WO2023284537A1

WO2023284537A1 - Kras g12d inhibitors and uses thereof

Info

Publication number: WO2023284537A1
Application number: PCT/CN2022/101554
Authority: WO
Inventors: Ding Zhou; Zheng Wang; Ziqiang CHENG; Shuai Chen
Original assignee: Shanghai Zion Pharma Co. Limited
Priority date: 2021-07-16
Filing date: 2022-06-27
Publication date: 2023-01-19
Also published as: CN117157292A

Abstract

Providing compounds having Formula (I), Formula (II), Formula (III) and Formula (IV) useful as KRas G12D inhibitors, as well as pharmaceutical compositions comprising these compounds and uses of these compounds in the manufacture of medicaments for inhibiting KRas G12D activity, or treating cancer.

Description

KRAS G12D INHIBITORS AND USES THEREOF

FIELD OF THE DISCLOSURE

The present disclosure generally relates to novel compounds useful as inhibitors of the KRAS G12D, as well as pharmaceutical compositions comprising these compounds and methods of treatment by administration of these compounds or the pharmaceutical compositions.

BACKGROUND OF THE DISCLOSURE

RAS is one of the most well-known proto-oncogenes. Its gain-of-function mutations occur in approximately 30%of all human cancers. As the most frequently mutated RAS isoform, KRAS (Kirsten-rat sarcoma viral oncogene homolog) is intensively studied in the past years. KRAS and the highly related NRAS and HRAS GTPases hydrolyze guanosine triphosphate (GTP) to guanosine diphosphate (GDP) . They control diverse cellular functions by cycling between an active, GTP-bound and an inactive, GDP-bound conformation (Hobbs, G.A., et al. J. Cell Sci. 129, 1287–1292. (2016) ) .

KRAS is a prominent oncogene that has been proven to drive tumorigenesis (G G Jinesh, et al. Oncogene volume 37, pages 839–846 (2018) ) . KRAS also modulates numerous genetic regulatory mechanisms and forms a large tumorigenesis network. KRAS gene encodes a 21 kDa protein, called KRAS, part of the RAS/MAPK pathway. The KRAS protein is a GTPase, which means it binds to guanine nucleotides GDP and guanosine-triphosphate (GTP) with high affinity and can hydrolyze GTP to GDP (Dhirendra K. Simanshu, et al. Cell. 2017 Jun 29; 170 (1) : 17–33) . GDP/GTP cycling is tightly regulated by a diverse family of multi-domain proteins: guanine nucleotide exchange-factors (GEFs) and GTPase-activating proteins (GAPs) . GEFs stimulate the dissociation of GDP and subsequent association of GTP, activating RAS proteins, while GAPs act to accelerate intrinsic GTP hydrolysis, converting RAS to its inactive state (Dhirendra K. Simanshu, et al. Cell. 2017 Jun 29; 170 (1) : 17–33) . The GTP bound form of KRAS is considered the active form, and downstream signaling effectors specifically bind to the GTP-bound form of KRAS. The KRAS protein is turned off (inactivated) when the protein is bound to GDP and does not relay signals to the cell's nucleus.

The cancer-promoting KRAS mutations most commonly occur at codon 12, 13, or 61 (Jozsef Timar, et al. Cancer and Metastasis Reviews volume 39, pages 1029–1038 (2020) ) . Among these mutation sites, G12 is the most frequently mutated residue (89%) and it most often mutates to aspartate (G12D, 36%) followed by valine (G12V, 23%) and cysteine (G12C, 14%) . G12 is located at the protein active site, which consists of a phosphate binding loop (P-loop, residues 10–17) and two switch regions (Switch-I (SI) , residues 25–40, and Switch-II (SII) , residues 60–74) (Prior, I.A., et al. Cancer Res 72, 2457–2467, (2012) ) . The residues in the active site bind to the phosphate groups of GTP and are responsible for the GTPase function of KRAS. The switch regions SI and SII are additionally responsible for controlling binding to effector and regulator proteins. The mutation of glycine at position 12 to aspartate (G12D) in the P-loop leads to impair GTP hydrolysis and freeze KRAS in its active (GTP-bound) state, which causes uncontrollable cellular growth and evasion of apoptotic signals (Malumbres, M. & Barbacid, M. Nat Rev Cancer 3, 459–465, (2003) ) . The G12D mutation causes a shift in the population of local conformational states of KRAS, especially in Switch-II (SII) and α3-helix regions, in favor of a conformation that is associated with a catalytically impaired state through structural changes; it also causes SII motions to anti-correlate with other regions (Sezen Vatansever, et al. Sci Rep . 2019 Aug 13; 9 (1) : 11730) .

KRAS mutations are present in up to 25%of cancers, the oncogenic variants have different prevalence rates in different cancers. In pancreatic ductal adenocarcinoma cases, the most common KRAS alteration is the G12D substitution. The G12D variant is also the focus of drug discovery efforts by Mirati, which plans to bring its lead compound, MRTX1133 to clinical trials. Based on epidemiology data reported in Globocan 2022 (accessed November 2019) and frequencies by mutation, KRAS G12D mutation is present in an estimated around 36%of Pancreatic cancer, in 4%colorectal cancer, in around 6%endometrial cancer and in around 4%NSCLC. This significant patient population with high unmet need.

Therefore, KRAS G12D is very commonly observed in pancreatic cancer, which can be considered a representative of the various intractable cancers. KRAS G12D is one of the most important chemotherapy drug targets. To investigate highly selective and potent small molecule inhibitor of KRAS G12D designed to treat patients with high unmet need.

SUMMARY OF THE DISCLOSURE

Disclosed herein are novel compounds that are capable of inhibiting KRAS G12D proteins. As a result, the compounds of the present disclosure are useful in the treatment of KRAS G12D-associated diseases such as cancers.

In one aspect, the present disclosure provides a compound having Formula (I) , Formula (II) , Formula (III) or Formula (IV) :

or a pharmaceutically acceptable salt thereof,

wherein

Ring A is heterocyclyl or heteroaryl, wherein

represents N-linked Ring A, and

represents C-linked Ring A;

each R ¹ is independently selected from oxo, hydroxyl, halogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, -C (O) OR ^a, -C (O) N (R ^a) ₂, -N (R ^a) ₂ or heteroaryl, wherein the alkyl, alkenyl, alkynyl and heteroaryl are optionally substituted with one or more groups independently selected from cyano, hydroxyl, halogen, -OR ^b, or -N (R ^b) ₂;

each R ^a and R ^b is independently hydrogen, alkyl, alkenyl or alkynyl;

Ring B is cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with one or more R ^c;

each R ^c is independently selected from the group consisting of oxo, hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alknynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, wherein alkyl, alkenyl, alknynyl, heteroalkyl, heteroalkenyl, heteroalkynyl and heteroaryl are optionally substituted with one or more group independently consisting of hydroxyl, halogen, cyano, -OR ^a, -N (R ^a) ₂, and heteroaryl;

Ring W is cycloalkyl, heterocyclyl, aryl or heteroaryl;

R’ is selected from hydrogen, hydroxyl, halogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, -C (O) OR ^a, -C (O) N (R ^a) ₂, -N (R ^a) ₂ or heteroaryl, wherein the alkyl, alkenyl, alkynyl and heteroaryl are optionally substituted with one or more groups independently selected from cyano, hydroxyl, halogen, -OR ^b, or -N (R ^b) ₂;

each R ² is independently selected from the group consisting of hydrogen, oxo, hydroxyl, halogen, cyano, amino, nitro, alkyl, alkenyl, alknynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein alkyl, alkenyl, alknynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more group independently consisting of hydroxyl, halogen, cyano, amino, nitro, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

X is O or S;

M is O or S;

Y is aryl or heteroaryl, wherein aryl or heteroaryl is optionally substituted with one or more R ^c;

L is a bond, -O-, -S-, -N (R ^a) -, alkenyl, cycloalkyl or alkynyl;

L’ is a bond, -S-, -N (R ^a) -, alkenyl, cycloalkyl or alkynyl, provided that when ring B is

L’ is alkenyl, cycloalkyl or alkynyl; and when B is not

L’ is a bond, -S-, -N (R ^a) -, alkenyl or cycloalkyl;

is optionally substituted with hydroxyl, halogen, cyano or amino;

Q is a bond, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl;

Z is selected from the group consisting of hydrogen, -N (R ^a) ₂, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -COOH, -NHC (=NH) NH ₂, -C (O) N (R ^a) ₂, -OR ^a, - (CH ₂OR ^a) (CH ₂) _pOR ^a, -N (R ^a) C (O) -aryl and - (CH ₂) _p-heterocyclyl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R ^d, and the aryl portion in -N (R ^a) C (O) -aryl and the heterocyclyl portion in - (CH ₂) _p-heterocyclyl are optionally substituted with one or more R ^e;

each R ^d is independently selected from hydroxyl, halogen, -C (O) H, alkyl, alkoxy, haloalkyl, hydroxyalkyl, or -N (R ^a) ₂;

each R ^e is independently selected from oxo, hydroxyl, halogen, alkyl, heteroalkyl, hydroxyalkyl, haloalkyl, alkoxy, -T-phenyl, -T-phenylSO ₂F, -N (R ^a) ₂, -SO ₂F, -C (O) (alkyl) , or -C (O) (haloalkyl) , wherein the alkyl, heteroalkyl, hydroxyalkyl, haloalkyl, and alkoxy are optionally substituted with one or more groups independently selected from aryl, heteroaryl, or tert-butyldimethylsilyloxy;

T is a bond, -O-, or -NHC (O) -;

m is 0 or 1;

n is 0 or 1;

s is an integer from 0 to 5;

t is an integer from 0 to 4; and

p is an integer from 0 to 4.

In another aspect, the present disclosure provides a compound having a formula selected from:

or a pharmaceutically acceptable salt thereof,

wherein U is N or CH, R ³ is hydrogen, hydroxyl, halogen, cyano, alkyl, or alkynyl, wherein the alkyl and alkynyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, and cyano.

In another aspect, the present disclosure provides a compound having Formula (IIa) :

or a pharmaceutically acceptable salt thereof,

wherein

L’ is alkenyl, alkynyl or C _3-7 cycloalkyl; and

R ³ is hydrogen, hydroxyl, halogen, cyano, alkyl, or alkynyl, wherein the alkyl and alkynyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, and cyano.

In another aspect, the present disclosure provides a compound having Formula (IIb) , Formula (IIc) , or Formula (IId) :

or a pharmaceutically acceptable salt thereof,

wherein

L’ is a bond, -S-, -N (R ^a) -, alkenyl or C _3-7 cycloalkyl;

U is N or CH; and

or a pharmaceutically acceptable salt thereof,

In another aspect, the present disclosure provides a compound having Formula (IVa) or Formula (IVb) :

or a pharmaceutically acceptable salt thereof,

wherein

G ¹ is N or C (R ^f) ;

G ² is N or C (R ^f) ; and

R ^f is selected from the group consisting of hydrogen, halogen, cyano, amino, nitro, hydroxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl and heterocyclyl.

In another aspect, the present disclosure provides a pharmaceutical composition comprising the compound of the present disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In a further aspect, the present disclosure provides a method for inhibiting KRas G12D activity in a subject in need thereof, comprising administering an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure to the subject.

In a further aspect, the present disclosure provides a method for treating a KRas G12D-associated cancer comprising administering an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure to a subject in need thereof.

In a further aspect, the present disclosure provides a method for treating cancer in a subject in need thereof, the method comprising:

(a) acquiring the knowledge that the cancer is associated with a KRas G12D mutation; and

(b) administering to the subject an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure.

In another aspect, the present disclosure provides use of the compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure in the manufacture of a medicament for treating cancer.

In another aspect, the present disclosure provides a compound of present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure, for use in the treatment of cancer.

DETAILED DESCRIPTION OF THE DISCLOSURE

Reference will now be made in detail to certain embodiments of the present disclosure, examples of which are illustrated in the accompanying structures and formulas. While the present disclosure will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the present disclosure to those embodiments. On the contrary, the present disclosure is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present disclosure as defined by the claims. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present disclosure. The present disclosure is in no way limited to the methods and materials described. In the event that one or more of the incorporated references and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, the present disclosure controls. All references, patents, patent applications cited in the present disclosure are hereby incorporated by reference in their entireties.

It is appreciated that certain features of the present disclosure, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the present disclosure, which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable sub-combination. It must be noted that, as used in the specification and the appended claims, the singular forms “a, ” “an, ” and “the” include plural forms of the same unless the context clearly dictates otherwise. Thus, for example, reference to “a compound” includes a plurality of compounds.

DEFINITIONS

Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 ^th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, 2 ^nd Edition, University Science Books, Sausalito, 2006; Smith and March March’s Advanced Organic Chemistry, 6 ^th Edition, John Wiley & Sons, Inc., New York, 2007; Larock, Comprehensive Organic Transformations, 3 ^rd Edition, VCH Publishers, Inc., New York, 2018; Carruthers, Some Modern Methods of Organic Synthesis, 4 ^th Edition, Cambridge University Press, Cambridge, 2004; the entire contents of each of which are incorporated herein by reference.

At various places in the present disclosure, linking substituents are described. It is specifically intended that each linking substituent includes both the forward and backward forms of the linking substituent. For example, -NR (CR’R”) -includes both -NR (CR’R”) -and - (CR’R”) NR-. Where the structure clearly requires a linking group, the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists “alkyl” , then it is understood that the “alkyl” represents a linking alkylene group.

When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such formula. Combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds.

As used herein, a dash “-” at the front or end of a chemical group is used, a matter of convenience, to indicate a point of attachment for a substituent. For example, -OH is attached through the carbon atom; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line drawn through a line in a structure indicates a point of attachment of a group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which a chemical group is written or named. As used herein, a solid line coming out of the center of a ring indicates that the point of attachment for a substituent on the ring can be at any ring atom. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such formula. Combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds.

When any variable (e.g., R ⁱ) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R ⁱ moieties, then the group may optionally be substituted with up to two R ⁱ moieties and R ⁱ at each occurrence is selected independently from the definition of R ⁱ. Also, combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds.

As used herein, the term “compounds provided herein” , or “compounds disclosed herein” or “compounds of the present disclosure” refers to the compounds of Formula (I) , Formula (II) , Formula (III) , Formula (Ia) , Formula (Ib) , Formula (IIa) , Formula (IIb) , Formula (IIIa) , Formula (IIIb) as well as the specific compounds disclosed herein.

As used herein, the term “C _i-j” indicates a range of the carbon atoms numbers, wherein i and j are integers and the range of the carbon atoms numbers includes the endpoints (i.e. i and j) and each integer point in between, and wherein j is greater than i. For examples, C _1-6 indicates a range of one to six carbon atoms, including one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms and six carbon atoms. In some embodiments, the term “C _1-12” indicates 1 to 12, particularly 1 to 10, particularly 1 to 8, particularly 1 to 6, particularly 1 to 5, particularly 1 to 4, particularly 1 to 3 or particularly 1 to 2 carbon atoms.

As used herein, the term “alkyl” , whether as part of another term or used independently, refers to a saturated linear or branched-chain hydrocarbon radical, which may be optionally substituted independently with one or more substituents described below. The term “C _i-j alkyl” refers to an alkyl having i to j carbon atoms. In some embodiments, alkyl groups contain 1 to 10 carbon atoms. In some embodiments, alkyl groups contain 1 to 9 carbon atoms. In some embodiments, alkyl groups contain 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of “C _1-10 alkyl” include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. Examples of “C _1-6 alkyl” are methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3, 3-dimethyl-2-butyl, and the like.

As used herein, the term “alkenyl” , whether as part of another term or used independently, refers to linear or branched-chain hydrocarbon radical having at least one carbon-carbon double bond, which may be optionally substituted independently with one or more substituents described herein, and includes radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations. In some embodiments, alkenyl groups contain 2 to 12 carbon atoms. In some embodiments, alkenyl groups contain 2 to 11 carbon atoms. In some embodiments, alkenyl groups contain 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, alkenyl groups contain 2 carbon atoms. Examples of alkenyl group include, but are not limited to, ethylenyl (or vinyl) , propenyl (allyl) , butenyl, pentenyl, 1-methyl-2 buten-1-yl, 5-hexenyl, and the like.

As used herein, the term “alkynyl” , whether as part of another term or used independently, refers to a linear or branched hydrocarbon radical having at least one carbon-carbon triple bond, which may be optionally substituted independently with one or more substituents described herein. In some embodiments, alkenyl groups contain 2 to 12 carbon atoms. In some embodiments, alkynyl groups contain 2 to 11 carbon atoms. In some embodiments, alkynyl groups contain 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, alkynyl groups contain 2 carbon atoms. Examples of alkynyl group include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and the like.

As used herein, the term “alkoxy” , whether as part of another term or used independently, refers to an alkyl group, as previously defined, attached to the parent molecule through an oxygen atom. The term “C _i-j alkoxy” means that the alkyl moiety of the alkoxy group has i to j carbon atoms. In some embodiments, alkoxy groups contain 1 to 10 carbon atoms. In some embodiments, alkoxy groups contain 1 to 9 carbon atoms. In some embodiments, alkoxy groups contain 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of “C _1-6 alkoxy” include, but are not limited to, methoxy, ethoxy, propoxy (e.g. n-propoxy and isopropoxy) , t-butoxy, neopentoxy, n-hexoxy, and the like.

As used herein, the term “amino” refers to –NH ₂ group. Amino groups may also be substituted with one or more groups such as alkyl, aryl, carbonyl or other amino groups.

As used herein, the term “aryl” , whether as part of another term or used independently, refers to monocyclic and polycyclic ring systems having a total of 5 to 20 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 12 ring members. Examples of “aryl” include, but are not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl” , as it is used herein, is a group in which an aromatic ring is fused to one or more additional rings. In the case of polycyclic ring system, only one of the rings needs to be aromatic (e.g., 2, 3-dihydroindole) , although all of the rings may be aromatic (e.g., quinoline) . The second ring can also be fused or bridged. Examples of polycyclic aryl include, but are not limited to, benzofuranyl, indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like. Aryl groups can be substituted at one or more ring positions with substituents as described above.

