 Hz, 1H), 5.13 (s, 1H), 4.80 (d, J = 6.6 Hz, 1H), 4.31 - 3.70 (m, 6H), 3.23 (m, 1H), 2.93 (m, 1H), 2.80 (m, 2H), 2.60 - 2.44 (m, 1H), 2.18 (m, 1H), 1.90 (m, 1H), 1.29 - 1.18 (m, 3H), 1.12 (d, J = 7.0 Hz, 3H), 0.87 (d, J = 6.6 Hz, 3H).

[0208] Example 3 (S)-2-(1-Acryloyl-4-(2 6 ,3 6 -Difluoro-1 2 -Isopropyl-2 2 ,5-Dioxo-2 1 ,2 2 -Dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidine-1(3,4)-pyridine-3(1,2)-benzocycloheptafan-2 4 -yl)piperazin-2-yl)acetonitrile

Chemical formula

[0209] Step 1 Benzyl (S)-4-(1-(4-(3-(tert-Butoxy)-3-oxopropyl)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

Chemical formula

[0210] From the product of Step 4 of Example 1 (150 mg, 0.325 mmol) and (S)-benzyl 2-(cyanomethyl)piperazine-1-carboxylate hydrochloride (192 mg, 0.649 mmol), the title product (256 mg) was obtained according to the conditions described in Step 8 of Example 1. MS (ESI+): 703.9[M+H] +

[0211] Step 2 Benzyl (2S)-4-(7-(2-Amino-6-fluorophenyl)-1-(4-(3-(tert-Butoxy)-3-oxopropyl)-2-isopropylpyridin-3-yl)-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

Chemical formula

[0212] The product of step 1 of example 1 (217 mg, 0.308 mmol) and 3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (146 mg, 0.616 mmol) was subjected to the conditions described in step 5 of example 1 to give the title product (158 mg). MS (ESI+): 779.0[M+H] + .

[0213] Step 3: 3-(3-(7-(2-amino-6-fluorophenyl)-4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-6-fluoro-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-isopropylpyridin-4-yl)propanoic acid [ka]

[0214] The product of step 2 (158 mg, 0.203 mmol) was subjected to the conditions described in step 6 of example 1 to give the title product (152 mg). MS (ESI+): 722.9 [M+H] + .

[0215] Step 4 Benzyl (S)-2-(cyanomethyl)-4-(2 6 ,3 6 -Difluoro-1 2 -Isopropyl-2 2 ,5-Dioxo-2 1 ,2 2 -Dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidina-1(3,4)-pyridina-3(1,2)-benzenacycloheptaphane-2 4 -yl)piperazine-1-carboxylate [ka]

[0216] From the product of Step 3 (152 mg, 0.211 mmol), the title product (96 mg) was obtained according to the conditions described in Step 7 of Example 1. MS (ES+): 704.9 [M+H] + .

[0217] Step 5 (S)-2-(4-(2 6 ,3 6 -difluoro-1 2 -isopropyl-2 2 ,5-dioxo-2 1 ,2 2 -dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidine-1(3,4)-pyridina-3(1,2)-benzena cycloheptafan-2 4 -yl)piperazin-2-yl)acetonitrile

Chemical formula

[0218] To a solution of the product of Step 4 (70 mg, 0.099 mmol) stirred in MeOH (4 ml), 10% Pd / C (70 mg) was added at rt. The resulting mixture was stirred with H2 at 30 °C for 1.5 h. The reaction mixture was filtered and concentrated to give the title product as a yellow solid (48 mg). MS (ES+): 570.9 [M+H] + .

[0219] Step 6 (S)-2-(1-acryloyl-4-(2 6 ,3 6 -difluoro-1 2 -isopropyl-2 2 ,5-dioxo-2 1 ,2 2 -dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidine-1(3,4)-pyridina-3(1,2)-benzena cycloheptafan-2 4 -yl)piperazin-2-yl)acetonitrile

Chemical formula

[0220] To a solution of the product of Step 7 (48 mg, 0.084 mmol) and DIPEA (44 mg, 0.341 mmol) stirred in MeOH (4 ml) was added acryloyl chloride at 5 - 10 °C. After stirring at room temperature for 1 hour, the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by Prep-TLC (EtOAc:MeOH = 10:1) to give 9 mg of the title product as a yellow solid. MS (ES+): 625.0[M+H] + 。

[0221] 1 1H NMR spectrum: (400 MHz, CDCl3) δ 8.92 (s, 1H), 8.54 - 8.53 (d, J = 4.4 Hz, 1H), 7.99 - 7.96 (m, 1H), 7.52 - 7.21 (m, 3H), 7.01 (m, 1H), 6.62 (m, 1H), 6.48 (m, 1H), 5.90 - 5.88 (d, J = 11.2 Hz, 1H), 5.0 - 3.7 (m, 7H), 3.0 - 2.8 (m, 5H), 2.61 (m, 1H), 2.33 (m, 1H), 1.32 - 1.25 (m, 3H), 1.08 - 1.06 (m, 3H).

[0222] Example 4 (S)-2 4 -(4 - acryloyl - 2 - methylpiperazin - 1 - yl)-2 6 ,3 6 -difluoro - 1 2 -isopropyl - 4 - methyl - 2 1 ,2 2 -dihydro - 4 - aza - 2(1,7)-pyrido[2,3 - d]pyrimidin - 1(3,4)-pyridina - 3(1,2)-benzena - cycloheptafan - 2 2 -one

Chemical Structure

[0223] To a solution of the product of Example 2 (50 mg, 0.085 mmol) and Cs2CO3 (111 mg, 0.342 mmol) stirred in DMF (2 ml) was added CH3I (42 mg, 0.299 mmol) at rt. After stirring at 40 °C for 5 h, the reaction mixture was treated with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by Prep-TLC (EA: MeOH = 15:1) to give 15 mg of the title product as a yellow solid. MS (ES+): 599.9 [M+1] + 。

[0224] 1 1H NMR spectrum: (400 MHz, CDCl3) δ 8.54 - 8.53 (d, J = 4 Hz, 1H), 7.88 - 7.76 (m, 1H), 7.40 - 7.26 (q, 1H), 7.09 - 7.05 (m, 2H), 6.93 - 6.89 (t, 1H), 6.65 (s, 1H), 6.44 - 6.39 (d, J = 20 Hz, 1H), 5.83 - 5.80 (d, J = 12 Hz, 1H), 5.51 - 4.57 (m, 2H), 4.28 - 3.17 (m, 4H), 2.95 - 2.86 (m, 3H), 2.66 - 2.63 (d, J = 12 Hz, 1H), 2.48 - 2.42 (m, 5H), 1.89 (s, 1H), 1.46 - 1.44 (d, J = 8 Hz, 2H), 1.38 - 1.22 (t, 5H), 1.15 - 0.86 (m, 3H).

[0225] Example 5 (S)-2 4 -(4-acryloyl-2-methylpiperazin-1-yl)-2 6 ,3 6 -difluoro-1 2 -isopropyl-2 1 ,2 2 -dihydro-4,6-diaza-2(1,7)-pyrido[2,3-d]pyrimidin-1(3,4)-pyridina-3(1,2)-benzenaoctafan-2 2 ,5-dione [Chemical formula]

[0226] Step 1 2 6 ,3 6 -difluoro-1 2 -isopropyl-2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-4,6-diaza-2(1,7)-pyrido[2,3-d]pyrimidine-1(3,4)-pyridine-3(1,2)-benzocyclooctafuran-2 2 ,2 4 ,5-trione [Chemical formula]

[0227] To a solution of the product of Step 6 of Example 1 (408 mg, 0.85 mmol) and TEA (430.06 mg, 4.25 mmol) stirred in toluene (15 ml) was added diphenylphosphoryl azide (701.76 mg, 2.55 mmol). After stirring the mixture at 75 °C for 1 hour, water (5 ml) and EtOAc (3 ml) were added. The mixture was stirred for 0.5 hour, and the resulting solid was collected by filtration and dried to give 180 mg of the title product as a yellow solid. MS (ES+): 478.9[M+1] + .

[0228] Step 2 (S)-2 4 -(4-acryloyl-2-methylpiperazin-1-yl)-2 6 ,3 6 -difluoro-1 2 -isopropyl-2 1 ,2 2 -dihydro-4,6-diaza-2(1,7)-pyrido[2,3-d]pyrimidine-1(3,4)-pyridine-3(1,2)-benzocyclooctafuran-2 2 ,5-dione [Chemical formula]

[0229] From the product of Step 1, under the reaction conditions described in Steps 8 and 9 of Example 1, the title product was obtained as a yellow solid. MS (ES+): 614.9 [M+1] +

[0230] 1 HNMR spectrum: (400 MHz, CDCl3) δ 11.23 (s, 1H), 8.59 (s, 1H), 7.89 (s, 1H), 7.43 (s, 1H), 7.19 (s, 1H), 7.03 (s, 1H), 6.63 (s, 1H), 6.44 - 6.40 (d, J = 16, 1H), 5.84 - 5.81 (d, J = 12, 1H), 4.77 (s, 2H), 4.12 - 3.75 (m, 2H), 3.65 (m, 2H), 3.22 (m, 2H), 2.66 (m, 1H), 1.43 (m, 5H), 1.32 (m, 3H), 1.02 (m, 3H).

[0231] Example 6A & 6B 2 6 ,3 6 -difluoro-2 4 -((2S,5R)-4-(2-fluoroacryloyl)-2,5-dimethylpiperazin-1-yl)-1 2 -isopropyl-2 1 ,2 2 -dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidin-1(3,4)-pyridina-3(1,2)-benzena cycloheptafan-2 2 -one

Chemical Structure

[0232] Step 1 tert-butyl (2R,5S)-4-(2 6 ,3 6 -difluoro-1 2 -isopropyl-22 -oxo-2 1 ,2 2 -dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidine-1(3,4)-pyridina-3(1,2)-benzenacycloheptafan-2 4 -yl)-2,5-dimethylpiperazine-1-carboxylate

Chem.

[0233] To a solution of the product of Step 1 of Example 2 (120 mg, 0.27 mmol) being stirred in CH3CN (18 ml) were added DIPEA (345 mg, 2.7 mmol) and POCl3 (414 mg, 2.7 mmol). The mixture was stirred at 80 °C for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in DMF (1 ml). The resulting solution was treated at 0 °C with DIEA (172 mg, 1.4 mmol) and (2R,5S)-tert-butyl 2,5-dimethylpiperazine-1-carboxylate (64 mg, 0.3 mmol). After stirring at 0 °C for 10 minutes, the reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to give 182 mg of the title compound as a yellow solid. MS (ES+): 645.9[M+1] +

[0234] Step 2 2 4 -((2S,5R)-2,5-dimethylpiperazin-1-yl)-2 6 ,3 6 -difluoro-1 2 -isopropyl-2 1 ,2 2 -dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidine-1(3,4)-pyridina-3(1,2)-benzenacycloheptafan-2 2 -one

Chem.

[0235] To a solution of the product of Step 1 (182 mg, 0.28 mmol) stirred in DCM (1 ml) was added TFA (1 ml). After stirring at room temperature for 1 hour, the reaction mixture was concentrated, basified with aqueous NaHCO3 at pH 7 - 8, and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to obtain 141 mg of the target compound as a yellow solid. MS (ES+): 545.9[M + 1] + 。

[0236] Step 3 2 6 ,3 6 -difluoro-2 4 -((2S,5R)-4-(2-fluoroacryloyl)-2,5-dimethylpiperazin-1-yl)-1 2 -isopropyl-2 1 ,2 2 -dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidin-1(3,4)-pyridina-3(1,2)-benzeneazacycloheptafan-2 2 -one

Chemical Structure

[0237] To a solution of the product of Step 2 (70 mg, 0.13 mmol) stirred in DCM (3 ml) were added 2-fluoroprop-2-enoic acid (9.37 mg, 0.1 mmol), DIPEA (84 mg, 0.65 mmol) and T3P (124 mg, 0.39 mmol). After stirring at room temperature for 10 minutes, the reaction was quenched with saturated aqueous NaHCO3 (15 ml) and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by Prep-TLC (MeOH / EA = 5%) to obtain 15.5 mg of Example 6A (fast elution) as a yellow solid (MS (ES+): 617.9[M + 1] + ) and 15.2 mg of Example 6B (slow elution) as a yellow solid (MS (ES+): 617.9[M + 1] + ).

[0238] 1 1H NMR spectrum (Example 6A): (400 MHz, CDCl3) δ 8.47 - 8.46 (d, J = 4 Hz, 2H), 7.34 - 7.26 (m, 2H), 6.72 - 6.54 (m, 2H), 5.37 - 5.32 (m, 2H), 4.87 - 4.88 (m, 2H), 4.75 - 4.25 (m, 1H), 4.12 - 4.01 (m, 2H), 3.78 - 3.63 (m, 1H), 3.17 (s, 1H), 2.84 (m, 1H), 2.76 - 2.73 (m, 1H), 2.45 (m, 1H), 2.12 - 1.93 (m, 2H), 1.27 - 1.09 (m, 10H), 0.84 - 0.82 (d, J = 8 Hz, 3H).

[0239] 1 1H NMR spectrum (Example 6B): (400 MHz, CDCl3) δ 8.47 - 8.45 (d, J = 4 Hz, 1H), 8.11 (m, 1H), 7.33 - 7.24 (m, 2H), 6.71 - 6.55 (m, 2H), 5.37 - 5.32 (d, J = 20 Hz, 2H), 4.88 - 4.61 (m, 3H), 4.52 - 4.11 (m, 1H), 3.88 - 3.46 (m, 2H), 3.25 (m, 1H), 2.89 - 2.73 (m, 2H), 2.57 (m, 1H), 2.18 - 1.91 (m, 2H), 1.50 - 1.48 (d, J = 8 Hz, 2H), 1.38 - 1.25 (m, 4H), 1.08 - 1.06 (d, J = 8 Hz, 3H), 0.93 - 0.91 (d, J = 8 Hz, 3H).

