WO2024120419A1 - Fused tetracyclic compounds as kras g12d modulators and uses thereof - Google Patents
Fused tetracyclic compounds as kras g12d modulators and uses thereof Download PDFInfo
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- WO2024120419A1 WO2024120419A1 PCT/CN2023/136651 CN2023136651W WO2024120419A1 WO 2024120419 A1 WO2024120419 A1 WO 2024120419A1 CN 2023136651 W CN2023136651 W CN 2023136651W WO 2024120419 A1 WO2024120419 A1 WO 2024120419A1
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- Prior art keywords
- compound
- optionally substituted
- alkyl
- pharmaceutically acceptable
- acceptable salt
- Prior art date
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Definitions
- This application relates to KRAS G12D modulators, their preparation and uses thereof.
- Rat sarcoma encoded by the proto-oncogenes HRAS, NRAS and KRAS, is a GTP-binding protein that is in an activated state when binding with GTP, and is in an inactive state when binding with GDP.
- RAS is distributed on the inner surface of the cell membrane and is activated when it binds to GTP and inactivated when it binds to GDP.
- the upstream of RAS is receptor tyrosine kinase (RTK) , which regulates downstream signaling pathways such as PI3K and RAF after activation, thereby regulating cell growth, survival, migration and differentiation functions. Since RAS proteins are central to the axis of many important cellular signaling networks, and these signals are associated with multiple tumor markers, overactive RAS signaling may ultimately lead to tumorigenesis.
- KRAS oncogenic mutations are most commonly found in KRAS (85%) , and aberrant expression of KRAS accounts for up to 20%of all cancers, with G12D mutations accounting for 25%of pancreatic cancer (PDAC) , colon cancer (CRC) 13.3%, rectal cancer (RC) 10.1%, non-small cell lung cancer (NSCLC) 4.1%.
- PDAC pancreatic cancer
- CRC colon cancer
- RC rectal cancer
- NSCLC non-small cell lung cancer
- KRAS G12D inhibitors There are two main difficulties in the development of KRAS G12D inhibitors.
- the RAS protein has a smooth structure and there is no obvious pocket on the surface for small molecules to bind to; on the other hand, the affinity of KRAS protein for GTP is as high as a picomolar level and endogenous GTP levels are high. Thus, it is difficult for small-molecule drugs to block the binding of the two.
- no targeted drug for KRAS G12D mutation has entered the clinical research stage, and there is a large unmet clinical need.
- Q 1 , Q 2 , and Q 3 are independently selected from N, C-H, C-CF 3 , C-OH, C-Cl, C-F, C-CH 3 , C-CH (CH 3 ) 2 , C-cyclopropyl, C-OCH 3 , C-SCF 3 , C-OCF 3 , and C-CN;
- R 1 is selected from L-5-12 membered heterocyclyl which is either monocyclic or bicyclic, and L-C 3-8 cycloalkyl, wherein each of the 5-12 membered heterocyclyl and C 3-8 cycloalkyl is optionally substituted with one or more W;
- L is selected from -CH 2 -, -CH (CH 3 ) -, CH 2 -CH 2 -, and a bond;
- R 2 is selected from H, C 1-6 alkyl optionally substituted with one or more W, C 3-6 cycloalkyl optionally substituted with one or more W, and 4-6 membered heterocyclyl optionally substituted with one or more W;
- Ring A is selected from a 4-12 membered heterocyclyl, a C 4-10 cycloalkyl, and a 9-12 membered fused bicyclic heteroaryl, each of which is optionally substituted with one or more W;
- R 3 is selected from aryl and heteroaryl, wherein the aryl and heteroaryl is optionally substituted with one or more W;
- X is selected from O, S and NR 5 ;
- Y is selected from a bond and -O-;
- R 5 is selected from H and C 1-6 alkyl
- R 8 and R 9 are independently selected from H and C 1-6 alkyl, or R 8 and R 9 , together with the nitrogen to which they are attached, independently form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, and C 1-6 alkyl; and
- R 10 and R 11 are independently selected from H and C 1-6 alkyl.
- Q 1 is N, and either (i) Q 2 is N and Q 3 is C-H, C-CF 3 , C-OH, C-Cl, C-F, C-CH 3 , C-CH (CH 3 ) 2 , C-cyclopropyl, C-OCH 3 , C-SCF 3 , C-OCF 3 , or C-CN, or (ii) Q 2 is C-H, C-CF 3 , C-OH, C-Cl, C-F, C-CH 3 , C-CH (CH 3 ) 2 , C-cyclopropyl, C-OCH 3 , C-SCF 3 , C-OCF 3 , or C-CN, and Q 3 is N.
- Q 1 is N
- Q 2 is N
- Q 3 is C-H or C-F.
- Q 3 is C-H.
- Q 3 is C-F.
- Q 1 is N
- Q 2 is N, C-H, C-CF 3 , C-OH, C-Cl, C-F, C-CH 3 , C-CH (CH 3 ) 2 , C-cyclopropyl, C-OCH 3 , C-SCF 3 , C-OCF 3 , or C-CN
- Q 3 is C-H, C-CF 3 , C-OH, C-Cl, C-F, C-CH 3 , C-CH (CH 3 ) 2 , C-cyclopropyl, C-OCH 3 , C-SCF 3 , C-OCF 3 , or C-CN.
- Q 1 is N
- Q 2 is N, C-H, C-CF 3 , C-OH, C-Cl, C-F, C-CH 3 , C-CH (CH 3 ) 2 , C-cyclopropyl, C-OCH 3 , C-SCF 3 , C-OCF 3 , or C-CN
- Q 3 is C-H or C-F.
- Q 1 is N
- Q 2 is C-H, C-CF 3 , C-OH, C-Cl, C-F, C-CH 3 , C-CH (CH 3 ) 2 , C-cyclopropyl, C-OCH 3 , C-SCF 3 , C-OCF 3 , or C-CN
- Q 3 is C-H or C-F.
- Q 3 is C-H.
- Q 3 is C-F.
- R 3 is an aryl selected from phenyl, naphthyl, and 1H-indenyl, or a heteroaryl selected from pyridinyl, benzothiazolyl, benzothiophenyl, 1H-indazolyl, or 1H-indolyl, and the aryl or heteroaryl is optionally substituted with one or more W, and wherein optionally, W is independently selected from halo, C 1-3 alkyl, C 2 alkenyl, C 2 alkynyl, C 1 alkyl substituted with one or more F, optionally CF 3 , C 3 cycloalkyl, -NR 8 R 9 , -CN, and OH; and wherein optionally, R 8 is H and R 9 is H.
- R 3 is aryl and said aryl is phenyl, naphthyl, or 1H-indenyl, each of which is optionally substituted with one or more W. In some embodiments, R 3 is aryl and said aryl is phenyl or naphthyl, each of which is optionally substituted with one or more W. In some embodiments, R 3 is aryl and said aryl is phenyl, optionally substituted with one or more W. In some embodiments, R 3 is aryl and said aryl is naphthyl, optionally substituted with one or more W.
- R 3 is heteroaryl and said heteroaryl is pyridinyl, benzothiazolyl, benzothiophenyl, 1H-indazolyl, or 1H-indolyl, each of which is optionally substituted with one or more W.
- R 3 is heteroaryl and said heteroaryl is pyridinyl, 1H-indazolyl, or 1H-indolyl, each of which is optionally substituted with one or more W.
- R 3 is phenyl, naphthyl, pyridinyl, benzothiazolyl, benzothiophenyl, 1H-indenyl, 1H-indazolyl, or 1H-indolyl, each of which is optionally substituted with one or more W.
- R 3 is phenyl, naphthyl, pyridinyl, benzothiazolyl, benzothiophenyl, 1H- indenyl, 1H-indazolyl, or 1H-indolyl, each of which is optionally substituted with one or more W, and wherein optionally, W is independently selected from halo, C 1-3 alkyl, C 2 alkenyl, C 2 alkynyl, C 1 alkyl substituted with one or more F, optionally CF 3 , C 3 cycloalkyl, -NR 8 R 9 , -CN, and OH; and wherein optionally, R 8 is H and R 9 is H.
- W is halo
- halo is selected from F and Cl.
- R 3 is selected from
- R 3 is selected from
- Y is O.
- X is O.
- L is CH 2, CH (CH 3 ) , or CH 2 CH 2 .
- R 1 is selected from L-7-10 membered heterocyclyl which is monocyclic or bicyclic comprising at least one heteroatom selected from nitrogen and oxygen, and L-C 4-7 cycloalkyl, wherein each of the 7-10 membered heterocyclyl and L-C 4-7 cycloalkyl is optionally substituted with one or more W.
- R 1 is optionally substituted with one or more W independently selected from F, C 1-3 alkylidene optionally substituted with 1-5 F, and C 1-3 alkyl optionally substituted with -OC (O) NR 8 R 9 or –NR 8 R 9 , with R 8 and R 9 independently being selected from H and C 1-6 alkyl, or R 8 and R 9 , together with the nitrogen to which they are attached, form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, C 1- 6 alkyl.
- R 8 and R 9 are methyl or R 8 and R 9 , together with the nitrogen to which they are attached, form a morpholine.
- R 1 is L-C 3-8 cycloalkyl optionally substituted with one or more W. In some embodiments, R 1 is L-C 3-8 cycloalkyl optionally substituted with methyl, wherein the methyl is optionally substituted with -OC (O) NR 8 R 9 or –NR 8 R 9 , with R 8 and R 9 independently being selected from H and C 1-6 alkyl, or R 8 and R 9 , together with the nitrogen to which they are attached, form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, C 1-6 alkyl.
- R 1 is L-C 3-8 cycloalkyl optionally substituted with methyl, wherein the methyl is optionally substituted with -O (CO) N (CH 3 ) 2 , -O (CO) -morpholine, -N (CH 3 ) 2 , or morpholine.
- R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- L is CH 2 or CH (CH 3 ) .
- R 2 is selected from H, 4-6 membered heterocyclyl optionally substituted with one or more substituent selected from methyl and ethyl, C 3-6 cycloalkyl optionally substituted with one or more substituent selected from OH, -NR 8 R 9 , and C 1-6 alkyl optionally substituted with one or more groups selected from OH, F, Cl, C 1-6 alkyl, C 1-6 alkoxy, and oxo, and C 1-6 alkyl optionally substituted with one or more substituent selected from OH, -NR 8 R 9 , -NR 10 C (O) R 11 , and 4 or 5 membered heterocyclyl optionally substituted with one or more groups selected from OH, F, Cl, C 1-6 alkyl, C 1-6 alkoxy, and oxo, wherein R 8 and R 9 are independently selected from H and C 1-6 alkyl, or R 8 and R 9 , together with the nitrogen to which they are attached, independently form a 5, 6, or
- R 2 is selected from H, methyl, ethyl, - (CH 2 ) 2 OH, - (CH 2 ) 3 OH, - (CH 2 ) 2 NH 2 , - (CH 2 ) 2 NHC (O) CH 3 ,
- R 2 is a C 1-6 alkyl optionally substituted with one or more W.
- R 2 is selected from methyl, ethyl, - (CH 2 ) 2 OH, - (CH 2 ) 3 OH, - (CH 2 ) 2 NH 2, - (CH 2 ) 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , , - (CH 2 ) 2 NHC (O) CH 3 , -CH 2 C (O) NH 2 , - (CH 2 ) 2 C (O) NH 2 , -C (NH) NH 2 , -C (NH) CH 3 , -CH (CH 3 ) CH 2 NHCH 3 , -CH (CH 2 CH 3 ) CH 2 NHCH 3 , -CH (CH 2 CH 3 ) CH 2 NHCH 3 , -CH (CH 2 OH) CH 2 NHCH 3 , -CH (CH 2 OH) CH 2 NHCH 3 , -CH (CH 2 OH) CH 2 OH,
- R 2 is a 4-6 membered heterocyclyl optionally substituted with one or more W.
- R 2 is a 4-6 membered heterocyclyl optionally substituted with one or more substituent selected from methyl and ethyl, each of which is optionally substituted with one or more groups selected from OH, F, Cl, C 1-6 alkyl, C 1-6 alkoxy, -NR 8 R 9 , and oxo, wherein R 8 and R 9 are independently selected from H and C 1-6 alkyl, or R 8 and R 9 , together with the nitrogen to which they are attached, independently form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, and C 1-6 alkyl.
- R 2 is selected from
- R 2 is a C 3-6 cycloalkyl optionally substituted with one or more W.
- R 2 is a C 3-6 cycloalkyl optionally substituted with one or more substituent selected from F, Cl, OH, -NR 8 R 9 , and C 1-6 alkyl optionally substituted with one or more group selected from F, CL, OH, C 1-6 alkoxy, -NR 8 R 9 , -OC (O) NR 8 R 9 , and oxo, wherein R 8 and R 9 are independently selected from H and C 1-6 alkyl, or R 8 and R 9 , together with the nitrogen to which they are attached, independently form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, and C 1-6 alkyl.
- R 2 is selected from cyclopropanyl, cyclobutanyl,
- ring A is a 4-9 membered heterocyclyl which contains only one heteroatom, wherein the only one heteroatom is the nitrogen to which R 4 is attached. In some embodiments, ring A is a 4-7 membered monocyclic heterocyclyl optionally substituted with one or more W. In some embodiments, ring A is a 4-7 membered monocyclic cycloalkyl optionally substituted with one or more W. In some embodiments, ring A is a 8-12 membered fused, bridged, or spiro bicyclic heterocyclyl optionally substituted with one or more W.
- ring A is a heterocyclyl selected from each of which is optionally substituted with one or more group selected from OH, F, Cl, CN, NH 2 , oxo, OC (O) NR 8 R 9 , -C (O) NR 8 R 9 , -NR 10 C (O) R 11 , -NR 10 C (O) NR 8 R 9 , -S (O) 2 NR 8 NR 9 , - NR 10 S (O) 2 R 11 , and C 1-6 alkyl optionally substituted with one or more groups selected from OH, F, Cl, C 1-6 alkoxy, -NR 8 R 9 , and oxo, wherein R 8 and R 9 are independently selected from H and C 1-6 alkyl, or R 8 and R 9 , together with the nitrogen to which they are attached, independently form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, and C 1-6 alkyl,
- ring A is a heterocyclyl selected from
- ring A is a 9-12 membered fused bicyclic heteroaryl, which is optionally substituted with one or more W.
- the 9-12 membered fused bicyclic heteroaryl has one ring as being aromatic and the other non-aromatic.
- ring A is which is optionally substituted with one or more group selected from OH, F, Cl, CN, NH 2 , oxo, OC (O) NR 8 R 9 , -C (O) NR 8 R 9 , -NR 10 C (O) R 11 , -NR 10 C (O) NR 8 R 9 , -S (O) 2 NR 8 NR 9 , -NR 10 S (O) 2 R 11 , and C 1-6 alkyl optionally substituted with one or more groups selected from OH, F, Cl, C 1-6 alkyl, C 1-6 alkoxy, -NR 8 R 9 , and oxo, wherein R 8 and R 9 are independently selected from H and C 1-6 alkyl, or R 8 and R 9 , together with the nitrogen to which they are attached, independently form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, and C 1-6 alkyl, and R 10 and
- ring A is
- ring A is a C 4-7 monocyclic cycloalkyl optionally substituted with one or more W.
- ring A is cyclobutyl, cyclopentanyl, cyclohexanyl, and cyclohepanyl, which is optionally substituted with one or more groups selected from C 1-6 alkyl optionally substituted with 1-5 F or Cl, OH, F, Cl, CN, OC (O) NR 8 R 9 , -C (O) NR 8 R 9 , -NR 10 C (O) R 11 , -NR 10 C (O) NR 8 R 9 , -S (O) 2 NR 8 NR 9 , -NR 10 S (O) 2 R 11 , wherein R 8 and R 9 are independently selected from H and C 1-6 alkyl, or R 8 and R 9 , together with the nitrogen to which they are attached, independently form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups
- ring A is a cyclopentyl
- the compound as disclosed herein is:
- the compound as disclosed herein is:
- the compound as disclosed herein is or a pharmaceutically acceptable salt thereof; optionally, or a pharmaceutically acceptable salt thereof.