As used herein, the term “cyano” refers to –CN.

As used herein, the term “cyanoalkyl” refers to an alkyl, as defined above, substituted with one or more cyano.

As used herein, the term “cycloalkyl” , whether as part of another term or used independently, refer to a monovalent non-aromatic, saturated or partially unsaturated monocyclic and polycyclic ring system, in which all the ring atoms are carbon and which contains at least three ring forming carbon atoms. In some embodiments, the cycloalkyl may contain 3 to 12 ring forming carbon atoms, 3 to 10 ring forming carbon atoms, 3 to 9 ring forming carbon atoms, 3 to 8 ring forming carbon atoms, 3 to 7 ring forming carbon atoms, 3 to 6 ring forming carbon atoms, 3 to 5 ring forming carbon atoms, 4 to 12 ring forming carbon atoms, 4 to 10 ring forming carbon atoms, 4 to 9 ring forming carbon atoms, 4 to 8 ring forming carbon atoms, 4 to 7 ring forming carbon atoms, 4 to 6 ring forming carbon atoms, 4 to 5 ring forming carbon atoms. Cycloalkyl groups may be saturated or partially unsaturated. Cycloalkyl groups may be substituted. In some embodiments, the cycloalkyl group may be a saturated cyclic alkyl group. In some embodiments, the cycloalkyl group may be a partially unsaturated cyclic alkyl group that contains at least one double bond or triple bond in its ring system. In some embodiments, the cycloalkyl group may be monocyclic or polycyclic. The fused, spiro and bridged ring systems are also included within the scope of this definition. Examples of monocyclic cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. Examples of polycyclic cycloalkyl group include, but are not limited to, adamantyl, norbornyl, fluorenyl, spiro-pentadienyl, spiro [3.6] -decanyl, bicyclo [1, 1, 1] pentenyl, bicyclo [2, 2, 1] heptenyl, and the like.

As used herein, the term “halogen” refers to an atom selected from fluorine (or fluoro) , chlorine (or chloro) , bromine (or bromo) and iodine (or iodo) .

As used herein, the term “haloalkyl” refers to an alkyl, as defined above, that is substituted by one or more halogens, as defined above. Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, trichloromethyl, 2, 2, 2-trifluoroethyl, 1, 2-difluoroethyl, 3-bromo-2-fluoropropyl, 1, 2-dibromoethyl, and the like.

As used herein, the term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen (including N-oxides) .

As used herein, the term “heteroalkyl” refers to an alkyl, at least one of the carbon atoms of which is replaced with a heteroatom selected from N, O, or S. The heteroalkyl may be a carbon radical or heteroatom radical (i.e., the heteroatom may appear in the middle or at the end of the radical) , and may be optionally substituted independently with one or more substituents described herein. The term “heteroalkyl” encompasses alkoxy and heteroalkoxy radicals.

As used herein, the term “heteroalkenyl” refers to an alkenyl, at least one of the carbon atoms of which is replaced with a heteroatom selected from N, O, or S. The heteroalkenyl may be a carbon radical or heteroatom radical (i.e., the heteroatom may appear in the middle or at the end of the radical) , and may be optionally substituted independently with one or more substituents described herein.

As used herein, the term “heteroalkynyl” refers to an alkynyl, at least one of the carbon atoms of which is replaced with a heteroatom selected from N, O, or S. The heteroalkynyl may be a carbon radical or heteroatom radical (i.e., the heteroatom may appear in the middle or at the end of the radical) , and may be optionally substituted independently with one or more substituents described herein.

As used herein, the term “heteroaryl” , whether as part of another term or used independently, refers to an aryl group having, in addition to carbon atoms, one or more heteroatoms. The heteroaryl group can be monocyclic. Examples of monocyclic heteroaryl include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, benzofuranyl and pteridinyl. The heteroaryl group also includes polycyclic groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Examples of polycyclic heteroaryl include, but are not limited to, indolyl, isoindolyl, benzothienyl, benzofuranyl, benzo [1, 3] dioxolyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

As used herein, the term “heterocyclyl” refers to a saturated or partially unsaturated carbocyclyl group in which one or more ring atoms are heteroatoms independently selected from oxygen, sulfur, nitrogen, phosphorus, and the like, the remaining ring atoms being carbon, wherein one or more ring atoms may be optionally substituted independently with one or more substituents. In some embodiments, the heterocyclyl is a saturated heterocyclyl. In some embodiments, the heterocyclyl is a partially unsaturated heterocyclyl having one or more double bonds in its ring system. In some embodiments, the heterocyclyl may contains any oxidized form of carbon, nitrogen or sulfur, and any quaternized form of a basic nitrogen. “Heterocyclyl” also includes radicals wherein the heterocyclyl radicals are fused with a saturated, partially unsaturated, or fully unsaturated (i.e., aromatic) carbocyclic or heterocyclic ring. The heterocyclyl radical may be carbon linked or nitrogen linked where such is possible. In some embodiments, the heterocycle is carbon linked. In some embodiments, the heterocycle is nitrogen linked. For example, a group derived from pyrrole may be pyrrol-1-yl (nitrogen linked) or pyrrol-3-yl (carbon linked) . Further, a group derived from imidazole may be imidazol-1-yl (nitrogen linked) or imidazol-3-yl (carbon linked) .

In some embodiments, the term “3-to 12-membered heterocyclyl” refers to a 3-to 12-membered saturated or partially unsaturated monocyclic or polycyclic heterocyclic ring system having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. The fused, spiro and bridged ring systems are also included within the scope of this definition. Examples of monocyclic heterocyclyl include, but are not limited to oxetanyl, 1, 1-dioxothietanylpyrrolidyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, piperidyl, piperazinyl, piperidinyl, morpholinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyridonyl, pyrimidonyl, pyrazinonyl, pyrimidonyl, pyridazonyl, pyrrolidinyl, triazinonyl, and the like. Examples of fused heterocyclyl include, but are not limited to, phenyl fused ring or pyridinyl fused ring, such as quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, quinolizinyl, quinazolinyl, azaindolizinyl, pteridinyl, chromenyl, isochromenyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzothienyl, benzothiazolyl, carbazolyl, phenazinyl, phenothiazinyl, phenanthridinyl, hexahydro-1H-pyrrolizinyl, imidazo [1, 2-a] pyridinyl, [1, 2, 4] triazolo [4, 3-a] pyridinyl, [1, 2, 3] triazolo [4, 3-a] pyridinyl groups, and the like. Examples of spiro heterocyclyl include, but are not limited to, spiropyranyl, spirooxazinyl, and the like. Examples of bridged heterocyclyl include, but are not limited to, morphanyl, hexamethylenetetraminyl, 3-aza-bicyclo [3.1.0] hexane, 8-aza- bicyclo [3.2.1] octane, 1-aza-bicyclo [2.2.2] octane, 1, 4-diazabicyclo [2.2.2] octane (DABCO) , and the like.

As used herein, the term “hydroxyl” or “hydroxy” refers to –OH.

As used herein, the term “hydroxyalkyl” refers to an alkyl, as defined above, substituted with one or more hydroxyl.

As used herein, the term “oxo” refers to =O substituent.

As used herein, the term “partially unsaturated” refers to a radical that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (i.e., fully unsaturated) moieties.

As used herein, the term “substituted” , whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and that the substitution results in a stable or chemically feasible compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted” , references to chemical moieties herein are understood to include substituted variants. For example, reference to an “aryl” group or moiety implicitly includes both substituted and unsubstituted variants.

COMPOUNDS

or a pharmaceutically acceptable salt thereof,

wherein

Ring A is heterocyclyl or heteroaryl, wherein

represents N-linked Ring A, and

represents C-linked Ring A;

each R ^a and R ^b is independently hydrogen, alkyl, alkenyl or alkynyl;

Ring W is cycloalkyl, heterocyclyl, aryl or heteroaryl;

X is O or S;

M is O or S;

L is a bond, -O-, -S-, -N (R ^a) -, alkenyl, cycloalkyl or alkynyl;

L’ is alkenyl, cycloalkyl or alkynyl; and when B is not

L’ is a bond, -S-, -N (R ^a) -, alkenyl or cycloalkyl;

is optionally substituted with hydroxyl, halogen, cyano or amino;

T is a bond, -O-, or -NHC (O) -;

m is 0 or 1;

n is 0 or 1;

s is an integer from 0 to 5;

t is an integer from 0 to 4; and

p is an integer from 0 to 4.

In some embodiments, Ring A is heterocyclyl. In certain embodiments, Ring A is a 6-to 12-membered heterocyclyl. In certain embodiments, Ring A is a 6-to 10-membered heterocyclyl. In certain embodiments, Ring A is a 8-to 10-membered heterocyclyl.

In some embodiments, Ring A is heteroaryl. In certain embodiments, Ring A is a 6-to 12-membered heteroaryl. In certain embodiments, Ring A is a 6-to 10-membered heteroaryl. In certain embodiments, Ring A is a 8-to 10-membered heteroaryl.

In some embodiments, Ring A is a bridged heterocyclyl optionally containing at least one further heteroatom selected from the group consisting of N, S and O. In certain embodiments, Ring A is a 6-to 12-membered bridged heterocyclyl optionally containing at least one further heteroatom selected from the group consisting of N, S and O. In certain embodiments, Ring A is a 6-to 10-membered bridged heterocyclyl optionally containing at least one further heteroatom selected from the group consisting of N, S and O. In certain embodiments, Ring A is a 8-to 10-membered bridged heterocyclyl optionally containing at least one further heteroatom selected from the group consisting of N, S and O.

In certain embodiments, Ring A is selected from the group consisting of:

wherein

represents a single bond or a double bond.

In some embodiments, Ring A is a spiro or fused ring optionally containing at least one further heteroatom selected from the group consisting of N, S and O.

In certain embodiments, Ring A is selected from the group consisting of:

wherein r is an integer from 0 to 3, and q is an integer from 1 to 4.

In some embodiments, Ring B is cycloalkyl optionally substituted with one or more R ^c. In certain embodiments, Ring B is C _5-12 cycloalkyl optionally substituted with one or more R ^c. In certain embodiments, Ring B is C _5-10 cycloalkyl optionally substituted with one or more R ^c. In certain embodiments, Ring B is C _5-8 cycloalkyl optionally substituted with one or more R ^c. In certain embodiments, Ring B is C _5-7 cycloalkyl optionally substituted with one or more R ^c. In certain embodiments, Ring B is C _5-6 cycloalkyl optionally substituted with one or more R ^c.

In some embodiments, Ring B is heterocyclyl optionally substituted with one or more R ^c. In certain embodiments, Ring B is 5-to 12-membered heterocyclyl optionally substituted with one or more R ^c. In certain embodiments, Ring B is 5-to 10-membered heterocyclyl optionally substituted with one or more R ^c. In certain embodiments, Ring B is 5-to 8-membered heterocyclyl optionally substituted with one or more R ^c. In certain embodiments, Ring B is 5-to 7-membered heterocyclyl optionally substituted with one or more R ^c. In certain embodiments, Ring B is 5-to 6-membered heterocyclyl optionally substituted with one or more R ^c.

In certain embodiments, Ring B is piperidinyl, dihydropyridazinyl, dihydropyridinyl, azaspiro [2.5] octenyl, or 1, 2, 3, 6-tetrahydropyridinyl, each optionally substituted with one or more R ^c independently selected from oxo, alkyl, alkynyl, heteroalkyl, or cyano, wherein the alkyl, alkynyl, heteroalkyl are optionally substituted with one or more groups selected from cyano, halogen, -OR ^a, -N (R ^a) ₂, or heteroaryl, wherein R ^a is hydrogen or alkyl.

In some embodiments, Ring B is aryl optionally substituted with one or more R ^c. In certain embodiments, Ring B is C _5-12 aryl optionally substituted with one or more R ^c. In certain embodiments, Ring B is C _5-10 aryl optionally substituted with one or more R ^c. In certain embodiments, Ring B is C _5-8 aryl optionally substituted with one or more R ^c. In certain embodiments, Ring B is C _5-7 aryl optionally substituted with one or more R ^c. In certain embodiments, Ring B is C _5-6 aryl optionally substituted with one or more R ^c.

In certain embodiments, Ring B is phenyl optionally substituted with one or more R ^c independently selected from amino, hydroxyl, halogen or haloalkyl.

In some embodiments, Ring B is heteroaryl optionally substituted with one or more R ^c. In certain embodiments, Ring B is 5-to 12-membered heteroaryl optionally substituted with one or more R ^c. In certain embodiments, Ring B is 5-to 10-membered heteroaryl optionally substituted with one or more R ^c. In certain embodiments, Ring B is 5-to 8-membered heteroaryl optionally substituted with one or more R ^c. In certain embodiments, Ring B is 5-to 7-membered heteroaryl optionally substituted with one or more R ^c. In certain embodiments, Ring B is 5-to 6-membered heteroaryl optionally substituted with one or more R ^c.

In certain embodiments, Ring B is pyridinyl or pyrimidinyl optionally substituted with one or more R ^c independently selected from amino, hydroxyl, halogen or haloalkyl.

In some embodiments, R’ is selected from hydrogen, hydroxyl, halogen, or cyano.

In some embodiments, Ring W is cycloalkyl, heterocyclyl, aryl or heteroaryl.

In some embodiments, Ring W is cycloalkyl. In certain embodiments, Ring W is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In some embodiments, Ring W is heterocyclyl. In certain embodiments, Ring W is selected from tetrahydrofuranyl, pyrrolidinyl, tetrahydro-2H-pyranyl, piperidinyl, or piperazinyl,

In certain embodiments, Ring W is aryl. In certain embodiments, Ring W is C _5-12 aryl, C _5-10 aryl, C _5-8 aryl, C _5-7 or C _5-6 aryl.

In certain embodiments, Ring W is phenyl or naphthalenyl.

In some embodiments, Ring W is heteroaryl. In certain embodiments, Ring W is 5-to 12-membered heteroaryl, 5-to 10-membered heteroaryl, 5-to 8-membered heteroaryl, 5-to 7-membered heteroaryl, 5-to 6-membered heteroaryl.

In certain embodiments, Ring W is selected from the group consisting of pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, benzofuranyl, benzothienyl, indolyl, benzimidazolyl, benzopyrazolyl, purinyl, quinolinyl, isoquinolinyl, isoquinoline-1 (2H) -one group, isoindolin-1-one group, benzo [d] oxazole-2 (H) -one group and 1, 3-dihydro-2H-benzo [d] imidazol-2-one group.

In some embodiments, Y is aryl optionally substituted with one or more R ^c. In certain embodiments, Y is C _5-12 aryl optionally substituted with one or more R ^c. In certain embodiments, Y is C _5-11 aryl optionally substituted with one or more R ^c. In certain embodiments, Y is C _5-10 aryl optionally substituted with one or more R ^c. In certain embodiments, Y is C _5-8 aryl optionally substituted with one or more R ^c. In certain embodiments, Y is C _5-7 aryl optionally substituted with one or more R ^c. In certain embodiments, Y is C _5-6 aryl optionally substituted with one or more R ^c.

In certain embodiments, Y is phenyl or naphthyl, each optionally substituted with one or more R ^c.

In certain embodiments, R ^c is hydroxyl, halogen, amino, alkyl, alkenyl, alkynyl, haloalkyl, haloalknyl, or cycloalkyl.

In some embodiments, Y is heteroaryl optionally substituted with one or more R ^c. In certain embodiments, Y is 5-to 12-membered heteroaryl optionally substituted with one or more R ^c. In certain embodiments, Y is 5-to 11-membered heteroaryl optionally substituted with one or more R ^c. In certain embodiments, Y is 5-to 10-membered heteroaryl optionally substituted with one or more R ^c. In certain embodiments, Y is 5-to 8-membered heteroaryl optionally substituted with one or more R ^c. In certain embodiments, Y is 5-to 7-membered heteroaryl optionally substituted with one or more R ^c. In certain embodiments, Y is 5-to 6-membered heteroaryl optionally substituted with one or more R ^c.

In certain embodiments, Y is benzothiophenyl, benzoimidazolyl, quinazolinyl, benzotriazolyl, thiophenyl, thienopyridinyl, isoquinolinyl, indolyl, or indazolyl, each optionally substituted with one or more R ^c.

In certain embodiments, R ^c is hydroxyl, halogen, amino, alkyl, alkenyl, alkynyl, haloalkyl, haloalknyl, or heteroaryl.

In some embodiments, Y is aryl optionally substituted with one or more R ^c and n is 0.

In some embodiments, L is -O-.

In some embodiments, L is –S-.

In some embodiments, L is -N (R ^a) -, wherein R ^a is hydrogen or alkyl.

In some embodiments, L is alkynyl. In certain embodiments, L is C _2-3 alkynyl.

In some embodiments, L is alkenyl. In certain embodiments, L is C _2-3 alkenyl.

In some embodiments, L is cycloalkyl. In certain embodiments, L is C _3-6 cycloalkyl. In certain embodiments, L is cyclopropyl.

In some embodiments, L’ is alkenyl, cycloalkyl or alkynyl, and ring B is

In certain embodiments, L’ is C _2-3 alkenyl, C _3-6 cycloalkyl or C _2-3 alkynyl, and ring B is

In some embodiments, L’ is a bond, -S-, -N (R ^a) -, alkenyl or cycloalkyl, and ring B is not

In certain embodiments, L’ is a bond, -S-, -N (R ^a) -, C _2-3 alkenyl or C _3-6 cycloalkyl, and ring B is not

In some embodiments, Q is a bond.

In some embodiments, Q is alkyl. In certain embodiments, Q is C _1-6 alkyl, C _1-5 alkyl, C _1-4 alkyl, or C _1-3 alkyl.

In some embodiments, Q is cycloalkyl or heteroaryl, each optionally substituted with one or more of halogen or alkyl.

In some embodiments, Z is cycloalkyl, heterocyclyl, aryl, heteroaryl, or - (CH ₂) _p-heterocyclyl, wherein the heterocyclyl and the heterocyclyl portion in - (CH ₂) _p-heterocyclyl are optionally substituted with one or more R ^e, wherein each R ^e is independently selected from hydroxyl, halogen, alkyl, heteroalkyl, or alkoxy.