[0240] Examples 7A & 7B 2 4 -((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-2 6 ,3 6 -difluoro-1 2 -isopropyl-2 1 ,2 2-Dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidin-1(3,4)-pyridina-3(1,2)-benzocycloheptafan-2 2 -one

Chemical formula

[0241] To the product of step 2 of Example 6A (0.07 g, 0.128 mmol), acrylic acid (0.007 g, 0.103 mmol) and DIPEA (0.083 g, 0.642 mmol) stirred in DCM (3 ml), T3P (0.123 g, 0.385 mmol) was added. After stirring at room temperature for 0.5 h under Ar, the reaction was quenched with NaHCO3 (aqueous solution), extracted with DCM, the organic layer was washed with brine, dried over Na2SO 4 and filtered, concentrated. The residue was purified by Prep-TLC (MeOH / EA = 7.5%) to give 9.8 mg of Example 7A (fast elution) as a yellow solid (MS (ES+): 599.9[M+1] + ) and 9.8 mg of Example 7B (slow elution) as a yellow solid (MS (ES+): 599.9[M+1] + ).

[0242] 1 1H NMR spectrum (Example 7A): (400 MHz, CDCl3) δ 8.49 (m, 2H), 7.34 - 7.26 (m, 1H), 6.86 - 6.70 (m, 2H), 6.59 - 6.55 (m, 1H), 6.22 - 6.17 (m, 1H), 5.77 - 5.74 (m, 1H), 4.97 - 4.87 (m, 2H), 4.75 - 4.25 (m, 1H), 4.07 - 3.86 (m, 4H), 2.84 - 2.66 (m, 3H), 2.13 - 1.78 (m, 3H), 1.36 - 1.24 (d, 2H), 1.18 (d, 1H), 1.17 - 1.06 (m, 3H), 0.88 - 0.78 (d, 4H).

[0243] 11H NMR spectrum (Example 7B): (400 MHz, CDCl3) δ 8.46 - 8.45 (d, J = 4 Hz, 1H), 8.12 - 8.06 (m, 1H), 7.33 - 7.26 (m, 2H), 6.87 - 6.55 (m, 3H), 6.21 - 6.16 (m, 1H), 5.78 - 5.75 (m, 1H), 4.89 - 4.47 (m, 4H), 4.27 - 3.56 (m, 3H), 2.84 - 2.78 (m, 2H), 2.46 - 1.87 (m, 2H), 1.48 - 1.45 (m, 3H), 1.32 - 1.28 (m, 3H), 1.10 - 1.06 (m, 3H), 0.92 - 0.78 (m, 3H).

[0244] Example 8 (S)-2 4 -(4 - acryloyl - 2 - methylpiperazin - 1 - yl)-2 6 ,3 6 -difluoro - 12 - isopropyl - 2 1 ,2 2 -dihydro - 8 - thia - 4 - aza - 2(1,7)-pyrido[2,3 - d]pyrimidin - 1(3,4)-pyridina - 3(1,2)-benzena - cyclooctafane - 2 2 -one

Chem.

[0245] Step 1 Methyl 3-(3 - amino - 2 - isopropylpyridin - 4 - ylthio)propanoate

Chem.

[0246] A mixture of 4-iodo-2-isopropylpyridin-3-amine (625 mg, 2.385 mmol), methyl 3-sulfanylpropanoate (716 mg, 5.964 mmol), DIPEA (1.231 g, 9.542 mmol), Pd2(dba)3 (437 mg, 0.477 mmol), and Xantphos (552 mg, 0.954 mmol) in 1,4-dioxane (15 ml) was stirred at 80 °C for 2 h under Ar. The reaction mixture was treated with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (EA:PE = 1:1) to afford 582 mg of the title product as a yellow solid. MS (ES+): 255 [M+1] + .

[0247] Step 2 Methyl 3-(3-(3-(2,6-dichloro-5-fluoronicotinoyl)ureido)-2-isopropylpyridin-4-ylthio)propanoate

Chemical formula

[0248] The title product was obtained as a yellow solid from 2,6-dichloro-5-fluoronicotinamide and the product of Step 1 according to the procedure described in Step 3 of Example 1.

[0249] Step 3 Methyl 3-(3-(7-chloro-6-fluoro-4-hydroxy-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-isopropylpyridin-4-ylthio)propanoate

Chemical formula

[0250] A mixture of the product of Step 2 (900 mg, 1.844 mmol) and K2CO3 (509 mg, 3.689 mmol) in DMF (15 ml) was stirred at room temperature for 18 h. Water was added and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to give 804 mg of the title product as a yellow solid. MS (ES+): 453 [M+1] + 。

[0251] Step 4 Methyl 3-(3-(7-(2-Amino-6-fluorophenyl)-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)-2-isopropylpyridin-4-ylthio)propanoate

Chem.

[0252] The title product was obtained as a yellow solid from the product of Step 3 and 3-Fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline according to the procedure described in Step 5 of Example 1. MS (ES+): 527.8 [M+1] +

[0253] Step 5 3-(3-(7-(2-Amino-6-fluorophenyl)-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)-2-isopropylpyridin-4-ylthio)propanoic acid

Chem.

[0254] The mixture of the product from Step 4 (300 mg, 28.8 mmol) in 6 N HCl / THF (30 ml / 5 ml) was stirred overnight at room temperature. The pH of the reaction mixture was adjusted to 5 - 6 with NaHCO₃ (aqueous solution), and then extracted with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated to obtain 360 mg of the title product as a brown solid. MS (ES+): 513.8 [M+1] + .

[0255] Step 6 2 6 ,3 6 -difluoro-12-isopropyl-2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-8-thia-4-aza-2(1,7)-pyrido[2,3-d]pyrimidine-1(3,4)-pyridina-3(1,2)-benzenacyclooctafuran-2 2 ,2 4 ,5-trione

Chemical Structure

[0256] To the solution of the product from Step 5 (360 mg, 0.70 mmol) stirred in DCE (12 ml), T3P in EtOAc (50%wt, 2.2 g, 3.5 mmol) was added under Ar at rt. The mixture was stirred at 55 °C overnight. The pH of the reaction mixture was adjusted to 5 - 6 with NaHCO₃ (aqueous solution), and then extracted with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by Prep-TLC (EA: MeOH = 15:1) to obtain 130 mg of the title product as a yellow solid. MS (ES+): 495.8 [M+1] +

[0257] Step 7 2 6 ,3 6 -difluoro-1 2 -isopropyl-2 1 ,2 2 ,2 3 ,24 -Tetrahydro-8-thia-4-aza-2(1,7(-pyrido[2,3-d]pyrimidin-1(3,4(-pyridina-3(1,2(-benzenacyclooctafane-2 2 ,2 4 -dione

Chem.

[0258] To the product of Step 6 (130 mg, 0.26 mmol) being stirred in THF (7 ml) was added a borane-tetrahydrofuran complex in THF (1.0 M, 1.3 ml, 1.3 mmol) at 0 °C under Ar. After stirring at room temperature for 1 h, an additional borane-tetrahydrofuran complex in THF (1.0 M, 0.8 ml, 0.8 mmol) was added at 0 °C under Ar. The mixture was stirred at room temperature for an additional 1 h, then quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by Prep-TLC (EA:MeOH = 15:1) to afford 69 mg of the title product as a white solid. MS (ES+): 481.9 [M+1] + .

[0259] Step 8 tert-Butyl (S)-4-(2 6 ,3 6 -difluoro-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-8-thia-4-aza-2(1,7)-pyrido[2,3-d]pyrimidin-1(3,4)-pyridina-3(1,2)-benzenacyclooctafane-2 4 -yl)-3-methylpiperazine-1-carboxylate

Chem.

[0260] From the products of Steps 7 and 3 and tert-butyl (S)-3-methylpiperazine-1-carboxylate, the title product was obtained as a yellow solid according to the procedure described in Step 2 of Example 2.

[0261] Step 9 (S)-2 4 -(4-acryloyl-2-methylpiperazin-1-yl)-2 6 ,3 6 -difluoro-1 2 -isopropyl-2 1 ,2 2 -dihydro-8-thia-4-aza-2(1,7)-pyrido[2,3-d]pyrimidin-1(3,4)-pyridina-3(1,2)-benzenacyclooctafan-2 2 -one

Chemical formula

[0262] From the product of Step 8, the title product was obtained as a yellow solid according to the procedure described in Step 3 of Example 2. MS (ES+): 617.8 [M+1] + .

[0263] 1 HNMR spectrum: (400 MHz, CDCl3) δ 8.53-8.52 (d, J = 4 Hz, 1H), 7.83 (m, 1H), 7.26-7.21 (m, 1H), 7.15-7.13 (d, J = 8 Hz, 1H), 6.64 (s, 2H), 6.42-6.38 (m, 3H), 5.82-5.80 (d, J = 8 Hz, 1H), 4.98-4.41 (m, 2H), 4.38-3.61 (m, 3H), 3.47-3.32 (m, 3H), 3.14-3.02 (m, 3H), 2.78 (m, 1H), 2.22 (m, 1H), 2.07-1.68 (m, 3H), 1.64-1.55 (m, 2H), 1.39-1.37 (d, J = 8 Hz, 2H), 1.01-0.99 (d, J = 8 Hz, 3H).

[0264] Example 9 (S)-2 4 -(4-acryloyl-2-methylpiperazin-1-yl)-2 6 ,3 6 -difluoro-1 2 -isopropyl-2 1 ,2 2 -dihydro-7-thia-4-aza-2(1,7)-pyrido[2,3-d]pyrimidin-1(3,4)-pyridina-3(1,2)-benzena cycloheptafan-2 2 -one

Chem.

[0265] Step 1 2-Isopropyl-4-((4-methoxybenzyl)thio)pyridin-3-amine

Chem.

[0266] A mixture of 4-iodo-2-isopropylpyridin-3-amine (320 mg, 1.2 mmol), (4-methoxyphenyl)methanethiol (376 mg, 2.4 mmol), DIPEA (630 mg, 4.9 mmol), Xantphos (283 mg, 0.49 mmol), and Pd2(dba)3 (224 mg, 0.24 mmol) in dioxane (10 ml) was stirred at 90 °C for 2 h. The reaction was quenched with water at room temperature and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 5:1) to give 382 mg of the title product as a yellow solid. MS (ES+): 288.8 [M+1] + .

[0267] Step 2 7-Chloro-6-fluoro-4-hydroxy-1-(2-isopropyl-4-((4-methoxybenzyl)thio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

Chem.

[0268] From the product of Step 1 and 2,6-dichloro-5-fluoronicotinamide, following the procedures described in Steps 3 and 4 of Example 1, the title product was obtained as a white solid. MS (ES+): 486.9 [M+1] + .

[0269] Step 3 7-Chloro-6-fluoro-4-hydroxy-1-(2-isopropyl-4-mercaptopyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

Chemical Structure

[0270] To a solution of the product of Step 2 (538 mg, 1.1 mmol) stirred in TFA (12 ml) was added trifluoromethanesulfonic anhydride (620.7 mg, 2.2 mmol, dissolved in 1 ml of TFA) with Ar at rt. The mixture was stirred at 80 °C for 2.5 h and concentrated to dryness. The residue was dissolved in DMF (12 ml), and the resulting solution was treated with TEA (2.0 g, 19.8 mmol) and ethyl bromoacetate (171.6 mg, 0.88 mmol, dissolved in 1 ml of DMF). After stirring for 30 min, water was added and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 1:1) to give 144 mg of the title product as a yellow solid. MS (ES+): 480.9 [M+1] + .

[0271] Step 4 2 6 ,3 6 -Difluoro-2 4 -Hydroxy-1 2 -Isopropyl-2 1 ,2 2-Dihydro-7-thia-4-aza-2(1,7)-pyrido[2,3-d]pyrimidine-1(3,4)-pyridina-3(1,2)-benzacycloheptafan-2 2 ,5-dione

Chem.

[0272] From the product of Step 3 and 3-fluoro-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedures described in Steps 5, 6, and 7 of Example 1, the title product was obtained as a white solid. MS (ES+): 481.8[M+1] + .

[0273] Step 5 (S)-2 4 -(4-acryloyl-2-methylpiperazin-1-yl)-2 6 ,3 6 -difluoro-1 2 -isopropyl-2 1 ,2 2 -dihydro-7-thia-4-aza-2(1,7)-pyrido[2,3-d]pyrimidine-1(3,4)-pyridina-3(1,2)-benzacycloheptafan-2 2 -one

Chem.

[0274] From the product of Step 4, following the procedures described in Steps 7, 8, and 9 of Example 8, the title product was obtained as a yellow solid. MS (ES+): 604.1[M+1] + .

[0275] 11H NMR spectrum: (400 MHz, DMSO-d6) δ 8.54-8.50 (m, 1H), 8.48-8.47 (d, J=4 Hz, 1H), 8.34-8.32 (m, 1H), 7.62-7.60 (m, 1H), 7.46-7.42 (m, 1H), 7.35-7.25 (m, 2H), 6.88-6.84 (m, 1H), 6.70-6.68 (m, 1H), 6.65-6.60 (t, 1H), 6.23-6.19 (d, J=16 Hz, 1H), 5.79-5.76 (m, 1H), 4.24 (m, 1H), 4.31-4.20 (m, 1H), 3.99-3.95 (m, 2H), 3.63-3.60 (m, 2H), 3.01-2.93 (m, 3H), 2.91-2.80 (m, 1H), 2.57-2.54 (m, 1H), 1.43 (m, 1H), 1.24 (m, 3H), 1.16-1.13 (m, 2H), 1.12-1.11 (m, 3H), 0.91-0.89 (d, J=8 Hz, 3H).

[0276] Example 10 (S)-2 4 -(4-acryloyl-2-methylpiperazin-1-yl)-3 6 -chloro-2 6 -fluoro-1 2 -isopropyl-2 1 ,2 2 -dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidin-1(3,4)-pyridin-3(1,2)-benzena cycloheptafan-2 2 -one

Chemical Structure

[0277] Step 1 3-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

Chemical Structure

[0278] A mixture of 2-bromo-3-chloroaniline (10 g, 48.43 mmol), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (15.99 g, 62.96 mmol), potassium acetate (14.26 g, 145.29 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3.54 g, 4.84 mmol) in 1,4-dioxane (150 ml) was stirred at 105 °C for 14 h under Ar. The mixture was cooled to room temperature, filtered through a pad of celite and the filter cake was washed with EtOAc. The filtrate was washed with brine, dried over Na2SO4, filtered and concentrated to give 17.51 g of the crude product as a black oil.