- the compound as disclosed herein is or a pharmaceutically acceptable salt thereof; optionally, or a pharmaceutically acceptable salt thereof.
- the compound as disclosed herein is or a pharmaceutically acceptable salt thereof; optionally, or a pharmaceutically acceptable salt thereof.
- the compound as disclosed herein is or a pharmaceutically acceptable salt thereof; optionally, or a pharmaceutically acceptable salt thereof.
- the compound as disclosed herein is or a pharmaceutically acceptable salt thereof; optionally, or a pharmaceutically acceptable salt thereof.
- the compound as disclosed herein is or a pharmaceutically acceptable salt thereof; optionally, or a pharmaceutically acceptable salt thereof.
- the compound as disclosed herein is or a pharmaceutically acceptable salt thereof; optionally, or a pharmaceutically acceptable salt thereof.
- composition comprising a compound or a pharmaceutically acceptable salt thereof as disclosed herein and a pharmaceutically acceptable excipient.
- the disease or disorder associated with KRAS G12D mutation is cancer.
- the cancer is selected from carcinoma, squamous carcinoma, pancreatic cancer, prostate cancer, rectal cancer, colon cancer, colorectal cancer, non-small cell lung cancer, prostate cancer, small intestine cancer, sarcoma, leukemia, melanoma, and lymphoma.
- the method further comprises administering to the subject in need thereof an additional known anti-cancer agent.
- a dash ( "-" ) at the left hand side of a substituent is used to indicate a point of attachment for a substituent.
- -CONH 2 is attached through the carbon atom.
- alkyl herein refers to a straight or branched hydrocarbon chain containing 1-14 carbons.
- the symbol of C subscripted with a number range that precedes the term “alkyl” stands for the number of carbons in the alkyl.
- C 1-5 alkyl represents an alkyl containing 1, 2, 3, 4, or 5 carbon atoms.
- Examples of C 1-5 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, and pentyl.
- alkylidene here refers to a divalent group derived from a straight or branched hydrocarbon chain containing 1-14 carbons by removal of two hydrogen atoms from the same carbon atom so that the hydrocarbon chain attaches to an atom through a double bond formed by the same carbon and the atom.
- C 1-6 alkylidene can be represented by the formula wherein R a and R b are selected from H and C 1-5 alkyl provided that the carbon atoms from R 1 and R 2 are at most 5 in total.
- alkenyl herein refers to an unsaturated branched or straight hydrocarbon chain containing at least one carbon-carbon double bond. The group may be in either the cis or trans configuration about the double bond.
- alkenyl stands for the number of carbons in the alkenyl. For example, C 2-8 alkenyl represents an alkenyl containing 2, 3, 4, 5, 6, 7, or 8 carbon atoms.
- alkenyl includes, but are not limited to, ethylenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl) , prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1, 3-dien-1-yl, buta-1, 3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1, 3-dien-1-yl; and the like.
- an alkenyl group has from 2 to 10 carbon atoms and in other embodiments, from 2 to
- alkynyl herein refers to an unsaturated branched or straight hydrocarbon chain containing at least one carbon-carbon triple bond.
- the symbol of C subscripted with a number range that precedes the term “alkynyl” stands for the number of carbons in the alkynyl.
- C 2-8 alkynyl represents an alkynyl containing 2, 3, 4, 5, 6, 7, or 8 carbon atoms.
- alkynyl includes, but are not limited to, ethynyl; propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl; butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl; and the like.
- an alkynyl group has from 2 to 10 carbon atoms and in other embodiments, from 2 to 6 carbon atoms containing one carbon-carbon triple bond.
- alkoxyl refers to -O-alkyl.
- the symbol of C subscripted with a number range that precedes the term “alkoxy” stands for the number of carbons in the alkoxy.
- C 1-5 alkoxy represents an alkoxy containing 1, 2, 3, 4, or 5 carbon atoms.
- Examples of C 1-5 alkoxy groups include, but are not limited to, methoxy, ethoxy, propyloxy, butoxy, and pentoxy.
- aryl refers to a 6-10 ring membered monocyclic aromatic hydrocarbon ring, such as phenyl.
- Aryl also refers to a 8-14 ring membered spiro, fused, or bridged bi-, or multi-cyclic ring system, wherein at least one of the cyclics or rings is aromatic and does not comprise a heteroatom selected from O, S, and N as ring atom, the remaining cyclic (s) or ring (s) may be saturated, partially saturated, or aromatic, provided (1) when the remaining cyclic (s) or ring (s) is aromatic, it does not comprise a heteroatom selected from O, S, and N as ring atom, and (2) when the remaining cyclic (s) or ring (s) is not aromatic, it may or may not comprise a heteroatom selected from O, S, and N as ring atom.
- the point of attachment can be any ring atom. For example, are aryls.
- cycloalkyl herein refers to a 3-14 ring membered saturated or partially unsaturated mono-cyclic, or spiro, fused, or bridged bi-, or multi-cyclic hydrocarbon group only having carbon atom as the ring atom.
- the symbol of C subscripted with a number range that precedes the term “cycloalkyl” stands for the carbon ring numbers in the cycloalkyl.
- C 3-5 cycloalkyl represents a cycloalkyl containing 3, 4, or 5 carbon ring atoms, i.e., cyclopropyl, cyclobutyl, or cyclopentyl.
- the ring may be saturated or have one or more double bonds (i.e., partially unsaturated) , but not fully conjugated.
- cycloalkyl is spiro, fused, or bridged bi-, or multi-cyclic, none of the cycles or rings is aromatic.
- heteroaryl refers to 5-14 ring membered, such as 5 or 6 ring membered, mono-cyclic aromatic ring containing one or more, for example, from 1 to 4, or, in some embodiments, from 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon.
- Heteroaryl also refers to 7-14 ring membered spiro, fused, or bridged bi-, or multi-cyclic ring system, wherein at least one of the cyclics or rings is aromatic containing one or more, for example, from 1 to 4, or, in some embodiments, from 1 to 3, heteroatoms selected from N, O, and S as ring atoms, the remaining cyclic (s) or ring (s) (1) may or may not contain heteroatoms selected from N, O, and S and (2) may be saturated, partially saturated, or aromatic.
- the point of the attachment can be any ring atom.
- heteroaryl include, but are not limited to, pyridinyl, pyrazinyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolinyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothienyl, furyl, benzofuryl, benzoimidazolinyl, indolinyl, pyridizinyl, triazolyl, quinolinyl, pyrazolyl, and 5, 6, 7, 8-tetrahydroisoquinoline.
- heterocyclyl refers to a 5 to 14 ring membered, saturated or partially unsaturated mono-cyclic ring, or fused, spiro, or bridged bicyclic or multicyclic ring, containing one or more, for example, from 1 to 4, or, in some embodiments, from 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon.
- the point of the attachment can be any ring atom.
- heterocyclyl includes but are not limited to pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydro-furanyl, 5, 6, 7, 8-tetrahydroimidazo [1, 2-a] pyrazinyl, tetrahydro-2H-pyranyl, 8-oxa-3-azabicyclo [3.2.1] octanyl, 3-oxa-9-azaspiro [5.5] undecanyl, 7-oxa-2-azaspiro [3.5] nonanyl, and 2-oxa-7-azaspiro [3.5] nonanyl, azepanyl, 1, 2, 5-triazepanyl, 6, 7, 8, 9-tetrahydro-1H, 5H- [1, 2, 4] triazolo [1, 2-a] [1, 2, 5] triazepinyl, diazepanyl, 1, 2, 5-oxadiazepanyl.
- Halo refers to F. Cl, Br or I.
- “Pharmaceutically acceptable salt” refers to a salt form of a compound (e.g., a drug) having at least one group capable of salt formation that causes no significant adverse toxicological effects to the subject.
- Pharmaceutically acceptable salts include, for example, salts prepared by reaction with an inorganic acid, organic acid, or a base depending on the nature of the compound (e.g., drug) .
- the inorganic acid can be hydrochloric acid, hydrobromic acid, carbonic acid, sulfuric acid, phosphoric acid, and the like;
- the organic acid can be fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, methanesulfonic acid and the like.
- the base that can form a salt with an acid drug can be an amine containing compound or inorganic base such as sodium hydroxide, sodium carbonate, and the like.
- Suitable pharmaceutically acceptable salt forms can be found in, for example, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim/Zürich: Wiley-VCH/VHCA, 2002; P.H. Stahl and C.G. Wermuth, Eds.
- treating refers to slowing or arresting the development of a disease, providing relief from the symptoms or side-effects of the disease, and/or causing regression of the disease.
- the terms also refer to reduction of the occurrence of the disease in the subject when compared with a subject without the treatment.
- a “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use.
- “A pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient.
- subject refers to animal (such as mammal) or human.
- Compounds of formula (I) or a pharmaceutically acceptable salt thereof as described herein include, but are not limited to, their solvates, optical isomers, racemates, and other mixtures thereof.
- the single enantiomers or diastereomers i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates or mixtures of diastereomers.
- Resolution of the racemates or mixtures of diastereomers can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral high-pressure liquid chromatography (HPLC) column.
- HPLC high-pressure liquid chromatography
- compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein also include compounds of formula (I) or a pharmaceutically acceptable salt thereof wherein certain atoms in formula (I) are replaced with their corresponding isotopes, such as certain H is replaced by D (deuterium) .
- Compounds disclosed herein will be administered in a therapeutically effective amount by any of the accepted administration modes for agents in the form of a pharmaceutical composition that serve similar utilities.
- Therapeutically effective amount of the compounds disclosed herein may range from 0.01 to 500 mg per kg subject body weight, which can be administered in single or multiple doses per day.
- the pharmaceutical compositions can be provided in the form of tablets or capsules containing 1.0 to 1000 mg of the compound disclosed herein, such as, 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, and 1000 mg of the compound disclosed herein.
- the compound disclosed herein can also be administered as pharmaceutical compositions by, for example, transdermal, intranasal, suppository, intramuscular, intravenous or subcutaneous administration.
- compositions comprising the compound disclosed herein and a pharmaceutically acceptable excipient.
- the pharmaceutical compositions can comprise from 1 mg to 1000 mg of the compound disclosed herein.
- Exemplary solid pharmaceutical excipient includes starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
- Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e g, peanut oil, soybean oil, mineral oil, sesame oil, etc.
- Preferred liquid excipients, particularly for injectable solutions include water, saline, aqueous dextrose, and glycols.
- a method of inhibiting KRAS G12D activity in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound described herein.
- a method of treating a disease or disorder associated with KRAS G12D mutation in a subject in need thereof comprising administering to the patient a therapeutically effective amount of the compound described herein.
- the disease or disorder associated with KRAS G12D mutation can be cancer.
- the cancer includes but not limited to carcinoma, squamous carcinoma, pancreatic cancer, prostate cancer, rectal cancer, colon cancer, colorectal cancer, non-small cell lung cancer, prostate cancer, small intestine cancer, sarcoma, leukemia, melanoma, and lymphoma.
- anti-cancer agents can be Paclitaxel, cisplatin, carboplatin and oxaliplatin, PARP inhibitor (such as niraparib, Olaparib) , anti-PD-1 antibody, anti-PD-L1 antibody, anti-CTLA-4 antibody, mTOR inhibitor, IGF1R inhibitor, HADC inhibitor, EGFR inhibitor, for example, anti-EGFR antibody (such as panitumumab) , HIF-1 inhibitor, VEGF/VEGFR inhibitors (such as sorafenib, bevacizumab) .
- Step 1 synthesis of 2, 6-dichloro-3-fluoropyridin-4-amine (Intermediate 1-1) .
- Step 2 synthesis of tert-butyl (tert-butoxycarbonyl) (2, 6-dichloro-3-fluoropyridin-4-yl) carbamate (Intermediate 1-2) .
- Step 3 synthesis of tert-butyl 4- ( (tert-butoxycarbonyl) amino) -2, 6-dichloro-5-fluoronicotinate (Intermediate 1-3) .
- Step 4 synthesis of 4-amino-2, 6-dichloro-5-fluoronicotinic acid hydrochloride (Intermediate 1-4) .
- Step 5 synthesis of 5, 7-dichloro-8-fluoro-2-mercaptopyrido [4, 3-d] pyrimidin-4-ol (Intermediate 1-5) .
- Step 6 synthesis of 5, 7-dichloro-8-fluoro-2- (methylthio) pyrido [4, 3-d] pyrimidin-4-ol (Intermediate 1) .
- Step 1 synthesis of 7-bromo-6-chloro-5, 8-difluoro-2-mercaptoquinazolin-4-ol (Intermediate 3-1) .
- Step 2 synthesis of 7-bromo-6-chloro-5, 8-difluoro-2- (methylthio) quinazolin-4-ol (Intermediate 3) .
- Step 1 synthesis of (3R, 4S) -4- ( (4-methoxybenzyl) amino) tetrahydrofuran-3-ol (Int-1a-1)
- Step 2 synthesis of (3R, 4S) -4- ( (4-methoxybenzyl) (methyl) amino) tetrahydrofuran-3-ol (Int-1a-2) .
- This intermediate was synthesized following the method described for the synthesis of Int-1a, using (3R, 4S) -4-aminotetrahydro-2H-pyran-3-ol replace (3R, 4S) -4-aminotetrahydrofuran-3-ol.
- Compound 1 synthesis of (7aR, 11aS) -5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -12-methyl-7a, 8, 10, 11, 11a, 12-hexahydro-7, 9-dioxa-1, 3, 6, 12-tetraazapleiadene (Compound 1) .
- Step 1 synthesis of (3R, 4S) -4- ( (5, 7-dichloro-8-fluoro-2- (methylthio) pyrido [4, 3-d] pyrimidin-4-yl) amino) tetrahydro-2H-pyran-3-ol (compound 1-1) .
- Step 2 synthesis of (3R, 4S) -4- ( (5, 7-dichloro-8-fluoro-2- (methylthio) pyrido [4, 3-d] pyrimidin-4-yl) (methyl) amino) tetrahydro-2H-pyran-3-ol (compound 1-2) .
- Step 3 synthesis of (7aR, 11aS) -5-chloro-4-fluoro-12-methyl-2- (methylthio) -7a, 8, 10, 11, 11a, 12-hexahydro-7, 9-dioxa-1, 3, 6, 12-tetraazapleiadene (compound 1-3) .
- Step 4 synthesis of (7aR, 11aS) -4-fluoro-5- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -12-methyl-2- (methylthio) -7a, 8, 10, 11, 11a, 12-hexahydro-7, 9-dioxa-1, 3, 6, 12-tetraazapleiadene (compound 1-4) .
- Step 5 synthesis of (7aR, 11aS) -4-fluoro-5- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -12-methyl-2- (methylsulfinyl) -7a, 8, 10, 11, 11a, 12-hexahydro-7, 9-dioxa-1, 3, 6, 12-tetraazapleiadene (compound 1-5) .
- Step 6 synthesis of (7aR, 11aS) -4-fluoro-5- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -12-methyl-7a, 8, 10, 11, 11a, 12-hexahydro-7, 9-dioxa-1, 3, 6, 12-tetraazapleiadene (compound 1-6) .
- Step 7 synthesis of (7aR, 11aS) -5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -12-methyl-7a, 8, 10, 11, 11a, 12-hexahydro-7, 9-dioxa-1, 3, 6, 12-tetraazapleiadene (compound 1) .