In certain embodiments, Z is selected from hexahydro-1H-pyrrolizinyl or pyrrolidinyl, each optionally substituted with one or more groups independently selected from halogen, hydroxyl, hydroxyalkyl, haloalkyl, alkoxy, phenyl, tert-butyldimethylsilyloxyCH ₂-or pyrazolyl.

In some embodiments, L is –O-, and m is 1.

In some embodiments, L is alkynyl, and m is 0.

In some embodiments, s is 0.

In some embodiments, s is an integer from 1 to 3, each R ¹ is independently selected from oxo, cyano, alkyl, or alkynyl, wherein the alky and alkynyl are optionally substituted with one or more groups selected from cyano, hydroxyl, halogen, -OR ^1b, or -N (R ^1b) ₂.

In some embodiments, t is an integer from 1 to 3, each R ² is independently selected from the group consisting of hydroxyl, halogen, cyano, alkyl, alkenyl, alkynyl, or cycloalkyl, wherein alkyl, alkenyl, alkynyl, and cycloalkyl are optionally substituted with one or more groups independently selected from cyano, hydroxyl, halogen, or alkyl.

In a further aspect, the present disclosure provides a compound having a formula selected from:

or a pharmaceutically acceptable salt thereof,

or a pharmaceutically acceptable salt thereof,

wherein

L’ is alkenyl, alkynyl or C _3-7 cycloalkyl; and

In a further aspect, the present disclosure provides a compound having Formula (IIb) , Formula (IIc) or Formula (IId) :

or a pharmaceutically acceptable salt thereof,

wherein

L’ is a bond, -S-, -N (R ^a) -, alkenyl or C _3-7 cycloalkyl;

U is N or CH; and

or a pharmaceutically acceptable salt thereof,

In a further aspect, the present disclosure provides a compound having having Formula (IVa) or Formula (IVb) :

or a pharmaceutically acceptable salt thereof,

wherein

G ¹ is N or C (R ^f) ;

G ² is N or C (R ^f) ; and

In some embodiments, the present disclosure provides a compound having a formula selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

Compounds provided herein are described with reference to both generic formulae and specific compounds. In addition, the compounds of the present disclosure may exist in a number of different forms or derivatives, including but not limited to prodrugs, soft drugs, active metabolic derivatives (active metabolites) , and their pharmaceutically acceptable salts, all within the scope of the present disclosure.

As used herein, the term “prodrugs” refers to compounds or pharmaceutically acceptable salts thereof which, when metabolized under physiological conditions or when converted by solvolysis, yield the desired active compound. Prodrugs include, without limitation, esters, amides, carbamates, carbonates, ureides, solvates, or hydrates of the active compound. Typically, the prodrug is inactive, or less active than the active compound, but may provide one or more advantageous handling, administration, and/or metabolic properties. For example, some prodrugs are esters of the active compound; during metabolysis, the ester group is cleaved to yield the active drug. Also, some prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound. Prodrugs may proceed from prodrug form to active form in a single step or may have one or more intermediate forms which may themselves have activity or may be inactive. Preparation and use of prodrugs is discussed in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems” , Vol. 14 of the A.C.S. Symposium Series, in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987; in Prodrugs: Challenges and Rewards, ed. V. Stella, R. Borchardt, M. Hageman, R. Oliyai, H. Maag, J. Tilley, Springer-Verlag New York, 2007, all of which are hereby incorporated by reference in their entirety.

As used herein, the term “soft drug” refers to compounds that exert a pharmacological effect but break down to inactive metabolites degradants so that the activity is of limited time. See, for example, “Soft drugs: Principles and methods for the design of safe drugs” , Nicholas Bodor, Medicinal Research Reviews, Vol. 4, No. 4, 449-469, 1984, which is hereby incorporated by reference in its entirety.

As used herein, the term “metabolite” , e.g., active metabolite overlaps with prodrug as described above. Thus, such metabolites are pharmacologically active compounds or compounds that further metabolize to pharmacologically active compounds that are derivatives resulting from metabolic process in the body of a subject. For example, such metabolites may result from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound or salt or prodrug. Of these, active metabolites are such pharmacologically active derivative compounds. For prodrugs, the prodrug compound is generally inactive or of lower activity than the metabolic product. For active metabolites, the parent compound may be either an active compound or may be an inactive prodrug.

Prodrugs and active metabolites may be identified using routine techniques know in the art. See, e.g., Bertolini et al, 1997, J Med Chem 40: 2011-2016; Shan et al., J Pharm Sci 86: 756-757; Bagshawe, 1995, DrugDev Res 34: 220-230; Wermuth, supra.

As used herein, the term “pharmaceutically acceptable” indicates that the substance or composition is compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the subjects being treated therewith.

As used herein, the term “pharmaceutically acceptable salt” , unless otherwise indicated, includes salts that retain the biological effectiveness of the free acids and bases of the specified compound and that are not biologically or otherwise undesirable. Contemplated pharmaceutically acceptable salt forms include, but are not limited to, mono, bis, tris, tetrakis, and so on. Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations at which they are administered. The preparation of such salts can facilitate the pharmacological use by altering the physical characteristics of a compound without preventing it from exerting its physiological effect. Useful alterations in physical properties include lowering the melting point to facilitate transmucosal administration and increasing the solubility to facilitate administering higher concentrations of the drug.

Pharmaceutically acceptable salts include acid addition salts such as those containing sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate. Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.

Pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, t-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc, when acidic functional groups, such as carboxylic acid or phenol are present. For example, see Remington's Pharmaceutical Sciences, 19 ^thed., Mack Publishing Co., Easton, PA, Vol. 2, p. 1457, 1995; “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth, Wiley-VCH, Weinheim, Germany, 2002. Such salts can be prepared using the appropriate corresponding bases.

Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the free-base form of a compound can be dissolved in a suitable solvent, such as an aqueous or aqueous-alcohol solution containing the appropriate acid and then isolated by evaporating the solution. Thus, if the particular compound is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

Similarly, if the particular compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary) , an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include organic salts derived from amino acids, such as L-glycine, L-lysine, and L-arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as hydroxyethylpyrrolidine, piperidine, morpholine or piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

It is also to be understood that the compounds of present disclosure can exist in unsolvated forms, solvated forms (e.g., hydrated forms) , and solid forms (e.g., crystal or polymorphic forms) , and the present disclosure is intended to encompass all such forms.

As used herein, the term “solvate” or “solvated form” refers to solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H ₂O. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

As used herein, the terms “crystal form” , “crystalline form” , “polymorphic forms” and “polymorphs” can be used interchangeably, and mean crystal structures in which a compound (or a salt or solvate thereof) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectral, melting points, density hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Crystal polymorphs of the compounds can be prepared by crystallization under different conditions.

The present disclosure is also intended to include all isotopes of atoms in the compounds. Isotopes of an atom include atoms having the same atomic number but different mass numbers. For example, unless otherwise specified, hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, bromide or iodine in the compounds of present disclosure are meant to also include their isotopes, such as but not limited to ¹H, ²H, ³H, ¹¹C, ¹²C, ¹³C, ¹⁴C, ¹⁴N, ¹⁵N, ¹⁶O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³²S, ³³S, ³⁴S, ³⁶S, ¹⁷F, ¹⁸F, ¹⁹F, ³⁵Cl, ³⁷Cl, ⁷⁹Br, ⁸¹Br, ¹²⁴I, ¹²⁷I and ¹³¹I. In some embodiments, hydrogen includes protium, deuterium and tritium. In some embodiments, carbon includes ¹²C and ¹³C.

Those of skill in the art will appreciate that compounds of the present disclosure may exist in different tautomeric forms, and all such forms are embraced within the scope of the present disclosure. The term “tautomer” or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. The presence and concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution. By way of examples, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol, amide-imidic acid, lactam-lactim, imine-enamine isomerizations and annular forms where a proton can occupy two or more positions of a heterocyclic system. Valence tautomers include interconversions by reorganization of some of the bonding electrons. Tautomers can be in equilibrium or sterically locked into one form by appropriate substitution. Compounds of the present disclosure identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

SYNTHESIS OF COMPOUNDS

The compounds provided herein can be prepared using any known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes

Reactions for preparing compounds of the present disclosure can be carried out in suitable solvents, which can be readily selected by one skilled in the art of organic synthesis. Suitable solvents can be substantially non-reactive with starting materials (reactants) , intermediates, or products at the temperatures at which the reactions are carried out, e.g. temperatures that can range from the solvent’s freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by one skilled in the art.

Preparation of compounds of the present disclosure can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in T. W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley & Sons, Inc., New York (1999) , in P. Kocienski, Protecting Groups, Georg Thieme Verlag, 2003, and in Peter G.M. Wuts, Greene's Protective Groups in Organic Synthesis, 5 ^th Edition, Wiley, 2014, all of which are incorporated herein by reference in its entirety.

Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g. ¹H or ¹³C) , infrared spectroscopy, spectrophotometry (e.g. UV-visible) , mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC) , liquid chromatography-mass spectroscopy (LCMS) , or thin layer chromatography (TLC) . Compounds can be purified by one skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) ( “Preparative LC-MS Purification: Improved Compound Specific Method Optimization” Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem. 2004, 6 (6) , 874-883, which is incorporated herein by reference in its entirety) , and normal phase silica chromatography.

USE OF COMPOUNDS

In an aspect, the present disclosure provides compounds capable of inhibiting KRAS protein, in particular KRAS G12D protein.

As used herein, the term “therapy” is intended to have its normal meaning of dealing with a disease in order to entirely or partially relieve one, some or all of its symptoms, or to correct or compensate for the underlying pathology, thereby achieving beneficial or desired clinical results. For purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total) , whether detectable or undetectable. “Therapy” can also mean prolonging survival as compared to expected survival if not receiving it. Those in need of therapy include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented. The term “therapy” also encompasses prophylaxis unless there are specific indications to the contrary. The terms “therapeutic” and “therapeutically” should be interpreted in a corresponding manner.

As used herein, the term “prophylaxis” is intended to have its normal meaning and includes primary prophylaxis to prevent the development of the disease and secondary prophylaxis whereby the disease has already developed and the patient is temporarily or permanently protected against exacerbation or worsening of the disease or the development of new symptoms associated with the disease.

The term “treatment” is used synonymously with “therapy” . Similarly the term “treat” can be regarded as “applying therapy” where “therapy” is as defined herein.

In a further aspect, the present disclosure provides use of the compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure for use in therapy, for example, for use in therapy associated with KRAS protein, in particular, in therapy associated with KRAS G12D protein.

In a further aspect, the present disclosure provides use of the compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure, in the manufacture of a medicament for treating cancer.

In some embodiments, the cancer is mediated by KRAS protein. In some embodiments, the cancer is mediated by KRAS G12D protein.

PHARMACEUTICAL COMPOSITIONS

In a further aspect, there is provided pharmaceutical compositions comprising one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof.

In another aspect, there is provided pharmaceutical composition comprising one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical acceptable excipient.

As used herein, the term “pharmaceutical composition” refers to a formulation containing the molecules or compounds of the present disclosure in a form suitable for administration to a subject.

As used herein, the term “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 excipient that is acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceutically acceptable excipient” as used herein includes both one and more than one such excipient. The term “pharmaceutically acceptable excipient” also encompasses “pharmaceutically acceptable carrier” and “pharmaceutically acceptable diluent” .

The particular excipient used will depend upon the means and purpose for which the compounds of the present disclosure is being applied. Solvents are generally selected based on solvents recognized by persons skilled in the art as safe to be administered to a mammal including humans. In general, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG 300) , etc. and mixtures thereof.

In some embodiments, suitable excipients may include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol) ; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes) ; and/or non-ionic surfactants such as TWEEN ^TM, PLURONICS ^TM or polyethylene glycol (PEG) .

In some embodiments, suitable excipients may include one or more stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present disclosure or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament) . The active pharmaceutical ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly- (methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980) . A “liposome” is a small vesicle composed of various types of lipids, phospholipids and/or surfactant which is useful for delivery of a drug (such as the compounds disclosed herein and, optionally, a chemotherapeutic agent) to a mammal including humans. The components of the liposome are commonly arranged in a bilayer formation, similar to the lipid arrangement of biological membranes.

The pharmaceutical compositions provided herein can be in any form that allows for the composition to be administered to a subject, including, but not limited to a human, and formulated to be compatible with an intended route of administration.

A variety of routes are contemplated for the pharmaceutical compositions provided herein, and accordingly the pharmaceutical composition provided herein may be supplied in bulk or in unit dosage form depending on the intended administration route. For example, for oral, buccal, and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, gelcaps, and caplets may be acceptable as solid dosage forms, and emulsions, syrups, elixirs, suspensions, and solutions may be acceptable as liquid dosage forms. For injection administration, emulsions and suspensions may be acceptable as liquid dosage forms, and a powder suitable for reconstitution with an appropriate solution as solid dosage forms. For inhalation administration, solutions, sprays, dry powders, and aerosols may be acceptable dosage form. For topical (including buccal and sublingual) or transdermal administration, powders, sprays, ointments, pastes, creams, lotions, gels, solutions, and patches may be acceptable dosage form. For vaginal administration, pessaries, tampons, creams, gels, pastes, foams and spray may be acceptable dosage form.

The quantity of active ingredient in a unit dosage form of composition is a therapeutically effective amount and is varied according to the particular treatment involved. As used herein, the term “therapeutically effective amount” refers to an amount of a molecule, compound, or composition comprising the molecule or compound to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; the rate of administration; the therapeutic or combination of therapeutics selected for administration; and the discretion of the prescribing physician. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.

In some embodiments, the pharmaceutical compositions of the present disclosure may be in a form of formulation for oral administration.

In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of tablet formulations. Suitable pharmaceutically-acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case using conventional coating agents and procedures well known in the art.

In certain embodiments, the pharmaceutical compositions of the present disclosure may be in a form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.

In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of aqueous suspensions, which generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate) , or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid) , coloring agents, flavoring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame) .

In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of oily suspensions, which generally contain suspended active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin) . The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these. Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavoring and preservative agents.

In certain embodiments, the pharmaceutical compositions provided herein may be in the form of syrups and elixirs, which may contain sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, a demulcent, a preservative, a flavoring and/or coloring agent.

In some embodiments, the pharmaceutical compositions of the present disclosure may be in a form of formulation for injection administration.

In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents, which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1, 3-butanediol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.

In some embodiments, the pharmaceutical compositions of the present disclosure may be in a form of formulation for inhalation administration.

In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of aqueous and nonaqueous (e.g., in a fluorocarbon propellant) aerosols containing any appropriate solvents and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these. The carriers and stabilizers vary with the requirements of the particular compound, but typically include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol) , innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.

In some embodiments, the pharmaceutical compositions of the present disclosure may be in a form of formulation for topical or transdermal administration.

In certain embodiments, the pharmaceutical compositions provided herein may be in the form of creams, ointments, gels and aqueous or oily solutions or suspensions, which may generally be obtained by formulating an active ingredient with a conventional, topically acceptable excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

In certain embodiments, the pharmaceutical compositions provided herein may be formulated in the form of transdermal skin patches that are well known to those of ordinary skill in the art.

Besides those representative dosage forms described above, pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are thus included in the present disclosure. Such excipients and carriers are described, for example, in “Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991) , in “Remington: The Science and Practice of Pharmacy” , Ed. University of the Sciences in Philadelphia, 21 ^st Edition, LWW (2005) , which are incorporated herein by reference.

In some embodiments, the pharmaceutical compositions of the present disclosure can be formulated as a single dosage form. The amount of the compounds provided herein in the single dosage form will vary depending on the subject treated and particular mode of administration.

In some embodiments, the pharmaceutical compositions of the present disclosure can be formulated so that a dosage of between 0.001-1000 mg/kg body weight/day, for example, 0.01-800 mg/kg body weight/day, 0.01-700 mg/kg body weight/day, 0.01-600 mg/kg body weight/day, 0.01-500 mg/kg body weight/day, 0.01-400 mg/kg body weight/day, 0.01-300 mg/kg body weight/day, 0.1-200 mg/kg body weight/day, 0.1-150 mg/kg body weight/day, 0.1-100 mg/kg body weight/day, 0.5-100 mg/kg body weight/day, 0.5-80 mg/kg body weight/day, 0.5-60 mg/kg body weight/day, 0.5-50 mg/kg body weight/day, 1-50 mg/kg body weight/day, 1-45 mg/kg body weight/day, 1-40 mg/kg body weight/day, 1-35 mg/kg body weight/day, 1-30 mg/kg body weight/day, 1-25 mg/kg body weight/day of the compounds provided herein, or a pharmaceutically acceptable salt thereof, can be administered. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day. For further information on routes of administration and dosage regimes, see Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board) , Pergamon Press 1990, which is specifically incorporated herein by reference.

In some embodiments, the pharmaceutical compositions of the present disclosure can be formulated as short-acting, fast-releasing, long-acting, and sustained-releasing. Accordingly, the pharmaceutical formulations of the present disclosure may also be formulated for controlled release or for slow release.

In a further aspect, there is also provided veterinary compositions comprising one or more molecules or compounds of the present disclosure or pharmaceutically acceptable salts thereof and a veterinary carrier. Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route.

The pharmaceutical compositions or veterinary compositions may be packaged in a variety of ways depending upon the method used for administering the drug. For example, an article for distribution can include a container having deposited therein the compositions in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass) , sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings. The compositions may also be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injection immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.

In a further aspect, there is also provided pharmaceutical compositions comprise one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, as a first active ingredient, and a second active ingredient.

In some embodiments, the second active ingredient has complementary activities to the compound provided herein such that they do not adversely affect each other. Such ingredients are suitably present in combination in amounts that are effective for the purpose intended.

METHOD OF TREATMENT OF DISEASE

In a further aspect, the present disclosure provides a method for treating cancer, comprising administering an effective amount of the compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition provided herein to a subject in need thereof.