[0279] Step 2 tert-Butyl 3-(3-(7-(2-amino-6-chlorophenyl)-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)-2-isopropylpyridin-4-yl)propanoate

Chemical formula

[0280] To a solution of the product of Step 4 of Example 1 being stirred in 1,4-dioxane and potassium acetate (0.64 g, 6.48 mmol) was added dichloropalladium (0.18 g, 0.22 mmol), H2O (1 ml) and [1,1'-bis(diphenylphosphino)ferrocene]dichloromethane complex (II). The resulting mixture was stirred at 80 °C for 2 h under Ar. Water was added and the reaction mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (EA:PE = 1:1) to give 2.39 g of the title product as a yellow oil. MS (ES+): 553.8 [M+1] + .

[0281] Step 3 3-(3-(7-(2-Amino-6-chlorophenyl)-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)-2-isopropylpyridin-4-yl)propanoic acid

Chem.

[0282] The product of Step 2 (600 mg, 1.085 mmol) was stirred in TFA (6 ml) at room temperature for 0.5 h. The reaction mixture was concentrated to dryness to give 859 mg of the title product as a brown oil. MS (ES+): 497.8 [M+1] + .

[0283] Step 4 3 6 -Chloro-2 6 -Fluoro-1 2 -Isopropyl-2 1 ,2 2 ,2 3 ,24-Tetrahydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidin-1(3,4)-pyridina-3(1,2)-benzena cycloheptafan-2 2 ,2 4 ,5-Trione

Chem.

[0284] To a solution of the product of Step 3 (590 mg, 1.18 mmol) stirred in DCE (30 ml) was added T3P (3.78 g, 5.93 mmol) via Ar at rt. After stirring at 50 °C for 1 h, the reaction was quenched rapidly with sat. Extracted with NaHCO3 (aqueous solution) and EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (MeOH / EA = 2%) to give 165 mg of the title product as a yellow solid. MS (ES+): 479.8 [M+1] + .

[0285] Step 53 6 -Chloro-2 6 -Fluoro-1 2 -Isopropyl-2 1 ,2 2 ,2 3 ,2 4 -Tetrahydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidine-1(3,4)-pyridine-3(1,2)-benzacycloheptafan-2 2 ,2 4 -Dione

Chem.

[0286] From the product of Step 4, according to the reaction conditions described in Step 1 of Example 2, the title compound was obtained as a yellow solid. MS (ES+): 465.8 [M+1] + .

[0287] Step 6 (S)-2 4 -(4-Acryloyl-2-methylpiperazin-1-yl)-3 6 -Chloro-2 6 -Fluoro-1 2 -Isopropyl-2 1 ,2 2 -Dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidine-1(3,4)-pyridine-3(1,2)-benzacycloheptafan-2 2 -One

Chem.

[0288] From the product of Step 5, according to the procedures described in Steps 2 and 3 of Example 2, the title product was obtained as a yellow solid. MS (ES+): 601.8 [M+1] + .

[0289] 11H NMR spectrum: (400 MHz, CDCl3) δ 8.58 - 8.57 (d, J = 4 Hz, 1H), 7.93 - 7.87 (m, 1H), 7.26 - 7.15 (m, 2H), 6.88 - 6.86 (d, J = 8 Hz, 1H), 6.73 - 6.71 (d, J = 8 Hz, 1H), 6.60 (s, 1H), 6.44 - 6.40 (m, 1H), 5.84 - 5.81 (d, J = 12 Hz, 1H), 5.46 - 5.30 (m, 1H), 4.78 - 4.23 (m, 4H), 3.85 - 3.39 (m, 3H), 2.91 - 2.71 (m, 3H), 2.30 - 1.94 (m, 2H), 1.68 - 1.58 (m, 3H), 1.39 - 1.37 (d, J = 8 Hz, 2H), 1.29 - 1.26 (m, 3H), 1.06 - 1.04 (d, J = 8 Hz, 3H).

[0290] Example 11 (S)-2 6 ,3 6 -difluoro-2 4 -(4-(2-fluoroacryloyl)-2-methylpiperazin-1-yl)-12-isopropyl-2 1 ,2 2 -dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidin-1(3,4)-pyridina-3(1,2)-benzenacycloheptafan-2 2 -one

Chemical Structure

[0291] In the stirred solution of the product of Step 2 of Example 2 and 2-fluoroacrylic acid, the title compound was obtained as a yellow solid according to the reaction conditions described in Steps 2 and 3 of Examples 6A and 6B. MS (ES+): 603.9[M + 1] + .

[0292] 11H NMR spectrum: (400 MHz, DMSO-d6) δ 8.47 - 8.45 (m, 2H), 7.73 - 7.25 (m, 2H), 6.70 - 6.55 (m, 2H), 5.41 - 5.36 (m, 3H), 4.8 - 4.79 (m, 1H), 4.50 - 3.45 (m, 6H), 2.80 - 2.78 (m, 2H), 2.51 - 2.44 (m, 2H), 2.23 - 2.22 (m, 1H), 1.98 - 1.88 (m, 1H), 1.40 - 0.08 (m, 11H).

[0293] Example 12 (S)-4-Acetyl-2 4 -(4-Acryloyl-2-methylpiperazin-1-yl)-2 6 ,3 6 -Difluoro-1 2 -Isopropyl-2 1 ,2 2 -Dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidin-1(3,4)-pyridina-3(1,2)-benzena cycloheptafan-2 2 -one [Chemical Structure]

[0294] To a solution of the product of Example 2 (50 mg, 0.085 mmol) and DIPEA (58 mg, 0.45 mmol) stirred in DCM (2 ml) at room temperature, acetyl chloride (17.6 mg, 0.22 mmol) was added. After stirring at 40 °C for 2 hours, the reaction was quenched with saturated NaHCO3 (aqueous solution) and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by Prep-TLC (EA: MeOH = 5:1) to give 21 mg of the title product as a yellow solid. MS (ES+): 627.9 [M+1] + .

[0295] 11H NMR spectrum: (400 MHz, CDCl3) δ 8.49 - 8.48 (d, J = 4 Hz, 1H), 7.88 - 7.83 (t, 1H), 7.47 (q, 1H), 7.18 (t, 1H), 6.99 (t, 2H), 6.62 (s, 1H), 6.43 (d, 1H), 5.84 - 5.81 (d, J = 12 Hz, 1H), 5.13 - 4.37 (m, 2H), 4.26 - 3.28 (m, 5H), 3.26 - 2.66 (m, 3H), 2.65 - 2.36 (m, 2H), 2.04 (s, 1H), 1.43 - 1.41 (d, J = 8 Hz, 2H), 1.31 - 1.18 (m, 8H), 1.01 - 0.99 (d, J = 8 Hz, 3H).

[0296] Example 13 (S)-2 4 -(4-acryloyl-2-methylpiperazin-1-yl)-2 6 ,3 6 -difluoro-1 2 -isopropyl-N,N-dimethyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidin-1(3,4)-pyridin-3(1,2)-benzena cycloheptafan-4-carboxamide

Chemical formula

[0297] To a solution of the product of Example 2 (50 mg, 0.085 mmol) being stirred in DCE (3 ml) were added dimethylcarbamyl chloride (18 mg, 0.171 mmol), DIEA (33 mg, 0.256 mmol) and DMAP (10 mg, 0.085 mmol). The resulting mixture was stirred at 80 °C overnight, then quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by Prep-TLC (MeOH / EA = 1:9) to afford 24.5 mg of the title product as a yellow solid. MS (ES+): 656.9 [M+1] + .

[0298] 1 1H NMR spectrum: (400 MHz, CDCl3) δ 8.52 (s, 1H), 7.88 - 7.86 (d, J = 8 Hz, 1H), 7.36 (s, 1H), 7.21 (s, 1H), 7.07 - 7.05 (d, J = 8 Hz, 2H), 6.64 - 6.63 (d, J = 4 Hz, 1H), 6.44 - 6.40 (d, J = 16 Hz, 1H), 5.84 - 5.81 (m, 1H), 4.82 - 4.80 (m, 1H), 4.78 - 3.56 (m, 4H), 3.20 (s, 1H), 2.89 (s, 1H), 2.80 - 2.76 (d, J = 16 Hz, 2H), 2.49 (s, 3H), 1.46 (m, 3H), 1.40 - 1.25 (m, 9H), 1.08 - 0.97 (m, 5H).

[0299] Example 14 (S)-2 4 -(4-acryloyl-2-methylpiperazin-1-yl)-2 6 ,3 6 -difluoro-1 2 -isopropyl-4-nicotinoyl-2 1 ,2 2 -dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidin-1(3,4)-pyridina-3(1,2)-benzena cycloheptafan-2 2 -one [Chem.]

[0300] To a solution of the product of Example 2 (35 mg, 0.060 mmol) being stirred in NMP (3 ml) at room temperature were added pyridine-3-carboxylic acid (29 mg, 0.239 mmol), 2-chloro-1,3-dimethylimidazolinium hexafluorophosphate (99 mg, 0.359 mmol) and DIPEA (46 mg, 0.359 mmol). After stirring at 80 °C overnight, the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by Prep-TLC (MeOH / EA = 1:9) to give 5.8 mg of the title product as a yellow solid. MS (ES+): 690.8 [M+1] +.

[0301] 1 1H NMR spectrum: (400 MHz, CDCl3) δ 8.52 - 8.48 (m, 2H), 8.34 (s, 1H), 7.90 - 7.85 (m, 1H), 7.44 - 7.42 (d, J = 8 Hz, 1H), 7.11 (s, 1H), 7.07 - 7.03 (m, 3H), 6.78 (s, 1H), 6.68 (s, 1H), 6.62 - 6.58 (m, 1H), 6.44 - 6.40 (d, J = 16 Hz, 1H), 5.85 - 5.82 (d, J = 12 Hz, 1H), 5.34 - 4.81 (m, 1H), 4.81 - 4.16 (m, 2H), 4.11 - 3.93 (m, 3H), 3.75 - 3.32 (m, 3H), 2.81 - 2.64 (m, 3H), 2.29 - 2.02 (m, 2H), 1.15 - 0.73 (m, 9H).

[0302] Example 15 (S)-2 4 -(4-acryloyl-2-methylpiperazin-1-yl)-2 6 ,3 6-Difluoro-4-(2-hydroxy-2-methylpropanoyl)-1 2 -Isopropyl-2 1 ,2 2 -Dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidin-1(3,4)-pyridina-3(1,2)-benzeneazacycloheptafan-2 2 -One

Chem.

[0303] To a solution of the product of Example 2 (40 mg, 0.0816 mmol), 2-hydroxy-2-methylpropanoic acid (25.6 mg, 0.245 mmol) and DIPEA (8064 mg, 0.49 mmol) stirred in NMP (2 ml) at room temperature was added CIP (45.6 mg, 0.164 mmol). The resulting mixture was stirred at 50 °C for 4 hours and then quenched with water. The reaction mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by Prep-TLC (EA:MeOH = 5:1) to give 9 mg of the title product as a yellow solid. MS (ES+): 671.8 [M+1] + .

[0304] 11H NMR spectrum: (400 MHz, CDCl3) δ 8.52 - 8.50 (d, J = 8 Hz, 1H), 7.85 (m, 1H), 7.44 (m, 1H), 7.20 (m, 1H), 7.16 - 7.04 (m, 2H), 6.62 - 6.55 (dd, 1H), 6.44 - 6.39 (d, J = 20 Hz, 1H), 5.82 - 5.74 (m, 1H), 4.74 (s, 1H), 4.55 - 4.15 (m, 1H), 4.03 - 3.82 (m, 1H), 3.82 - 3.48 (m, 2H), 3.49 (s, 1H), 2.82 (m, 1H), 2.54 - 2.37 (m, 2H), 1.81 (s, 1H), 1.65 (s, 1H), 1.54 - 1.41 (m, 8H), 0.99 - 0.97 (d, J = 8 Hz, 3H), 0.90 - 0.76 (m, 8H).

[0305] Example 16 (S)-2 4 -(4 - acryloyl - 2 - methylpiperazin - 1 - yl)-2 6 ,3 6 -difluoro - 1 2 -isopropyl - 4 - methyl - 2 1 ,2 2 -dihydro - 4,6 - diaza - 2(1,7)-pyrido[2,3 - d]pyrimidin - 1(3,4)-pyridina - 3(1,2)-benzenacyclooctafan - 2 2 ,5 - dione

Chemical Structure

[0306] A solution of the product of Example 5 (5.2 mg, 0.007 mmol) and cesium carbonate (27.5 mg, 0.084 mmol) stirred in DMF (0.9 ml) was added with iodomethane (48.0 mg, 0.336 mmol). The mixture was stirred overnight at room temperature, then quenched with water and extracted with EA. It was dried over Na2SO4, filtered and concentrated. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give 3.7 mg of the title product as a yellow solid. MS (ES+): 628.8[M+1] + .

[0307] 1 1H NMR spectrum: (400 MHz, CDCl3) δ 8.57 - 8.56 (d, J = 4 Hz, 1H), 7.85 - 7.83 (d, J = 8 Hz, 1H), 7.52 (m, 1H), 7.16 - 7.11 (m, 3H), 6.65 (s, 1H), 6.44 - 6.40 (m, 1H), 5.84 - 5.81 (d, J = 12 Hz, 1H), 5.36 - 5.33 (m, 1H), 4.78 - 4.46 (m, 3H), 4.21 (m, 1H), 4.01 - 3.64 (m, 1H), 3.58 - 3.20 (m, 1H), 3.12 (m, 4H), 2.85 (m, 1H), 2.62 (m, 1H), 2.21 (m, 1H), 2.01 (m, 1H), 1.47 - 1.41 (m, 3H), 1.29 - 1.25 (m, 4H), 1.01 (m, 3H).