- Step 1 synthesis of tert-butyl (R) -2- ( ( ( (1S, 2S) -2-hydroxycyclopentyl) amino) methyl) pyrrolidine-1-carboxylate (Compound 2-1) .
- Step 2 synthesis of tert-butyl (R) -2- ( ( (5, 7-dichloro-8-fluoro-2- (methylthio) pyrido [4, 3-d] pyrimidin-4-yl) ( (1S , 2S) -2-hydroxycyclopentyl) amino) methyl) pyrrolidine-1-carboxylate (Compound 2-2) .
- Step 3 synthesis of tert-butyl (R) -2- ( ( (7aS, 10aS) -5-chloro-4-fluoro-2- (methylthio) -8, 9, 10, 10a-tetrahydro-7-oxa-1, 3, 6, 11-tetraazanaphtho [1, 8-fg] azulen-11 (7aH) -yl) methyl) pyrrolidine-1-carboxylate (Compound 2-3) .
- Step 4 synthesis of tert-butyl (R) -2- ( ( (7aS, 10aS) -4-fluoro-5- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (methylthio) -8, 9, 10, 10a-tetrahydro-7-oxa-1, 3, 6, 11-tetraazanaphtho [1, 8-fg] azulen-11 (7aH) -yl) methyl) pyrrolidine-1-carboxylate (Compound 2-4) .
- Step 5 synthesis of tert-butyl (2R) -2- ( ( (7aS, 10aS) -4-fluoro-5- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (methylsulfinyl) -8, 9, 10, 10a-tetrahydro-7-oxa-1, 3, 6, 11-tetraazanaphtho [1, 8-fg] azulen-11 (7aH) -yl) methyl) pyrrolidine-1-carboxylate (Compound 2-5) .
- Step 6 synthesis of tert-butyl (R) -2- ( ( (7aS, 10aS) -4-fluoro-5- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen -1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 9, 10, 10a-tetrahydro-7-oxa-1, 3, 6, 11-tetraazanaphtho [1, 8-fg] azulen-11 (7aH) -yl) methyl) pyrrolidine-1-carboxylate (Compound 2-6) .
- Step 7 synthesis of tert-butyl (R) -2- ( ( (7aS, 10aS) -5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 9, 10, 10a-tetrahydro-7-oxa-1, 3, 6, 11-tetraazanaphtho [1, 8-fg] azulen-11 (7aH) -yl) methyl) pyrrolidine-1-carboxylate (Compound 2-7) .
- Step 8 synthesis of (7aS, 10aS) -5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -11- ( ( (R) -pyrrolidin-2-yl) methyl) -7a, 8, 9, 10, 10a, 11-hexahydro-7-oxa-1, 3, 6, 11-tetraazanaphtho [1, 8-fg] azulene (Compound 2) .
- Step 1 synthesis of (3R, 4S) -4- ( (7-bromo-6-chloro-5, 8-difluoro-2- (methylthio) quinazolin-4-yl) (methyl) amino) tetrahydro-2H-pyran-3-ol (6-1) .
- Step 2 synthesis of (7aR, 11aS) -5-bromo-6-chloro-4-fluoro-12-methyl-2- (methylthio) -7a, 8, 10, 11, 11a, 12-hexahydropyrano [3', 4': 2, 3] [1, 4] oxazepino [5, 6, 7-de] quinazoline (6-2) .
- Step 3 synthesis of (7aR, 11aS) -5-bromo-6-chloro-4-fluoro-12-methyl-2- (methylsulfinyl) -7a, 8, 10, 11, 11a, 12-hexahydropyrano [3', 4': 2, 3] [1, 4] oxazepino [5, 6, 7-de] quinazoline (6-3) .
- Step 4 synthesis of (7aR, 11aS) -5-bromo-6-chloro-4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -12-methyl-7a, 8, 10, 11, 11a, 12-hexahydropyrano [3', 4': 2, 3] [1, 4] oxazepino [5, 6, 7-de] quinazoline (6-4) .
- Step 5 synthesis of tert-butyl (4- ( (7aR, 11aS) -6-chloro-4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -12-methyl-7a, 8, 10, 11, 11a, 12-hexahydropyrano [3', 4': 2, 3] [1, 4] oxazepino [5, 6, 7-de] quinazolin-5-yl) -3-cyano-7-fluorobenzo [b] thiophen-2-yl) carbamate (6-5) .
- Step 6 synthesis of 2-amino-4- ( (7aR, 11aS) -6-chloro-4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -12-methyl-7a, 8, 10, 11, 11a, 12-hexahydropyrano [3', 4': 2, 3] [1, 4] oxazepino [5, 6, 7-de] quinazolin-5-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (compound 6) .
- Compound 7 and Compound 8 were obtained by SFC separation of Compound 6 on a Compound 7 was the first fraction and Compound 8 was the second fraction eluting from the column.
- Example 3 In vitro TR-FRET GDP-KRAS binding assay.
- This example illustrates the exemplary compounds of the present invention bind to GDP-form KRAS G12D and capable of displacing a labeled tracer ligand occupying the KRAS G12D GDP binding site.
- the ability of a compound to bind to KRAS G12D was measured using a TR-FRET assay.
- Biotinylated GDP-loaded recombinant human KRAS G12D (His-Avi-KRAS 1-185, produced by ChemPartner) is incubated with a customed Cy5 labelled tracer, europium labelled streptavidin and a series of compound (1%DMSO final) in buffer (50 mM HEPES, 5 mM MgCl 2 , 0.05 ⁇ Tween20, and 1mM DTT) .
- the Em665/620 fluorescence signal is read out after an hour incubation using the PE EnVision instrument.
- Inh % 100- (Sample-Min) / (Max-Min) *100%
- the data is normalized to obtain the enzyme activity inhibition rate Inh %of each concentration point (wherein Max is the Em665/620 value containing enzyme-positive wells, Min is the Em665/620 value of the enzyme-free negative wells, Sample is the Em665/620 value of the compound-treated sample wells)
- Example 4 GTP-KRAS G12D /RAF1 binding assay.
- This example illustrates the exemplary compounds of the present application’s inhibitory effect of the interactions between GTP bound KRAS G12D and RAF1 protein.
- Tag1-RAF1 and Tag2-KRAS G12D are detected by using anti-Tag1-Eu and anti-Tag2-XL665, when the antibodies are brought into close proximity due to RAF1 and GTP-KRAS G12D binding, fluorescent resonance energy transfer (FRET) occurs.
- FRET fluorescent resonance energy transfer
- the inhibitory efficacy was measured using a TR-FRET assay.
- the RAF1 protein and GTP-KRAS G12D and a series of compound (1%DMSO final) was incubated for 20 mins.
- the Em665/620 fluorescence signal was read out after 2 hours after anti-EU and anti-XL665 addition using the PE EnVision instrument.
- Inh % 100- (Sample-Min) / (Max-Min) *100%
- Example 5 Cell Based p-ERK Assay.
- This Example illustrates that exemplary compounds disclosed herein inhibit the intracellular phosphorylation of ERK downstream of KRAS G12D.
- FRET fluorescence resonance energy transfer
- PK-59 cells expressing KRAS G12D mutation were cultured in DMEM medium containing 10%FBS. Seed the cells in the 3D assay plate and cultured at 37 °C for 3 days. Treated with a series of compounds at a final concentration of 0.5%DMSO. After incubation for 2 hours or 24 hours, remove the supernatant, add 1*lysate to lyse the cells, transfer the lysate to a new assay plate, add the mixed antibody solution (Cisbio, Cat. No. 64AERPEH) was incubated overnight at room temperature. The microplate was placed on the EnVision instrument to read the Em665/620 fluorescence signal.
- Inh % 100- (Sample-Min) / (Max-Min) *100%
- the data is normalized to obtain the enzyme activity inhibition rate Inh %of each concentration point (wherein Max is the Em665/620 value containing enzyme-positive wells, Min is the Em665/620 value of the enzyme-free negative wells, Sample is the Em665/620 value of the compound-treated sample wells)
- Example 6 Cell Based p-ERK Assay.
- the 3D CTG assay is a homogeneous method to determine the number of viable cells in 3D cell culture based on quantitation of the ATP present.
- the CTG luminescence value is proportional to ATP, which is proportional to the number of living cells.
- PK-59 cells expressing KRAS G12D mutation were cultured in DMEM medium containing 10%FBS. Seed the cells in the 3D assay plate and cultured at 37 °C 5%CO 2 overnight. Treated with a series of compounds at a final concentration of 0.5%DMSO. After incubation for 168 hours, add the CTG detection buffer (Promega, Cat. No. G9681) mixing well. The microplate was placed on the EnVision instrument to read the luminescence signal.
- Inh % 100- (Sample-Min) / (Max-Min) *100%
- the data is normalized to obtain the activity inhibition rate Inh %of each concentration point (wherein Max is the value containing DMSO wells, Min is the value of the cell-free negative wells, Sample is the value of the compound-treated sample wells)
- Inh% (Y) corresponding to each concentration (X) in EXCEL
- 3D CTG assays can be carried out with cells with different KRAS mutations, such as GP2D (G12D) , NCI-H358 (G12C) , A549 (G12S) , NCI-H727 (G12V) and MKN1 (WT amplified) .
- KRAS mutations such as GP2D (G12D) , NCI-H358 (G12C) , A549 (G12S) , NCI-H727 (G12V) and MKN1 (WT amplified) .
- the IC 50 data were listed in the table below: “++++” represents IC 50 ⁇ 300 nM, “+++” represents 300 nM ⁇ IC 50 ⁇ 1 ⁇ M, “++” represents 1 ⁇ M ⁇ IC 50 ⁇ 5 ⁇ M, “+” represents IC 50 ⁇ 5 ⁇ M.
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Abstract
This application discloses compounds of formula (I), which can be inhibitors of KRAS G12D, and their uses.
Description
This application relates to KRAS G12D modulators, their preparation and uses thereof.
Rat sarcoma (RAS) , encoded by the proto-oncogenes HRAS, NRAS and KRAS, is a GTP-binding protein that is in an activated state when binding with GTP, and is in an inactive state when binding with GDP. RAS is distributed on the inner surface of the cell membrane and is activated when it binds to GTP and inactivated when it binds to GDP. The upstream of RAS is receptor tyrosine kinase (RTK) , which regulates downstream signaling pathways such as PI3K and RAF after activation, thereby regulating cell growth, survival, migration and differentiation functions. Since RAS proteins are central to the axis of many important cellular signaling networks, and these signals are associated with multiple tumor markers, overactive RAS signaling may ultimately lead to tumorigenesis.
Among RAS family members, oncogenic mutations are most commonly found in KRAS (85%) , and aberrant expression of KRAS accounts for up to 20%of all cancers, with G12D mutations accounting for 25%of pancreatic cancer (PDAC) , colon cancer (CRC) 13.3%, rectal cancer (RC) 10.1%, non-small cell lung cancer (NSCLC) 4.1%.
Although there is a high clinical need, so far there is no drug that directly targets the KRAS G12D mutation on the market. There are two main difficulties in the development of KRAS G12D inhibitors. On the one hand, the RAS protein has a smooth structure and there is no obvious pocket on the surface for small molecules to bind to; on the other hand, the affinity of KRAS protein for GTP is as high as a picomolar level and endogenous GTP levels are high. Thus, it is difficult for small-molecule drugs to block the binding of the two. At present, no targeted drug for KRAS G12D mutation has entered the clinical research stage, and there is a large unmet clinical need.
Provided is a compound of formula (I) :
or a pharmaceutically acceptable salt thereof wherein
Q1, Q2, and Q3 are independently selected from N, C-H, C-CF3, C-OH, C-Cl, C-F, C-CH3, C-CH (CH3) 2, C-cyclopropyl, C-OCH3, C-SCF3, C-OCF3, and C-CN;
R1 is selected from L-5-12 membered heterocyclyl which is either monocyclic or bicyclic, and L-C3-8 cycloalkyl, wherein each of the 5-12 membered heterocyclyl and C3-8 cycloalkyl is optionally substituted with one or more W;
L is selected from -CH2-, -CH (CH3) -, CH2-CH2-, and a bond;
R2 is selected from H, C1-6 alkyl optionally substituted with one or more W, C3-6 cycloalkyl optionally substituted with one or more W, and 4-6 membered heterocyclyl optionally substituted with one or more W;
Ring A is selected from a 4-12 membered heterocyclyl, a C4-10 cycloalkyl, and a 9-12 membered fused bicyclic heteroaryl, each of which is optionally substituted with one or more W;
R3 is selected from aryl and heteroaryl, wherein the aryl and heteroaryl is optionally substituted with one or more W;
X is selected from O, S and NR5;
Y is selected from a bond and -O-;
R5 is selected from H and C1-6 alkyl; and
W is independently selected from OH, CN, halo, C2-4 alkenyl, C2-4 alkynyl, -NR8R9, =NR8, oxo, -OC (O) NR8R9, -C (O) NR8R9, -NR10C (O) R11, -NR10C (O) NR8R9, -S (O) 2NR8NR9, -NR10S (O) 2R11, 4-6 membered heterocyclyl, C3-8 cycloalkyl, C1-6 alkoxy, C1-6 alkylidene, and C1-6 alkyl, wherein each of the 4-6 membered heterocyclyl, C3-8 cycloalkyl, C1-6 alkoxy, C1-6 alkylidene, and C1-6 alkyl is optionally substituted with one or more groups selected from OH, F, Cl, C1-6 alkyl, C1-6 alkoxy, -NR8R9, -OC (O) NR8R9, and oxo;
R8 and R9 are independently selected from H and C1-6 alkyl, or R8 and R9, together with the nitrogen to which they are attached, independently form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, and C1-6 alkyl; and
R10 and R11 are independently selected from H and C1-6 alkyl.
In some embodiments, Q1 is N, and either (i) Q2 is N and Q3 is C-H, C-CF3, C-OH, C-Cl, C-F, C-CH3, C-CH (CH3) 2, C-cyclopropyl, C-OCH3, C-SCF3, C-OCF3, or C-CN, or (ii) Q2 is C-H, C-CF3, C-OH, C-Cl, C-F, C-CH3, C-CH (CH3) 2, C-cyclopropyl, C-OCH3, C-SCF3, C-OCF3, or C-CN, and Q3 is N. In some embodiments, Q1 is N, Q2 is N, and Q3 is C-H or C-F. In some embodiments, Q3 is C-H. In some embodiments, Q3 is C-F. In some embodiments, Q1 is N, Q2 is N, C-H, C-CF3, C-OH, C-Cl, C-F, C-CH3, C-CH (CH3) 2, C-cyclopropyl, C-OCH3, C-SCF3, C-OCF3, or C-CN, and Q3 is C-H, C-CF3, C-OH, C-Cl, C-F, C-CH3, C-CH (CH3) 2, C-cyclopropyl, C-OCH3, C-SCF3, C-OCF3, or C-CN. In some embodiments, Q1 is N, Q2 is N, C-H, C-CF3, C-OH, C-Cl, C-F, C-CH3, C-CH (CH3) 2, C-cyclopropyl, C-OCH3, C-SCF3, C-OCF3, or C-CN, and Q3 is C-H or C-F. In some embodiments, Q1 is N, Q2 is C-H, C-CF3, C-OH, C-Cl, C-F, C-CH3, C-CH (CH3) 2, C-cyclopropyl, C-OCH3, C-SCF3, C-OCF3, or C-CN, and Q3 is C-H or C-F. In some embodiments, Q3 is C-H. In some embodiments, Q3 is C-F.
In some embodiments, R3 is an aryl selected from phenyl, naphthyl, and 1H-indenyl, or a heteroaryl selected from pyridinyl, benzothiazolyl, benzothiophenyl, 1H-indazolyl, or 1H-indolyl, and the aryl or heteroaryl is optionally substituted with one or more W, and wherein optionally, W is independently selected from halo, C1-3 alkyl, C2 alkenyl, C2 alkynyl, C1 alkyl substituted with one or more F, optionally CF3, C3 cycloalkyl, -NR8R9, -CN, and OH; and wherein optionally, R8 is H and R9 is H.