In some embodiments, the compounds or pharmaceutically acceptable salts thereof and the compositions provided herein may be used for the treatment of a KRAS G12D-associated cancer in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound provided herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof.

In some embodiments, the compounds or pharmaceutically acceptable salts thereof and the compositions provided herein may be used for the treatment of a wide variety of cancers including tumors such as lung, prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc. More particularly, cancers that may be treated by the compounds or pharmaceutically acceptable salts thereof and the compositions provided herein include, but are not limited to tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas. More specifically, the compounds or pharmaceutically acceptable salts thereof and the compositions provided herein can be used to treat:

(i) Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma) , myxoma, rhabdomyoma, fibroma, lipoma and teratoma;

(ii) Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma) , alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;

(iii) Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma) , stomach (carcinoma, lymphoma, leiomyosarcoma) , pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma) , small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma) , large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma) ;

(iv) Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma) , lymphoma, leukemia) , bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma) , prostate (adenocarcinoma, sarcoma) , testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma) ;

(v) Liver: hepatoma (hepatocellular carcinoma) , cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;

(vi) Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma) , fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma) , multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses) , benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors;

(vii) Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans) , meninges (meningioma, meningiosarcoma, gliomatosis) , brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma) , glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors) , spinal cord neurofibroma, meningioma, glioma, sarcoma) ;

(viii) Gynecological: uterus (endometrial 'carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma) , granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma) , vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma) , vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma) , fallopian tubes (carcinoma) ;

(ix) Hematologic: blood (myeloid leukemia (acute and chronic) , acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome) , Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma) ;

(x) Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and

(xi) Adrenal glands: neuroblastoma.

In certain embodiments, the cancer that can be treated with the compounds or pharmaceutically acceptable salts thereof and the compositions provided herein is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer.

The concentration and route of administration to the subject will vary depending on the cancer to be treated. In certain embodiments, the administering is conducted via a route selected from the group consisting of parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, intracerebrospinal, intrasynovial, intrathecal administration, intramuscular injection, intravitreous injection, intravenous injection, intra-arterial injection, oral, buccal, sublingual, transdermal, topical, intratracheal, intrarectal, subcutaneous, and topical administration.

The compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising such compounds and salts also may be co-administered with other anti-neoplastic compounds, e.g., chemotherapy, or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively.

In some embodiments, the compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising such compounds and salts can be administered simultaneously, separately or sequentially with one or more additional therapeutic agents. In certain embodiments, the additional therapeutic agent is selected from an anti-PD-1 antagonist, an MEK inhibitor, a SHP2 inhibitor, a platinum agent or pemetrexed. In certain embodiments, the anti-PD-1 antagonist is selected from nivolumab, pembrolizumab, or AMB 404. In certain embodiments, the MEK inhibitor is trametinib. In certain embodiments, the SHP2 inhibitor is RMC-4630.

In another aspect, the present disclosure also provides a method for treating cancer in a subject in need thereof, the method comprising:

(a) acquiring the knowledge that the cancer is associated with KRAS G12D mutation; and

(b) administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure.

In another aspect, the present disclosure provides a method for inhibiting KRAS G12D activity in a subject in need thereof, comprising administering the compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure to the subject.

EXAMPLES

For the purpose of illustration, the following examples are included. However, it is to be understood that these examples do not limit the present disclosure and are only meant to suggest a method of practicing the present disclosure.

General Synthetic Route

In some embodiments, compounds of Formula (Ia) provided herein may be prepared by the synthetic route as shown in Scheme 1:

Scheme 1

Step 1:

The starting material of Formula (I-1) is commercially available. Compound of Formula (I-2) may be prepared by the acylation of a compound of Formula (I-1) with acetylchloride under standard conditions.

Step 2:

Compound of Formula (I-3) may be prepared by the carbonylation reaction of Formula (I-2) with carbon monoxide in the presence of Palladium catalyst (e.g, Pd (Ph ₃P) ₄) and base (e.g, triethylamine) under standard conditions.

Step 3:

Compound of Formula (I-4) may be prepared by the nucleophilic substitution reaction with 4- (bromomethyl) -1, 2-dimethoxybenzene under standard conditions.

Step 4:

Compound of Formula (1-5) may be prepared by the intramolecular cyclization of a compound of Formula (I-4) in the presence of base (e.g, KHMDS) under standard conditions.

Step 5:

Compound of Formula (I-6) may be prepared by the chlorination reaction of a compound of Formula (I-5) with chloride reagents (e.g, POCl ₃) under standard conditions.

Step 6:

Compound of Formula (I-8) may be prepared by the Suzuki coupling reaction of Formula (I-6) with a compound of Formula (I-8) in the presence of Palladium catalyst (e.g, Pd (dppf) Cl ₂) and base (e.g, Cs ₂CO ₃) under standard conditions.

Step 7:

Compound of Formula (I-10) may be prepared by the Buchwald coupling reaction of Formula (I-8) with a compound of Formula (I-9) in the presence of Palladium catalyst (e.g, Pd (OAc) ₂) , ligand (e.g, BINAP) and base (e.g, Cs ₂CO ₃) under standard conditions.

Step 8:

Compound of Formula (I-11) may be prepared by the removing the PMB protective group with acid (e.g, TFA) under standard condition.

Step 9:

Compound of Formula (I-12) may be prepared by the chlorination reaction of Formula (I-11) with chloride reagents (e.g, POCl ₃) under standard conditions.

Step 10:

Compound of Formula (Ia) may be prepared by nucleophilic substitution reaction with a compound of Formula (I-13) under standard conditions.

In some embodiments, compounds of Formula (Ia) provided herein may also be prepared by the synthetic route as shown in Scheme 2.

Scheme 2

Step 1:

Formula (II-2) can be prepared can be prepared via benzyl bromide protection Formula (II-1) under standard reaction condition.

Step 2:

Formula (II-3) can be prepared can be prepared via base (e.g, KHMDS) mediated cyclization of Formula (II-2) under standard reaction condition.

Step 3:

Formula (II-4) can be prepared can be prepared via chloronation reaction of Formula (II-3) with POCl ₃ in presence of a base (e.g, DIPEA) under standard reaction condition.

Step 4:

Formula (II-6) can be prepared via SNAr between commercially available Formula (II-5) and Formula (II-4) in presence of a base (e.g, CsF) under standard reaction condition.

Step 5:

Formula (II-7) can be prepared via methanesulfonic acid mediated benzyl deprotection of Formula (II-6) under standard reaction condition.

Step 6:

Formula (II-8) can be prepared via Boc protection of Formula (II-7) under standard reaction condition.

Step 7:

Formula (II-10) can be prepared via Mitsunobu reaction between commercially available alcohol Formula (II-9) and Formula (II-8) in presence of cyanomethylenetributylphosphorane (CMBP) under standard reaction condition

Step 8:

Formula (II-12) can be prepared can be prepared via Suzuki coupling between aryl boronic ester (II-11) and Formula (II-10) in presence of a palladium precatalyst (e.g, RuPhos Pd G3) and a base under standard condition.

Step 9:

Formula (Ia) can be prepared via acid promoted Boc deprotection of Formula (II-12) under standard conditions.

In some embodiments, compounds of Formula (IIa) provided herein may be prepared by the synthetic route as shown in Scheme 3.

Scheme 3

Step 1:

Formula (III-1) can be prepared can be prepared using conventional method, for example as described in WO2021/41671. Formula (III-3) can be prepared via SNAr between commercially available Formula (III-2) and Formula (III-1) .

Step 2:

Formula (III-5) can be prepared can be prepared via Sonagashira coupling between alkyne (III-4) and Formula (III-3) in presence of a Cu (I) catalyst and palladium catalyst in TEA.

Step 3:

Formula (III-7) can be prepared can be prepared via Suzuki coupling between boronic ester (III-6) and Formula (III-5) in presence of a palladium precatalyst (e.g, X-Phos Pd G2) and a base under standard condition.

Step 4:

Formula (IIa) can be prepared via acid promoted Boc deprotection of Formula (III-7) under standard conditions.

In some embodiments, compounds of Formula (IIa) provided herein may be prepared by the synthetic route as shown in Scheme 4.

Scheme 4

Step 1:

Formula (IV-1) can be prepared by previous described method, for example as described in WO2021/41671. Formula (IV-2) can be prepared via Ruthinium catalyzed hydroboration reaction between (IV-1) and 4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane under standard conditions.

Step 2:

Formula (IV-4) can be prepared via Suzuki coupling between Formula (IV-2) and Formula (IV-3) in presence of a palladium (II) catalyst (e.g, Pd (dppf) Cl ₂) and a base (e.g, CsF) under standard condition as trans alkene product.

Step 3:

Formula (IV-6) can be prepared can be prepared via Suzuki coupling between aryl boronic ester (IV-5) and Formula (IV-4) in presence of a palladium precatalyst (e.g, XPhos Pd G2) and a base (e.g, K ₃PO ₄) under standard condition.

Step 4:

Formula (IIa) can be prepared via acid promoted Boc deprotection of Formula (IV-6) under standard conditions.

In some embodiments, compounds of Formula (IIc) provided herein may be prepared by the synthetic route as shown in Scheme 5

Scheme 5

Step 1:

Formula (V-3) can be prepared via SNAr reaction between commercially available starting material of Formula (V-1) and Formula (V-2) in presence of a base (e.g, DIPEA) under standard conditions.

Step 2:

Formula (V-4) can be prepared via palladium catalyzed reaction between Formula (V-3) and an alcohol (R ¹-OH) in presence of ligand (e.g, BINAP) a base (e.g, Cs ₂CO ₃) under standard conditions.

Step 3:

Formula (V-5) can be prepared via acid promoted Boc deprotection under standard conditions.

Step 4:

Formula (V-7) can be prepared via Buchwald coupling between Formula (V-5) and Formula (V-6) in presence of a palladium catalyst, a ligand (e.g, BINAP) and a base (e.g, Cs ₂CO ₃) under standard conditions.

Step 5:

Formula (IIc) can be prepared via Lewis acid (e.g, BCl ₃) promoted Cbz deprotection of Formula (V-7) under standard conditions.

In some embodiments, compounds of Formula (IIIa) provided herein may be prepared by the synthetic route as shown in Scheme 6:

Scheme 6

Step 1:

The starting material of Formula (VI-1) is commercially available. Compound of Formula (VI-2) may be prepared by the Curtius rearrangement reaction with a compound of Formula (VI-1) in the presence of diphenyl phosphorazidate (DPPA) under standard conditions.

Step 2:

Compound of Formula (VI-3) may be prepared by the removing the PMB protective group with acid (e.g, TFA) under standard condition.

Step 3:

Compound of Formula (VI-4) may be prepared by the iodination reaction of Formula (VI-3) with N-Iodosuccinimide (NIS) under standard conditions.

Step 4:

Compound of Formula (VI-5) may be prepared by the carbonylation reaction of Formula (VI-4) with carbon monoxide in the presence of Palladium catalyst (e.g, Pd (Ph ₃P) ₄) and base (e.g, triethylamine) under standard conditions.

Step 5:

Compound of Formula (VI-6) may be prepared by the hydrolysis reaction of Formula (VI-5) with base under standard conditions.

Step 6:

Compound of Formula (VI-7) may be prepared by the pyrimidinedione cyclization reaction of a compound of Formula (VI-6) with ammonium thiocyanate in the presence of acylating chlorination reagent (e.g, oxalyl chloride) under standard conditions.

Step 7:

Compound of Formula (VI-8) may be prepared by the methylation reaction of Formula (VI-7) with methylation reagents (e.g, MeI) under standard conditions.

Step 8:

Compound of Formula (VI-9) may be prepared by the chlorination reaction of Formula (VI-8) with chloride reagents (e.g, POCl ₃) in the presence of base (e.g, DIPEA) under standard conditions.

Step 9:

Compound of Formula (VI-11) may be prepared by the Suzuki coupling reaction of a compound of Formula (VI-9) with a compound of Formula (VI-10) in the presence of Palladium catalyst (e.g, PddppfCl ₂) and base (e.g, Na ₂CO ₃) under standard conditions.

Step 10:

Compound of Formula (VI-13) may be prepared by the Stille coupling reaction of a compound of Formular (VI-11) with a compound of Formula (VI-12) in the presence of Palladium catalyst (e.g, PddppfCl ₂) , ligand (e.g, NINAP) , copper addition (e.g, CuI) and base (e.g, triethylamine) under standard conditions.

Step 11:

Compound of Formula (VI-14) may be prepared by the oxidation reaction of Formula (VI-13) with oxidative reagents (e.g, mCPBA) under standard conditions.

Step 12:

Compound of Formula (VI-16) may be prepared by nucleophilic substitution reaction with a compound of Formula (VI-15) under standard conditions.

Step 13:

Compound of Formula (IIIa) may be prepared by the deprotection of Formula (VI-16) with acid (e.g, HCl or TFA) under standard conditions.

In some embodiments, compounds of Formula (IVa) provided herein may be prepared by the synthetic route as shown in Scheme 7:

Scheme 7

Step 1:

The starting material of Formula (VII-1) is commercially available or can be prepared using conventional method, for example as described in Journal of Heterocyclic Chemistry (1993) , 30 (4) , 855-9.

Compound of Formula (VII-2) may be prepared by the amination of a compound of Formula (VII-1) with ammonium hydroxide under standard conditions.

Step 2:

Compound of Formula (VII-4) may be prepared by the pyrimidinedione cyclization reaction of a compound of Formula (VII-3) with a compound of Formula (VII-2) in the presence of acylating chlorination reagent (e.g, oxalyl chloride) and base (e.g, LiHMDS) under standard conditions.

Step 3:

Compound of Formula (VII-6) may be prepared by the Suzuki coupling reaction of a compound of Formular (VII-4) with a compound of Formula (VII-5) in the presence of Palladium catalyst (e.g, PddppfCl ₂) and base (e.g, Cs ₂CO ₃) under standard conditions.

Step 4:

Compound of Formula (VII-7) may be prepared by the chlorination reaction of Formula (VII-6) with chloride reagents (e.g, POCl ₃) under standard conditions.

Step 5:

Compound of Formula (VII-9) may be prepared by the Suzuki coupling reaction of Formular (VII-7) with a compound of Formula (III-8) in the presence of Palladium catalyst (e.g, PddppfCl ₂) and base (e.g, Cs ₂CO ₃) under standard conditions.

Step 6:

Compound of Formula (IVa) may be prepared by deprotection of Formula (VII-9) with acid (e.g, HCl or TFA) under standard conditions.

In some embodiments, INT 1 may be prepared by the synthetic route as shown in Scheme 8.

Scheme 8

Step 1:

Formula (VIII-2) can be prepared via alkylation reaction between Formula (VIII-1) and 1-chloro-3-iodopropane in presence of a base under standard conditions.

Step 2:

Formula (VIII-3) can be prepared via reduction of Formula (VIII-2) in presence of a reductant (e.g, LiBH ₄) under standard conditions.

Step 3:

Formula (VIII-4) can be prepared via oxidation reaction of Formula (VIII-3) in presence of an oxidant (e.g, Dess-Martin periodinane) under standard conditions.

Step 4:

Formula (VIII-5) can be prepared via Seyferth-Gilbert homologation of Formula (VIII-4) in presence of dimethyl (diazomethyl) phosphonate under standard conditions.

Step 5:

Formula (VIII-6) can be prepared via acid promoted Boc deprotection of Formula (VIII-5) under standard conditions.

Step 6:

INT 1 can be prepared via intermolecular alkylation of Formula (VII-6) in presence of a base under standard conditions.

In some embodiments, INT 2 may be prepared by the synthetic route as shown in Scheme IX.

Scheme 9

Step 1:

Formula (IX-2) can be prepared via Swern oxidation of Formula (IX-1) under standard conditions.

Step 2:

INT 2 can be prepared via Seyferth-Gilbert homologation of Formula (IX-2) in presence of dimethyl (diazomethyl) phosphonate under standard conditions.

In some embodiments, Formula (Ia) may be prepared by the synthetic route as shown in Scheme 10.

Scheme 10

Step 1:

Formula (X-2) can be prepared can be prepared via Sonagashira coupling between trimethylsilyl acetylene and Formula (X-1) in presence of a Cu (I) catalyst (e.g, CuI) and palladium catalyst (e.g, Pd (PPh ₃) ₂Cl ₂) in TEA under standard conditions.

Step 2:

Formula (X-3) can be prepared can be prepared via TBAF mediated TMS deprotection of Formula (X-2) under standard conditions.

Step 3:

Formula (X-4) can be prepared via silver-catalyzed carbon dioxide incorporation and intramolecular rearrangement of Formula (X-3) under standard conditions (see, for example, Org. Lett. 2013, 15, 14, 3710–3713) .

Step 4:

Formula (X-5) can be prepared via chlorination reaction mediated by a chlorine source (e.g, POCl ₃) under standard conditions.

Step 5:

Formula (X-7) can be prepared can be prepared via Sonagashira coupling between trimethylsilyl acetylene Formula (X-6) and Formula (X-5) in presence of a Cu (I) catalyst (e.g, CuI) and palladium catalyst (e.g, Pd (PPh ₃) ₂Cl ₂) in TEA under standard conditions.

Step 6:

Formula (X-9) can be prepared can be prepared via SNAr reaction between Formula (X-8) and Formula (X-7) in presence of a base (e.g, CsF) under standard conditions.

Step 7:

Formula (X-11) may be prepared by the Suzuki coupling reaction of Formula (X-9) with a compound of Formula (X-10) in the presence of palladium precatalyst (e.g, XPhos-Pd-G ₂) and base (e.g, K ₂CO ₃) under standard conditions.

Step 8:

Formula (Ia) may be prepared via TMSOTf/TFA mediated deprotection of Formula (X-11) under standard conditions.

The following example can be prepared by the method described in Scheme 5.