[0308] Example 17 (S)-2 4 -(4-acryloyl-2-methylpiperazin-1-yl)-2 6 ,3 6 -difluoro-1 6 -isopropyl-2 1 ,2 2 -dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidine-1,3(1,2)-dibenzena cycloheptafan-2 2 -one

Chemical Structure

[0309] Step 1 2-Bromo-6-isopropyl aniline

Chem.

[0310] NBS (1.31 g, 7.4 mmol) was added all at once to a solution of 2-isopropyl aniline (1.00 g, 7.4 mmol) in benzene (40.0 mL). After stirring overnight at room temperature, the volume of the reaction mixture was reduced to one-fourth under reduced pressure, and the solid was removed by filtration. The filtrate was concentrated, ice was added to pentane, and then acetic anhydride (0.4 mL) was added. After about 15 minutes, the solid was filtered off. The pentane solution was separated from the filtrate, washed with NH4OH, and concentrated. The residue was distilled at 83 °C under 0.2 mmHg to obtain the title compound (600.0 mg).

[0311] 1 H NMR (400 MHz, DMSO-d6): δ 7.22 (d, 1H), 7.04 (d, 1H), 6.53 - 6.49 (t, 1H), 4.98 (s, 2H), 3.07 - 3.03 (m, 1H), 6.15 (d, 6H).

[0312] Step 2 tert-Butyl (E)-3-(2-amino-3-isopropylphenyl) acrylate

Chem.

[0313] A solution of 2-bromo-6-isopropylaniline (50.0 mg, 4.70 mmol), tert-butyl acrylate (59.6 mg, 0.467 mmol), K2CO3 (64.0 mg, 0.46 mmol), Pd(OAc)2 (10.0 mg, 0.045 mmol) and tri-o-tolylphosphane (28.0 mg, 0.093 mmol) in DMF (15 mL) was heated at 100 o °C for 2 h under an Ar atmosphere. The reaction was quenched with water and extracted with EtOAc (10 mL x 2). The combined organic phases were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with a gradient of EtOAc / Hexane (0 - 10%) to give the title compound (40 mg). MS (ESI+): 262.1 [M+1] + .

[0314] 1 1H NMR (400 MHz, DMSO-d6): δ 7.86 (d, 1H), 7.27 (d, 1H), 7.07 (d, 1H), 6.58 - 6.54 (t, 1H), 6.21 (d, 1H), 5.23 (s, 2H), 3.06 - 3.00 (m, 1H), 1.48 (s, 9H), 1.13 (d, 6H).

[0315] Step 3 tert-butyl (E)-3-(2-(3-(2,6-dichloro-5-fluoronicotinoyl)ureido)-3-isopropylphenyl)acrylate

Chemical formula

[0316] The title product was obtained as a yellow solid from 2,6-dichloro-5-fluoronicotinamide and the product of Step 2 according to the procedure described in Step 3 of Example 1. MS (ESI+): 496.1 [M+1] + .

[0317] 11H NMR (400 MHz, DMSO-d6): δ 11.37 (s, 1H), 9.60 (s, 1H), 8.52 (d, 1H), 7.72 - 7.66 (m, 2H), 7.44 (d, 1H), 7.38 - 7.34 (t, 1H), 6.47 (d, 1H), 3.31 - 3.12 (m, 1H), 1.47 (s, 9H), 1.17 (d, 6H).

[0318] Step 4 tert-Butyl (E)-3-(2-(7-chloro-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)-3-isopropylphenyl)acrylate

Chemical formula

[0319] From the product of Step 3, following the procedure described in Step 3 of Example 8, the title product was obtained as a yellow solid.

[0320] 1 1H NMR (400 MHz, CDCl3-d1): δ 8.55 (s, 1H), 8.24 (d, 1H), 7.64 - 7.62 (dd, 1H), 7.55 - 7.50 (m, 2H), 7.25 (d, 1H), 6.36 (d, 1H), 2.58 - 2.54 (m, 1H), 1.45 (s, 9H), 1.18 (d, 3H), 1.07 (d, 3H).

[0321] Step 5 2-Fluoro-6-nitrophenyl trifluoromethanesulfonate

Chemical formula

[0322] A solution of 2-fluoro-6-nitrophenol (10.0 g, 63.69 mmol) in DCM (200.0 mL) was added to 0 oCooled with C, and pyridine (6.15 mL, 76.43 mmol) and Tf2O (12.86 mL, 76.43 mmol) were added thereto. After stirring for 2 hours, the reaction was quenched with NaHCO3(aq) and extracted with DCM. The DCM layer was washed with 1N HCl, dried over MgSO4, and concentrated to obtain the crude title compound (17.0 g).

[0323] 1 HNMR (400 MHz, CDCl3): δ 8.00 - 7.97 (m, 1H), 7.64 - 7.54 (m, 2H).

[0324] Step 6 2-(2-Fluoro-6-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Chemical formula

[0325] To a solution of the product from Step 5 (290.0 mg, 1.0 mmol) in dioxane (3.0 mL) were added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (381.0 mg, 1.50 mmol), KOAc (295.0 mg, 3.0 mmol), Pd(dppf)Cl2 (82.0 mg, 0.1 mmol), and 4 drops of water. After stirring at 80 °C for 2.5 hours, the reaction mixture was filtered through a pad of celite. The filtrate was concentrated, and the residue was purified by silica gel chromatography eluted with a gradient of EtOAc / Hexane (0 - 20%) to obtain the title compound (250.0 mg).

[0326] 1 HNMR (400 MHz, CDCl3): δ 8.03 (d, 1H), 7.56 - 7.50 (m, 1H), 7.39 - 7.35 (t, 1H), 1.45 (s, 12H).

[0327] Step 7 3-Fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline [Chemical formula]

[0328] To a solution of 2-(2-fluoro-6-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.49 g, 9.32 mmol) in EtOAc (40 mL) was added 10% Pd / C (992 mg, 0.93 mmol) under a nitrogen atmosphere. Next, the mixture was stirred at room temperature for 16.5 h under a hydrogen atmosphere. The solution was filtered through a pad of celite, and the pad was washed with ethyl acetate. The filtrate was concentrated to give the title compound (2.2 g). MS (ESI+): 238.1 [M+1] + .

[0329] Step 8 tert-Butyl (E)-3-(2-(7-(2-amino-6-fluorophenyl)-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)-3-isopropylphenyl)acrylate [Chemical formula]

[0330] In dioxane (3.0 mL), to a solution of the product of Step 4 (100.0 mg, 0.218 mmol) and the product of Step 7 (155.0 mg, 0.654 mmol) was added K2CO3 (60.0 mg, 0.436 mmol) and Pd(dppf)Cl2 (18.0 mg, 0.022 mmol) under a nitrogen atmosphere. After stirring at 80 °C for 2 hours, the reaction was quenched with water (10 mL) and extracted with EtOAc (10 mL × 2). The combined extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluted with a gradient of EtOAc / Hexane (0 - 20%) to give the title compound (120 mg). MS (ESI+): 479.1 [M - 55] + .

[0331] Step 9 tert-Butyl 3-(2-(7-(2-amino-6-fluorophenyl)-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)-3-isopropylphenyl)propanoate

Chemical formula

[0332] To a solution of the product of Step 4 (120.0 mg, 0.225 mmol) in MeOH (5 mL) and 7M NH3 / MeOH (0.05 mL) was added Pd / C (24 mg, 0.023 mmol). The mixture was stirred at room temperature for 2 hours, then filtered through a pad of celite, and the filtrate was concentrated to give the title compound (118.0 mg). MS (ESI+): 481.1 [M - 55] + .

[0333] Step 10 3-(2-(7-(2-Amino-6-fluorophenyl)-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)-3-isopropylphenyl)propanoic acid

Chemical formula

[0334] A solution of 4NHCl / dioxane (4.0 mL) was added to 0 o The product of step 9 (118.0 mg, 0.22 mmol) at 0 °C. After stirring for 10 minutes at 0 °C, the reaction mixture was maintained at room temperature for 2 hours. The reaction mixture was concentrated to dryness to obtain the crude title compound (100.0 mg). MS (ESI+): 481.1 [M+1] + .

[0335] Step 11 2 6 ,3 6 -difluoro-1 6 -isopropyl-2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidine-1,3(1,2)-dibenzena[1,7]cycloheptaphane-2 2 ,2 4 ,5-trione

Chem.

[0336] From the product of step 10, the title product was obtained as a yellow solid according to the procedure described in step 7 of Example 1. MS (ESI+): 463.1 [M+1] + .

[0337] Step 12 2 6 ,3 6 -difluoro-1 6 -isopropyl-2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidine-1,3(1,2)-dibenzena[1,7]cycloheptaphane-2 2 ,2 4 -dione

Chem.

[0338] From the product of Step 11, following the procedure described in Step 1 of Example 2, the title product was obtained as a yellow solid. MS (ESI+): 449.1 [M+1] + .

[0339] Step 13 (S)-2 4 -(4-acryloyl-2-methylpiperazin-1-yl)-2 6 ,3 6 -difluoro-1 6 -isopropyl-2 1 ,2 2 -dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidine-1,3(1,2)-dibenzena[7]annulene-2 2 -one

Chemical Structure

[0340] To the product of Step 12 (10.0 mg, 0.022 mmol) and DIPEA (28.4 mg, 0.22 mmol) in CH3CN at room temperature under Ar, POCl3 (20 mg, 0.134 mmoL) was added. After stirring at 80 °C for 1 hour, the reaction mixture was then concentrated to dryness. The residue was dissolved in DMF (1.0 mL), and the resulting solution was treated with DIPEA (28.4 mg, 0.22 mmol) and Intermediate 2 (13.0 mg, 0.044 mmol). After stirring overnight at room temperature, EtOAc (10 mL) was added, and the EtOAc layer was washed with water (8 mL x 3) and brine (8 mL x 2), dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography eluted with a gradient of MeOH / DCM (0 - 5%) to give the title compound (6.0 mg). MS (ESI+): 585.1 [M+1] + .

[0341] 1HNMR (400 MHz, CDCl3): δ 7.88 - 7.81 (m, 1H), 7.41 - 7.37 (t, 1H), 7.29 - 7.20 (m, 3H), 7.69 - 7.59 (m, 1H), 6.55 - 6.47 (m, 2H), 6.43 - 6.39 (m, 1H), 5.82 (d, 1H), 4.87 - 4.73 (m, 1H), 4.68 - 4.56 (m, 1H), 4.18 - 4.13 (m, 1H), 3.97 - 3.87 (m, 1H), 3.78 - 3.68 (m, 1H), 3.56 - 3.36 (m, 1H), 3.30 - 3.23 (m, 1H), 3.00 - 2.94 (m, 1H), 2.88 - 2.84 (m, 1H), 2.67 - 2.61 (m, 1H), 2.41 - 2.31 (m, 2H), 2.03 - 1.99 (m, 2H), 1.23 - 1.22 (m, 3H), 1.21 - 1.20 (m, 3H), 0.95 - 0.94 (m, 3H).

[0342] Example 18 (S)-2 4 -(4 - acryloyl - 2 - methylpiperazin - 1 - yl)-2 6 ,3 6 -difluoro - 1 6 -isopropyl - 2 1 ,2 2 -dihydro - 4 - aza - 2(1,7)-pyrido[2,3 - d]pyrimidine - 1,3(1,2)-dibenzena - cycloheptafan - 2 2 ,5 - dione

Chemical Structure

[0343] The title product was obtained as a yellow solid from the product of Step 11 of Example 17 and Intermediate 2 according to the procedure described in Step 13 of Example 17.

[0344] 1HNMR (400 MHz, CDCl3-d1): δ 7.89-7.80 (m, 1H), 7.73-7.70 (m, 1H), 7.53-7.33 (m, 4H), 7.16-7.10 (m, 1H), 7.03-6.97 (m, 1H), 6.86-6.77 (m, 1H), 6.69-6.51 (m, 1H), 6.45-6.38 (m, 1H), 5.84-5.81 (m, 1H), 4.33-3.98 (m, 4H), 3.77-3.60 (m, 2H), 3.09-2.98 (m, 1H), 2.93-2.85 (m, 1H), 2.82-2.76 (m, 1H), 2.63-2.57 (m, 1H), 2.37-2.33 (m, 1H), 2.22-2.20 (m, 1H), 1.22-1.06 (m, 6H), 0.90-0.89 (m, 3H).

[0345] Example 19 (S)-2 4 -(4-acryloyl-2-methylpiperazin-1-yl)-2 6 ,3 6 -difluoro-1 6 -isopropyl-4-methyl-2 1 ,2 2 -dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidine-1,3(1,2)-dibenzocycloheptafan-2 2 -one

Chemical Structure

[0346] To a solution of the product of Example 17 (25 mg, 0.043 mmol) in DMF (1.0 mL) were added K2CO3 (11.8 mg, 0.086 mmol) and CH3I (18.2 mg, 0.13 mmol). After stirring the reaction mixture at 40 °C for 3 h, additional CH3I (36.4 mg, 0.26 mmol) was added and the reaction mixture was stirred overnight at room temperature. Water (5 mL) was added and the mixture was extracted with EtOAc (10 mL). The organic layer was washed with water (5 mL x 3) and brine (5 mL), dried over Na2SO4, and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography eluting with a gradient of MeOH / DCM (0 - 3%) to give the title compound (10 mg, 39% yield). MS (ESI+): 599.1 [M+1] + .

[0347] 1 1H NMR (400 MHz, CDCl3-d1): δ 7.75 - 7.73 (m, 1H), 7.34 - 26 (m, 3H), 7.14 - 7.12 (m, 1H), 7.02 - 7.00 (m, 1H), 6.88 - 6.83 (m, 1H), 6.68 - 6.54 (m, 1H), 6.41 (d, 1H), 5.81 (d, 1H), 5.40 - 5.33 (m, 1H), 4.90 - 4.75 (m, 1H), 4.68 - 4.50 (m, 1H), 4.19 - 4.14 (m, 1H), 3.98 - 3.86 (m, 1H), 3.81 - 3.71 (m, 1H), 3.59 - 3.50 (m, 1H), 3.46 - 3.38 (m, 1H), 3.26 - 3.12 (m, 1H), 3.06 - 3.00 (m, 1H), 2.81 - 2.74 (m, 1H), 2.59 - 2.54 (m, 1H), 2.44 - 2.42 (m, 4H), 1.94 - 1.85 (m, 1H), 1.25 - 1.23 (m, 3H), 0.98 - 0.96 (m, 3H).