In some embodiments, R3 is aryl and said aryl is phenyl, naphthyl, or 1H-indenyl, each of which is optionally substituted with one or more W. In some embodiments, R3 is aryl and said aryl is phenyl or naphthyl, each of which is optionally substituted with one or more W. In some embodiments, R3 is aryl and said aryl is phenyl, optionally substituted with one or more W. In some embodiments, R3 is aryl and said aryl is naphthyl, optionally substituted with one or more W. In some embodiments, R3 is heteroaryl and said heteroaryl is pyridinyl, benzothiazolyl, benzothiophenyl, 1H-indazolyl, or 1H-indolyl, each of which is optionally substituted with one or more W. In some embodiments, R3 is heteroaryl and said heteroaryl is pyridinyl, 1H-indazolyl, or 1H-indolyl, each of which is optionally substituted with one or more W. In some embodiments, R3 is phenyl, naphthyl, pyridinyl, benzothiazolyl, benzothiophenyl, 1H-indenyl, 1H-indazolyl, or 1H-indolyl, each of which is optionally substituted with one or more W. In some embodiments, R3 is phenyl, naphthyl, pyridinyl, benzothiazolyl, benzothiophenyl, 1H-
indenyl, 1H-indazolyl, or 1H-indolyl, each of which is optionally substituted with one or more W, and wherein optionally, W is independently selected from halo, C1-3 alkyl, C2 alkenyl, C2 alkynyl, C1 alkyl substituted with one or more F, optionally CF3, C3 cycloalkyl, -NR8R9, -CN, and OH; and wherein optionally, R8 is H and R9 is H. In some embodiments, wherein W is halo, halo is selected from F and Cl.
In some embodiments, R3 is selected from
In some embodiments, R3 is selected from
In some embodiments, Y is O.
In some embodiments, X is O.
In some embodiments, L is CH2, CH (CH3) , or CH2CH2.
In some embodiments, R1 is selected from L-7-10 membered heterocyclyl which is monocyclic or bicyclic comprising at least one heteroatom selected from nitrogen and oxygen, and L-C4-7 cycloalkyl, wherein each of the 7-10 membered heterocyclyl and L-C4-7 cycloalkyl is optionally substituted with one or more W.
In some embodiments, R1 is optionally substituted with one or more W independently selected from F, C1-3 alkylidene optionally substituted with 1-5 F, and C1-3 alkyl optionally substituted with -OC (O) NR8R9 or –NR8R9, with R8 and R9 independently being selected from H and C1-6 alkyl, or R8 and R9, together with the nitrogen to which they are attached, form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, C1-
6 alkyl. In some embodiments, R8 and R9 are methyl or R8 and R9, together with the nitrogen to which they are attached, form a morpholine.
In some embodiments, R1 is L-C3-8 cycloalkyl optionally substituted with one or more W. In some embodiments, R1 is L-C3-8 cycloalkyl optionally substituted with methyl, wherein the methyl is optionally substituted with -OC (O) NR8R9 or –NR8R9, with R8 and R9 independently being selected from H and C1-6 alkyl, or R8 and R9, together with the nitrogen to which they are attached, form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, C1-6 alkyl. In some embodiments, R1 is L-C3-8 cycloalkyl optionally substituted with methyl, wherein the methyl is optionally substituted with -O (CO) N (CH3) 2, -O (CO) -morpholine, -N (CH3) 2, or morpholine.
In some embodiments, R1 is
In some embodiments, L is CH2 or CH (CH3) .
In some embodiments, R2 is selected from H, 4-6 membered heterocyclyl optionally substituted with one or more substituent selected from methyl and ethyl, C3-6 cycloalkyl optionally substituted with one or more substituent selected from OH, -NR8R9, and C1-6 alkyl optionally substituted with one or more groups selected from OH, F, Cl, C1-6 alkyl, C1-6 alkoxy, and oxo, and C1-6 alkyl optionally substituted with one or more substituent selected from OH, -NR8R9, -NR10C (O) R11, and 4 or 5 membered heterocyclyl optionally substituted with one or more groups selected from OH, F, Cl, C1-6 alkyl, C1-6 alkoxy, and oxo, wherein R8 and R9 are independently selected from H and C1-6 alkyl, or R8 and R9, together with the nitrogen to which they are attached, independently form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, and C1-6 alkyl, and R10 and R11 are independently selected from H and C1-6 alkyl.
In some embodiments, R2 is selected from H, methyl, ethyl, - (CH2) 2OH,
- (CH2) 3OH, - (CH2) 2NH2, -
(CH2) 2NHC (O) CH3,
In some embodiments, R2 is a C1-6 alkyl optionally substituted with one or more W. In some embodiments, R2 is a C1-6 alkyl optionally substituted with one or more substituent selected from halo, OH, =NR8, -NR8R9, -C (O) NR8R9, -NR10C (O) R11, and 4 or 5 membered heterocyclyl optionally substituted with one or more groups selected from OH, F, Cl, C1-6 alkyl, C1-6 alkoxy, and oxo, wherein R8 and R9 are independently selected from H and C1-6 alkyl, or R8 and R9, together with the nitrogen to which they are attached, independently form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, and C1-6 alkyl, and R10 and R11 are independently selected from H and C1-6 alkyl.
In some embodiments, R2 is selected from methyl, ethyl, - (CH2) 2OH,
- (CH2) 3OH, - (CH2) 2NH2, - (CH2) 2F, -CH2CHF2, -CH2CF3, , - (CH2) 2NHC (O) CH3, -CH2C (O) NH2, - (CH2) 2C (O) NH2, -C (NH) NH2, -C (NH) CH3, -CH (CH3) CH2NHCH3, -CH (CH2CH3) CH2NHCH3, -CH (CH2OH) CH2NHCH3, -CH (CH2OH) CH2OH,
In some embodiments, R2 is a 4-6 membered heterocyclyl optionally substituted with one or more W. In some embodiments, R2 is a 4-6 membered heterocyclyl optionally substituted with one or more substituent selected from methyl and ethyl, each of which is optionally substituted with one or more groups selected from OH, F, Cl, C1-6 alkyl, C1-6 alkoxy, -NR8R9, and oxo, wherein R8 and R9 are independently selected from H and C1-6 alkyl, or R8 and R9, together with the nitrogen to which they are attached, independently form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, and C1-6 alkyl.
In some embodiments, R2 is selected from
In some embodiments, R2 is a C3-6 cycloalkyl optionally substituted with one or more W. In some embodiments, R2 is a C3-6 cycloalkyl optionally substituted with one or more substituent selected from F, Cl, OH, -NR8R9, and C1-6 alkyl optionally substituted with one or more group selected from F, CL, OH, C1-6 alkoxy, -NR8R9, -OC (O) NR8R9, and oxo, wherein R8 and R9 are independently selected from H and C1-6 alkyl, or R8 and R9, together with the nitrogen to which they are attached, independently form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, and C1-6 alkyl.
In some embodiments, R2 is selected from cyclopropanyl, cyclobutanyl,
In some embodiments, ring A is a 4-9 membered heterocyclyl which contains only one heteroatom, wherein the only one heteroatom is the nitrogen to which R4 is attached. In some embodiments, ring A is a 4-7 membered monocyclic heterocyclyl optionally substituted with one or more W. In some embodiments, ring A is a 4-7 membered monocyclic cycloalkyl optionally substituted with one or more W. In some embodiments, ring A is a 8-12 membered fused, bridged, or spiro bicyclic heterocyclyl optionally substituted with one or more W. In some embodiments, ring A is a heterocyclyl selected from
each of which is optionally substituted with one or more group selected from OH, F, Cl, CN, NH2, oxo, OC (O) NR8R9, -C (O) NR8R9, -NR10C (O) R11, -NR10C (O) NR8R9, -S (O) 2NR8NR9, -
NR10S (O) 2R11, and C1-6 alkyl optionally substituted with one or more groups selected from OH, F, Cl, C1-6 alkoxy, -NR8R9, and oxo, wherein R8 and R9 are independently selected from H and C1-6 alkyl, or R8 and R9, together with the nitrogen to which they are attached, independently form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, and C1-6 alkyl, and R10 and R11 are independently selected from H and C1-6 alkyl.
In some embodiments, ring A is a heterocyclyl selected from
In some embodiments, ring A is a 9-12 membered fused bicyclic heteroaryl, which is optionally substituted with one or more W. In some embodiments, the 9-12 membered fused bicyclic heteroaryl has one ring as being aromatic and the other non-aromatic. In some embodiments, ring A iswhich is optionally substituted with one or more group selected from OH, F, Cl, CN, NH2, oxo, OC (O) NR8R9, -C (O) NR8R9, -NR10C (O) R11, -NR10C (O) NR8R9, -S (O) 2NR8NR9, -NR10S (O) 2R11, and C1-6 alkyl optionally substituted with one or more groups selected from OH, F, Cl, C1-6 alkyl, C1-6 alkoxy, -NR8R9, and oxo, wherein R8 and R9 are independently selected from H and C1-6 alkyl, or R8 and R9, together with the nitrogen to which they are attached, independently form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, and C1-6 alkyl, and R10 and R11 are independently selected from H and C1-6 alkyl.
In some embodiments, ring A is
In some embodiments, ring A is a C4-7 monocyclic cycloalkyl optionally substituted with one or more W. In some embodiments, ring A is cyclobutyl, cyclopentanyl, cyclohexanyl, and cyclohepanyl, which is optionally substituted with one or more groups selected from C1-6 alkyl optionally substituted with 1-5 F or Cl, OH, F, Cl, CN, OC (O) NR8R9, -C (O) NR8R9, -NR10C (O) R11, -NR10C (O) NR8R9, -S (O) 2NR8NR9, -NR10S (O) 2R11, wherein R8 and R9 are independently selected from H and C1-6 alkyl, or R8 and R9, together with the nitrogen to which they are attached, independently form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, and C1-6 alkyl, and R10 are independently selected from H and C1-6 alkyl.
In some embodiments, ring A is a cyclopentyl.
In some embodiments, the compound as disclosed herein is:
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound as disclosed herein is:
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound as disclosed herein is or a pharmaceutically acceptable salt thereof; optionally, or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound as disclosed herein is or a pharmaceutically acceptable salt thereof; optionally, or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound as disclosed herein is or a pharmaceutically acceptable salt thereof; optionally, or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound as disclosed herein is or a pharmaceutically acceptable salt thereof; optionally,
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound as disclosed herein isor a pharmaceutically acceptable salt thereof; optionally, or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound as disclosed herein is or a pharmaceutically acceptable salt thereof; optionally, or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound as disclosed herein is or a pharmaceutically acceptable salt thereof; optionally, or a pharmaceutically acceptable salt thereof.
Also provided is a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof as disclosed herein and a pharmaceutically acceptable excipient.
Also provided is a method of inhibiting KRAS G12D activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition as disclosed herein.
Also provided is a method of treating a disease or disorder associated with KRAS G12D mutation in a subject in need thereof, comprising administering to the patient a therapeutically effective amount of a composition as disclosed herein.
In some embodiments, the disease or disorder associated with KRAS G12D mutation is cancer. In some embodiments, the cancer is selected from carcinoma, squamous carcinoma, pancreatic cancer, prostate cancer, rectal cancer, colon cancer, colorectal cancer, non-small cell lung cancer, prostate cancer, small intestine cancer, sarcoma, leukemia, melanoma, and lymphoma.
In some embodiments, the method further comprises administering to the subject in need thereof an additional known anti-cancer agent.
I. Definitions
The substituents as disclosed herein intend to result in a chemical structure that is stable. Any substitution pattern that will render a compound known to be chemically unstable to a skilled artisan is not contemplated herein.
Notwithstanding the title, nothing in this application indicates that the compounds as disclosed herein can be only used as KRAS G12D modulators.
A dash ( "-" ) at the left hand side of a substituent is used to indicate a point of attachment for a substituent. For example, -CONH2 is attached through the carbon atom.
The term "alkyl" herein refers to a straight or branched hydrocarbon chain containing 1-14 carbons. The symbol of C subscripted with a number range that precedes the term “alkyl” stands for the number of carbons in the alkyl. For example, C1-5 alkyl represents an alkyl containing 1, 2, 3, 4, or 5 carbon atoms. Examples of C1-5 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, and pentyl.
The term “alkylidene” here refers to a divalent group derived from a straight or branched hydrocarbon chain containing 1-14 carbons by removal of two hydrogen atoms from the same carbon atom so that the hydrocarbon chain attaches to an atom through a double bond formed by the same carbon and the atom. C1-6 alkylidene can be represented by the formulawherein Ra and Rb are selected from H and C1-5 alkyl provided that the carbon atoms from R1 and R2 are at most 5 in total.
The term “alkenyl” herein refers to an unsaturated branched or straight hydrocarbon chain containing at least one carbon-carbon double bond. The group may be in either the cis or trans configuration about the double bond. The symbol of C subscripted with a number range that precedes the term “alkenyl” stands for the number of carbons in the alkenyl. For example, C2-8 alkenyl represents an alkenyl containing 2, 3, 4, 5, 6, 7, or 8 carbon atoms. Exemplary alkenyl includes, but are not limited to, ethylenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl) , prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1, 3-dien-1-yl, buta-1, 3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1, 3-dien-1-yl; and the like. In certain embodiments, an alkenyl group has from 2 to 10 carbon atoms and in other embodiments, from 2 to 6 carbon atoms containing one carbon-carbon double bond.
The term “alkynyl” herein refers to an unsaturated branched or straight hydrocarbon chain containing at least one carbon-carbon triple bond. The symbol of C subscripted with a number range that precedes the term “alkynyl” stands for the number of carbons in the alkynyl. For example, C2-8 alkynyl represents an alkynyl containing 2, 3, 4, 5, 6, 7, or 8 carbon atoms. Exemplary alkynyl includes, but are not limited to, ethynyl; propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl; butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl; and the like. In certain embodiments, an alkynyl group has from 2 to 10 carbon atoms and in other embodiments, from 2 to 6 carbon atoms containing one carbon-carbon triple bond.
The term “alkoxyl” or “alkoxy” herein refers to -O-alkyl. The symbol of C subscripted with a number range that precedes the term “alkoxy” stands for the number of carbons in the alkoxy. For example, C1-5 alkoxy represents an alkoxy containing 1, 2, 3, 4, or 5 carbon atoms. Examples of C1-5 alkoxy groups include, but are not limited to, methoxy, ethoxy, propyloxy, butoxy, and pentoxy.
The term “aryl” refers to a 6-10 ring membered monocyclic aromatic hydrocarbon ring, such as phenyl. Aryl also refers to a 8-14 ring membered spiro, fused, or bridged bi-, or multi-cyclic ring system, wherein at least one of the cyclics or rings is aromatic and does not comprise a heteroatom selected from O, S, and N as ring atom, the remaining cyclic (s) or ring (s) may be saturated, partially saturated, or aromatic, provided (1) when the remaining cyclic (s) or ring (s) is aromatic, it does not comprise a heteroatom selected from O, S, and N as ring atom, and (2) when the remaining cyclic (s) or ring (s) is not aromatic, it may or may not comprise a heteroatom selected from O, S, and N as ring atom. The point of attachment can be any ring atom. For example, are aryls.
The term "cycloalkyl" herein refers to a 3-14 ring membered saturated or partially unsaturated mono-cyclic, or spiro, fused, or bridged bi-, or multi-cyclic hydrocarbon group only having carbon atom as the ring atom. The symbol of C subscripted with a number range that precedes the term “cycloalkyl” stands for the carbon ring numbers in the cycloalkyl. For example, C3-5 cycloalkyl represents a cycloalkyl containing 3, 4, or 5 carbon ring atoms, i.e., cyclopropyl, cyclobutyl, or cyclopentyl. The ring may be saturated or have one or more double bonds (i.e., partially unsaturated) , but not fully conjugated. When cycloalkyl is spiro, fused, or bridged bi-, or multi-cyclic, none of the cycles or rings is aromatic.