Example 1: 5-chloro-4- (4- {3, 8-diazabicyclo [3.2.1] octan-3-yl} -2- [ (hexahydro-1H-pyrrolizin-7a-yl) methoxy] -5H, 6H, 7H, 8H-pyrido [3, 4-d] pyrimidin-7-yl) naphthalen-2-ol (Compound 1)

Step 1: Tert-butyl 4- ( (1R, 5S) -8- ( (benzyloxy) carbonyl) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -2-chloro-5, 8-dihydropyrido [3, 4-d] pyrimidine-7 (6H) -carboxylate

To a solution of benzyl (1R, 5S) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (1.58 g, 6.41 mmol) in DMSO (10 mL) was added DIPEA (1.4 mL, 8.47 mmol) followed by tert-butyl 2, 4-dichloro-5H, 6H, 7H, 8H-pyrido [3, 4-d] pyrimidine-7-carboxylate (1.3 g, 4.27 mmol) and the mixture was stirred at 80 ℃ for 16 hrs. The reaction mixture was diluted with EtOAc (40 mL) , washed with water and brine, dried over anhydrous Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0～28%EtOAc in PE) to give tert-butyl 4- ( (1R, 5S) -8- ( (benzyloxy) carbonyl) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -2-chloro-5, 8-dihydropyrido [3, 4-d] pyrimidine-7 (6H) -carboxylate (1.2 g, 54.7%yield) as a yellow solid. MS (ESI) m/z: 514 (M+H) ⁺.

Step 2: Tert-butyl 4- ( (1R, 5S) -8- ( (benzyloxy) carbonyl) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 8-dihydropyrido [3, 4-d] pyrimidine-7 (6H) -carboxylate

To a mixture of tert-butyl 4- ( (1R, 5S) -8- ( (benzyloxy) carbonyl) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -2-chloro-5, 8-dihydropyrido [3, 4-d] pyrimidine-7 (6H) -carboxylate (500 mg, 0.97 mmol) and (hexahydro-1H-pyrrolizin-7a-yl) methanol (330 mg, 2.33 mmol) in toluene (15 mL) was added Pd (OAc) ₂ (40 mg, 0.20 mmol) , BINAP (240 mg, 0.39 mmol) and Cs ₂CO ₃ (950 mg, 2.91 mmol) under N ₂ atmosphere. The mixture was degassed under N ₂ atmosphere for three times and stirred at 100 ℃ under N ₂ atmosphere for 16 hrs. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0～13%MeOH in DCM) to give tert-butyl 4- ( (1R, 5S) -8- ( (benzyloxy) carbonyl) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 8-dihydropyrido [3, 4-d] pyrimidine-7 (6H) -carboxylate (210 mg, 35%yield) as a brown solid. MS (ESI) m/z: 619 (M+H) ⁺.

Step 3: Benzyl (1R, 5S) -3- (2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

To a mixture of benzyl 3- {7- [ (tert-butoxy) carbonyl] -2- [ (hexahydro-1H-pyrrolizin-7a-yl) methoxy] -5H, 6H, 7H, 8H-pyrido [3, 4-d] pyrimidin-4-yl} -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (0.6 g, 0.97 mmol) in DCM (6 mL) was added TFA (2 mL, 26.1 mmol) and the mixture was stirred at 25 ℃ for 1.5 hrs. The reaction mixture was concentrated to dryness and the residue was neutralized with saturated aq. NaHCO ₃ solution. The mixture was extracted with DCM (3 x 15 mL) . The combined organic layers were washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated under reduced pressure to dryness to give crude benzyl 3- {2- [ (hexahydro-1H-pyrrolizin-7a-yl) methoxy] -5H, 6H, 7H, 8H-pyrido [3, 4-d] pyrimidin-4-yl} -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (500 mg, 100%yield) as a yellow solid, which was used in the next reaction directly. MS (ESI) m/z: 260 (0.5M+H) ⁺.

Step 4: Benzyl 3- {7- [8-chloro-3- (methoxymethoxy) naphthalen-1-yl] -2- [ (hexahydro-1H-pyrrolizin-7a-yl) methoxy] -5H, 6H, 7H, 8H-pyrido [3, 4-d] pyrimidin-4-yl} -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

To a mixture of benzyl 3- {2- [ (hexahydro-1H-pyrrolizin-7a-yl) methoxy] -5H, 6H, 7H, 8H-pyrido [3, 4-d] pyrimidin-4-yl} -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (500 mg, 0.96 mmol) and 1-bromo-8-chloro-3- (methoxymethoxy) naphthalene (400 mg, 1.33 mmol) in 1, 4-dioxane (10 mL) was added Pd ₂ (dba) ₃ (80 mg, 0.087 mmol) , BINAP (120 mg, 0.193 mmol) and Cs ₂CO ₃ (200 mg, 2.08 mmol) under N ₂ atmosphere. The mixture was degassed under N ₂ atmosphere for three times and stirred in a CEM microwave reactor at 100 ℃ for 2 hrs. The reaction mixture was diluted with EtOAc (20 mL) , washed with water and brine, dried over anhydrous Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0～20%EtOAc in PE) to give benzyl (1R, 5S) -3- (7- (8-chloro-3- (methoxymethoxy) naphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (380 mg, 53%yield) as a brown solid. MS (ESI) m/z: 370 (0.5 M+H) ⁺.

Step 5: 5-chloro-4- (4- {3, 8-diazabicyclo [3.2.1] octan-3-yl} -2- [ (hexahydro-1H-pyrrolizin-7a-yl) methoxy] -5H, 6H, 7H, 8H-pyrido [3, 4-d] pyrimidin-7-yl) naphthalen-2-ol

To a solution of benzyl (1R, 5S) -3- (7- (8-chloro-3- (methoxymethoxy) naphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (100 mg, 0.13 mmol) in DCM (5 mL) was added Boron trichloride (0.7 mL, 1M) drop-wisely at 0 ℃ and the mixture was stirred at 25 ℃ for 5 hrs. The reaction mixture was quenched by drop-wise addition of MeOH (3 mL) at 0 ℃ and the mixture was concentrated to dryness. The residue was purified by prep-HPLC (C18, 0～50 %acetonitrile in H ₂O with 0.1%FA) to give 5-chloro-4- (4- {3, 8-diazabicyclo [3.2.1] octan-3-yl} -2- [ (hexahydro-1H-pyrrolizin-7a-yl) methoxy] -5H, 6H, 7H, 8H-pyrido [3, 4-d] pyrimidin-7-yl) naphthalen-2-ol (26 mg, 34.3%yield) .

¹H NMR (400 MHz, CD ₃OD) δ 8.53 (s, 1H) , 7.57 (d, J = 7.7 Hz, 1H) , 7.29 –7.19 (m, 2H) , 6.96 –6.83 (m, 2H) , 4.42 –4.26 (m, 4H) , 3.82 (d, J = 12.4 Hz, 1H) , 3.74 –3.62 (m, 3H) , 3.60 –3.47 (m, 3H) , 3.43 (d, J = 12.8 Hz, 1H) , 3.22 –3.05 (m, 5H) , 2.63 (d, J = 14.2 Hz, 1H) , 2.26 –1.81 (m, 12H) . MS (ESI) m/z: 561 (M+H) ⁺.

The following examples can be prepared by the method described in Scheme 3:

Example 2: 5-Chloro-4- (4- {3, 8-diazabicyclo [3.2.1] octan-3-yl} -8-fluoro-2- [2- (hexahydro-1H-pyrrolizin-7a-yl) ethynyl] pyrido [4, 3-d] pyrimidin-7-yl) naphthalen-2-ol (Compound 2)

Step 1: Tert-butyl 3- {7-chloro-8-fluoro-2- [2- (hexahydro-1H-pyrrolizin-7a-yl) ethynyl] pyrido [4, 3-d] pyrimidin-4-yl} -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

To a mixture of tert-butyl 3- {2, 7-dichloro-8-fluoropyrido [4, 3-d] pyrimidin-4-yl} -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (500 mg, 1.17 mmol) and 7a- ethynyl-hexahydro-1H-pyrrolizine (158 mg, 1.17 mmol) in TEA (10 mL) were added Pd (PPh ₃) ₂Cl ₂ (84 mg, 0.12 mmol) and CuI (23 mg, 0.12 mmol) . The mixture was degassed under N ₂ atmosphere for three times and stirred at 80 ℃ in a sealed tube for 16 hrs. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-15%MeOH in DCM) to give tert-butyl 3- {7-chloro-8-fluoro-2- [2- (hexahydro-1H-pyrrolizin-7a-yl) ethynyl] pyrido [4, 3-d] pyrimidin-4-yl} -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (310 mg, 50%yield) as a yellow solid. MS (ESI) m/z: 527 (M+H) ⁺.

Step 2: Tert-butyl 3- (7- {8-chloro-3- [ (2, 2-dimethylpropanoyl) oxy] naphthalen-1-yl} -8-fluoro-2- [2- (hexahydro-1H-pyrrolizin-7a-yl) ethynyl] pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

To a solution of tert-butyl 3- {7-chloro-8-fluoro-2- [2- (hexahydro-1H-pyrrolizin-7a-yl) ethynyl] pyrido [4, 3-d] pyrimidin-4-yl} -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (270 mg, 0.51 mmol) in THF (3 mL) was added 5-chloro-4- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-2-yl 2, 2-dimethylpropanoate (219 mg, 0.56 mmol) and aq. K ₃PO ₄ solution (3.1 mL, 1.54 mmol, 0.5 M in water) , followed by X-Phos Pd G ₂ (40 mg, 0.05 mmol) . The mixture was degassed under N ₂ for three times and stirred at 40 ℃ for 16 hrs. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-5%MeOH in DCM) to give tert-butyl 3- (7- {8-chloro-3- [ (2, 2-dimethylpropanoyl) oxy] naphthalen-1-yl} -8-fluoro-2- [2- (hexahydro-1H-pyrrolizin-7a- yl) ethynyl] pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (80 mg, 21%yield) as a yellow solid. MS (ESI) m/z: 753 (M+H) ⁺.

Step 3: 4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) ethynyl) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloronaphthalen-2-yl pivalate

To a solution of tert-butyl 3- (7- {8-chloro-3- [ (2, 2-dimethylpropanoyl) oxy] naphthalen-1-yl} -8-fluoro-2- [2- (hexahydro-1H-pyrrolizin-7a-yl) ethynyl] pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (80 mg, 0.11 mmol) in DCM (2 mL) was added TFA (1 mL) at 0 ℃ and the mixture was stirred at 0 ℃ for 2 hrs. The mixture was basified with saturated aq. NaHCO ₃ solution to pH～8 and extracted with DCM (3 x 5 mL) . The combined organic layers was washed with water and brine, dried over Na ₂SO ₄, filtered and concentrated to dryness to give 5-chloro-4- (4- {3, 8-diazabicyclo [3.2.1] octan-3-yl} -8-fluoro-2- [2- (hexahydro-1H-pyrrolizin-7a-yl) ethynyl] pyrido [4, 3-d] pyrimidin-7-yl) naphthalen-2-yl 2, 2-dimethylpropanoate (70 mg, 100%yield) as a yellow solid. MS (ESI) m/z: 653 (M+H) ⁺.

Step 4: 5-Chloro-4- (4- {3, 8-diazabicyclo [3.2.1] octan-3-yl} -8-fluoro-2- [2- (hexahydro-1H-pyrrolizin-7a-yl) ethynyl] pyrido [4, 3-d] pyrimidin-7-yl) naphthalen-2-ol

To a solution of 5-chloro-4- (4- {3, 8-diazabicyclo [3.2.1] octan-3-yl} -8-fluoro-2- [2- (hexahydro-1H-pyrrolizin-7a-yl) ethynyl] pyrido [4, 3-d] pyrimidin-7-yl) naphthalen-2-yl 2, 2-dimethylpropanoate (60 mg, 0.09 mmol) in 1, 4-dioxane (3 mL) was added Cs ₂CO ₃ (60 mg, 0.18 mmol) . The mixture was stirred at 70 ℃ for 16 hrs. The mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by prep-HPLC to give 5-chloro-4- (4- {3, 8-diazabicyclo [3.2.1] octan-3-yl} -8-fluoro-2- [2- (hexahydro-1H-pyrrolizin-7a-yl) ethynyl] pyrido [4, 3-d] pyrimidin-7-yl) naphthalen-2-ol (1.3 mg, 2%yield) .

¹H NMR (400 MHz, DMSO-d ₆) δ 9.16 (s, 1H) , δ 7.86 -7.84 (m, 1H) δ 7.44 -7.32 (m, 3H) , δ 7.16 -7.15 (m, 1H) , 5.32 (s, 1H) , 4.50 -4.33 (m, 2H) , 3.57 (m, 2H) , 3.04 (m, 3H) , 2.15 -2.10 (m, 2H) , 2.03 -1.97 (m, 4H) , 1.93 -1.82 (m, 6H) , 1.67 -1.56 (m, 4H) . MS (ESI) m/z: 569 (M+H) ⁺.

The following examples were prepared in similar manners as compound 2 with an alkyne prepared by the method described in Scheme 8.

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) ethynyl) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol (Compound 9)

¹H NMR (400 MHz, DMSO-d ₆) δ 9.19 (s, 1H) , 7.77 (dd, J = 9.0, 6.0 Hz, 1H) , 7.43 -7.28 (m, 2H) , 7.04 (d, J = 2.5 Hz, 1H) , 5.49 -5.23 (m, 1H) , 4.53 -4.28 (m, 2H) , 3.72 -3.58 (m, 4H) , 3.32 -3.27 (m, 2H) , 3.07 -3.00 (m, 1H) , 2.90 -2.77 (m, 1H) , 2.66 -2.57 (m, 1H) , 2.49 -2.42 (m, 1H) , 2.40 -2.20 (m, 2H) , 2.17 -2.06 (m, 2H) , 2.05 -1.99 (m, 1H) , 1.93 -1.83 (m, 2H) , 1.74 -1.49 (m, 4H) , 0.70 (t, J = 7.4 Hz, 3H) . MS (ESI) m/z: 599 (M+H) ⁺.

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) ethynyl) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Compound 10)

¹H NMR (400 MHz, DMSO-d ₆) δ 10.20 (s, 1H) , 9.13 (s, 1H) , 8.01 -7.97 (dd, J = 9.2, 5.9 Hz, 1H) , 7.50 -7.45 (t, J = 9.0 Hz, 1H) , 7.41 -7.40 (d, J = 2.5 Hz, 1H) , 7.20 -7.19 (d, J = 2.6 Hz, 1H) , 5.36 -5.23 (m, 1H) , 4.46 -4.36 (m, 2H) , 3.92 (s, 1H) , 3.69 -3.54 (m, 4H) , 3.11 -2.97 (m, 2H) , 2.93 -2.84 (m, 1H) , 2.82 -2.73 (m, 1H) , 2.69 -2.53 (m, 2H) , 2.34 -2.27 (m, 1H) , 2.22 -2.07 (m, 2H) , 2.06 -1.94 (m, 3H) , 1.94 -1.79 (m, 3H) . MS (ESI) m/z: 595 (M+H) ⁺.

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) ethynyl) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol (Compound 18)

MS (ESI) m/z: 599 [M+H] ⁺.

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) ethynyl) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Compound 19)

MS (ESI) m/z: 595 [M+H] ⁺.

4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-2- ( (2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) ethynyl) pyrido [4, 3-d] pyrimidine (Compound 20)

MS (ESI) m/z: 579 [M+H] ⁺.

The following example can be prepared by the method described in Scheme 2:

Example 3: 4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -1, 6-naphthyridin-7-yl) -5-chloronaphthalen-2-ol (Compound 3)

Step 1: Ethyl 4- (N-benzylacetamido) -6-chloro-5-fluoronicotinate

To a mixture of ethyl 6-chloro-4-acetamido-5-fluoropyridine-3-carboxylate (18 g, 69.06 mmol) in DMF (150 mL) was added KOH (4.26 g, 75.9 mmol) followed by drop-wise addition of a solution of (bromomethyl) benzene (8.9 mL, 76.1 mmol) in DMF (150 mL) at 0 ℃. The resulting mixture was stirred at r. t. for 16 hrs. The mixture was poured into ice-water and extracted with EtOAc (2 x 50 mL) . The combined organic layers were washed with brine, dried over Na ₂SO ₄, filtered and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0～10%of EtOAc in PE) to give ethyl 6-chloro-5-fluoro-4- {N- [ (4-methoxyphenyl) methyl] acetamido} pyridine-3-carboxylate (21.2 g, 87%yield) as a yellow oil. MS (ESI) m/z: 351 (M+H) ⁺.

Step 2: 1-Benzyl-7-chloro-8-fluoro-4-hydroxy-1, 6-naphthyridin-2 (1H) -one

To a mixture of ethyl 4- (N-benzylacetamido) -6-chloro-5-fluoronicotinate (11 g, 31.4 mmol) in THF (110 mL) was added LiHMDS (34.5 mL, 34.5 mmol, 1M in THF) drop-wisely at 0 ℃ and the mixture was stirred at 0 ℃ to r. t. for 16 hrs. The reaction was quenched with ice-water and adjusted pH to 4～5 with 1N aq. HCl. The mixture was extracted with EtOAc (2 x 150 mL) and the combined organic layers were washed with brine, dried over Na ₂SO ₄, filtered and concentrated under reduced pressure to dryness. The residue was triturated with PE/EtOAc (5/1, v/v) at r. t. and filtered. The filtrate cake was washed with PE and dried under vacuum to give 1-benzyl-7-chloro-8-fluoro-4-hydroxy-1, 2-dihydro-1, 6-naphthyridin-2-one (7.4 g, 77%yield) as a white solid. MS (ESI) m/z: 305 (M+H) ⁺.

Step 3: 1-Benzyl-4, 7-dichloro-8-fluoro-1, 6-naphthyridin-2 (1H) -one

To a solution of 1-benzyl-7-chloro-8-fluoro-4-hydroxy-1, 2-dihydro-1, 6-naphthyridin-2-one (4 g, 13.1 mmol) in POCl ₃ (40 mL) was added DIPEA (6.5 mL, 39.4 mmol) at 0 ℃ and the reaction mixture was stirred at 110 ℃ for 16 hrs. The mixture was concentrated under reduced pressure to dryness. The residue was poured into ice-water and extracted with EtOAc (2 x 100 mL) . The combined organic layers were washed with brine, dried over anhydrous Na ₂SO ₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0～9%of EtOAc in PE) to give 1-benzyl-4, 7-dichloro-8-fluoro-1, 2-dihydro-1, 6-naphthyridin-2-one (2.5 g, 59%yield) as a light yellow solid. MS (ESI) m/z: 323 (M+H) ⁺.