[0348] Example 20 2 4 -((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-26 ,3 6 -Difluoro-1 6 -Isopropyl-2 1 ,2 2 -Dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidine-1,3(1,2)-dibenzenaazacycloheptafan-2 2 -One

Chemical formula

[0349] Step 1 2 4 -((2S,5R)-4-(3-Chloropropanoyl)-2,5-dimethylpiperazin-1-yl)-2 6 ,3 6 -Difluoro-1 6 -Isopropyl-2 1 ,2 2 -Dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidine-1,3(1,2)-dibenzenaazacycloheptafan-2 2 -One

Chemical formula

[0350] From the product of Step 12 of Example 17 (25 mg) and Intermediate 4 (46 mg), following the procedure described in Step 13 of Example 17, the title product was obtained as a yellow solid. MS (ESI+): 635.1 [M+1] + .

[0351] Step 2 2 4 -((2S,5R)-4-Acryloyl-2,5-dimethylpiperazin-1-yl)-2 6 ,3 6 -Difluoro-1 6 -Isopropyl-2 1 ,2 2 -Dihydro-4-aza-2(1,7)-pyrido[2,3-d]pyrimidine-1,3(1,2)-dibenzenaazacycloheptafan-2 2 -One

Chemical formula

[0352] Et3N (112.7 mg) was added to a solution of the product of Step 1 (20 mg) in CH3CN (1.0 mL). After stirring at 80 °C for 12 hours, the reaction mixture was diluted with EtOAc (10 mL), washed with water (8 mL x 2) and brine (8 mL), and dried over Na2SO4. The solution was concentrated to give the title compound (20 mg). MS (ESI+): 599.1 [M+1] + .

[0353] Example 20A & 20B The product of Example 20 (~20 mg) was separated by silica gel chromatography eluted with a gradient of MeOH / DCM (0 - 5%) to give the product of Example 20A (8 mg, rapid elution) and the product of Example 20B (7.0 mg, slow elution) as yellow solids.

[0354] Example 20A: 1 HNMR (400 MHz, CDCl): δ 7.83 - 7.78 (m, 1H), 7.41 - 7.38 (m, 1H), 7.28 - 7.20 (m, 3H), 6.61 - 6.47 (m, 3H), 6.44 - 6.35 (t, 1H), 5.81 - 5.78 (m, 1H), 5.12 - 5.10 (m, 1H), 5.01 - 4.97 (m,1H), 4.41 - 4.30 (m, 1H), 4.15 - 4.08 (m, 1H), 4.00 - 3.00 (m, 2H), 3.72 - 3.64 (m, 1H), 3.32 - 3.29 (m, 1H), 3.01 - 2.96 (m, 1H), 2.89 - 2.82 (m, 1H), 2.66 - 2.58 (m, 1H), 2.44 - 2.32 (m, 2H), 2.02 - 1.99 (m, 1H), 1.40 - 1.39 (m, 3H), 1.22 - 1.17 (m, 6H), 0.91 - 0.89 (m, 3H).

[0355] MS (ESI+): 599.1 [M+1] +.

[0356] Example 20B: 1 HNMR (400 MHz, CDCl): δ 7.89 - 7.82 (m, 1H), 7.40 - 7.36 (m, 1H), 7.28 - 7.19 (m, 3H), 6.66 - 6.55 (m, 1H), 6.53 - 6.40 (m, 3H), 5.83 - 5.78 (m, 1H), 5.20 - 5.13 (m, 1H), 4.94 - 4.88 (m, 1H), 4.80 - 4.74 (m, 1H), 4.54 - 4.46 (m, 1H), 4.44 - 4.39 (m, 1H), 3.74 - 3.63 (m, 2H), 3.58 - 3.53 (m, 1H), 3.31 - 3.26 (m, 1H), 3.22 - 3.19 (m, 1H), 3.00 - 2.95 (m, 1H), 2.89 - 2.84 (m, 1H), 2.64 - 2.58 (m, 1H), 2.38 - 2.33 (m, 1H), 2.00 - 1.97 (m, 1H), 1.64 - 1.62 (m, 3H), 1.50 - 1.48 (m, 3H), 1.22 - 1.17 (m, 3H), 1.00 - 0.96 (m, 3H).

[0357] MS (ESI+): 599.1 [M+1] + .

[0358] Example 21 (S)-2 4 -(4 - acryloyl - 2 - methylpiperazin - 1 - yl)-2 6 ,3 6 -difluoro - 1 6 -isopropyl - 2 1 ,2 2 -dihydro - 4,8 - dioxo - 2(1,7)-pyrido[2,3 - d]pyrimidine - 1,3(1,2)-dibenzena - spirooctaphane - 22 ,5 - dione

Chemical Structure

[0359] Step 1 tert-Butyl 3-((3-bromo-2-nitrophenyl)amino)propanoate

Chem.

[0360] A solution of 1-bromo-3-fluoro-2-nitrobenzene (0.6918 g, 3.145 mmol), tert-butyl 3-aminopropanoate hydrochloride (0.6436 g, 3.543 mmol) and [compound not specified in the original] (1.55 mL, 9.38 mmol) in DMA (15 mL) was stirred at 80 °C for 23 h. Water (80 mL) was added and the mixture was extracted with EtOAc (4 × 20 mL). The combined organic layers were washed with water (3 × 20 mL), brine, dried over Na2SO4, filtered and concentrated to give the title compound (1.0 g) as a yellow oil.

[0361] 1 1H NMR (400 MHz, CDCl3) δ 7.15 (t, J = 8.2 Hz, 1H), 6.96 (dd, J = 7.8, 0.9 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 5.84 (s, 1H), 3.46 (dd, J = 12.3, 6.3 Hz, 2H), 2.55 (t, J = 6.5 Hz, 2H), 1.47 (s, 9H).

[0362] Step 2 tert-Butyl 3-((3-bromo-2-nitrophenyl)(tert-butoxycarbonyl)amino)propanoate

Chem.

[0363] In dry DMF (5 mL), a solution of the product of Step 1 (0.4405 g, 1.276 mmol), 4-dimethylaminopyridine (0.1614 g, 1.321 mmol), and DIPEA (0.86 mL, 5.22 mmol) was added with di-tert-butyl dicarbonate (1.20 mL, 5.22 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 23 h. Water (80 mL) was added, and the reaction mixture was extracted with EtOAc (4 × 20 mL). The combined organic layers were washed with water (3 × 20 mL), brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluent: EtOAc:hexane / 0:100 to 10:90) to give the title compound (0.3688 g) as a brown oil. MS (ESI+): 467.1, 469.1 [M+23] + .

[0364] Step 3 tert-Butyl 3-((tert-butoxycarbonyl)(2-nitro-3-(prop-1-en-2-yl)phenyl)amino)propanoate [Chemical formula]

[0365] In 1,4-dioxane (20 mL) and H2O (4 mL), a solution of the product of Step 2 (0.36 g, 1.04 mmol), isopropenylboronic acid pinacol ester (0.45 mL, 2.39 mmol), tetrakis(triphenylphosphine)palladium (0.0956 g, 0.0827 mmol), and (0.4138 g, 2.994 mmol) was stirred with Ar at 80 °C for 3 h. EtOAc (20 mL) and 20 mL of brine were added. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by silica gel column chromatography eluted with a gradient of petroleum ether / EtOAc (100:0 to 90:10) to give the title compound (0.2838 g) as a red oil. MS (ESI+): 429.2 [M+23] + .

[0366] tert-Butyl 3-((2-amino-3-isopropylphenyl)(tert-butoxycarbonyl)amino)propanoate [Chemical formula]

[0367] A mixture of the product of Step 3 (0.28 g, 0.69 mmol) and 10% Pd / C (0.164 g, 0.155 mmol) in EtOAc (25 mL) was stirred at room temperature for 1 hour with a balloon of H2. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated. The residue was dissolved in 20 mL of methanol and treated with Raney nickel (3.1 g). The reaction mixture was stirred at 30 °C for 2 hours with a balloon of H2. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated to give the title compound (0.2514 g) as a colorless oil. MS (ESI+): 379.2 [M+1] + .

[0368] tert-Butyl 3-((tert-butoxycarbonyl)(2-(3-(2,6-dichloro-5-fluoronicotinoyl)ureido)-3-isopropylphenyl)amino)propanoate [Chemical formula]

[0369] The title product was obtained as a white solid (3.8 g) from 2,6-dichloro-5-fluoronicotinamide (3.67 g) and the product of Step 4 (3.58 g) according to the procedure described in Step 3 of Example 1.

[0370] tert-Butyl 3-((tert-butoxycarbonyl)(2-(7-chloro-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)-3-isopropylphenyl)amino)propanoate [Chemical formula]

[0371] From 2,6-dichloro-5-fluoronicotinamide (3.67 g) and the product of Step 5 (3.35 g), the title product was obtained as a white solid (1.94 g) according to the procedure described in Step 3 of Example 8. MS (ESI+): 575.1 [M-1] + .

[0372] Step 7 3-((2-(7-chloro-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)-3-isopropylphenyl)amino)propanoic acid

Chemical formula

[0373] A solution of the product of Step 6 (0.8295 g, 1.437 mmol) in TFA (10.0 mL) and dichloromethane (10 mL) was stirred at room temperature for 5 h. Toluene (10 mL) was added and the mixture was concentrated to give the title compound as a gray solid (0.80 g). MS (ESI+): 421.1 [M+1] + .

[0374] Step 8 3-((2-(7-(2-amino-6-fluorophenyl)-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)-3-isopropylphenyl)amino)propanoic acid

Chemical formula

[0375] From the product of Step 7 (0.6 g) and 3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.50 g), the title product was obtained as a white solid (0.66 g) according to the procedure described in Step 8 of Example 17. MS (ESI+): 496.2 [M+1] + .

[0376] Step 92 6 ,3 6 -difluoro-1 6 -isopropyl-2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-4,8-diaza-2(1,7)-pyrido[2,3-d]pyrimidine-1,3(1,2)-dibenzena[1,7]cyclooctaphan-2 2 ,2 4 ,5-trione

Chem.

[0377] From the product of Step 8 (0.24 g), following the procedure described in Step 7 of Example 1, the title product was obtained as a gray solid (0.11 g). MS (ESI+): 632.0 [M+1] + .

[0378] Step 10 (S)-2 4 -(4-acryloyl-2-methylpiperazin-1-yl)-2 6 ,3 6 -difluoro-1 6 -isopropyl-2 1 ,2 2 -dihydro-4,8-diaza-2(1,7)-pyrido[2,3-d]pyrimidine-1,3(1,2)-dibenzena[1,7]cyclooctaphan-2 2 ,5-dione

Chem.

[0379] The title product was obtained as a white solid (12 mg) according to the procedure described in Step 13 of Example 17, except that the crude product was purified by reverse-phase column chromatography (C-18, particle size: 40 μm, pore size distribution: 120 Å) eluted with CH3CN / H2O (10 - 80%) from the product of Step 9 (44 mg) and Intermediate 1 (69 mg). MS (ESI+): 614.3 [M+1] + .

[0380] Example 22 (S)-2 4 -(4-acryloyl-2-methylpiperazin-1-yl)-2 6 ,3 6 -difluoro-1 6 -isopropyl-2 1 ,2 2 -dihydro-4,8-diaza-2(1,7)-pyrido[2,3-d]pyrimidine-1,3(1,2)-dibenzena[1,7]cyclooctaphane-2 2 -one

Chemical Structure

[0381] Step 12 6 ,3 6 -difluoro-1 6 -isopropyl-2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-4,8-diaza-2(1,7)-pyrido[2,3-d]pyrimidine-1,3(1,2)-dibenzena[1,7]cyclooctaphane-2 2 ,2 4 -dione

Chemical Structure

[0382] The title product was obtained as a yellow solid (70 mg) according to the procedure described in Step 7 of Example 1 from the product of Step 9 (190 mg) of Example 21. MS (ESI+): 464.2 [M+1] + .

[0383] Step 2 (S)-2 4 -(4-acryloyl-2-methylpiperazin-1-yl)-2 6 ,3 6 -difluoro-1 6 -isopropyl-2 1 ,2 2 -dihydro-4,8-diaza-2(1,7)-pyrido[2,3-d]pyrimidine-1,3(1,2)-dibenzena[1,7]cyclooctaphane-2 2 -one

Chemical Structure

[0384] The title product was obtained as a white solid (2.3 mg) according to the procedure described in Step 13 of Example 17, except that the crude product was purified by reverse-phase column chromatography (C-18, particle size: 40 μm, pore size distribution: 120 Å) eluted with CH3CN / H2O (10 - 80%) from the product of Step 1 (50 mg) and Intermediate 1 (101 mg). MS (ESI+): 600.3 [M+1] + .

[0385] Examples 23A & 23B 2 4 -((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-2 6 ,3 6 -difluoro-1 6 -isopropyl-2 1 ,2 2 -dihydro-4,8-diaza-2(1,7)-pyrido[2,3-d]pyrimidine-1,3(1,2)-dibenzena[1,7]cyclooctaphane-2 2 -one

Chemical Structure

[0386] Example 24A & 24B 2 4 -((2S,5R)-4-Acryloyl-2,5-dimethylpiperazin-1-yl)-2 6 ,3 6 -difluoro-1 6 -isopropyl-2 1 ,2 2 -dihydro-4,8-diaza-2(1,7)-pyrido[2,3-d]pyrimidine-1,3(1,2)-dibenzenacyclooctafane-2 2 ,5-dione [Chemical Structure]

[0387] To a solution of the product of step 9 of Example 21 (0.0470 g, 0.0984 mmol) and DIPEA (0.18 mL, 1.03 mmol) in dry MeCN (5 mL) was added POCl3 (0.0600 mL, 0.644 mmol). The reaction mixture was stirred under reflux for 1 hour. The MeCN was evaporated and the residue was treated with a solution of intermediate 3 (0.0744 g, 0.264 mmol) and DIPEA (0.22 mL, 1.26 mmol) in 5 mL of dry MeCN. The residue was first purified by silica gel column chromatography eluted with DCM / MeOH (100:0 to 90:10) and then by reverse phase column chromatography (C-18, particle size: 40 μm, pore size distribution: 120 Å) eluted with CH3CN / H2O (10 - 80%) to obtain Example 24A (0.0012 g, fast elution) and Example 24B (0.0018 g, slow elution) as yellow solids. MS (ESI+): 628.3 [M+1] + .