The term "heteroaryl" refers to 5-14 ring membered, such as 5 or 6 ring membered, mono-cyclic aromatic ring containing one or more, for example, from 1 to 4, or, in some embodiments, from 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. Heteroaryl also refers to 7-14 ring membered spiro, fused, or bridged bi-, or multi-cyclic ring system, wherein at least one of the cyclics or rings is aromatic containing one or more, for example, from 1 to 4, or, in some embodiments, from 1 to 3, heteroatoms selected from N, O, and S as ring atoms, the remaining cyclic (s) or ring (s) (1) may or may not contain heteroatoms selected from N, O, and S and (2) may be saturated, partially saturated, or aromatic. The point of the attachment can be any ring atom. For example,
are heteroaryls.
Further exemplary heteroaryl include, but are not limited to, pyridinyl, pyrazinyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolinyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothienyl, furyl, benzofuryl, benzoimidazolinyl, indolinyl, pyridizinyl, triazolyl, quinolinyl, pyrazolyl, and 5, 6, 7, 8-tetrahydroisoquinoline.
The term “heterocyclyl" herein refers to a 5 to 14 ring membered, saturated or partially unsaturated mono-cyclic ring, or fused, spiro, or bridged bicyclic or multicyclic ring, containing one or more, for example, from 1 to 4, or, in some embodiments, from 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. The point of the attachment can be any ring atom. When heterocyclyl is spiro, fused, or bridged bi-, or multi-cyclic, none of the cycles or rings is aromatic.
Exemplary heterocyclyl includes but are not limited to pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydro-furanyl, 5, 6, 7, 8-tetrahydroimidazo [1, 2-a] pyrazinyl, tetrahydro-2H-pyranyl, 8-oxa-3-azabicyclo [3.2.1] octanyl, 3-oxa-9-azaspiro [5.5] undecanyl, 7-oxa-2-azaspiro [3.5] nonanyl, and 2-oxa-7-azaspiro [3.5] nonanyl, azepanyl, 1, 2, 5-triazepanyl, 6, 7, 8, 9-tetrahydro-1H, 5H- [1, 2, 4] triazolo [1, 2-a] [1, 2, 5] triazepinyl, diazepanyl, 1, 2, 5-oxadiazepanyl.
“Halo” refers to F. Cl, Br or I.
“Oxo” refers to = (O) .
“Pharmaceutically acceptable salt” refers to a salt form of a compound (e.g., a drug) having at least one group capable of salt formation that causes no significant adverse toxicological effects to the subject. Pharmaceutically acceptable salts include, for example, salts prepared by reaction with an inorganic acid, organic acid, or a base depending on the nature of the compound (e.g., drug) . The inorganic acid can be hydrochloric acid, hydrobromic acid, carbonic acid, sulfuric acid, phosphoric acid, and the like; the organic acid can be fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, methanesulfonic acid and the like. The base that can form a salt with an acid drug can be an amine containing compound or inorganic base such as sodium hydroxide, sodium carbonate, and the like. Suitable pharmaceutically acceptable salt forms can be found in, for example, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim/Zürich: Wiley-VCH/VHCA, 2002; P.H. Stahl and C.G. Wermuth, Eds.
The terms “treating” , “treatment” , or “treat” (of) a disease refers to slowing or arresting the development of a disease, providing relief from the symptoms or side-effects of the disease, and/or causing regression of the disease. The terms also refer to reduction of the occurrence of the disease in the subject when compared with a subject without the treatment.
A "pharmaceutically acceptable excipient" means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use. "A pharmaceutically acceptable excipient" as used in the specification and claims includes both one and more than one such excipient.
The term “subject” as used herein refers to animal (such as mammal) or human.
Compounds of formula (I) or a pharmaceutically acceptable salt thereof as described herein include, but are not limited to, their solvates, optical isomers, racemates, and other mixtures thereof. In those situations, the single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates or mixtures of diastereomers. Resolution of the racemates or mixtures of diastereomers can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral high-pressure liquid chromatography (HPLC) column. Where compounds described herein exist in various tautomeric forms, the term "compound" is intended to include all tautomeric forms of the
compound. Moreover, compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein also include compounds of formula (I) or a pharmaceutically acceptable salt thereof wherein certain atoms in formula (I) are replaced with their corresponding isotopes, such as certain H is replaced by D (deuterium) .
II. Compounds and uses thereof
Compounds disclosed herein (the term “compound (s) disclosed herein” includes pharmaceutically acceptable salt thereof) will be administered in a therapeutically effective amount by any of the accepted administration modes for agents in the form of a pharmaceutical composition that serve similar utilities. Therapeutically effective amount of the compounds disclosed herein may range from 0.01 to 500 mg per kg subject body weight, which can be administered in single or multiple doses per day. For oral administration, the pharmaceutical compositions can be provided in the form of tablets or capsules containing 1.0 to 1000 mg of the compound disclosed herein, such as, 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, and 1000 mg of the compound disclosed herein.
In addition to oral administration, the compound disclosed herein can also be administered as pharmaceutical compositions by, for example, transdermal, intranasal, suppository, intramuscular, intravenous or subcutaneous administration.
Thus, also provided is a pharmaceutical composition comprising the compound disclosed herein and a pharmaceutically acceptable excipient. When prepared for unit dosage form, the pharmaceutical compositions can comprise from 1 mg to 1000 mg of the compound disclosed herein.
Exemplary solid pharmaceutical excipient includes starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e g, peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid excipients, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.
Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E.W. Martin (Mack Publishing Company, 20th ed., 2000) .
Further provided is a method of inhibiting KRAS G12D activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound described herein.
Further provided is a method of treating a disease or disorder associated with KRAS G12D mutation in a subject in need thereof, comprising administering to the patient a therapeutically effective amount of the compound described herein.
The disease or disorder associated with KRAS G12D mutation can be cancer. The cancer includes but not limited to carcinoma, squamous carcinoma, pancreatic cancer, prostate cancer, rectal cancer, colon cancer, colorectal cancer, non-small cell lung cancer, prostate cancer, small intestine cancer, sarcoma, leukemia, melanoma, and lymphoma.
The compound disclosed herein may be administered in combination with other anti-cancer agents, or in combination with radiation therapy or surgery. Other anti-cancer agents can be Paclitaxel, cisplatin, carboplatin and oxaliplatin, PARP inhibitor (such as niraparib, Olaparib) , anti-PD-1 antibody, anti-PD-L1 antibody, anti-CTLA-4 antibody, mTOR inhibitor, IGF1R inhibitor, HADC inhibitor, EGFR inhibitor, for example, anti-EGFR antibody (such as panitumumab) , HIF-1 inhibitor, VEGF/VEGFR inhibitors (such as sorafenib, bevacizumab) .
EXAMPLES
The compounds and processes of the present disclosure will be better understood in connection with the following examples, which are intended as an illustration only and not limiting the scope of the disclosure. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and such changes and modifications including, without limitation, those relating to the chemical structures, substituents, derivatives, formulations, and/or method of the invention may be made without departing from the spirit of the invention and the scope of the appended claims.
Example 1: Intermediate Synthesis.
1a: synthesis of 5, 7-dichloro-8-fluoro-2- (methylthio) pyrido [4, 3-d] pyrimidin-4-ol (Intermediate 1) .
Step 1: synthesis of 2, 6-dichloro-3-fluoropyridin-4-amine (Intermediate 1-1) .
To a solution of 2, 6-dichloropyridin-4-amine (50 g, 307 mmol) in methanol (500 mL) and water (100 mL) was added Selectfluor (130 g, 367 mmol) at room temperature. After stirring at ~45 ℃ for 16 hours, the reaction mixture was concentrated. The residue was diluted with ethyl acetate (500 mL) , washed with water (500 mLx3) , brine, dried over sodium sulfate, and concentrated to afford Intermediate 1-1 (50 g, 90%yield) as a white solid. LC-MS: m/z = 181.0 [M+H] +.
Step 2: synthesis of tert-butyl (tert-butoxycarbonyl) (2, 6-dichloro-3-fluoropyridin-4-yl) carbamate (Intermediate 1-2) .
To a solution of Intermediate 1-1 (50 g, 277.79 mmol) in tetrahydrofuran (500 mL) were added 4-dimethylaminopyridine (1.7 g, 13.89 mmol) and di-tert-butyl dicarbonate (150 g, 694.38 mmol) portion-wise at room temperature. The mixture was stirred at 60 ℃ for 4 hours and then concentrated under vacuum. The crude product was triturated with methanol (200 mL) to give Intermediate 1-2 (50 g, 47.5%yield) as a white solid. LC-MS: m/z = 381.0 [M+H] +.
Step 3: synthesis of tert-butyl 4- ( (tert-butoxycarbonyl) amino) -2, 6-dichloro-5-fluoronicotinate (Intermediate 1-3) .
To a solution of diisopropylamine (22.3 g, 219 mmol) in anhydrous tetrahydrofuran (180 mL) was added n-butyllithium (2.7 M, 81 mL, 218.7 mmol) dropwise at -78 ℃ under nitrogen. The mixture was stirred for another hour at the same temperature. To the above lithium solution was added a solution of Intermediate 1-2 (30 g, 78.9 mmol) in tetrahydrofuran (150 mL) dropwise at -78 ℃ under nitrogen. After stirring for one hour, the reaction mixture was carefully quenched with acetic acid and diluted with ethyl acetate (1500 mL) . The resulting mixture was washed with water (500 mLx3) , brine (500 mL) , dried over sodium sulfate, and concentrated.
The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 20/1) to give Intermediate 1-3 (15 g, 50%yield) as a white solid. LC-MS: m/z = 381.0 [M+H] +.
Step 4: synthesis of 4-amino-2, 6-dichloro-5-fluoronicotinic acid hydrochloride (Intermediate 1-4) .
To Intermediate 1-3 (10 g, 26.25 mmol) was added 4M HCl in 1, 4-dioxane solution (100 mL) and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to afford Intermediate 1-4 (5.5 g, 93%yield) as a white solid. LC-MS: m/z = 224.9 [M+H] +.
Step 5: synthesis of 5, 7-dichloro-8-fluoro-2-mercaptopyrido [4, 3-d] pyrimidin-4-ol (Intermediate 1-5) .
To a solution of Intermediate 1-4 (5 g, 22.32 mmol) in thionyl chloride (150 mL) was added N, N-dimethylformamide (2 drops) . The reaction mixture was stirred at 90 ℃ for 3 hours and then concentrated. To the residue were added tetrahydrofuran (10 mL) and ammonia thiocyanate (5.10 g, 66.96 mmol) . The resulting mixture was stirred at room temperature for 2 hours and then diluted with ethyl acetate (600 mL) . The mixture was washed with water (200 mL) , brine, dried over sodium sulfate, and concentrated to afford Intermediate 1-5 (5.5 g, 94.8%yield) as a yellow solid.
Step 6: synthesis of 5, 7-dichloro-8-fluoro-2- (methylthio) pyrido [4, 3-d] pyrimidin-4-ol (Intermediate 1) .
To a solution of Intermediate 1-5 (5.4 g, 20.3 mmol) in methanol (400 mL) and water (400 mL) was added iodomethane (5.76 g, 40.6 mmol) followed by sodium hydroxide (1.62 g, 40.6 mmol) . The reaction was stirred at room temperature for 2 hours. The resulting mixture was then diluted with water (400 mL) and adjusted the pH to ~7 with 2 M hydrochloric acid. The resulting precipitate was collected by filtration, and the filter cake was washed with water (100 mL) and oven dried to afford Intermediate 1 (3.8 g, 67.1%yield) as a yellow solid. LC-MS: m/z = 279.9 [M+H] +.
1b: Synthesis of 4, 5, 7-trichloro-8-fluoro-2- (methylthio) pyrido [4, 3-d] pyrimidine (Intermediate 2) .
To a solution of 5, 7-dichloro-8-fluoro-2- (methylthio) pyrido [4, 3-d] pyrimidin-4-ol (Intermediate 1) (1.0 g, 3.57 mmol) in phosphorus oxychloride (8 mL) was added N, N-diisopropylethylamine (2.3 g, 17.85 mmol) at 25 ℃. The mixture was heated at 130 ℃ for 4 hours. The mixture was cooled to room temperature and concentrated. The crude was diluted with ethyl acetate (200 mL) , washed with cold water (200 mLx2) , cold brine (100 mL) , dried over Na2SO4, and concentrated at 25 ℃ to afford Intermediate 2 (1.2 g, crude) as a brown solid, which was used in the next step without further purification.
1c: synthesis of 7-bromo-6-chloro-5, 8-difluoro-2- (methylthio) quinazolin-4-ol (Intermediate 3) .
Step 1: synthesis of 7-bromo-6-chloro-5, 8-difluoro-2-mercaptoquinazolin-4-ol (Intermediate 3-1) .
A mixture of 2-amino-4-bromo-5-chloro-3, 6-difluorobenzoic acid (10 g, 35.09 mmol) in SOCl2 (50 mL) was stirred at 80 ℃ for 1 h. The reaction was concentrated under vacuum and the residue was dissolved with acetone (25 mL) . The solution was then added dropwise to a mixture of NH4SCN (2.9 g, 38.15 mmol) in acetone (25 mL) at rt. After stirring at rt for 2 hrs, the mixture was poured into water (150 mL) and filtered. The filter cake was washed with water (25mL x2) . The filtrate was extracted with EtOAc (75 mL x2) . The organic phase and the cake were combined and concentrated under vacuum. The residue was slurried with petroleum ether/EtOAc (1/1) and filtered to afford Intermediate 3-1 (7 g, 61.2%) as a yellow solid. LC-MS: m/z = 326.8 [M+H] +.
Step 2: synthesis of 7-bromo-6-chloro-5, 8-difluoro-2- (methylthio) quinazolin-4-ol (Intermediate 3) .
To a stirred mixture of Intermediate 3-1 (7 g, crude) , NaOH solution (1.05 g, 26.25 mmol in 7 mL of water) and MeOH (70 mL) was added MeI (3.64 g, 25.6 mmol) at rt. The
resulting mixture was stirred at rt for 2 hrs. The reaction was poured into water (400 mL) and adjusted to pH to 6 by HCl (2M) . The filter cake was washed with water (60 mL x2) . The filtrate was extracted with DCM (90 mL x2) . The organic phase and the cake were combined and concentrated under vacuum. The residue was triturated with MeOH (140 mL) and filtered to afford Intermediate 3 (5 g, 68.3%yield) as a yellow solid. LC-MS: m/z = 341.0 [M+H] +.
1d: synthesis of (3R, 4S) -4- (methylamino) tetrahydrofuran-3-ol (Int-1a) .
Step 1: synthesis of (3R, 4S) -4- ( (4-methoxybenzyl) amino) tetrahydrofuran-3-ol (Int-1a-1)
To a solution of (3R, 4S) -4-aminotetrahydrofuran-3-ol (2 g, 19.39 mmol) in methanol (60 mL) were added acetic acid (1.16 g, 19.39 mmol) , anisic aldehyde (2.64 g, 19.39 mmol) and magnesium sulfate (7.0 g, 58.18 mmol) . The mixture was stirred at 25 ℃ for 3 hours before sodium cyanoborohydride (2.44 g, 38.79 mmol) was added. After stirring at 25 ℃ for additional 16 hours, the reaction mixture was concentrated under vacuum to remove most of the solvent. The residue was purified using silica gel chromatography to yield Int-1a-1 (2.5 g, yield: 57.7%) as a yellow liquid. LC-MS: m/z = 224.1 [M+H] +.