Step 4: Tert-butyl (1R, 5S) -3- (1-benzyl-7-chloro-8-fluoro-2-oxo-1, 2-dihydro-1, 6-naphthyridin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

To a mixture of 1-benzyl-4-bromo-7-chloro-8-fluoro-1, 2-dihydro-1, 6-naphthyridin-2-one (3.5 g, 10.8 mmol) and tert-butyl 3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (2.53 g, 11.9mmol) in DMSO (35 mL) was added CsF (3.78 g, 24.9 mmol) at r. t. and the mixture was stirred at 60 ℃ for 5 hrs. The mixture was poured into ice-water and extracted with EtOAc (2 x 50 mL) . The organic layers were washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0～30%of EtOAc in PE) to give tert-butyl 3- (1-benzyl-7-chloro-8-fluoro-2-oxo-1, 2-dihydro-1, 6-naphthyridin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (4.5 g, 83%yield) as a white solid. MS (ESI) m/z: 499 (M+H) ⁺.

Step 5: 4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7-chloro-8-fluoro-1, 6-naphthyridin-2 (1H) -one

A solution of tert-butyl 3- (1-benzyl-7-chloro-8-fluoro-2-oxo-1, 2-dihydro-1, 6-naphthyridin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (600 mg, 1.2 mmol) in methanesulfonic acid (10 mL, 154.1 mmol) was stirred at 80 ℃ for 6 hrs. The mixture was poured into ice-water and neutralized with saturated aq. Na ₂CO ₃ solution. The mixture was extracted with DCM (2 x 20 mL) and the combined organic layers were washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated under reduced pressure to dryness to give crude 7-chloro-4- {3, 8-diazabicyclo [3.2.1] octan-3-yl} -8-fluoro-1, 2-dihydro-1, 6-naphthyridin-2-one (370 mg, 100%yield) as a brown oil. MS (ESI) m/z: 309 (M+H) ⁺.

Step 6: Tert-butyl (1R, 5S) -3- (7-chloro-8-fluoro-2-oxo-1, 2-dihydro-1, 6-naphthyridin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

To a mixture of 7-chloro-4- {3, 8-diazabicyclo [3.2.1] octan-3-yl} -8-fluoro-1, 2-dihydro-1, 6-naphthyridin-2-one (370 mg, 1.3 mmol) in DCM (5 mL) was added TEA (0.54 mL, 3.88 mmol) followed by (Boc) ₂O (0.42 mL, 1.94 mmol) at 0 ℃ and the mixture was stirred at r. t. for 16 hrs. The mixture was diluted with DCM, washed with water and brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0～50%of EtOAc in PE) to give tert-butyl 3- (7-chloro-8-fluoro-2-oxo-1, 2-dihydro-1, 6-naphthyridin-4-yl) -3, 8- diazabicyclo [3.2.1] octane-8-carboxylate (310 mg, 58%yield) as a white solid. MS (ESI) m/z: 409 (M+H) ⁺.

Step 7: Tert-butyl (1R, 5S) -3- (7-chloro-8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -1, 6-naphthyridin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

To a mixture of tert-butyl 3- (7-chloro-8-fluoro-2-oxo-1, 2-dihydro-1, 6-naphthyridin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (300 mg, 0.73 mmol) in toluene (5 mL) were added (hexahydro-1H-pyrrolizin-7a-yl) methanol (155 mg, 1.1 mmol) and cyanomethylenetributylphosphorane (443 mg, 1.83 mmol) at 25 ℃ under N ₂ atmosphere. The mixture was degassed under N ₂ atmosphere for three times and stirred under N ₂ atmosphere at 100 ℃ for 2 hrs. The mixture was concentrated to dryness and the residue was purified by flash chromatography (silica gel, 0～15%of MeOH in DCM) to give tert-butyl 3- {7-chloro-8-fluoro-2- [ (hexahydro-1H-pyrrolizin-7a-yl) methoxy] -1, 6-naphthyridin-4-yl} -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (170 mg, 44%yield) as a brown solid. MS (ESI) m/z: 532 (M+H) ⁺.

Step 8: Tert-butyl (1R, 5S) -3- (7- (8-chloro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -1, 6-naphthyridin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

To a mixture of tert-butyl 3- [7-chloro-8-fluoro-2- (methylsulfanyl) pyrido [4, 3-d] pyrimidin-4-yl] -8-azabicyclo [3.2.1] oct-2-ene-8-carboxylate (20 mg, 0.046 mmol) and 2- [8-chloro-3- (methoxymethoxy) naphthalen-1-yl] -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (49 mg, 0.14 mmol) in 1, 4-dioxane (2 mL) were added RuPhos Pd G3 (1.77 mg, 0.002 mmol) , RuPhos (4.4 mg, 0.009 mmol) and aq. K ₃PO ₄ solution (0.075 mL, 0.038 mmol, 0.5 M) at 20 ℃ under N ₂ atmosphere. The mixture was degassed under N ₂ atmosphere for three times and stirred at 95 ℃ for 16 hrs. The resulting mixture was diluted with water and extracted with EtOAc (2 x 10 mL) . The combined organic layers were washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0～12%of MeOH in DCM) to give tert-butyl 3- {7- [8-chloro-3- (methoxymethoxy) naphthalen-1-yl] -8-fluoro-2- [ (hexahydro-1H-pyrrolizin-7a-yl) methoxy] -1, 6-naphthyridin-4-yl} -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (20 mg, 30%yield) as a brown solid. MS (ESI) m/z: 718 (M+H) ⁺.

Step 9: 4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -1, 6-naphthyridin-7-yl) -5-chloronaphthalen-2-ol

To a mixture of tert-butyl 3- {7- [8-chloro-3- (methoxymethoxy) naphthalen-1-yl] -8-fluoro-2- [ (hexahydro-1H-pyrrolizin-7a-yl) methoxy] -1, 6-naphthyridin-4-yl} -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (20 mg, 0.028 mmol) in DCM (0.5 mL) was added TFA (0.5 mL) at 0 ℃ and the mixture was stirred at 0 ℃ for 2 hrs. The mixture was concentrated to dryness and the residue was dissolved in CH ₃CN (10 mL) . The mixture was neutralized with saturated aq. NaHCO ₃ solution to pH～8 and filtered. The filtrate was purified by pre-HPLC to give 5-chloro-4- (4- {3, 8-diazabicyclo [3.2.1] octan-3-yl} -8-fluoro-2- [ (hexahydro-1H-pyrrolizin-7a-yl) methoxy] -1, 6-naphthyridin-7-yl) naphthalen-2-ol (3.6 mg, 22%yield) .

¹H NMR (400 MHz, CDCl ₃) δ 9.09 (s, 1 H) , 7.61 -7.60 (d, J = 4 Hz, 1H) , 7.29 -7.28 (d, J = 4 Hz, 2H) , 7.16 -7.15 (d, J = 4 Hz, 2H) , 6.35 (s, 1H) , 5.34 (s, 2H ) , 4.38 -4.30 (m, 2H) , 3.63 (S, 2H) , 3.54 -3.51 (d, J = 12 Hz, 1H) , 3.35 -3.32 (d, J = 12 Hz, 1H) , 3.15 (s, 2H) , 3.04 -3.01 (d, J = 12 Hz, 2H) , 2.70 -2.68 (m, 2H) , 2.24 -2.20 (m, 2H) , 2.02 -1.97 (m, 4H) , 1.89 -1.84 (m, 4H) . MS (ESI) m/z: 574 (M+H) ⁺.

The following compounds were prepared in similar manners as compound 3:

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -1, 6-naphthyridin-7-yl) -5-chloronaphthalen-2-ol (Compound 5)

¹H NMR (400 MHz, MeOD) δ 9.09 (s, 1H) , 8.51 (s, 2H) , 7.76 (d, J = 6.7 Hz, 1H) , 7.37 –7.31 (m, 3H) , 7.16 (d, J = 2.5 Hz, 1H) , 6.67 (s, 1H) , 5.41 (s, 1H) , 5.27 (s, 1H) , 4.42 (dt, J = 19.3, 11.1 Hz, 3H) , 4.01 (s, 2H) , 3.65 (d, J = 12.3 Hz, 2H) , 3.37 (s, 2H) , 3.13 (s, 1H) , 2.37 (s, 1H) , 2.33 (d, J = 9.5 Hz, 2H) , 2.26 (s, 1H) , 2.19 (s, 1H) , 2.17 (s, 2H) , 2.04 (d, J = 8.1 Hz, 3H) , 1.95 (s, 1H) . MS (ESI) m/z: 592 [M+H] ⁺.

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -1, 6-naphthyridin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol (Compound 6)

¹H NMR (400 MHz, CD ₃OD) δ 9.14 (s, 1H) , 8.37 (s, 1H) , 7.71 –7.67 (m, 1H) , 7.32 (d, J = 2.6 Hz, 1H) , 7.26 (t, J = 9.4 Hz, 1H) , 7.05 (s, 1H) , 6.77 (s, 1H) , 5.34 (s, 1H) , 5.17 (s, 1H) , 4.19 (s, 3H) , 3.77 (s, 1H) , 3.73 (s, 1H) , 3.48 (s, 2H) , 3.40 (s, 2H) , 3.36 (s, 2H) , 3.13 (s, 1H) , 2.45 (s, 2H) , 2.43 (s, 2H) , 2.37 (s, 1H) , 2.21 (s, 1H) , 2.19 (s, 1H) , 2.17 (s, 1H) , 2.03 (s, 3H) , 1.60 (s, 3H) . MS (ESI) m/z: 604 (M+H) ⁺.

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -1, 6-naphthyridin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Compound 7)

¹H NMR (400 MHz, CD ₃OD) δ 9.08 (s, 1H) , 8.47 (s, 1H) , 7.87 (dd, J = 9.2, 5.7 Hz, 1H) , 7.38 –7.29 (m, 2H) , 7.22 (d, J = 2.4 Hz, 1H) , 6.70 (s, 1H) , 5.36 (d, J = 53.3 Hz, 1H) , 4.47 (ddd, J = 26.9, 11.4, 6.4 Hz, 2H) , 4.11 (s, 2H) , 3.75 (d, J = 13.8 Hz, 1H) , 3.65 (d, J = 12.9 Hz, 1H) , 3.44 (s, 2H) , 3.37 (d, J = 10.3 Hz, 3H) , 3.18 (d, J = 4.4 Hz, 1H) , 3.13 (s, 1H) , 2.41 (d, J = 8.5 Hz, 1H) , 2.38 (s, 1H) , 2.37 –2.32 (m, 1H) , 2.30 (s, 1H) , 2.22 (s, 1H) , 2.20 (s, 2H) , 2.08 (d, J = 6.7 Hz, 2H) , 1.96 (s, 1H) . MS (ESI) m/z: 600 (M+H) ⁺.

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -1, 6-naphthyridin-7-yl) -5-ethynylnaphthalen-2-ol (Compound 8)

¹H NMR (400 MHz, CD ₃OD) δ 9.08 (s, 1H) , 8.46 (s, 2H) , 7.83 (d, J = 7.8 Hz, 1H) , 7.50 (d, J = 6.6 Hz, 1H) , 7.42 –7.37 (m, 1H) , 7.34 (d, J = 2.5 Hz, 1H) , 7.17 (d, J = 2.5 Hz, 1H) , 6.71 (s, 1H) , 5.45 (s, 1H) , 4.49 (dd, J = 15.0, 5.7 Hz, 2H) , 4.12 (s, 2H) , 3.76 (d, J = 13.2 Hz, 1H) , 3.66 (d, J = 12.6 Hz, 2H) , 3.48 (s, 2H) , 3.38 (d, J = 11.5 Hz, 4H) , 2.39 (s, 3H) , 2.32 (s, 1H) , 2.21 (s, 3H) , 2.12 (s, 2H) , 2.03 (s, 1H) . MS (ESI) m/z: 582 (M+H) ⁺.

5-ethynyl-6-fluoro-4- (8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- (1-methyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) -1, 6-naphthyridin-7-yl) naphthalen-2-ol (Compound 12)

¹H NMR (400 MHz, Methanol-d ₄) δ 9.07 (s, 1H) , 7.86 (dd, J = 9.1, 5.7 Hz, 1H) , 7.37 –7.28 (m, 2H) , 7.22 (s, 1H) , 6.64 (s, 1H) , 5.32 (d, J = 53.5 Hz, 1H) , 4.38 (ddd, J = 29.9, 11.1, 6.8 Hz, 2H) , 3.82 (s, 1H) , 3.72 –3.52 (m, 2H) , 3.47 (d, J = 27.9 Hz, 1H) , 3.25 (s, 1H) , 3.21 –3.14 (m, 2H) , 3.10 –3.02 (m, 2H) , 2.39 –2.27 (m, 3H) , 2.24 (d, J = 9.8 Hz, 2H) , 2.19 –2.13 (m, 2H) , 2.09 –1.97 (m, 3H) , 1.92 (s, 1H) , 1.74 (d, J = 11.5 Hz, 2H) , 1.41 (d, J = 4.3 Hz, 3H) . MS (ESI) m/z: 614 (M+H) ⁺.

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -1, 6-naphthyridin-7-yl) -5-fluoronaphthalen-2-ol (compound 15)

¹H NMR (400 MHz, Methanol-d ₄) δ 9.11 (s, 1H) , 8.50 (s, 1H) , 7.60 (d, J = 7.9 Hz, 1H) , 7.39 (td, J = 8.0, 5.2 Hz, 1H) , 7.33 (t, J = 2.2 Hz, 1H) , 7.16 (d, J = 2.2 Hz, 1H) , 6.90 (dd, J = 13.2, 7.4 Hz, 1H) , 6.68 (s, 1H) , 5.35 (d, J = 53.1 Hz, 1H) , 4.58 (s, 1H) , 4.50 –4.38 (m, 2H) , 4.05 (s, 2H) , 3.68 (t, J = 13.6 Hz, 2H) , 3.37 (d, J = 21.7 Hz, 4H) , 3.13 (s, 1H) , 2.42 –2.26 (m, 4H) , 2.22 –1.93 (m, 6H) . LC/MS (ESI) m/z: 576.3 [M+H] ⁺.

4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoronaphthalen-1-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -1, 6-naphthyridine (compound 16)

¹H NMR (400 MHz, Methanol-d ₄) δ 9.15 (s, 1H) , 8.41 (s, 1H) , 8.07 (d, J = 7.3 Hz, 1H) , 7.94 (dd, J = 9.1, 6.0 Hz, 1H) , 7.58 –7.53 (m, 1H) , 7.47 (d, J = 6.8 Hz, 1H) , 7.37 (t, J = 9.4 Hz, 1H) , 6.78 (s, 1H) , 5.49 (s, 1H) , 4.20 (s, 2H) , 3.75 (d, J = 11.9 Hz, 3H) , 3.64 (d, J = 2.8 Hz, 2H) , 3.59 (d, J = 5.3 Hz, 2H) , 3.52 (s, 1H) , 3.42 (t, J = 12.9 Hz, 3H) , 2.48 (s, 1H) , 2.44 (d, J = 9.1 Hz, 2H) , 2.39 (s, 1H) , 2.24 (s, 3H) , 2.18 (d, J = 7.7 Hz, 4H) , 2.03 (s, 3H) . LC/MS (ESI) m/z: 588.3 [M+H] ⁺.

4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -1, 6-naphthyridine (compound 17)

¹H NMR (400 MHz, Methanol-d ₄) δ 9.09 (s, 1H) , 8.49 (s, 1H) , 8.17 –8.07 (m, 2H) , 7.70 –7.61 (m, 2H) , 7.45 (t, J = 8.9 Hz, 1H) , 6.69 (s, 1H) , 5.35 (d, J = 53.4 Hz, 1H) , 4.51 –4.36 (m, 2H) , 4.06 (s, 2H) , 3.74 (d, J = 13.6 Hz, 1H) , 3.67 –3.60 (m, 2H) , 3.38 (d, J = 14.8 Hz, 4H) , 3.25 (d, J = 3.9 Hz, 1H) , 3.15 –3.09 (m, 1H) , 2.43 –2.33 (m, 3H) , 2.28 (s, 1H) , 2.18 (s, 3H) , 2.06 (d, J = 7.5 Hz, 2H) , 1.96 (s, 1H) . LC/MS (ESI) m/z: 584.3 [M+H] ⁺.

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -1, 6-naphthyridin-7-yl) -5-chloro-6-fluoronaphthalen-2-ol (Compound 21)

LC/MS (ESI) m/z: 610.3 [M+H] ⁺.

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -1, 6-naphthyridin-7-yl) -5, 6-difluoronaphthalen-2-ol (Compound 22)

LC/MS (ESI) m/z: 594.2 [M+H] ⁺.

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -1, 6-naphthyridin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol (Compound 23)

LC/MS (ESI) m/z: 604.2 [M+H] ⁺.

The following example can be prepared by the method described in Scheme 4:

Example 4: 4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (E) -2- (tetrahydro-1H-pyrrolizin-7a (5H) -yl) vinyl) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloronaphthalen-2-ol (Compound 4)

Step 1: (Z) -7a- (2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) vinyl) hexahydro-1H-pyrrolizine

To a mixture of 7a-ethynyl-hexahydro-1H-pyrrolizine (500 mg, 3.7 mmol) and 4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (0.64 mL, 4.44 mmol) in THF (2 mL) were added TEA (1.54 mL, 11.1 mmol) , [Rh (cod) Cl] ₂ (5.5 mg, 0.011 mmol) and PCy ₃ (31 mg, 0.11 mmol) under N ₂ atmosphere. The mixture was degassed under N ₂ atmosphere for three times and stirred under N ₂ atmosphere at r. t. for 16 hrs. The mixture was concentrated under reduced pressure to dryness to give crude (Z) -7a- (2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) vinyl) hexahydro-1H-pyrrolizine (1 g, 100%yield) as a yellow oil. MS (ESI) m/z: 264 (M+H) ⁺.