[0388] Example 25 (S)-2 4 -(4-acryloyl-2-methylpiperazin-1-yl)-2 6 ,3 6 -difluoro-1 6 -isopropyl-2 1 ,2 2 -dihydro-4,7-diaza-2(1,7)-pyrido [2,3-d]pyrimidine-1,3(1,2)-dibenzenacycloheptafan-2 2 ,5-dione

Chemical formula

[0389] Step 1 tert-Butyl N-(3-bromo-2-nitrophenyl)-N-(tert-butoxycarbonyl)glycinate

Chemical formula

[0390] A solution of 3-bromo-2-nitroaniline (5 g, 23.0 mmol), which had been pre-cooled in drying (100 mL), was added portionwise with NaH (2.03 g, 50.7 mmol) in an ice bath under a nitrogen atmosphere. After stirring at 0 °C for 0.5 h, Boc2O (6.42 mL, 27.7 mmol) was added and stirring was continued for another 2 h. BrCH2CO2 t- Bu (4.07 mL, 27.7 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into a mixture of saturated NH4Cl (100 / 100 mL) and water, which was extracted with ethyl acetate (80 mL x 3). The combined extracts were concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate: 100 / 0~95 / 5) to obtain the title compound (6.664 g) as a yellow oil. MS (ESI): 275.0 / 277.0 [M+H-isobutylene-Boc] + .

[0391] 1 HNMR (400 MHz, CDCl3) δ 7.74-7.66 (m, 1H), 7.62 (dd, J = 8.2, 1.2 Hz, 1H), 7.42-7.32 (m, 1H), 4.52 (d, J = 17.2 Hz, 1H), 3.60 (d, J = 17.2 Hz, 1H), 1.51-1.43 (m, 13H), 1.34 (s, 6H).

[0392] Step 2 tert-Butyl N-(tert-butoxycarbonyl)-N-(2-nitro-3-(prop-1-en-2-yl)phenyl)glycinate

Chemical formula

[0393] From the product of Step 1 (6.66 g), the title product was obtained as a pale yellow oil (4.26 g) according to the procedure described in Step 3 of Example 21. MS (ESI): 237.1 [M+H-isobutylene-Boc] + .

[0394] 1 HNMR (400 MHz, CDCl3) δ 7.65 - 7.56 (m, 1H), 7.48 - 7.39 (m, 1H), 7.29 - 7.24 (m, 1H), 5.22 - 5.16 (m, 1H), 4.99 (s, 1H), 4.55 (d, J = 17.7 Hz, 1H), 3.65 (d, J = 17.7 Hz, 1H), 2.08 (s, 3H), 1.52 - 1.44 (m, 13H), 1.33 (s, 6H).

[0395] Step 3 tert-Butyl N-(2-amino-3-isopropylphenyl)-N-(tert-butoxycarbonyl)glycinate

Chem.

[0396] To a solution of the product from Step 2 (4.45 g, 11.3 mmol) in MeOH (50 mL) was added 7M NH3 in MeOH (0.5 mL) and 10% Pd / C (1.2 g, 1.13 mmol) under a nitrogen atmosphere. The mixture was stirred at room temperature for 11.5 h under a H2 atmosphere. The solution was filtered through Celite and the Celite pad was washed with EtOAc. The filtrate was concentrated to give the title compound (4.27 g) as a pale yellow oil. MS (ESI): 265.2 [M+H] + .

[0397] Step 4 tert-Butyl N-(tert-butoxycarbonyl)-N-(2-(3-(2,6-dichloro-5-fluoronicotinoyl)ureido)-3-isopropylphenyl)glycinate

Chem.

[0398] From 2,6-dichloro-5-fluoronicotinamide (2.34 g) and the product of Step 3 (3.31 g), the title product was obtained as a white solid (4.71 g) according to the procedure described in Step 3 of Example 1. MS (ESI): 597.0 [M-H] - .

[0399] Step 5 tert-Butyl N-(tert-butoxycarbonyl)-N-(2-(7-chloro-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)-3-isopropylphenyl)glycinate

Chem.

[0400] From the product of Step 4 (4.21 g), the title product was obtained as a white solid (2.73 g) according to the procedure described in Step 3 of Example 8. MS (ESI): 564.2 [M+H] + .

[0401] Step 6 (2-(7-Chloro-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)-3-isopropylphenyl)glycine

Chem.

[0402] TFA (4 mL) was added to a solution of the product of Step 5 (600 mg, 1.07 mmol) in DCM (6 mL). After stirring at room temperature for 16 h, 4 mL of 1,4-dioxane was added and the solution was concentrated to give a brown oil, which was used in the next step without further purification. MS (ESI): 407.1 [M+H] + .

[0403] Step 7 (2-(7-(2-Amino-6-fluorophenyl)-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)-3-isopropylphenyl)glycine

Chemical Structure

[0404] The title product was obtained as a white solid (637 mg) from the product of Step 6 (505.5 mg) and 3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (736.5 mg) according to the procedure described in Step 8 of Example 17. MS (ESI): 482.1 [M+H] + .

[0405] Step 8 2 6 ,3 6 -Difluoro-1 6 -Isopropyl-2 1 ,2 2 ,2 3 ,2 4 -Tetrahydro-4,7-diaza-2(1,7)-pyrido[2,3-d]pyrimidine-1,3(1,2)-dibenzanacycloheptafan-2 2 ,2 4 ,5-Trione

Chemical Structure

[0406] A turbid solution of the product of Step 7 (637 mg, 1.32 mmol) in dry MeCN (10 mL) was added with pyridine (320 μL, 3.97 mmol). N-Methylimidazole (320 μL, 3.97 mmol) was added, followed by the addition of dry DMF (10 mL) and TCFH (562.5 mg, 1.98 mmol). After stirring for 11 h, the reaction mixture was poured into 0.5 N HCl solution (12 mL) and extracted with EtOAc (15 mL × 4). The organic phase was washed with brine (5 mL x 2), and the aqueous phase was extracted with EtOAc (5 mL x 2). The combined organic phases were concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate: 100 / 0~50 / 50) to obtain the title product as a yellow solid (200 mg). MS (ESI): 464.1 [M+H] + .

[0407] Step 9 (S)-2 4 -(4-acryloyl-2-methylpiperazin-1-yl)-2 6 ,3 6 -difluoro-1 6 -isopropyl-2 1 ,2 2 -dihydro-4,7-diaza-2(1,7)-pyrido[2,3-d]pyrimidine-1,3(1,2)-dibenzena cycloheptafan-2 2 ,5-dione

Chem.

[0408] From the product of Step 8 (60 mg) and Intermediate 2 (69 mg), following the procedure described in Step 13 of Example 17, the title product was obtained as a white solid (2.14 mg). MS (ESI): 600.3 [M+H] + .

[0409] Example 26 2 4 -((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-2 6 ,3 6-Difluoro-1 6 -Isopropyl-2 1 ,2 2 -Dihydro-4,7-diaza-2(1,7)-pyrido[2,3-d]pyrimidine-1,3(1,2)-dibenzena[1,7]cycloheptaphane-2 2 ,5-dione

Chem.

[0410] From the product of Step 8 (55 mg) and Intermediate 3 (133 mg), following the procedure described in Step 13 of Example 17, the title product was obtained as a yellow solid (7.8 mg). MS (ESI): 614.3[M+H] + .

[0411] Example 27A & 27B 2 4 -((2S,5R)-4-Acryloyl-2,5-dimethylpiperazin-1-yl)-2 6 ,3 6 -Difluoro-16-isopropyl-2 1 ,2 2 -Dihydro-4,7-diaza-2(1,7)-pyrido[2,3-d]pyrimidine-1,3(1,2)-dibenzena[1,7]cycloheptaphane-2 2 -one

Chem.

[0412] Step 12 6 ,3 6 -Difluoro-1 6 -Isopropyl-2 1 ,2 2 ,2 3 ,2 4 -Tetrahydro-4,7-diaza-2(1,7)-pyrido[2,3-d]pyrimidine-1,3(1,2)-dibenzena[1,7]cycloheptaphane-2 2 ,2 4 -dione

Chem.

[0413] From the product (100 mg) of Step 8 of Example 25, following the procedure described in Step 7 of Example 1, the title product was obtained as a yellow solid (16 mg).

[0414] Step 22 4 -((2S,5R)-4-Acryloyl-2,5-dimethylpiperazin-1-yl)-2 6 ,3 6 -Difluoro-1 6 -Isopropyl-2 1 ,2 2 -Dihydro-4,7-diaza-2(1,7)-pyrido[2,3-d]pyrimidine-1,3(1,2)-dibenzena[1,7]cycloheptaphane-2 2 -One [Chemical formula]

[0415] To a solution of the product of Step 1 (20 mg, 0.04 mmol) in dry MeCN (2 mL) were added DIPEA (74 μL, 0.44 mmol) and POCl3 (25 μL, 0.27 mmol) under an Ar atmosphere. After stirring at 80 °C for 1 hour, the reaction mixture was concentrated. To the residue was added a solution of 1-((2R,5S)-2,5-dimethylpiperazin-1-yl)prop-2-en-1-one (Intermediate 3, 75, purity 30%, 0.13 mmol) in DIEA (74 μL, 0.44 mmol) and dry DMF (1.0 mL). After stirring at room temperature for 1.5 hours, the reaction mixture was poured into water (5 mL) and extracted with ethyl acetate (5 mL × 4). The combined extracts were washed with saturated NH4Cl (3 mL), concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate: 80 / 20 to 0 / 100, then DCM / EtOAc: 90 / 10 to 20 / 80, then DCM / MeOH: 100 / 0 to 92 / 8) to give the product of Example 27A (fast elution) as a yellow solid (5.4 mg), and a mixture of Example 27A and Example 27B (slow elution). The mixture was further purified by prep-TLC (petroleum ether:ethyl acetate = 1:5, eluted twice) to give an additional 1.0 mg of the product of Example 27A and the product of Example 27B (5.6 mg) as yellow solids. MS (ESI): 600.3 [M+H] + .

[0416] Example 27A: 11H NMR (400 MHz, CDCl3) δ 7.83 - 7.73 (m, 1H), 7.31 - 7.26 (m, 1H), 7.26 - 7.19 (m, 1H), 6.81 (dd, J = 17.4, 7.9 Hz, 2H), 6.66 - 6.54 (m, 1H), 6.54 - 6.45 (m, 2H), 6.44 - 6.34 (m, 1H), 5.84 - 5.75 (m, 1H), 5.38 - 5.27 (m, 1H), 5.14 (brs, 1H), 5.04 - 4.94 (m, 1H), 4.40 - 4.27 (m, 1H), 4.14 - 4.06 (m, 1H), 4.04 - 3.97 (m, 1H), 3.97 - 3.89 (m, 1H), 3.84 (d, J = 12.6 Hz, 1H), 3.71 - 3.61 (m, 1H), 3.33 - 3.18 (m, 2H), 3.18 - 3.08 (m, 1H), 2.70 - 2.58 (m, 1H), 1.39 (d, J = 6.8 Hz, 2H), 1.37 - 1.24 (m, 4H), 1.21 (d, J = 6.8 Hz, 2H), 1.16 (d, J = 6.8 Hz, 2H), 0.84 (d, J = 6.8 Hz, 2H).

[0417] Example 27B: 11H NMR (400 MHz, CDCl3) δ 7.82 (dd, J = 19.6, 9.2 Hz, 1H), 7.30 - 7.27 (m, 1H), 7.25 - 7.19 (m, 1H), 6.88 - 6.74 (m, 2H), 6.67 (dd, J = 16.9, 10.9 Hz, 1H), 6.59 - 6.34 (m, 3H), 5.87 - 5.75 (m, 1H), 5.21 - 5.12 (m, 1H), 4.98 (d, J = 14.5 Hz, 1H), 4.90 - 4.71 (m, 1H), 4.61 - 4.48 (m, 1H), 4.45 - 4.36 (m, 1H), 3.92 - 3.81 (m, 1H), 3.79 - 3.53 (m, 3H), 3.33 - 3.06 (m, 3H), 2.67 - 2.56 (m, 1H), 1.64 (d, J = 6.8 Hz, 1H), 1.56 - 1.41 (m, 7H), 1.20 (d, J = 6.8 Hz, 2H), 0.99 - 0.89 (m, 2H).

[0418] Example 28 (S)-2 4 -(4 - acryloyl - 2 - methylpiperazin - 1 - yl)-2 6 ,3 6 -difluoro - 1 6 -isopropyl - 8 - methyl - 2 1 ,2 2 -dihydro - 4,8 - diaza - 2(1,7)-pyrido[2,3 - d]pyrimidine - 1,3(1,2)-dibenzena - cyclooctafane - 2 2 -one

Chemical Structure

[0419] Step 1 Ethyl 3 - ((3 - bromo - 2 - nitrophenyl)(methyl)amino)propanoate

Chemical Structure

[0420] Ethyl 3-(methylamino)propanoate and 1-bromo-3-fluoro-2-nitrobenzene were used to obtain the title product as a yellow oil according to the procedure described in Step 1 of Example 21. MS: (ESI+): 353.7 [M+23] + .

[0421] Step 2 Ethyl 3-(methyl(2-nitro-3-(prop-1-en-2-yl)phenyl)amino)propanoate

Chemical formula

[0422] The product of Step 1 and isopropenylboronic acid pinacol ester were used to obtain the title product as a yellow oil according to the procedure described in Step 3 of Example 21. MS: (ESI+): 293.1 [M+1] + .