Step 2: synthesis of (3R, 4S) -4- ( (4-methoxybenzyl) (methyl) amino) tetrahydrofuran-3-ol (Int-1a-2) .
To a solution of Int-1a-1 (2.45 g, 10.97 mmol) in methanol (50 mL) were added acetic acid (658.96 mg, 10.97 mmol) and formaldehyde (37%in water, 2.67 g, 32.92 mmol) , ) and the reaction mixture was stirred at 25 ℃ for 1 hour. Then sodium cyanoborohydride (1.38 g, 21.95 mmol) was added and the reaction mixture was stirred at 25 ℃ for additonal16 hours. The reaction was quenched with aq. hydrochloric acid (1N) to adjust pH = 6. The resulting mixture was diluted with aqueous sodium hydroxide solution (1N, 150 mL) and extracted with ethyl acetate (200 mL x3) . The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified using silica gel column chromatography (eluting with ethyl acetate in petroleum ether 0-60%) to afford Int-1a-2 (2.2 g, yield: 84.5%) as a yellow liquid. LC-MS: m/z = 238.1 [M+H] +.
Step 3: synthesis of (3R, 4S) -4- (methylamino) tetrahydrofuran-3-ol acetate (Int-1a)
To a solution of Int-1a-2 (2.1 g, 8.85 mmol) in methanol (30 mL) were added acetic acid (1.06 g, 17.70 mmol) and wet Pd/C (10%) (420 mg) , and the reaction suspension was stirred at
45 ℃ for 16 hours under 1 atm of H2 atmosphere. The reaction was then filtered through a silica gel pad and the filtrate was concentrated to afford compound Int-1a as an acetate salt (800 mg, yield: 77.2%) as a yellow solid. LC-MS: m/z = 118.1 [M+H] +.
1e: synthesis of (3R, 4S) -4- (methylamino) tetrahydro-2H-pyran-3-ol (Int-1b) .
This intermediate was synthesized following the method described for the synthesis of Int-1a, using (3R, 4S) -4-aminotetrahydro-2H-pyran-3-ol replace (3R, 4S) -4-aminotetrahydrofuran-3-ol.
Example 2: Compound Synthesis.
Compound 1: synthesis of (7aR, 11aS) -5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -12-methyl-7a, 8, 10, 11, 11a, 12-hexahydro-7, 9-dioxa-1, 3, 6, 12-tetraazapleiadene (Compound 1) .
Step 1: synthesis of (3R, 4S) -4- ( (5, 7-dichloro-8-fluoro-2- (methylthio) pyrido [4, 3-d] pyrimidin-4-yl) amino) tetrahydro-2H-pyran-3-ol (compound 1-1) .
To a solution of 4, 5, 7-trichloro-8-fluoro-2- (methylthio) pyrido [4, 3-d] pyrimidine (Intermediate 2) (400 mg, 1.34 mmol) in dichloromethane (20 mL) at 0 ℃ under N2 atmosphere were added N, N-diisopropylethylamine (692 mg, 5.36 mmol) and (3R, 4S) -4-aminotetrahydro-2H-pyran-3-ol hydrochloride (247 mg, 1.61 mmol) and the mixture was stirred at 0 ℃ for 1 hour. The mixture was diluted with ethyl acetate (150 mL) and water (100 mL) . The organic layer was separated, washed with brine (100 mL) , dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate in petroleum ether, 25%-50%) to afford compound 1-1 (394 mg, yield: 77%) as a yellow solid. LC-MS: m/z = 379.1 [M+H] +.
Step 2: synthesis of (3R, 4S) -4- ( (5, 7-dichloro-8-fluoro-2- (methylthio) pyrido [4, 3-d] pyrimidin-4-yl) (methyl) amino) tetrahydro-2H-pyran-3-ol (compound 1-2) .
To a solution of compound 1-1 (110 mg, 0.290 mmol) in N, N-dimethylformamide (10 mL) were added potassium carbonate (120 mg, 0.870 mmol) and iodomethane (123 mg, 0.870 mmol) . The mixture was stirred at 50 ℃ for 4 hours. The mixture was cooled to room temperature and diluted with ethyl acetate (100 mL) and water (100 mL) . The organic layer was separated, washed with water (2 x 100 mL) , brine (100 mL) , dried over Na2SO4, and concentrated to afford compound 1-2 (125 mg) as a yellow solid. It was directly used in the next step without further purification. LC-MS: m/z = 393.1 [M+H] +.
Step 3: synthesis of (7aR, 11aS) -5-chloro-4-fluoro-12-methyl-2- (methylthio) -7a, 8, 10, 11, 11a, 12-hexahydro-7, 9-dioxa-1, 3, 6, 12-tetraazapleiadene (compound 1-3) .
A mixture of crude compound 1-2 (125 mg) , triethylenediamine (32 mg, 0.870 mmol) and cesium carbonate (283 mg, 0.870 mmol) in N, N-dimethylformamide (2 mL) and tetrahydrofuran (2 mL) was stirred at 70 ℃ for 16 hours. The mixture was cooled to room temperature and diluted with ethyl acetate (150 mL) and water (150 mL) . The organic layer was separated, washed with water (2 x 150 mL) , brine (100 mL) , dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate in petroleum ether, 25~50%) to afford compound 1-3 (28 mg, yield of two steps: 27%) as a yellow solid. LC-MS: m/z = 357.1 [M+H] +.
Step 4: synthesis of (7aR, 11aS) -4-fluoro-5- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -12-methyl-2- (methylthio) -7a, 8, 10, 11, 11a, 12-hexahydro-7, 9-dioxa-1, 3, 6, 12-tetraazapleiadene (compound 1-4) .
A mixture of compound 1-3 (28 mg, 0.078 mmol) , ( (2-fluoro-8- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (71 mg, 0.156 mmol) , potassium phosphate tribasic (50 mg, 0.234 mmol) and methanesulfonato (diadamantyl-n-butylphosphino) -2'-amino-1, 1'-biphenyl-2-yl) palladium (II) (11 mg, 0.0156 mmol) in 1, 4-dioxane/water (4/1 mL) was heated at 120 ℃ for 1.5 hours under N2 atmosphere under microwave condition. The mixture was cooled to room temperature and diluted with ethyl acetate (100 mL) and water (100 mL) . The organic layer was separated, washed with brine (100 mL) , dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate in petroleum ether, 0~50%) to afford compound 1-4 (25 mg, yield: 49%) as a yellow solid.
Step 5: synthesis of (7aR, 11aS) -4-fluoro-5- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -12-methyl-2- (methylsulfinyl) -7a, 8, 10, 11, 11a, 12-hexahydro-7, 9-dioxa-1, 3, 6, 12-tetraazapleiadene (compound 1-5) .
To a solution of compound 1-4 (25 mg, 0.0386 mmol) in dichloromethane (10 mL) at 0 ℃ under N2 atmosphere was added 3-chloroperoxybenzoic acid (8.6 mg, 0.0425 mmol, wt 85%) . The mixture was stirred at 0 ℃ for 20 minutes. The mixture was diluted with ethyl acetate (120 mL) and washed with sat. NaHCO3 (100 mL) , water (100 mL) and brine (100 mL) successively. The organic layer was dried over Na2SO4, filtered, and concentrated to afford compound 1-5 (32 mg) as a yellow solid. It was directly used in the next step without further purification.
Step 6: synthesis of (7aR, 11aS) -4-fluoro-5- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -12-methyl-7a, 8, 10, 11, 11a, 12-hexahydro-7, 9-dioxa-1, 3, 6, 12-tetraazapleiadene (compound 1-6) .
To a solution of above crude compound 1-5 (32 mg) and ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol (12 mg, 0.0772 mmol) in toluene (5 mL) at 0 ℃ under N2 atmosphere was added sodium tert-butoxide (8 mg, 0.077 mmol) . The mixture was stirred at 0 ℃ for 30 minutes and quenched with water (100 mL) . The mixture was extracted with ethyl acetate (2 x 100 mL) . The combined organic layers were washed with brine (100 mL) , dried over
Na2SO4, and concentrated to afford compound 1-6 (35 mg) as a yellow solid. It was directly used in the next step without further purification. LC-MS: m/z = 758.4 [M+H] +.
Step 7: synthesis of (7aR, 11aS) -5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -12-methyl-7a, 8, 10, 11, 11a, 12-hexahydro-7, 9-dioxa-1, 3, 6, 12-tetraazapleiadene (compound 1) .
To a solution of above crude compound 1-6 (35 mg) in N, N-dimethylformamide (3 mL) was added cesium fluoride (176 mg, 1.16 mmol) . The mixture was stirred at room temperature for 2 hours and diluted with ethyl acetate (100 mL) and water (100 mL) . The organic layer was separated, washed with water (2x100 mL) , brine (100 mL) , dried over Na2SO4, and concentrated. The residue was purified by Prep-TLC (dichloromethane/methanol = 10: 1) to afford compound 1 (3 mg, yield of three steps: 13%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.27-8.12 (m, 2H) , 7.73-7.53 (m, 3H) , 5.43-5.21 (m, 1H) , 4.50-4.38 (m, 1H) , 4.30-3.86 (m, 6H) , 3.53-3.37 (m, 2H) , 3.27-2.78 (m, 9H) , 2.26-2.00 (m, 3H) , 1.95-1.75 (m, 3H) ; 19F NMR (377 MHz, DMSO-d6) δ -105.33, -145.29, -170.83; LC-MS: m/z = 602.3 [M+H] +
Compound 2: synthesis of 7aS, 10aS) -5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -11- ( ( (R) -pyrrolidin-2-yl) methyl) -7a, 8, 9, 10, 10a, 11-hexahydro-7-oxa-1, 3, 6, 11-tetraazanaphtho [1, 8-fg] azulene (Compound 2)
Step 1: synthesis of tert-butyl (R) -2- ( ( ( (1S, 2S) -2-hydroxycyclopentyl) amino) methyl) pyrrolidine-1-carboxylate (Compound 2-1) .
A solution of (1S, 2S) -2-aminocyclopentan-1-ol (500 mg, 4.94 mmol) and tert-butyl (R) -2-formylpyrrolidine-1-carboxylate (983.6 mg, 4.94 mmol) in MeOH (10 mL) was stirred at 25 ℃ for 1 hour before NaBH3CN (627.14 mg, 9.88 mmol) was added. The resulting mixture was stirred at 25 ℃ for 15 hours. The reaction mixture was diluted with water (20 mL) and extracted with DCM/MeOH =10: 1 (5x20 mL) . The combined organics were dried over sodium sulphate and concentrated under reduced pressure to give Compound 2-1 (300 mg) as colorless oil, which was directly used in the next step without further purification. LC-MS: m/z = 285.3 [M+H] +.
Step 2: synthesis of tert-butyl (R) -2- ( ( (5, 7-dichloro-8-fluoro-2- (methylthio) pyrido [4, 3-d] pyrimidin-4-yl) ( (1S , 2S) -2-hydroxycyclopentyl) amino) methyl) pyrrolidine-1-carboxylate (Compound 2-2) .
To a solution of 5, 7-dichloro-8-fluoro-2- (methylthio) pyrido [4, 3-d] pyrimidin-4-ol (500 mg, 1.79 mmol) in acetonitrile (15 mL) were added K3PO4 (950.97 mg, 4.48 mmol) and HCCP (622.31 mg, 1.79 mmol) and the reaction was stirred at 25 ℃ for 1 hour. Then Compound 2-1 (559.8 mg, 1.97 mmol) was added, and the reaction was stirred at 25℃ for 15 hours. The resulting mixture was concentrated, and the residue was purified using silica gel column
chromatography (eluting with MeOH in DCM 0-10%) to afford Compound 2-2 (650 mg, yield: 66.4%) as a yellow solid. LC-MS: m/z = 546.2 [M+H] +.
Step 3: synthesis of tert-butyl (R) -2- ( ( (7aS, 10aS) -5-chloro-4-fluoro-2- (methylthio) -8, 9, 10, 10a-tetrahydro-7-oxa-1, 3, 6, 11-tetraazanaphtho [1, 8-fg] azulen-11 (7aH) -yl) methyl) pyrrolidine-1-carboxylate (Compound 2-3) .
To a solution of Compound 2-2 (800 mg, 1.47 mmol) in THF (10 mL) were added DABCO (164.89 mg, 1.47 mmol) and Cs2CO3 (1.44 g, 4.41 mmol) . The reaction suspension was stirred at 25 ℃ for 3 hours and then diluted with water (20 mL) . The mixture was extracted with EtOAc (3 x 20 mL) . The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography (DCM: MeOH = 10: 1) to give Compound 2-3 (400 mg, 53.4%) as yellow oil. LC-MS: m/z = 510.2 [M+H] +.
Step 4: synthesis of tert-butyl (R) -2- ( ( (7aS, 10aS) -4-fluoro-5- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (methylthio) -8, 9, 10, 10a-tetrahydro-7-oxa-1, 3, 6, 11-tetraazanaphtho [1, 8-fg] azulen-11 (7aH) -yl) methyl) pyrrolidine-1-carboxylate (Compound 2-4) .
A mixture of Compound 2-3 (350 mg, 0.69 mmol) , ( (2-fluoro-8- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (474.88 mg, 1.04 mmol) , A Pd G3 [CAS: 1651823-59-4] (101.92 mg, 0.14 mmol) and potassium phosphate tribasic (445.2 mg, 2.1 mmol) in dioxane (5.6 mL) and water (1.4 mL) was heated at 95 ℃ under nitrogen for 3 hours. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL) . The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified using silica gel column chromatography (MeOH in DCM = 0-10%) to give Compound 2-4 (550 mg, yield: 99.6%) as yellow oil. LC-MS: m/z = 800.4 [M+H] +.
Step 5: synthesis of tert-butyl (2R) -2- ( ( (7aS, 10aS) -4-fluoro-5- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (methylsulfinyl) -8, 9, 10, 10a-tetrahydro-7-oxa-1, 3, 6, 11-tetraazanaphtho [1, 8-fg] azulen-11 (7aH) -yl) methyl) pyrrolidine-1-carboxylate (Compound 2-5) .
To a solution of Compound 2-4 (300 mg, 0.375 mmol) in dichloromethane (6 mL) at 0 ℃was add m-CPBA (76.13 mg, 0.375 mmol) and the reaction was stirred at 0 ℃ for 30 min. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL) . The combined organic layers were washed with brine, dried over sodium sulfate, and
concentrated to give Compound 2-5, which was used in the next step without further purification. LC-MS: m/z = 816.2 [M+H] +.
Step 6: synthesis of tert-butyl (R) -2- ( ( (7aS, 10aS) -4-fluoro-5- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen -1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 9, 10, 10a-tetrahydro-7-oxa-1, 3, 6, 11-tetraazanaphtho [1, 8-fg] azulen-11 (7aH) -yl) methyl) pyrrolidine-1-carboxylate (Compound 2-6) .
To a solution of ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol (194.91 mg, 1.225 mmol) in toluene (5 mL) was added t-BuONa (117.72 mg , 1.225 mmol) . The reaction was stirred at 0 ℃ for 5 min before compound 2-5 (200 mg, 0.245 mmol) was added. The reaction mixture was allowed to warm up to 25 ℃ and stirred for 1 hour. The reaction mixture was then diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL) . The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified using silica gel column chromatography (eluting with MeOH in DCM 0-5%) to afford Compound 2-6 (180 mg, two-step yield: 52.7%) as a yellow solid. LC-MS: m/z = 911.3 [M+H] +.
Step 7: synthesis of tert-butyl (R) -2- ( ( (7aS, 10aS) -5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 9, 10, 10a-tetrahydro-7-oxa-1, 3, 6, 11-tetraazanaphtho [1, 8-fg] azulen-11 (7aH) -yl) methyl) pyrrolidine-1-carboxylate (Compound 2-7) .