Step 2: Tert-butyl (1R, 5S) -3- (7-chloro-8-fluoro-2- ( (E) -2- (tetrahydro-1H- pyrrolizin-7a (5H) -yl) vinyl) pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

To a mixture of tert-butyl 3- {2, 7-dichloro-8-fluoropyrido [4, 3-d] pyrimidin-4-yl} -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (500 mg, 1.17 mmol) and (Z) -7a- (2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) vinyl) hexahydro-1H-pyrrolizine (1 g, 3.7 mmol) in 1, 4-dioxane/water (5 mL, v/v = 3/1) was added CsF (532 mg, 3.50 mmol) followed by Pd (dppf) Cl ₂ (128 mg, 0.17 mmol) under N ₂ atmosphere. The reaction mixture was degassed under N ₂ atmosphere for three times and stirred at 100 ℃ for 16 hrs. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na ₂SO _4, filtered and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0-40%EtOAc in PE) to give tert-butyl (1R, 5S) -3- (7-chloro-8-fluoro-2- ( (Z) -2- (tetrahydro-1H-pyrrolizin-7a (5H) -yl) vinyl) pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (100 mg, 16%yield) as a light yellow solid. MS (ESI) m/z: 529 (M+H) ⁺.

Step 3: Tert-butyl (1R, 5S) -3- (7- (8-chloro-3- (pivaloyloxy) naphthalen-1-yl) -8-fluoro-2- ( (E) -2- (tetrahydro-1H-pyrrolizin-7a (5H) -yl) vinyl) pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

To a mixture of tert-butyl (1R, 5S) -3- (7-chloro-8-fluoro-2- ( (E) -2- (tetrahydro-1H-pyrrolizin-7a (5H) -yl) vinyl) pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (40 mg, 0.076 mmol) and 2- [8-chloro-3- (methoxymethoxy) naphthalen-1-yl] -4, 4, 5-trimethyl-1, 3, 2-dioxaborolane (32 mg, 0.095 mmol) in 2-MeTHF (1 mL) and H ₂O (1 mL) were added K ₃PO ₄ (20 mg, 0.095 mmol) followed by X-Phos Pd G ₂ (1 mg, 0.001 mmol) . The mixture was degassed under N ₂ atmosphere for three times and stirred under N ₂ atmosphere at 50 ℃ for 16 hrs. The reaction mixture was concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0-20%MeOH in DCM) to give tert-butyl (1R, 5S) -3- (7- (8-chloro-3- (pivaloyloxy) naphthalen-1-yl) -8-fluoro-2- ( (E) -2- (tetrahydro-1H-pyrrolizin-7a (5H) -yl) vinyl) pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (20 mg, 35%yield) as a yellow solid. MS (ESI) m/z: 755 (M+H) ⁺.

Step 4: 4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (E) -2- (tetrahydro-1H-pyrrolizin-7a (5H) -yl) vinyl) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloronaphthalen-2-yl pivalate TFA salt

To a solution of tert-butyl (1R, 5S) -3- (7- (8-chloro-3- (pivaloyloxy) naphthalen-1-yl) -8-fluoro-2- ( (E) -2- (tetrahydro-1H-pyrrolizin-7a (5H) -yl) vinyl) pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (20 mg, 0.026 mmol) in DCM (0.5 mL) was added TFA (1 mL) at 0 ℃ and the mixture was stirred at 0 ℃for 1 hr. The mixture was concentrated to dryness to give crude 4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (E) -2- (tetrahydro-1H-pyrrolizin-7a (5H) -yl) vinyl) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloronaphthalen-2-yl pivalate TFA salt (20 mg, 100%yield) as a yellow solid. MS (ESI) m/z: 655 (M+H) ⁺.

Step 5: 4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (E) -2- (tetrahydro-1H-pyrrolizin-7a (5H) -yl) vinyl) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloronaphthalen-2-ol

To a solution of 4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (E) -2- (tetrahydro-1H-pyrrolizin-7a (5H) -yl) vinyl) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloronaphthalen-2-yl pivalate TFA salt (20 mg, 0.026 mmol) in 1, 4-dioxane (2 mL) was added Cs ₂CO ₃ (42 mg, 0.13 mmol) and the reaction mixture was stirred at 70 ℃for 16 hrs. The mixture was filtered, and the filtrate was concentrated to dryness. The residue was purified by prep-HPLC (C18, 30～90%acetonitrile in H ₂O with 0.1%formic acid) to give 4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (E) -2- (tetrahydro-1H-pyrrolizin-7a (5H) -yl) vinyl) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloronaphthalen-2-ol (2 mg, 14%yield) .

¹H NMR (400 MHz, CDCl ₃) δ 8.96 (s, 1H) , 7.69 -7.66 (m, 1H) , 7.52 (s, 1H) , 7.32 (s, 2H) , 7.31 (s, 1H) , 7.29 (s, 1H) , 7.00 (s, 1H) , 6.70 (d, J = 15.7 Hz, 1H) , 4.58 (d, J = 12.4 Hz, 1H) , 4.39 (d, J = 11.0 Hz, 1H) , 3.63 (s, 3H) , 3.49 (s, 1H) , 3.38 (d, J = 10.2 Hz, 2H) , 2.76 (d, J = 6.5 Hz, 2H) , 2.34 (t, J = 7.5 Hz, 4H) , 2.24 -2.20 (m, 5H) , 2.01 (d, J = 3.4 Hz, 4H) . MS (ESI) m/z: 571 (M+H) ⁺.

The following compound was prepared in similar manners as compound 4:

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (E) -2- (tetrahydro-1H-pyrrolizin-7a (5H) -yl) vinyl) pyrido [4, 3-d] pyrimidin-7-yl) -5-fluoronaphthalen-2-ol (Compound 11)

¹H NMR (400 MHz, CD ₃OD) δ 9.17 (s, 1H) , 7.61 (d, J = 8.0 Hz, 1H) , 7.55 (d, J = 15.7 Hz, 1H) , 7.43 –7.38 (m, 1H) , 7.35 (s, 1H) , 7.19 (d, J = 2.3 Hz, 1H) , 6.93 (dd, J = 13.5, 7.5 Hz, 1H) , 6.86 (d, J = 15.7 Hz, 1H) , 4.03 (s, 2H) , 3.92 –3.83 (m, 2H) , 3.75 –3.62 (m, 3H) , 3.28 –3.18 (m, 3H) , 2.46 –2.40 (m, 2H) , 2.29 –2.16 (m, 6H) , 2.05 –1.94 (m, 4H) . MS (ESI) m/z: 555 (M+H) ⁺.

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (E) -2- (2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) vinyl) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Compound 24)

LC/MS (ESI) m/z: 597.3 [M+H] ⁺.

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (E) -2- (2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) vinyl) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol (Compound 25)

LC/MS (ESI) m/z: 601.3 [M+H] ⁺.

4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-2- ( (E) -2- (2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) vinyl) pyrido [4, 3-d] pyrimidine (Compound 26)

LC/MS (ESI) m/z: 581.2 [M+H] ⁺.

The following example can be prepared by the method described in Scheme 10:

Example 5: 4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) ethynyl) -1, 6-naphthyridin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Compound 13)

Step 1: 2-chloro-3-fluoro-5- ( (trimethylsilyl) ethynyl) pyridin-4-amine.

To a solution of 2-chloro-3-fluoro-5-iodopyridin-4-amine (36.0 g, 118.9 mmol) in THF (200 mL) and Et ₃N (50 mL) was added ethynyltrimethylsilane (17.5 g, 178.38 mmol) , CuI (681 mg, 3.57 mmol) and Pd (PPh ₃) ₂Cl ₂ (1.80 g, 2.64 mmol) . The reaction was stirred at 25 ℃ for 1 h under N ₂. The reaction mixture was filtered. The filtrate was diluted with water (200 mL) and extracted with EtOAc (2 x 200 mL) . The combined organic phases were dried over Na ₂SO ₄ and concentrated to dryness. The residue was purified by flash silica gel chromatography eluted with PE/EtOAc (0～15%) to give 2-chloro-3-fluoro-5- [2- (trimethylsilyl) ethynyl] pyridin-4-amine (26.00 g, 81.1%yield) as a brown solid. LC/MS (ESI) m/z: 243 [M+H] ⁺.

Step 2: 2-chloro-5-ethynyl-3-fluoropyridin-4-amine

To a stirred solution of 2-chloro-3-fluoro-5- [2- (trimethylsilyl) ethynyl] pyridin-4-amine (26.00 g, 107.10 mmol) in THF (120 mL) was added TBAF (161 mL, 160.65 mmol, 1M in THF) at 0℃. The reaction mixture was stirred at 25 ℃ for 16 hours. The reaction was diluted with water (300 mL) and extracted with EtOAc (2 x 200 mL) . The combined organic phase was dried over Na ₂SO ₄ and evaporated to dryness. The residue was purified by column chromatography on silica gel eluted with PE/EtOAc (0～20%) to give 2-chloro-5-ethynyl-3-fluoropyridin-4-amine (16.00 g, 83.2%yield) as a white solid. LC/MS (ESI) m/z: 171 [M+H] ⁺.

Step 3: 7-chloro-8-fluoro-4-hydroxy-1, 6-naphthyridin-2 (1H) -one

To a stirred solution of 2-chloro-5-ethynyl-3-fluoropyridin-4-amine (5.00 g, 29.31 mmol) in DMSO (40 mL) was added DBU (4.46 g, 29.36 mmol) and AgNO ₃ (1.67 g, 35.76 mmol) . The reaction was stirred at 60 ℃ for 24 hours under CO ₂. The mixture was diluted with water (150 ml) and extracted with EtOAc (3 x 50 ml) . The aqueous phase was adjusted to pH=5 with 1 N HCl. The resulting solid was filtered and dried under reduced pressure to give 7-chloro-8-fluoro-4-hydroxy-1, 6-naphthyridin-2 (1H) -one (2.4 g, 36.3%yield) as a yellow solid. LC/MS (ESI) m/z: 215 [M+H] ⁺.

Step 4.2, 4, 7-trichloro-8-fluoro-1, 6-naphthyridine

To a single neck round bottom flask were added 7-chloro-8-fluoro-1, 6-naphthyridine-2, 4-diol (2.0 g, 9.3 mmol) , POCl ₃ (30 mL) , and the reaction was stirred at 110 ℃ for 6 hours. The reaction was adjusted pH=8 with saturated NaHCO ₃. The organic layer was separated, further washed with saturated NaCl solution, filtered and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (0%～3%) to afford the title compound 2, 4, 7-trichloro-8-fluoro-1, 6-naphthyridine (1.7 g, 72.6%) as a light-yellow solid.

LC/MS ESI (m/z) : 251 [M+H] ⁺

Step 5: 4, 7-dichloro-8-fluoro-2- ( ( (2R) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) ethynyl) -1, 6-naphthyridine

To a solution of 2, 4, 7-trichloro-8-fluoro-1, 6-naphthyridine (300 mg, 1.2 mmol) in TEA (1.5 mL) and MeCN (1.5 mL) were added (2R, 7aS) -7a-ethynyl-2-fluorohexahydro-1H-pyrrolizine (365 mg, 2.4 mmol) (INT2, prepared via method described in Scheme 9 ) , CuI (227 mg, 1.2 mmol) , and Pd (PPh ₃) ₂Cl ₂ (15.47 mg, 0.02 mmol) , and the reaction was stirred at 80℃ for 2 hours. The reaction was diluted with DCM and water. The organic layer was separated, washed with further saturated NaCl solution, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with methanol in dichloromethane (0%～5%) to afford the title compound 4, 7-dichloro-8-fluoro-2- {2- [ (2R) -2-fluoro-hexahydro-1H-pyrrolizin-7a-yl] ethynyl} -1, 6-naphthyridine (178 mg, 40.5%) as a colorless gum.

LC/MS ESI (m/z) : 368 [M+H] ⁺

Step 6: tert-butyl (1R, 5S) -3- (7-chloro-8-fluoro-2- ( ( (2R) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) ethynyl) -1, 6-naphthyridin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

To a stirred solution of 4, 7-dichloro-8-fluoro-2- {2- [ (2R) -2-fluoro-hexahydro-1H-pyrrolizin-7a-yl] ethynyl} -1, 6-naphthyridine (150 mg, 0.4 mmol) in DMSO (2 mL) under Argon was added CsF (124 mg, 0.8 mmol) , followed by adding tert-butyl 3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (104 mg, 0.5 mmol) and the reaction was stirred at 60 ℃ for 1 hour. The reaction mixture was quenched by H ₂O. The reaction was extracted by ethyl acetate and organic layer was washed with brine. The organic phase was concentrated in vacuo. The crude product was chromatographed on silica gel eluting with methanol in dichloromethane (0%～5%) to give the tert-butyl 3- (7-chloro-8-fluoro-2- {2- [ (2R) -2-fluoro-hexahydro-1H-pyrrolizin-7a-yl] ethynyl} -1, 6-naphthyridin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (80 mg, 36%) as white solid . LC/MS ESI (m/z) : 544 [M+H] ⁺

Step 7: tert-butyl (1R, 5S) -3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) ethynyl) -1, 6-naphthyridin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

A mixture of tert-butyl 3- (2- {2- [ (2R, 7aS) -2-fluoro-hexahydro-1H-pyrrolizin-7a-yl] ethynyl} -7-chloro-8-fluoro-1, 6-naphthyridin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (40 mg, 0.07 mmol) and {2- [2-fluoro-6- (methoxymethoxy) -8- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl] ethynyl} tris (propan-2-yl) silane (57 mg, 0.1 mmol) , K ₂CO ₃ (20 mg, 0.15 mmol) in THF (1 mL) and water (0.3 mL) was degassed with N ₂ three times, followed by the addition of XPhos-Pd-G ₂ (6 mg, 0.01 mmol) . The reaction tube was degassed with N ₂ for 10 min and then the mixture was stirred at 60 ℃ for 2.5 hours under N ₂. After completion, the mixture was diluted with ethyl acetate (5 mL) and water (2 mL) , and then separated. The aqueous phase was extracted with ethyl acetate (2 x 2 mL) . The combined organic layer was washed with saturated brine (5 mL) , dried over Na ₂SO ₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO ₂, dichloromethane/methanol=20/1) to give tert-butyl 3- (2- {3- [ (2R, 7aR) -2-fluoro-hexahydro-1H-pyrrolizin-7a-yl] prop-1-yn-1-yl} -8-fluoro-7- [7-fluoro-3- (methoxymethoxy) -8- {2- [tris (propan-2-yl) silyl] ethynyl} naphthalen-1-yl] -1, 6-naphthyridin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (25 mg, 37%) as a brown solid. LC/MS ESI (m/z) : 894 [M+H] ⁺.

Step 8: 4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) ethynyl) -1, 6-naphthyridin-7-yl) -6-fluoro-5- ( (triisopropylsilyl) ethynyl) naphthalen-2-ol

To a solution of tert-butyl (1R, 5S) -3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) ethynyl) -1, 6-naphthyridin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (17 mg, 0.01 mmol) in DCM (2 mL) were added HMDS (0.1 mL) and TMSOTf (0.1 mL) at 0 ℃, and the reaction was stirred at room temperature for 1 hr. Then the mixture was added TFA (0.2 mL, 2.7 mmol) and the reaction was stirred at room temperature for 1 hr. The mixture was concentrated in vacuo to afford 4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) ethynyl) -1, 6-naphthyridin-7-yl) -6-fluoro-5- ( (triisopropylsilyl) ethynyl) naphthalen-2-ol (14 mg, 98%) as a pale yellow solid.

LC/MS (ESI) m/z: 750 [M+H] ⁺.

Step 9: 4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) ethynyl) -1, 6-naphthyridin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol

To a flask containing 4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) ethynyl) -1, 6-naphthyridin-7-yl) -6-fluoro-5- ( (triisopropylsilyl) ethynyl) naphthalen-2-ol (13 mg, 0.01 mmol) was added DMF (2 mL) followed by the addition of tetrabutylammonium fluoride (0.2 mL, 1M in THF) . The mixture was stirred at room temperature for 1 hour. The result mixture was filtered and purified by prep-HPLC with (MeCN, H ₂O/NH ₃H ₂O) to afford 4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetra hydro-1H-pyrrolizin-7a (5H) -yl) ethynyl) -1, 6-naphthyridin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (1.1 mg, 11%) .

¹H NMR (400 MHz, Methanol-d ₄) δ 9.23 (s, 1H) , 7.89-7.86 (m, 1H) , 7.37-7.22 (m, 4H) , 5.33 (d, J = 52 Hz, 1H) , 4.04-4.00 (m, 2H) , 3.86-3.72 (m, 2H) , 3.46-3.37 (m, 4H) , 3.31-3.18 (m, 2H) , 3.03-2.97 (m, 1H) , 2.61-2.53 (m, 2H) , 2.45-2.30 (m, 2H) , 2.26-2.13 (m, 3H) , 2.10-1.99 (m, 3H) . LC/MS (ESI) m/z: 594 [M+H] ⁺.

The following compound was prepared in similar manners as compound 13:

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) ethynyl) -1, 6-naphthyridin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol (Compound 14)

¹H NMR (400 MHz, Methanol-d ₄) δ 9.26 (s, 1H) , 7.70-7.67 (m, 1H) , 7.31 (d, J = 3.6 Hz, 1H) , 7.27 (t, J = 8.8 Hz, 2H) , 7.31 (d, J = 2.4 Hz, 1H) , 5.32 (d, J = 52 Hz, 1H) , 3.72-3.69 (m, 4H) , 3.34-3.27 (m, 7H) , 2.98 (q, J = 6.8 Hz, 1H) , 2.52-2.43 (m, 3H) , 2.24-2.02 (m, 7H) , 0.74 (t, J = 6.8 Hz, 3H) . MS (ESI) m/z: 598 [M+H] ⁺.

The following compound was prepared in similar manners as compound 13:

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) ethynyl) -1, 6-naphthyridin-7-yl) -5-chloro-6-fluoronaphthalen-2-ol (Compound 27)

LC/MS (ESI) m/z: 576.3 [M+H] ⁺.