[0423] Step 3 Ethyl 3-((2-amino-3-isopropylphenyl)(methyl)amino)propanoate

Chemical formula

[0424] The product of Step 2 was used to obtain the title product as an oil according to the procedure described in Step 4 of Example 21. MS: (ESI+): 265.1 [M+1] + .

[0425] Step 4 Ethyl 3-((2-(3-(2,6-dichloro-5-fluoronicotinoyl)ureido)-3-isopropylphenyl)(methyl)amino)propanoate

Chemical formula

[0426] The product of Step 3 was used to obtain the title product as a yellow solid according to the procedure described in Step 5 of Example 21. MS: (ESI+): 499.1 [M+1]+ .

[0427] Step 5 Ethyl 3-((2-(7-chloro-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)-3-isopropylphenyl)(methyl)amino)propanoate

Chem.

[0428] From 2,6-dichloro-5-fluoronicotinamide (2.45 g), the title product was obtained as a brown solid (1.19 g) according to the procedure described in Step 3 of Example 8. MS: (ESI+): 265.1 [M+1] + .

[0429] Step 6 Ethyl 3-((2-(7-(2-amino-6-fluorophenyl)-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)-3-isopropylphenyl)(methyl)amino)propanoate

Chem.

[0430] From the product of Step 5 (0.67 g) and 3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.75 g), the title product was obtained as a brown solid (0.53 g) according to the procedure described in Step 8 of Example 17. MS: (ESI+): 538.2 [M+1] + .

[0431] Step 7 3-((2-(7-(2-amino-6-fluorophenyl)-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)-3-isopropylphenyl)(methyl)amino)propanoic acid

Chem.

[0432] To a solution of the product of Step 6 (420 mg) in THF (2.5 mL) was added LiOH (141 mg) in H2O (2.5 mL). After stirring at room temperature for 2 hours, the reaction mixture was concentrated to dryness, dissolved in water (10 mL), and washed with Et2O (2 mL × 5). The aqueous phase was acidified to pH = 7 with 1N HCl and concentrated to dryness under reduced pressure. The residue was co-evaporated with toluene (2 mL × 3) to give the title compound (400 mg, yellow solid) as the lithium salt. MS: (ESI+): 510.2 [M+1] + .

[0433] Step 8 2 6 ,3 6 -difluoro-1 6 -isopropyl-8-methyl-2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-4,8-diaza-2(1,7)-pyrido[2,3-d]pyrimidine-1,3(1,2)-dibenzocyclooctafane-2 2 ,2 4 ,5-trione

Chemical Structure

[0434] From the product of Step 7 (0.20 g), the title product was obtained as a yellow solid (0.14 g) according to the procedure described in Step 7 of Example 1. MS: (ESI+): 492.2 [M+1] + .

[0435] Step 9 2 6 ,3 6 -difluoro-1 6 -isopropyl-8-methyl-2 1 ,2 2 ,2 3 ,2 4-Tetrahydro-4,8-diaza-2(1,7)-pyrido[2,3-d]pyrimidine-1,3(1,2)-dibenzocyclooctafan-2 2 ,2 4 -dione

Chem.

[0436] From the product of Step 8 (10 mg), following the procedure described in Step 1 of Example 2, the title product was obtained as a yellow solid (13 mg, crude). MS: (ESI+): 478.1 [M+1] + .

[0437] Step 10 (S)-2 4 -(4-Acryloyl-2-methylpiperazin-1-yl)-2 6 ,3 6 -difluoro-1 6 -isopropyl-8-methyl-2 1 ,2 2 -dihydro-4,8-diaza-2(1,7)-pyrido[2,3-d]pyrimidine-1,3(1,2)-dibenzocyclooctafan-2 2 -one

Chem.

[0438] From the product of Step 9 (10 mg) and Intermediate 2 (47 mg), following the procedure described in Step 13 of Example 17, the title product was obtained as a brown solid (3.23 mg). MS (ESI+): 614.3 [M+1] + .

[0439] Example 29 (S)-2 4 -(4-Acryloyl-2-methylpiperazin-1-yl)-2 6 ,3 6 -difluoro-1 6 -isopropyl-8-methyl-2 1 ,2 2-Dihydro-4,8-diaza-2(1,7)-pyrido[2,3-d]pyrimidine-1,3(1,2)-dibenzocyclooctafan-2 2 ,5-dione [Chemical formula]

[0440] From the product of Step 8 of Example 28 (15 mg) and Intermediate 2 (30 mg), following the procedure described in Step 13 of Example 17, the title product was obtained as a yellow solid (0.85 mg). MS (ESI+): 628.3 [M+1] + .

[0441] Example 30 2 4 -((2S,5R)-4-Acryloyl-2,5-dimethylpiperazin-1-yl)-2 6 ,3 6 -Difluoro-1 6 -Isopropyl-8-methyl-2 1 ,2 2 -Dihydro-4,8-diaza-2(1,7)-pyrido[2,3-d]pyrimidine-1,3(1,2)-dibenzocyclooctafan-2 2 ,5-dione [Chemical formula]

[0442] From the product of Step 8 of Example 28 (40 mg) and Intermediate 3 (245 mg), except that the crude product was purified by C-18 reverse-phase column chromatography eluted with a gradient of 0.1% aqueous formic acid / MeCN (100% - 0%) to obtain the title compound (2.9 mg; yield: 5.68%) as a white solid, following the procedure described in Step 13 of Example 17, the title product was obtained as a white solid (12 mg).

[0443] Example 31 (S)-2 4 -(4-Acryloyl-2-methylpiperazin-1-yl)-2 6 ,36 -Difluoro-1 2 -Isopropyl-4-methyl-2 1 ,2 2 -Dihydro-7-thia-4-aza-2(1,7)-pyrido[2,3-d]pyrimidine-1(3,4)-pyridina-3(1,2)-benzena cyclohepta fan-2 2 -One

Chemical formula

[0444] Step 1 tert-Butyl 2-mercaptoacetate

Chemical formula

[0445] A mixture of tert-butyl 2-bromoacetate (20 g, 0.10 mol) and potassium ethanethioate (18 g, 0.16 mol) in EtOH (200 ml) was stirred at room temperature for 16 h. The reaction mixture was treated with 2N NaOH (205 ml) and stirred for 1 h. The pH of the mixture was adjusted to 7 with 1N HCl, and the reaction mixture was extracted with EA. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give 8.5 g of the crude product as a brown oil, which was used in the next step without further purification.

[0446]

Chemical formula

[0447] ​In 1,4-dioxane (30 ml), a mixture of intermediate 5 (6.25 g, 23.86 mmol), tert-butyl 2-mercaptoacetate (8.84 g, 59.64 mmol), DIPEA (12.31 g, 95.42 mmol), Pd2(dba)3 (4.37 g, 4.77 mmol), and Xantphos (5.52 g, 9.54 mmol) was heated to 90 °C and stirred with Ar for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, quenched with water, and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 1:1) to obtain 4.6 g of pure product as a yellow solid. MS (ES+): 283 [M+1] +

[0448] Step 3 tert-butyl 2-((3-(3-(2,6-dichloro-5-fluoronicotinoyl)ureido)-2-isopropylpyridin-4-yl)thio)acetate [Chemical formula]

[0449] From 2,6-dichloro-5-fluoronicotinamide (6.67 g) and the product of Step 2 (4.5 g), the title product was obtained as a yellow solid (3.1 g) according to the procedure described in Step 3 of Example 1. MS (ES+): 517 [M+1] + .

[0450] Step 4 tert-butyl 2-((3-(7-chloro-6-fluoro-4-hydroxy-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-isopropylpyridin-4-yl)thio)acetate [Chemical formula]

[0451] From the product of Step 3 (3.0 g), the title product was obtained as a white solid (2.1 g) according to the procedure described in Step 3 of Example 8. MS (ES+): 481 [M+1] + .

[0452] Step 5 tert-Butyl 2-((3-(7-(2-amino-6-fluorophenyl)-6-fluoro-4-hydroxy-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-isopropylpyridin-4-yl)thio)acetate

Chem.

[0453] From the product of Step 4 (700 mg) and 3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.45 g), the title product was obtained as a white solid (575 mg) according to the procedure described in Step 8 of Example 17. MS (ES+): 556 [M+1] + .

[0454] Step 6 2 6 ,3 6 -difluoro-2 4 -hydroxy-1 2 -isopropyl-2 1 ,2 2 -dihydro-7-thia-4-aza-2(1,7)-pyrido[2,3-d]pyrimidin-1(3,4)-pyridina-3(1,2)-benzenacycloheptafan-2 2 ,5-dione

Chem.

[0455] To a solution of the product of Step 5 (240 mg, 0.43 mmol) stirred in DCM (3 ml) was added TFA (3 ml) at room temperature. The resulting mixture was stirred at room temperature for 1 hour and then concentrated. The residue was dissolved in DMF (60 ml). NMI (532 mg, 6.49 mmol) and TCFH (393 mg, 1.30 mmol) were added at room temperature under Ar. The resulting mixture was stirred at room temperature for 1 hour, then quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by Prep-TLC (PE:EA = 1:1) to give 92 mg of the title product as a yellow solid. MS (ES+): 482 [M+1] + .

[0456] Step 7 2 6 ,3 6 -Difluoro-2 4 -Hydroxy-1 2 -Isopropyl-2 1 ,2 2 -Dihydro-7-thia-4-aza-2(1,7)-pyrido[2,3-d]pyrimidin-1(3,4)-pyridina-3(1,2)-benzenacycloheptafan-2 2 -One

Chem.

[0457] To a solution of the product of Step 6 (92 mg, 0.19 mmol) stirred in THF (1 ml) was added borane-tetrahydrofuran complex with an Ar balloon at 0 °C. The mixture was stirred under Ar at room temperature for 1 hour, then quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by Prep-TLC (PE:EA = 2:1) to give 57 mg of the title product as a yellow solid. MS (ES+): 468 [M+1] + .

[0458] Step 8 (S)-2 4-(4-Acryloyl-2-methylpiperazin-1-yl)-2 6 ,3 6 -Difluoro-1 2 -Isopropyl-2 1 ,2 2 -Dihydro-7-thia-4-aza-2(1,7)-pyrido[2,3-d]pyrimidin-1(3,4)-pyridina-3(1,2)-benzenacycloheptafan-2 2 -One

Chem.

[0459] From the product of Step 7 (57 mg) and Intermediate 2 (79 mg), following the procedure described in Step 8 of Example 17, the title product was obtained as a yellow solid (37 mg). MS (ES+): 604 [M+1] + .

[0460] Step 9 (S)-2 4 -(4-Acryloyl-2-methylpiperazin-1-yl)-2 6 ,3 6 -Difluoro-1 2 -Isopropyl-4-methyl-2 1 ,2 2 -Dihydro-7-thia-4-aza-2(1,7)-pyrido[2,3-d]pyrimidin-1(3,4)-pyridina-3(1,2)-benzenacycloheptafan-2 2 -One

Chem.

[0461] A solution of the product of Step 8 (35 mg, 0.06 mmol) being stirred in THF (1 ml) was added with HCHO (30%) (5 ml) and STAB (121 mg, 0.60 mmol) at room temperature. After stirring for 1 hour, the mixture was quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by Prep-TLC (EA) to obtain 17 mg of the title product as a yellow solid. MS (ES+): 618 [M+1] + .

[0462] Synthesis of Intermediate Intermediate 1 (S)-1-(3-Methylpiperazin-1-yl)prop-2-en-1-one 2,2,2-trifluoroacetate

Chemical Structure

[0463] Step 1 tert-Butyl (S)-4-acryloyl-2-methylpiperazine-1-carboxylate

Chemical Structure

[0464] To a solution of tert-butyl (S)-2-methylpiperazine-1-carboxylate (4.7971 g, 23.952 mmol) and triethylamine (8.0 mL, 57.4 mmol) being stirred in DCM (80 mL) was added acryloyl chloride (2.10 mL, 25.8 mmol) at 0 °C for 15 minutes. Next, the reaction mixture was treated with 20 mL of water and extracted with 200 mL of EtOAc. The organic layer was washed with 60 mL of 2N HCl(aq), 5 x 50 mL of water, and brine, and dried over Na2SO4. The solution was filtered and concentrated to obtain the title compound as a pale yellow oil. MS (ESI+): 277.1 [M+23] + .

[0465] (S)-1-(3-Methylpiperazin-1-yl)prop-2-en-1-one 2,2,2-trifluoroacetate

Chem.

[0466] A solution of tert-butyl (S)-4-acryloyl-2-methylpiperazine-1-carboxylate (3.57 g, 14.0 mmol) and TFA (8.0 mL, 107.7 mmol) in DCM (20 mL) was stirred at room temperature for 5 h. Next, 20 mL of toluene was added. The resulting mixture was evaporated to give the title compound (4.24 g) as a light oil. MS (ESI+): 155.1 [M+1] + .

[0467] Intermediate 2 (S)-1-(3-Methylpiperazin-1-yl)prop-2-en-1-one

Chem.

[0468] The crude Intermediate 1 (4.24 g) was dissolved in 25 mL of aqueous NaOH (2.67 g of NaOH). The reaction mixture was saturated with 10 g of NaCl and extracted with 3 × 30 mL of DCM. The combined organic layers were dried over Na2SO4 and concentrated to give Intermediate 2 (2.3 g).

[0469] Intermediate 3 1-((2R,5S)-2,5-Dimethylpiperazin-1-yl)prop-2-en-1-one 2,2,2-trifluoroacetate

Chem.

[0470] Step 1 tert-butyl (2S,5R)-4-acryloyl-2,5-dimethylpiperazine-1-carboxylate

Chem.

[0471] A solution of tert-butyl (2S,5R)-2,5-dimethylpiperazine-1-carboxylate (3.83 g, 17.9 mmol) and triethylamine (5.2 mL, 37.3 mmol) stirred in DCM (30 mL) was added acryloyl chloride (1.70 mL, 20.9 mmol) at 0 °C. After stirring at 0 °C for 15 minutes, water (10 mL) was added and the reaction mixture was stirred at room temperature for an additional 1 hour. The mixture was extracted with 50 mL of EtOAc and the organic layer was washed with 20 mL of 2N HCl (aqueous solution), 2 × 20 mL of 0.2M HCl (aqueous solution), 2 × 20 mL of water and brine, and dried over Na2SO4. The solution was filtered and concentrated to give the title compound as a light oil. MS (ESI+): 291.1 [M+23] + .