A mixture of Compound 2-6 (130 mg, 0.143 mmol) and cesium fluoride (217.22 mg, 1.43 mmol) in N, N-dimethylformamide (3 mL) was stirred at 60 ℃ for 1 hour and then diluted with water (100 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3x100 mL) . The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to afford Compound 2-7 (48 mg, yield: 79.3%) as a yellow solid. LC-MS: m/z = 755.4 [M+H] +.
Step 8: synthesis of (7aS, 10aS) -5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -11- ( ( (R) -pyrrolidin-2-yl) methyl) -7a, 8, 9, 10, 10a, 11-hexahydro-7-oxa-1, 3, 6, 11-tetraazanaphtho [1, 8-fg] azulene (Compound 2) .
To a solution Compound 2-7 (100 mg, 0.133 mmol) in methanol (1 mL) was added HCl (4M in dioxane) (1 mL) , and the reaction was stirred at 25 ℃ for 1 hour. The reaction mixture was concentrated, and then ammonia solution in methanol was added to adjust the pH to ~8. The
resulting NH4Cl solid was filtered off. The filtrate was concentrated in vacuum. The residue was purified by prep-HPLC (MeCN/water /HCO2H) to afford Compound 2 (17.07 mg, yield: 19.6%) as a white solid. 1H NMR (400 MHz, MeOD) δ 8.12-8.10 (m, 2H) , 7.72 –7.52 (m, 2H) , 7.44 (dd, J = 15.6, 8.8 Hz, 1H) , 5.44 (d, J = 52.8 Hz, 1H) , 5.02 –4.85 (m, 2H) , 4.67 –4.44 (m, 2H) , 4.38 –4.15 (m, 2H) , 4.10-3.75 (m, 2H) , 3.76 –3.47 (m, 5H) , 3.40 (dt, J = 17.6, 6.0 Hz, 1H) , 2.57 –1.75 (m, 16H) ; 19F NMR (376 MHz, MeOD) δ -106.8 (dd, J = 31.8, 22.3 Hz) , -146.2 (d, J = 127.6 Hz) , -174.4 (d, J = 24.2 Hz) ; LC-MS: m/z =655.6 [M+H] +.
Compound 3: synthesis of (7aS, 11aR) -5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -12-methyl-7a, 8, 10, 11, 11a, 12-hexahydro-7, 9-dioxa-1, 3, 6, 12-tetraazapleiadene (Compound 3) .
Compound 3 was synthesized by following procedures similar to the synthesis of Compound 1 described above. 1HNMR (400 MHz, DMSO-d6) δ 8.24-8.17 (m, 2H) , 7.68-7.55 (m, 3H) , 5.35-5.22 (m, 1H) , 4.48-4.39 (m, 1H) , 4.17-4.07 (m, 2H) , 4.03-4.01 (m, 2H) , 3.96-3.91 (m, 1H) , 3.45-3.37 (m, 2H) , 3.24 (d, J = 2.8Hz, 3H) , 3.11-3.03 (m, 3H) , 2.89-2.79 (m, 1H) , 2.46-2.38 (m, 1H) , 2.14-1.60 (m, 8H) .; 19FNMR (377 MHz, DMSO-d6) δ -105.61, -144.89, -172.10; LC-MS: m/z=602.3 [M+H] +.
Compound 4: synthesis of (7aR, 10aS) -5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -11-methyl-7a, 8, 9, 10, 10a, 11-hexahydro-7-oxa-1, 3, 6, 11-tetraazanaphtho [1, 8-fg] azulene (Compound 4) .
Compound 4 was synthesized by following procedures similar for the synthesis of Compound 1 described above. LC-MS: m/z = 657.6 [M+H] +.
Compound 5: Synthesis of (7aR, 10aS) -5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -11-methyl-7a, 8, 10a, 11-tetrahydro-10H-7, 9-dioxa-1, 3, 6, 11-tetraazanaphtho [1, 8-fg] azulene (Compound 5)
Compound 5 was synthesized by following procedures similar for the synthesis of Compound 1 described above. 1H NMR (400 MHz, DMSO-d6) δ 8.25-8.09 (m, 2H) , 7.76-7.50 (m, 3H) , 5.29 (d, J = 54.4 Hz, 1H) , 5.11 (tt, J = 11.2, 6.0 Hz, 1H) , 4.54 (t, J = 7.6 Hz, 1H) , 4.43-4.25 (m, 2H) , 4.18-3.95 (m, 5H) , 3.22 (d, J = 6.0 Hz, 3H) , 3.15-2.98 (m, 3H) , 2.84 (d, J = 6.4 Hz, 1H) , 2.08 (dd, J = 30.4, 16.8 Hz, 3H) , 1.90-1.68 (m, 3H) . 19F NMR (377 MHz, DMSO-d6) δ -105.8, -145.4, -172.2. LC-MS: m/z = 588.1 [M+H] +.
Compound 6: synthesis of 2-amino-4- ( (7aR, 11aS) -6-chloro-4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -12-methyl-7a, 8, 10, 11, 11a, 12-hexahydropyrano [3', 4': 2, 3] [1, 4] oxazepino [5, 6, 7-de] quinazolin-5-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (compound 6) .
Step 1: synthesis of (3R, 4S) -4- ( (7-bromo-6-chloro-5, 8-difluoro-2- (methylthio) quinazolin-4-yl) (methyl) amino) tetrahydro-2H-pyran-3-ol (6-1) .
To a solution of Intermediate 3 (1.15 g, 3.37 mmol) in acetonitrile (35 mL) was added potassium phosphate tribasic (3.93 g, 18.52 mmol) and phosphonitrilic chloride trimer (1.17 g, 3.37 mmol) . The mixture was stirred at room temperature for 1 hour, followed by
addition of Int-1b (441.66 mg, 3.37 mmol) . After stirring for additional 16 hours, the reaction mixture was diluted with H2O, extracted with ethyl acetate (3 x 300 mL) . The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (eluted with ethyl acetate in petroleum ether 0-60%) to afford the title compound 6-1 (520 mg, yield: 33.9%) as a yellow solid. LC-MS: m/z = 455.9 [M+H] +.
Step 2: synthesis of (7aR, 11aS) -5-bromo-6-chloro-4-fluoro-12-methyl-2- (methylthio) -7a, 8, 10, 11, 11a, 12-hexahydropyrano [3', 4': 2, 3] [1, 4] oxazepino [5, 6, 7-de] quinazoline (6-2) .
A suspension of Intermediate 4-a (500 mg, 1.10 mmol) , Cs2CO3 (1.07 g, 3.30 mmol) and 1, 4-diazabicyclo [2.2.2] octane (185.02 mg, 1.65 mmol, 1.65 mmol) in acetonitrile (10 mL) was stirred at 50 ℃ for 16 hours. The solvent was removed under vacuum, and the residue was purified using silica gel column chromatography (eluting with ethyl acetate in petroleum ether 0-60%) to afford the title compound 6-2 (300 mg, yield: 62.7%) as a white solid. LC-MS: m/z = 435.8 [M+H] +.
Step 3: synthesis of (7aR, 11aS) -5-bromo-6-chloro-4-fluoro-12-methyl-2- (methylsulfinyl) -7a, 8, 10, 11, 11a, 12-hexahydropyrano [3', 4': 2, 3] [1, 4] oxazepino [5, 6, 7-de] quinazoline (6-3) .
To a solution of compound 6-2 (290 mg, 0.667 mmol) in dichloromethane (6 mL) at 0 ℃ was added m-CPBA (162.52 mg, 0.800 mmol) , and the mixture was stirred at 0 ℃ for 30 min. The resulting mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x3) . The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated. The residue was purified using silica gel column chromatography (eluting with dichloromethane in methanol 0-10%) to afford the title compound 6-3 (260 mg, yield: 86.4%) as a yellow solid. LC-MS: m/z = 451.6 [M+H] +.
Step 4: synthesis of (7aR, 11aS) -5-bromo-6-chloro-4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -12-methyl-7a, 8, 10, 11, 11a, 12-hexahydropyrano [3', 4': 2, 3] [1, 4] oxazepino [5, 6, 7-de] quinazoline (6-4) .
To a solution of intermediate 4-a (441.54 mg, 2.77 mmol) in toluene (10 mL) was added sodium tert-butoxide (266.54 mg, 2.77 mmol) at 25 ℃. After 10 min, compound 6-3 (250 mg, 0.554 mmol) was added and the resulting mixture was stirred at 25 ℃ for 2 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x3) . The combined organic layers were washed with brine, dried over sodium sulfate, and
concentrated. The residue was purified using silica gel column chromatography (eluting with dichloromethane in methanol 0-10%) to afford the title compound 6-4 (170 mg, yield: 56.1%) as a yellow solid. LC-MS: m/z = 547.0 [M+H] +.
Step 5: synthesis of tert-butyl (4- ( (7aR, 11aS) -6-chloro-4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -12-methyl-7a, 8, 10, 11, 11a, 12-hexahydropyrano [3', 4': 2, 3] [1, 4] oxazepino [5, 6, 7-de] quinazolin-5-yl) -3-cyano-7-fluorobenzo [b] thiophen-2-yl) carbamate (6-5) .
A suspension of compound 6-4 (160 mg, 0.293 mmol) , intermediate 5-a (237.01 mg, 0.586 mmol) , bis (diphenylphosphinophenyl) ether palladium (II) dichloride (83.94 mg, 0.117 mmol) and cesium carbonate (286.54 mg, 0.879 mmol) in toluene (4 mL) was stirred at 110 ℃for 2 hours under N2 atmosphere. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL x3) . The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified using silica gel column chromatography (eluting with dichloromethane in methanol 0-10%) to afford the title compound 6-5 (150 mg, yield: 67.5%) as a yellow solid. LC-MS: m/z = 756.7 [M+H] +.
Step 6: synthesis of 2-amino-4- ( (7aR, 11aS) -6-chloro-4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -12-methyl-7a, 8, 10, 11, 11a, 12-hexahydropyrano [3', 4': 2, 3] [1, 4] oxazepino [5, 6, 7-de] quinazolin-5-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (compound 6) .
A solution of compound 6-5 (130 mg, 0.172 mmol) in DCM (21 mL) containing TFA (7 mL) was stirred at room temperature for three hours before diluted with DCM (100 mL) . The reaction was carefully neutralized with aqueous NaHCO3. The separated organic layer was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by Prep-TLC (DCM: MeOH=10: 1) to afford the title compound 6 (32 mg, yield: 28.3%) as an off-white solid. 1H NMR (400 MHz, DMSO) δ 8.09 (s, 2H) , 7.21 –7.26 (m, 1H) , 7.18 –7.10 (m, 1H) , 5.30 (d, J = 53.6 Hz, 1H) , 4.52 –4.20 (m, 1H) , 4.17 –3.87 (m, 5H) , 3.57 –3.35 (m, 2H) , 3.31 –2.27 (m, 1H) , 3.22 (s, 3H) , 3.18 –3.05 (m, 2H) , 2.93 –2.80 (m, 1H) , 2.40 –2.30 (m, 1H) , 2.24 –2.01 (m, 3H) , 1.94 –1.66 (m, 4H) ; 19F NMR (377 MHz, DMSO) δ -116.51, -130.08, -130.49; LC-MS: m/z = 657.4 [M+H] +.
Compound 7 and compound 8: synthesis of 2-amino-4- ( (5R, 7aR, 11aS) -6-chloro-4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -12-methyl-7a, 8, 10, 11, 11a, 12-
hexahydropyrano [3', 4': 2, 3] [1, 4] oxazepino [5, 6, 7-de] quinazolin-5-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (compound 7) and 2-amino-4- ( (5S, 7aR, 11aS) -6-chloro-4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -12-methyl-7a, 8, 10, 11, 11a, 12-
hexahydropyrano [3', 4': 2, 3] [1, 4] oxazepino [5, 6, 7-de] quinazolin-5-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (compound 8) .
Compound 7 and Compound 8 were obtained by SFC separation of Compound 6 on a Compound 7 was the first fraction and Compound 8 was the second fraction eluting from the column.
Compound 7: 1H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 2H) , 7.29-7.22 (m, 1H) , 7.17-7.09 (m, 1H) , 5.28 (d, J = 53.2 Hz, 1H) , 4.51-4.31 (m, 3H) , 4.19-4.07 (m, 2H) , 3.95-3.85 (m, 2H) , 3.54-3.40 (m, 1H) , 3.22 (s, 3H) , 3.12-3.06 (m, 2H) , 3.03-2.99 (m, 1H) , 2.89-2.77 (m, 1H) , 2.37-2.32 (m, 1H) , 2.14-2.10 (m, 1H) , 2.06-1.98 (m, 2H) , 1.90-1.70 (m, 4H) ; 19F NMR (376 MHz, DMSO-d6) δ -116.56, -130.50, -172.14; LC-MS: m/z = 657.2 [M+H] +.
Compound 8: 1H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 2H) , 7.26-7.20 (m, 1H) , 7.17-7.06 (m, 1H) , 5.27 (d, J = 54.8 Hz, 1H) , 4.30-4.19 (m, 1H) , 4.14-4.07 (m, 2H) , 4.04-3.96 (m, 2H) , 3.95-3.84 (m, 1H) , 3.54-3.39 (m, 2H) , 3.22 (s, 3H) , 3.16-2.98 (m, 3H) , 2.87-2.78 (m, 1H) , 2.38-2.30 (m, 1H) , 2.17-1.97 (m, 3H) , 1.92-1.65 (m, 4H) ; 19F NMR (376 MHz, DMSO-d6) δ -116.54, -130.07, -172.09; LC-MS: m/z = 657.1 [M+H] +.
Compound 9: synthesis of 2-amino-4- ( (7aR, 11aS) -6-chloro-4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -12- (2-hydroxyethyl) -7a, 8, 10, 11, 11a, 12-hexahydropyrano [3', 4': 2, 3] [1, 4] oxazepino [5, 6, 7-de] quinazolin-5-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (compound 9)
Compound 9 was synthesized by following procedures similar to the synthesis of Compound 6 described above. 1H NMR (400 MHz, DMSO-d6) δ 8.18-8.05 (br, 2H) , 7.31-7.20 (m, 1H) , 7.18-7.08 (m, 1H) , 5.32 (d, J = 52.8 Hz, 1H) , 5.06-4.91 (m, 1H) , 4.70-4.37 (m, 1H) , 4.29-3.85 (m, 6H) , 3.84-3.54 (m, 4H) , 3.26-2.80 (m, 4H) , 2.36-1.96 (m, 5H) , 1.95-1.72 (m, 3H) ; 19F NMR (376 MHz, DMSO) δ -116.45/-116.52, -130.23/-131.05 (amixture of atropisomers) , -172.21; LC-MS: m/z = 687.4 [M+H] +.
Compound 10: synthesis of 5-ethynyl-6-fluoro-4- ( (7aR, 11aS) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -12-methyl-7a, 8, 10, 11, 11a, 12-hexahydro-7, 9-dioxa-1, 3, 6, 12-tetraazapleiaden-5-yl) naphthalen-2-ol (compound 10)
Compound 10 was synthesized by following procedures similar to the synthesis of Compound 1 described above. 1H NMR (400 MHz, DMSO-d6) δ 7.87-7.81 (m, 1H) , 7.34-7.28 (m, 2H) , 7.20 (dd, J = 41.2, 2.4 Hz, 1H) , 5.41 (dd, J = 53.6, 3.2 Hz, 1H) , 4.53-4.39 (m, 3H) , 4.30-4.24 (m, 1H) , 4.11-3.99 (m, 2H) , 3.66 (d, J = 16.4 Hz, 1H) , 3.56-3.44 (m, 5H) , 3.37 (d, J = 3.6 Hz, 3H) , 3.24-3.17 (m, 1H) , 2.56-2.35 (m, 3H) , 2.32-2.22 (m, 1H) , 2.19-2.10 (m, 2H) , 2.06-1.93 (m, 1H) , 1.82-1.70 (m, 1H) . 19F NMR (377 MHz, DMSO-d6) δ -111.56/-111.70, -145.28/-145.59, -173.84/-173.91 (amixture of atropisomers) ; LC-MS: m/z = 618.2 [M+H] +.