[0472] Step 2 1-((2R,5S)-2,5-Dimethylpiperazin-1-yl)prop-2-en-1-one 2,2,2-trifluoroacetate

Chemical formula

[0473] A solution of the product from Step 1 (3.85 g, 14.3 mmol) and TFA (10.0 mL, 134.6 mmol) in DCM (40 mL) was stirred at room temperature for 1 hour. Toluene (40 mL) was added and the reaction mixture was evaporated to give the title compound (4.0 g) as a pale yellow oil. MS (ESI+): 169.2 [M+1] + .

[0474] Intermediate 3-Chloro-1-((2R,5S)-2,5-dimethylpiperazin-1-yl)propan-1-one hydrochloride

Chemical formula

[0475] The product of step 1 of intermediate 3 (200.0 mg, 0.746 mmol) was added to 4N HCl / dioxane solution (1.0 mL). After stirring at room temperature for 1 hour, the reaction mixture was concentrated to dryness to obtain the title compound (150 mg). MS (ESI+): 205.1 [M+1] + .

[0476] 1H NMR (400 MHz, DMSO-d6): δ 3.82 - 3.79 (m, 2H), 3.60 - 3.57 (m, 4H), 3.45 - 3.35 (m, 2H), 2.99 - 2.95 (m, 1H), 2.82 - 2.75 (m, 1H), 1.29 - 1.21 (m, 6H).

[0477] Intermediate 5 2-Iodo-4-isopropylpyridin-3-amine

Chemical formula

[0478] Step 1 2,4-Dichloropyridin-3-amine

Chemical formula

[0479] Step 2 4-Chloro-2-(prop-1-en-2-yl)pyridin-3-amine

Chemical formula

[0480] A solution of 2,4-dichloropyridin-3-amine (85 g, 0.52 mol), 1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethan-1-one (115 g, 0.68 mol) and K3PO4 (287 g, 1.36 mol) stirred in THF (1.7 L) / H2O (340 ml) was added with Ar Pd(dppf)Cl2.DCM (32 g, 0.039 mol) at room temperature. The mixture was stirred at 75 °C for 7 h, then quenched with water and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE: EA = 2:1) to give 84 g of the title product as a white solid. MS (ES+): 168.9 [M+1] + .

[0481] Step 3 4-Iodo-2-isopropylpyridin-3-amine

Chemical formula

[0482] A mixture of 4-chloro-2-(prop-1-en-2-yl)pyridin-3-amine (84 g, 0.5 mol) in HI (aqueous solution, 55 - 58%, 1.26 L) was stirred with Ar at 120 °C overnight. Next, the pH of the reaction mixture was adjusted to 9 - 10 with Na2CO3 (aqueous solution) and extracted with EA. The organic layer was washed with NaHSO3 (aqueous solution) and brine, dried over anhydrous Na2SO4, filtered and concentrated to give 90 g of the crude product as a brown oil, which was used in the next step without further purification. MS (ES+): 262.8 [M+1] + .

Industrial applicability

[0483] All documents mentioned in this application are hereby incorporated by reference as if each were individually incorporated by reference. Further, after reading the above teachings, those skilled in the art should understand that various changes and modifications can be made to the present invention. Its equivalents are also included within the scope defined by the appended claims.

Claims

1. A compound having the structural formula of Formula VII or a pharmaceutically acceptable salt thereof. 【Chemical 1】 [Wherein, Q has the structure shown below. [Chemical Formula 2] R a and R b are each independently selected from the group consisting of H, R c is selected from the group consisting of H and halogen. 【Chemical Formula 3】 is 【Chemical 4】 is. R 1 and R 2 are each independently hydrogen, halo, cyano, C(O)NH 2 , C(O)NHC 1-6 alkyl, C(O)N(C 1-6 alkyl) 2 , C 1-6 alkyl, and C(O)-C 1-6 alkyl (these C1-6 alkyls are saturated and branched or straight-chain, substituted or unsubstituted), C 1-6 heteroalkyl (this alkyl is saturated and branched or straight-chain, substituted or unsubstituted), and heterocyclyl and heterocyclylalkyl (this alkyl is saturated and branched or straight-chain, substituted or unsubstituted), and are selected from the group consisting of. Or, R 1 and R 2 together with the carbon atoms to which both are attached can form a 3- to 6-membered carbocyclic ring. R3 is selected from the group consisting of H and halo. R 4 is selected from the group consisting of hydrogen and halo. Z and Y are each independently N or CR 3 respectively. W is N. n and m are independently 2 or 3. R 17 is C1-6 alkyl (this C1-6 alkyl is saturated and branched or straight-chain and unsubstituted), R 18 is selected from the group consisting of H and halogen. L 3 is -NR 19 (CH 2 ) q NR 20 -,-(CH 2 ) q NR 20 -,-O(CH 2 ) q O-,-(CH 2 ) q C(O)NR 19 -,-O(CH 2 ) q C(O)NR 19 -,-S(CH 2 ) q O-,-O(CH 2 ) q S-,-S(CH 2 ) q S-,-NR 19 (CH 2 ) q is independently selected from the group consisting of -O- q is selected from 1 to 6 R 19 and R 20 each independently represents hydrogen, C 1-6 alkyl (this C1-6 alkyl is saturated and branched or straight-chain, substituted or unsubstituted), and C 3-6 cycloalkyl (this cycloalkyl is saturated), and is selected from the group consisting of.]

2. A compound having the structural formula of Formula VIIA or a pharmaceutically acceptable salt thereof. 【Chemical Formula 5】 [Wherein, [Chemical Formula 6] is 【Chemical Formula 7】 is. R 1 and R 2 are each independently selected from the group consisting of hydrogen, halo, cyano, C(O)NH2, C(O)NHC1-6 alkyl, C(O)N(C1-6 alkyl)2, C1-6 alkyl, and C(O)-C1-6 alkyl (wherein these C1-6 alkyls are saturated and branched or straight-chain and substituted or unsubstituted), C1-6 heteroalkyl (wherein this C1-6 alkyl is saturated and branched or straight-chain and substituted or unsubstituted), and heterocyclyl and heterocyclylalkyl (wherein this alkyl is saturated and branched or straight-chain and substituted or unsubstituted). Or, R 1 and R 2 together with the carbon atoms to which they are attached can form a 3- to 6-membered carbocyclic ring. n and m are independently 2 or 3. Z and Y are each independently N or CR 3 respectively. W is N. W 1 is CR 3 is the case. W 2 is CR 4 is the case. Z 1 、Z 2 、Z 3 、Z 4 and Z 5 is each independently N or CR 18 respectively. R 3 and R4 are selected from the group consisting of H and halo. R 17 is C1-6 alkyl (this C1-6 alkyl is saturated and branched or straight-chain and unsubstituted), R 18 is selected from the group consisting of H and halogen. L 3 is -(CH 2 ) q , -NR 19 (CH 2 ) q NR 20 , -(CH 2 ) q NR 20 , -O(CH 2 ) q O-, -(CH 2 ) q C(O)NR 19 , -(CH 2 ) q NR 19 C(O)-, -C(O)NR 19 (CH 2 ) q , -O(CH 2 ) q C(O)NR 19 , -O(CH 2 ) q C(O)NR 19 , -S(O) v (CH 2 ) q O-, -O(CH 2 ) q S(O) v , -S(O) v (CH 2 ) q , -(CH 2 ) q S(O) v , -S(O) v (CH 2 ) q S(O) v , -NR 19 (CH 2 ) q C(O)NR 20 , -NR 19 (CH 2 ) q , -NR 19 C(O)(CH 2 ) q , -NR 19 (CH 2 ) q , -(CH 2 ) q NR 19 C(O)NR 20 (CH 2 ) r -, -(CH 2 ) q S(O) v (CH 2 ) r -, -(CH 2 ) q S(CH 2 ) r -, -(CH 2 ) q O(CH 2 ) r -, and -(CH 2 ) q NR 19 (CH 2 ) r selected from the group consisting of. q and r are each independently selected from 0 to 10. Provided that when L3 is selected from the group consisting of S(O)v(CH2)qO-, -O(CH2)qS(O)v-, -S(O)v(CH2)q-, -(CH2)qS(O)v-, -S(O)v(CH2)qS(O)v- and -(CH2)qS(O)v(CH2)r-, v is 0. R 19 and R 20 are each independently hydrogen, C 1-6 alkyl (this C1-6 alkyl is saturated and branched or straight-chain and substituted or unsubstituted), C 3-10 heteroalkyl (this alkyl is saturated and branched or straight-chain and substituted or unsubstituted), C 3-10 cycloalkyl (this alkyl is saturated and branched or straight-chain and substituted or unsubstituted), C 6-10 aryl, C 1-5 heteroaryl and C 2-6 are selected from the group consisting of heterocyclyl. Q has the structure shown below. 【Chemical 8】 R a 、and R b are H, R c is H, halogen.

3. A compound having the structural formula of Formula VIIB or a pharmaceutically acceptable salt thereof. 【Chemical Formula 9】 [Wherein, 【Chemical 10】 is 【Chemical 11】 R1 and R2 are each independently selected from the group consisting of hydrogen, halo, cyano, C(O)NH2, C(O)NHC1-6 alkyl, C(O)N(C1-6 alkyl)2, C1-6 alkyl, and C(O)-C1-6 alkyl (these C1-6 alkyls are saturated and branched or straight-chain, substituted or unsubstituted), C1-6 heteroalkyl (this alkyl is saturated and branched or straight-chain, substituted or unsubstituted), and heterocyclyl and heterocyclylalkyl (this alkyl is saturated and branched or straight-chain, substituted or unsubstituted). Alternatively, R1 and R2, together with the carbon atoms to which they are attached, can form a 3- to 6-membered carbocyclic ring. n and m are independently 2 or 3. Q has the structure shown below. 【Chemical Formula 12】 Ra and Rb are H, and Rc is independently selected from the group consisting of H and halogen. Z is N or CR3. Y is CR3. W is N. W1 is CR3. W2 is CR4. Z5 is CR18. R3 and R4 are selected from the group consisting of H and halo. R 17 is selected from the group consisting of C 1-6 alkyl (this C 1-6 alkyl is saturated and branched or straight-chain and unsubstituted), R 18 is H, and halogen. L 3 is selected from the group consisting of -(CH 2 ) q -, -NR 19 (CH 2 ) q NR 20 -, -(CH 2 ) q NR 20 -, -O(CH 2 ) q O-, -(CH 2 ) q C(O)NR 19 -, -(CH 2 ) q NR 19 C(O)-, -C(O)NR 19 (CH 2 ) q -, -O(CH 2 ) q C(O)NR 19 -, -O(CH 2 ) q C(O)NR 19 -, -S(O) v (CH 2 ) q O-, -O(CH 2 ) q S(O) v -, -S(O) v (CH 2 ) q -, -(CH 2 ) q S(O) v -, -S(O) v (CH 2 ) q S(O) v -, -NR 19 (CH 2 ) q C(O)NR 20 -, -NR 19 (CH 2 ) q -, -NR 19 C(O)(CH 2 ) q -, -NR 19 (CH 2 ) q O-, -(CH 2 ) q NR 19 C(O)NR 20 (CH 2 ) r -, -(CH 2 ) q S(O) v (CH 2 ) r -, -(CH 2 ) q S(CH 2 ) r -, -(CH 2 ) q O(CH 2 ) r -, and -(CH 2 ) q NR 19 (CH 2 ) r -. q and r are each independently selected from 1 to 10. However, when L 3 is selected from the group consisting of S(O) v (CH 2 ) q O-, -O(CH 2 ) q S(O) v -, -S(O) v (CH 2 ) q -, -(CH 2 ) q S(O) v -, -S(O) v (CH 2 ) q S(O) v - and -(CH 2 ) q S(O) v (CH 2 ) r -, v is 0. R19 and R20 are each independently selected from the group consisting of hydrogen, C1-6 alkyl (wherein the C1-6 alkyl is saturated and branched or straight-chain and substituted or unsubstituted), C3-10 heteroalkyl (wherein the alkyl is saturated and branched or straight-chain and substituted or unsubstituted), C3-10 cycloalkyl (wherein the cycloalkyl is saturated), C6-10 aryl, C1-5 heteroaryl or C2-6 heterocyclyl. Alternatively, R19 and R20 can be connected to form a ring. L6 is -(CH2)q- (where q is 0). 【Chemical 13】 is an unsubstituted phenyl ring or a phenyl group substituted with one or more halogen atoms. L3 and L6 are 【Chemical 14】 connected to.

4. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is 【Chemical Formula 16】 【Chemical 17】 【Chemical Formula 18】 【Chemical Formula 19】 【Chemical 20】 【Chemical 21】 【Chemical 22】 【Chemical 23】 【Chemical 24】 【Chemical 25】 【Chemical 26】 【Chemical 27】 【Chemical 28】 【Chemical 29】 【Chemical Formula 30】 【Chemical 31】 【Chemical 32】 【Chemical 33】 【Chemical 34】 【Chemical 35】 【Chemical 36】 【Chemical 37】 【Chemical Formula 38】 【Chemical Formula 39】 【Chemical 40】 【Chemical 41】 selected from the group consisting of, a compound or a pharmaceutically acceptable salt thereof.

5. The compound according to any one of claims 1 to 4, in the form of a pharmaceutically acceptable salt and a pharmaceutically acceptable excipient.

6. A therapeutic agent containing the compound according to any one of claims 1 to 5, which inhibits intracellular KRASG12C and is for treating diseases mediated by KRASG12C.

7. The therapeutic agent according to claim 6, which is for treating cancer in a subject by administering a therapeutically effective amount of the compound to the subject.

8. The cancer is lung cancer, pancreatic cancer, colorectal cancer, the therapeutic agent according to claim 7.

9. The therapeutic agent according to claim 6, which is for treating cancer in a subject by administering a therapeutically effective amount of the compound to the subject together with a therapeutically effective amount of other anticancer agents.

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