Compound 11: synthesis of 2-amino-4- ( (7aS, 11aS) -6-chloro-4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -12-methyl-7a, 8, 10, 11, 11a, 12-hexahydro-9H-pyrido [4', 3': 2, 3] [1, 4] oxazepino [5, 6, 7-de] quinazolin-5-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (compound 11)
Compound 10 was synthesized by following procedures similar to the synthesis of Compound 6 described above. 1H NMR (400 MHz, CD3OD) : δ 7.22-7.17 (m, 1H) , 7.06-7.01 (m, 1H) , 5.53 (m, 0.5H) , 5.40-5.33 (m, 0.5H) , 4.57-4.25 (m, 3H) , 3.88-3.68 (m, 3H) , 3.60-3.49 (m, 2H) , 3.34 (d, J = 4.0 Hz, 3H) , 3.29-3.15 (m, 2H) , 2.67-2.50 (m, 2H) , 2.47-2.30 (m, 4H) , 2.23-2.17 (m, 2H) , 2.03-1.91 (m, 2H) ; 19F NMR (377 MHz, CD3OD) : δ -118.76, -132.21/-132.45 (amixture of atropisomers) , -173.92; LC-MS: m/z = 656.2 [M+H] +.
The following compounds or a pharmaceutically acceptable salt thereof could be synthesized using similar chemistry and procedures as described above:
Example 3: In vitro TR-FRET GDP-KRAS binding assay.
This example illustrates the exemplary compounds of the present invention bind to GDP-form KRAS G12D and capable of displacing a labeled tracer ligand occupying the KRAS G12DGDP binding site.
The ability of a compound to bind to KRAS G12D was measured using a TR-FRET assay. Biotinylated GDP-loaded recombinant human KRAS G12D (His-Avi-KRAS 1-185, produced by ChemPartner) is incubated with a customed Cy5 labelled tracer, europium labelled streptavidin and a series of compound (1%DMSO final) in buffer (50 mM HEPES, 5 mM MgCl2, 0.05‰Tween20, and 1mM DTT) . The Em665/620 fluorescence signal is read out after an hour incubation using the PE EnVision instrument. According to the formula Inh %=100- (Sample-Min) / (Max-Min) *100%, the data is normalized to obtain the enzyme activity inhibition rate Inh %of each concentration point (wherein Max is the Em665/620 value containing enzyme-positive wells, Min is the Em665/620 value of the enzyme-free negative wells, Sample is the Em665/620 value of the compound-treated sample wells) , enter the inhibition rate Inh% (Y) corresponding to each concentration (X) in EXCEL, IC50 was calculated with Graphpad Prism based on the four-parameter fitting formula Y=Bottom + (Top-Bottom) / (1+ (IC50/X) *HillSlope) .
Example 4: GTP-KRASG12D/RAF1 binding assay.
This example illustrates the exemplary compounds of the present application’s inhibitory effect of the interactions between GTP bound KRASG12D and RAF1 protein.
The interaction between Tag1-RAF1 and Tag2-KRAS G12D (GTP bound KRASG12D) is detected by using anti-Tag1-Eu and anti-Tag2-XL665, when the antibodies are brought into
close proximity due to RAF1 and GTP-KRASG12D binding, fluorescent resonance energy transfer (FRET) occurs. This specific FRET signal is directly proportional to the extent of GTP-KRASG12D/RAF1 interaction. GTP-KRASG12D/RAF1 inhibition by small molecules will lead to a reduction in signal because of compound blocking the interaction.
The inhibitory efficacy was measured using a TR-FRET assay. The RAF1 protein and GTP-KRASG12D and a series of compound (1%DMSO final) was incubated for 20 mins. The Em665/620 fluorescence signal was read out after 2 hours after anti-EU and anti-XL665 addition using the PE EnVision instrument. According to the formula Inh %=100- (Sample-Min) / (Max-Min) *100%, the data was normalized to obtain the enzyme activity inhibition rate Inh %of each concentration point (wherein Max was the Em665/620 value containing enzyme-positive wells, Min was the Em665/620 value of the enzyme-free negative wells, Sample was the Em665/620 value of the compound-treated sample wells) , enter the inhibition rate Inh% (Y) corresponding to each concentration (X) in EXCEL, IC50 was calculated with Graphpad Prism based on the four-parameter fitting formula Y=Bottom + (Top-Bottom) / (1+ (IC50/X) *HillSlope) .
Example 5: Cell Based p-ERK Assay.
This Example illustrates that exemplary compounds disclosed herein inhibit the intracellular phosphorylation of ERK downstream of KRAS G12D.
This experiment directly tested the inhibition of compounds on KRAS G12D at the cellular level by detesting the endogenous phosphorylation level of ERK1/2. After activation of the RAS-RAF-MEK pathway, ERK1/2 were phosphorylated, after cells lysis, 2 different specific antibodies (one labeled with Eu3+-Cryptate (donor) and the other with D2 (acceptor) to recognize phosphorylated ERK1/2 (Thr202/Tyr204) site and the ERK1/2 protein itself, respectively. When phosphorylation occurs, the two dyes are approached by a light source (laser or flashlight) to excite fluorescence resonance energy transfer (FRET) from the donor to the acceptor, which emits a fluorescence wavelength (665 nm) at a specific location. The specific signal is proportional to the level of phospho-ERK1/2 (Thr202/Tyr204) .
Procedures: PK-59 cells expressing KRAS G12D mutation (ECACC, Cat. No. 95090715) were cultured in DMEM medium containing 10%FBS. Seed the cells in the 3D assay plate and cultured at 37 ℃ for 3 days. Treated with a series of compounds at a final concentration of 0.5%DMSO. After incubation for 2 hours or 24 hours, remove the supernatant, add 1*lysate to lyse the cells, transfer the lysate to a new assay plate, add the mixed antibody solution (Cisbio, Cat.
No. 64AERPEH) was incubated overnight at room temperature. The microplate was placed on the EnVision instrument to read the Em665/620 fluorescence signal. According to the formula Inh %=100- (Sample-Min) / (Max-Min) *100%, the data is normalized to obtain the enzyme activity inhibition rate Inh %of each concentration point (wherein Max is the Em665/620 value containing enzyme-positive wells, Min is the Em665/620 value of the enzyme-free negative wells, Sample is the Em665/620 value of the compound-treated sample wells) , enter the inhibition rate Inh% (Y) corresponding to each concentration (X) in EXCEL, IC50 was calculated with Graphpad Prism based on the four-parameter fitting formula Y=Bottom + (Top-Bottom) / (1+ (IC50/X) *HillSlope) .
Example 6: Cell Based p-ERK Assay.
This Example illustrates that exemplary compounds disclosed herein inhibit the cellar proliferation.
The 3D CTG assay is a homogeneous method to determine the number of viable cells in 3D cell culture based on quantitation of the ATP present. The CTG luminescence value is proportional to ATP, which is proportional to the number of living cells.
Procedures: PK-59 cells expressing KRAS G12D mutation (COBIOER, Cat. No. CBP61184) were cultured in DMEM medium containing 10%FBS. Seed the cells in the 3D assay plate and cultured at 37 ℃ 5%CO2 overnight. Treated with a series of compounds at a final concentration of 0.5%DMSO. After incubation for 168 hours, add the CTG detection buffer (Promega, Cat. No. G9681) mixing well. The microplate was placed on the EnVision instrument to read the luminescence signal. According to the formula Inh %=100- (Sample-Min) / (Max-Min) *100%, the data is normalized to obtain the activity inhibition rate Inh %of each concentration point (wherein Max is the value containing DMSO wells, Min is the value of the cell-free negative wells, Sample is the value of the compound-treated sample wells) , enter the inhibition rate Inh% (Y) corresponding to each concentration (X) in EXCEL, IC50 was calculated with Graphpad Prism based on the four-parameter fitting formula Y=Bottom + (Top-Bottom) / (1+ (IC50/X) *HillSlope) .
3D CTG assays can be carried out with cells with different KRAS mutations, such as GP2D (G12D) , NCI-H358 (G12C) , A549 (G12S) , NCI-H727 (G12V) and MKN1 (WT amplified) .
The IC50 data were listed in the table below: “++++” represents IC50 < 300 nM, “+++” represents 300 nM ≤ IC50 < 1 μM, “++” represents 1 μM ≤ IC50 < 5 μM, “+” represents IC50 ≥ 5 μM.
Table 1
Claims (15)
- A compound of formula (I) :
whereinQ1, Q2, and Q3 are independently selected from N, C-H, C-CF3, C-OH, C-Cl, C-F, C-CH3, C-CH (CH3) 2, C-cyclopropyl, C-OCH3, C-SCF3, C-OCF3, and C-CN;R1 is selected from L-5-12 membered heterocyclyl which is either monocyclic or bicyclic, and L-C3-8 cycloalkyl, wherein each of the 5-12 membered heterocyclyl and C3-8 cycloalkyl is optionally substituted with one or more W;L is selected from -CH2-, -CH (CH3) -, CH2-CH2-, and a bond;R2 is selected from H, C1-6 alkyl optionally substituted with one or more W, C3-6 cycloalkyl optionally substituted with one or more W, and 4-6 membered heterocyclyl optionally substituted with one or more W;Ring A is selected from a 4-12 membered heterocyclyl, a C4-10 cycloalkyl, and a 9-12 membered fused bicyclic heteroaryl, each of which is optionally substituted with one or more W;R3 is selected from aryl and heteroaryl, wherein the aryl and heteroaryl is optionally substituted with one or more W;X is selected from O, S and NR5;Y is selected from a bond and -O-;R5 is selected from H and C1-6 alkyl; andW is independently selected from OH, CN, halo, C2-4 alkenyl, C2-4 alkynyl, -NR8R9, =NR8, oxo, -OC (O) NR8R9, -C (O) NR8R9, -NR10C (O) R11, -NR10C (O) NR8R9, -S (O) 2NR8NR9, -NR10S (O) 2R11, 4-6 membered heterocyclyl, C3-8 cycloalkyl, C1-6 alkoxy, C1-6 alkylidene, and C1-6 alkyl, wherein each of the 4-6 membered heterocyclyl, C3-8 cycloalkyl, C1-6 alkoxy, C1-6 alkylidene, and C1-6 alkyl is optionally substituted with one or more groups selected from OH, F, Cl, C1-6 alkyl, C1-6 alkoxy, -NR8R9, -OC (O) NR8R9, and oxo;R8 and R9 are independently selected from H and C1-6 alkyl, or R8 and R9, together with the nitrogen to which they are attached, independently form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, and C1-6 alkyl; andR10 and R11 are independently selected from H and C1-6 alkyl;or a pharmaceutically acceptable salt thereof. - The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Q1 is N, and either (i) Q2 is N and Q3 is C-H, C-CF3, C-OH, C-Cl, C-F, C-CH3, C-CH (CH3) 2, C-cyclopropyl, C-OCH3, C-SCF3, C-OCF3, or C-CN, or (ii) Q2 is C-H, C-CF3, C-OH, C-Cl, C-F, C-CH3, C-CH (CH3) 2, C-cyclopropyl, C-OCH3, C-SCF3, C-OCF3, or C-CN, and Q3 is N.
- The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein Q2 is N and Q3 is C-H or C-F.
- The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Q1 is N, Q2 is N, C-H, C-CF3, C-OH, C-Cl, C-F, C-CH3, C-CH (CH3) 2, C-cyclopropyl, C-OCH3, C-SCF3, C-OCF3, or C-CN, and Q3 is C-H, C-CF3, C-OH, C-Cl, C-F, C-CH3, C-CH (CH3) 2, C-cyclopropyl, C-OCH3, C-SCF3, C-OCF3, or C-CN, and optionally, wherein Q3 is C-H or C-F.
- The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein Q2 is C-H, C-CF3, C-OH, C-Cl, C-F, C-CH3, C-CH (CH3) 2, C-cyclopropyl, C-OCH3, C-SCF3, C-OCF3, or C-CN.
- The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R3 is an aryl selected from phenyl, naphthyl, and 1H-indenyl, or a heteroaryl selected from pyridinyl, benzothiazolyl, benzothiophenyl, 1H-indazolyl, or 1H-indolyl, and the aryl or heteroaryl is optionally substituted with one or more W, and wherein optionally, W is independently selected from halo, C1-3 alkyl, C2 alkenyl, C2 alkynyl, C1 alkyl substituted with one or more F, optionally CF3, C3 cycloalkyl, -NR8R9, -CN, and OH; and wherein optionally, R8 is H and R9 is H.
- The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y is O.
- The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X is O.
- The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein L is CH2, CH (CH3) or CH2CH2.
- The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from L-7-10 membered heterocyclyl which is monocyclic or bicyclic comprising at least one heteroatom selected from nitrogen and oxygen, and L-C4-7 cycloalkyl, wherein each of the 7-10 membered heterocyclyl and L-C4-7 cycloalkyl is optionally substituted with one or more W.
- The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 is a C1-6 alkyl optionally substituted with one or more W.
- The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is a 4-7 membered monocyclic heterocyclyl optionally substituted with one or more W.
- A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
- A method of inhibiting KRAS G12D activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 13.
- A method of treating a disease or disorder associated with KRAS G12D mutation in a subject in need thereof, comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of claim 13 and optionally further comprising administering to the subject in need thereof an additional anti-cancer agent, and wherein optionally the disease or disorder associated with KRAS G12D mutation is cancer, and wherein optionally the cancer is selected from carcinoma, squamous carcinoma, pancreatic cancer, prostate cancer, rectal cancer, colon cancer, colorectal cancer, non-small cell lung cancer, prostate cancer, small intestine cancer, sarcoma, leukemia, melanoma, and lymphoma.
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CNPCT/CN2022/136877 | 2022-12-06 | ||
CN2022136877 | 2022-12-06 | ||
CNPCT/CN2023/071698 | 2023-01-10 | ||
CN2023071698 | 2023-01-10 |
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WO2024120419A1 true WO2024120419A1 (en) | 2024-06-13 |
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2018206539A1 (en) * | 2017-05-11 | 2018-11-15 | Astrazeneca Ab | Heteroaryl compounds that inhibit g12c mutant ras proteins |
WO2019215203A1 (en) * | 2018-05-08 | 2019-11-14 | Astrazeneca Ab | Tetracyclic heteroaryl compounds |
WO2024031088A1 (en) * | 2022-08-05 | 2024-02-08 | Kumquat Biosciences Inc. | Heterocyclic compounds and uses thereof |
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- 2023-12-06 WO PCT/CN2023/136651 patent/WO2024120419A1/en unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2018206539A1 (en) * | 2017-05-11 | 2018-11-15 | Astrazeneca Ab | Heteroaryl compounds that inhibit g12c mutant ras proteins |
CN110603258A (en) * | 2017-05-11 | 2019-12-20 | 阿斯利康(瑞典)有限公司 | Heteroaryl compounds that inhibit G12C mutant RAS proteins |
WO2019215203A1 (en) * | 2018-05-08 | 2019-11-14 | Astrazeneca Ab | Tetracyclic heteroaryl compounds |
CN112074520A (en) * | 2018-05-08 | 2020-12-11 | 阿斯利康(瑞典)有限公司 | Tetracycloheteroaryl compounds |
WO2024031088A1 (en) * | 2022-08-05 | 2024-02-08 | Kumquat Biosciences Inc. | Heterocyclic compounds and uses thereof |
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