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) ethynyl) -1, 6-naphthyridin-7-yl) -5-ethynylnaphthalen-2-ol (Compound 28)

LC/MS (ESI) m/z: 604.5 [M+H] ⁺.

4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-2- ( (2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) ethynyl) -1, 6-naphthyridine (Compound 29)

LC/MS (ESI) m/z: 578.3 [M+H] ⁺.

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) ethynyl) -1, 6-naphthyridin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Compound 30)

LC/MS (ESI) m/z: 594.3 [M+H] ⁺.

4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) ethynyl) -1, 6-naphthyridin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol (Compound 31)

LC/MS (ESI) m/z: 598.2 [M+H] ⁺.

Biology assay

The following assays were used to measure the effects of the compounds of the present disclosure.

Phospho-ERK 1/2 assay:

Allow PNAC-1 cell growth in a T75 flask in DMEM and 10%1 fetal calf serum (FCS;

) , using standard tissue culture procedures until ～80%confluency is achieved. Day 1, seed 6000 cells/well in 384 well plate and incubate at 37℃, 5%CO2. Add diluted compound by Echo 550, final DMSO is 0.5%, incubate cells at 37℃, 5%CO2 for 3 hours. Then, remove medium and fix cells with 3.7%formaldehyde in PBS (PFA) by Apricot. Wash with PBS once. Permeabilize cells with cold 100%methanol and repeat wash once with PBS once. Add Li-Cor blocking buffer to each well and incubate 1.5 hours at RT. Remove blocking buffer and add primary antibody mixture (rabbit anti pERK, mouse anti GAPDH) . Incubate at 4℃ overnight. Day 2, wash with PBST (Tween-20 in PBS) with total 3 times and then add secondary antibody mixture (goat anti rabbit 800CW (1: 800 dilution in the combined solution) and goat anti mouse 680RD (1: 800 dilution in the combined solution) ) , incubate for 60 minutes at RT away from light. Repeat washing with PBST 3 times. After final wash, centrifuge plate up-side-down at 1000 rpm to remove wash solution completely from wells. Before plate scanning, clean the bottom plate surface and the

Imager scanning bed (if applicable) with moist, lint-free tissue to avoid any obstructions during scanning. Scan plate with detection in both 700 and 800 nm channels.

KRAS (G12D) : SOS1 Nucleotide Exchange Binding Assay

Thaw GDP loaded KRAS (G12D) on ice and dilute GDP loaded KRAS (G12D) to 500 nM in RBD-RAS binding buffer. Prepare the master mixture (6 μl) : 96 wells × (1 μl diluted GDP loaded KRAS (G12D) , 500 nM + 5 μl RBD-RAS binding buffer) . Add 6 μl of master mix to each well. Prepare serial dilutions of the test compound in DMSO at 200X testing concentration. Then dilute the compound 20-fold in deionized water to prepare the 10X intermediate solution. For positive and negative controls, use 5%DMSO in water as a 10X intermediate so that all wells contain the same amount of DMSO. Add 1 μl of 10X intermediate solution of the test compound to the testing wells. Add 1 μl 5%DMSO to the positive and negative control wells. Briefly centrifuge the plate and incubate for 30 minutes at room temperature. Thaw GTP (10 mM) and SOS1 on ice. Dilute SOS1 in RBD-RAS binding buffer at 5 μM. Combine GTP (10 mM) and diluted SOS1 (5 μM) at 1: 1 ratio. Initiate the exchange reaction by adding 2 μl of GTP/SOS1 mixture to the testing and the positive control wells. Thaw RBD-cRAF and dilute RBD-cRAF in RBD-RAS binding buffer at 25 nM. After the 30-minute incubation with SOS1/GTP (RBD-RAS buffer for the negative control) , add 1 μl of diluted RBD-cRAF (25 nM) to all wells. Briefly centrifuge the plate and incubate at room temperature for 30 minutes. Dilute 3X Immuno Buffer in deionized water to prepare 1X Immuno buffer. Add one volume of 3X Immuno Buffer to two volumes of deionized water. Dilute Glutathione Acceptor beads (PerkinElmer #AL109C) and Nickel chelate Donor beads (PerkinElmer #AS101D) at 1: 500 and 1: 250 respectively in 1x Immuno buffer. Add 20 μl of acceptor/donor beads mixture per well is needed. Therefore add 16 μl of Glutathione Acceptor beads and 32 μl of Nickel Donor beads to 8 mL of 1X Immuno buffer) . Incubate 30 min at room temperature. Read Alpha-counts using a compatible plate reader.

3D Cell Viability Assay

PANC-1 (ATCC CRL-1469) cells were purchased from ATCC, and each cell was cultured in medium supplemented with 10%fetal bovine serum (FBS) , according to the protocol recommended by the manufacture. Cells were seeded at 1000 cells/well in 96-well tissue culture plates in each growth media and allowed to adhere overnight on day 0. The day after plating, cells were treated with a 9 point 3-fold dilution series of test compounds (100 μl final volume per well) and cell viability was monitored 5 days later according to the manufacturer’s recommended instructions, where 50ml of CellTiter-Glo reagent was added, vigorously mixed, covered, and placed on aplate shaker for 20 min to ensure complete cell lysis prior to assessment of luminescent signal.

The Phospho-ERK 1/2 assay results for some exemplary compounds of the present disclosure are shown in Table 1 below.

Table 1.

Compound No.	PANC-1 activity IC ₅₀ (nM)
1	15
2	487
3	3400
4	1680
5	205
6	46
7	7.9
8	9.5
9	1358
10	253
11	283
12	24
13	439
14	305
15	40
16	1434
17	358

Other compounds of the present disclosure show IC ₅₀ value of 0.5 to 5000 nM. Some compounds of the present disclosure show IC ₅₀ value of 1-4000 nM. Some compounds of the present disclosure show IC ₅₀ value of 1-3000 nM. Some compounds of the present disclosure show IC ₅₀ value of 1-2000 nM. Some compounds of the present disclosure show IC ₅₀ value of 1-1000 nM. Some compounds of the present disclosure show IC ₅₀ value of 1-500 nM.

The foregoing description is considered as illustrative only of the principles of the present disclosure. Further, since numerous modifications and changes will be readily apparent to those skilled in the art, it is not desired to limit the invention to the exact construction and process shown as described above. Accordingly, all suitable modifications and equivalents may be considered to fall within the scope of the invention as defined by the claims that follow.

Claims

A compound having Formula (I) , Formula (II) , Formula (III) , or Formula (IV) :

or a pharmaceutically acceptable salt thereof,

wherein

Ring A is heterocyclyl or heteroaryl, wherein
represents N-linked Ring A, and
represents C-linked Ring A;

each R ¹ is independently selected from oxo, hydroxyl, halogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, -C (O) OR ^a, -C (O) N (R ^a) ₂, -N (R ^a) ₂ or heteroaryl, wherein the alkyl, alkenyl, alkynyl and heteroaryl are optionally substituted with one or more groups independently selected from cyano, hydroxyl, halogen, -OR ^b, or -N (R ^b) ₂;

each R ^a and R ^b is independently hydrogen, alkyl, alkenyl or alkynyl;

Ring B is cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with one or more R ^c;

each R ^c is independently selected from the group consisting of oxo, hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, wherein alkyl, alkenyl, alknynyl, heteroalkyl, heteroalkenyl, heteroalkynyl and heteroaryl are optionally substituted with one or more group independently consisting of hydroxyl, halogen, cyano, -OR ^a, -N (R ^a) ₂, and heteroaryl;

Ring W is cycloalkyl, heterocyclyl, aryl or heteroaryl;

R’ is selected from hydrogen, hydroxyl, halogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, -C (O) OR ^a, -C (O) N (R ^a) ₂, -N (R ^a) ₂ or heteroaryl, wherein the alkyl, alkenyl, alkynyl and heteroaryl are optionally substituted with one or more groups independently selected from cyano, hydroxyl, halogen, -OR ^b, or -N (R ^b) ₂;

each R ² is independently selected from the group consisting of hydrogen, oxo, hydroxyl, halogen, cyano, amino, nitro, alkyl, alkenyl, alknynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein alkyl, alkenyl, alknynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more group independently consisting of hydroxyl, halogen, cyano, amino, nitro, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

X is O or S;

M is O or S;

Y is aryl or heteroaryl, wherein aryl or heteroaryl is optionally substituted with one or more R ^c;

L is a bond, -O-, -S-, -N (R ^a) -, alkenyl, cycloalkyl or alkynyl;

L’ is a bond, -S-, -N (R ^a) -, alkenyl, cycloalkyl or alkynyl, provided that when ring B is
L’ is alkenyl, cycloalkyl or alkynyl; and when B is not
L’ is a bond, -S-, -N (R ^a) -, alkenyl or cycloalkyl;

is optionally substituted with hydroxyl, halogen, cyano or amino;

Q is a bond, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl;

Z is selected from the group consisting of hydrogen, -N (R ^a) ₂, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -COOH, -NHC (=NH) NH ₂, -C (O) N (R ^a) ₂, -OR ^a, - (CH ₂OR ^a) (CH ₂) _pOR ^a, -N (R ^a) C (O) -aryl and - (CH ₂) _p-heterocyclyl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R ^d, and the aryl portion in -N (R ^a) C (O) -aryl and the heterocyclyl portion in - (CH ₂) _p-heterocyclyl are optionally substituted with one or more R ^e;

each R ^d is independently selected from hydroxyl, halogen, -C (O) H, alkyl, alkoxy, haloalkyl, hydroxyalkyl, or -N (R ^a) ₂;

each R ^e is independently selected from oxo, hydroxyl, halogen, alkyl, heteroalkyl, hydroxyalkyl, haloalkyl, alkoxy, -T-phenyl, -T-phenylSO ₂F, -N (R ^a) ₂, -SO ₂F, -C (O) (alkyl) , or -C (O) (haloalkyl) , wherein the alkyl, heteroalkyl, hydroxyalkyl, haloalkyl, and alkoxy are optionally substituted with one or more groups independently selected from aryl, heteroaryl, or tert-butyldimethylsilyloxy;

T is a bond, -O-, or -NHC (O) -;

m is 0 or 1;

n is 0 or 1;

s is an integer from 0 to 5;

t is an integer from 0 to 4; and

p is an integer from 0 to 4.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is heterocyclyl.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is heteroaryl.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is a bridged heterocyclyl optionally containing at least one further heteroatom selected from the group consisting of N, S and O.
The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from the group consisting of:

wherein
represents a single bond or a double bond.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is a spiro or fused ring optionally containing at least one further heteroatom selected from the group consisting of N, S and O.
The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from the group consisting of:

wherein r is an integer from 0 to 3, and q is an integer from 1 to 4.
The compound of any one of preceding claims, or a pharmaceutically acceptable salt thereof, wherein Ring B is cycloalkyl optionally substituted with one or more R ^c.
The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein Ring B is heterocyclyl optionally substituted with one or more R ^c.
The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein Ring B is piperidinyl, dihydropyridazinyl, dihydropyridinyl, azaspiro [2.5] octenyl, or 1, 2, 3, 6-tetrahydropyridinyl, each optionally substituted with one or more R ^c independently selected from oxo, alkyl, alkynyl, heteroalkyl, or cyano, wherein the alkyl, alkynyl, heteroalkyl are optionally substituted with one or more groups selected from cyano, halogen, -OR ^a, -N (R ^a) ₂, or heteroaryl.
The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein Ring B is aryl optionally substituted with one or more R ^c.
The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein Ring B is phenyl optionally substituted with one or more R ^c independently selected from amino, hydroxyl, halogen or haloalkyl.
The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein Ring B is heteroaryl optionally substituted with one or more R ^c.
The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein Ring B is pyridinyl or pyrimidinyl optionally substituted with one or more R ^c independently selected from amino, hydroxyl, halogen or haloalkyl.
The compound of claim 1, wherein R’ is selected from hydrogen, hydroxyl, halogen, or cyano.
The compound of any one of preceding claims, or a pharmaceutically acceptable salt thereof, wherein Ring W is cycloalkyl or heterocyclyl.
The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein Ring W is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl,
The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein Ring W is aryl.
The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein Ring W is phenyl or naphthalenyl.
The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein Ring W is heteroaryl.
The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein Ring W is selected from pyridinyl, pyrimidinyl pyridazinyl, pyrazinyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, benzofuranyl, benzothienyl, indolyl, benzimidazolyl, benzopyrazolyl, purinyl, quinolinyl, isoquinolinyl, isoquinoline-1 (2H) -one group, isoindolin-1-one group, benzo [d] oxazole-2 (H) -one group and 1, 3-dihydro-2H-benzo [d] Imidazol-2-one group.
The compound of any one of preceding claims, or a pharmaceutically acceptable salt thereof, wherein Y is aryl optionally substituted with one or more R ^c.
The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein Y is phenyl or naphthyl, each optionally substituted with one or more R ^c.
The compound of claim 22 or 23, or a pharmaceutically acceptable salt thereof, wherein R ^c is hydroxyl, halogen, amino, alkyl, alkenyl, alkynyl, haloalkyl, haloalknyl, or cycloalkyl.
The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein Y is heteroaryl optionally substituted with one or more R ^c.
The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein Y is benzothiophenyl, benzoimidazolyl, quinazolinyl, benzotriazolyl, thiophenyl, thienopyridinyl, isoquinolinyl, indolyl, or indazolyl, each optionally substituted with one or more R ^c.
The compound of claim 25 or 26, or a pharmaceutically acceptable salt thereof, wherein R ^c is hydroxyl, halogen, amino, alkyl, alkenyl, alkynyl, haloalkyl, haloalknyl, or heteroaryl.
The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein L is –O-.
The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein L is –S-.
The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein L is -N (R ^a) -.
The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein L is alkenyl.
The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein L is alkynyl.
The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein L is cycloalkyl.
The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein L’ is alkenyl, cycloalkyl or alkynyl, and ring B is
The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein L’ is a bond, -S-, -N (R ^a) -, alkenyl or cycloalkyl, and ring B is not
The compound of any one of preceding claims, or a pharmaceutically acceptable salt thereof, wherein Q is a bond.
The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein Q is alkyl, cycloalkyl or heteroaryl, each optionally substituted with one or more of halogen or alkyl.
The compound of any one of preceding claims, or a pharmaceutically acceptable salt thereof, wherein Z is cycloalkyl, heterocyclyl, aryl, heteroaryl, or - (CH ₂) _p-heterocyclyl, wherein the heterocyclyl and the heterocyclyl portion in - (CH ₂) _p-heterocyclyl are optionally substituted with one or more R ^e, wherein each R ^e is independently selected from hydroxyl, halogen, alkyl, heteroalkyl, or alkoxy.
The compound of claim 38, or a pharmaceutically acceptable salt thereof, wherein Z is selected from hexahydro-1H-pyrrolizinyl or pyrrolidinyl, each optionally substituted with one or more groups independently selected from halogen, hydroxyl, hydroxyalkyl, haloalkyl, alkoxy, phenyl, tert-butyldimethylsilyloxyCH ₂-or pyrazolyl.
The compound of any one of preceding claims, or a pharmaceutically acceptable salt thereof, wherein s is 0.
The compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, wherein s is an integer from 1 to 3, each R ¹ is independently selected from oxo, cyano, alkyl, or alkynyl, wherein the alky and alkynyl are optionally substituted with one or more groups selected from cyano, hydroxyl, halogen, -OR ^1b, or -N (R ^1b) ₂.
The compound of any one of preceding claims, or a pharmaceutically acceptable salt thereof, wherein t is an integer from 1 to 3, each R ² is independently selected from the group consisting of hydroxyl, halogen, cyano, alkyl, alkenyl, alkynyl, or cycloalkyl, wherein alkyl, alkenyl, alkynyl, and cycloalkyl are optionally substituted with one or more groups independently selected from cyano, hydroxyl, halogen, or alkyl.
The compound of claim 1, having a formula selected from:

or a pharmaceutically acceptable salt thereof,

wherein U is N or CH, R ³ is hydrogen, hydroxyl, halogen, cyano, alkyl, or alkynyl, wherein the alkyl and alkynyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, and cyano.
The compound of claim 1, having Formula (IIa) :

or a pharmaceutically acceptable salt thereof,

wherein

L’ is alkenyl, alkynyl or C _3-7 cycloalkyl; and

R ³ is hydrogen, hydroxyl, halogen, cyano, alkyl, or alkynyl, wherein the alkyl and alkynyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, and cyano.
The compound of claim 1, having Formula Formula (IIb) , Formula (IIc) , or Formula (IId) :

or a pharmaceutically acceptable salt thereof,

wherein

L’ is alkenyl or C _3-7 cycloalkyl;

U is N or CH; and

R ³ is hydrogen, hydroxyl, halogen, cyano, alkyl, or alkynyl, wherein the alkyl and alkynyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, and cyano.
The compound of claim 1, having a formula selected from:

or a pharmaceutically acceptable salt thereof,

wherein U is N or CH, R ³ is hydrogen, hydroxyl, halogen, cyano, alkyl, or alkynyl, wherein the alkyl and alkynyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, and cyano.
The compound of claim 1, having Formula (IVa) or Formula (IVb) :

or a pharmaceutically acceptable salt thereof,

wherein

G ¹ is N or C (R ^f) ;

G ² is N or C (R ^f) ; and

R ^f is selected from the group consisting of hydrogen, halogen, cyano, amino, nitro, hydroxy, alkyl, alkynyl, alkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl and heterocyclyl.
A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition comprising the compound of any one of claims 1-48 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
A method for inhibiting KRas G12D activity in a subject in need thereof, comprising administering an effective amount of a compound of any one of claims 1-48 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 49 to the subject.
A method for treating a KRas G12D-associated cancer comprising administering an effective amount of a compound of any one of claims 1-48 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 49 to a subject in need thereof.
The method of claim 51, wherein the KRas G12D-associated cancer is selected from the group consisting of:

(i) Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma) , myxoma, rhabdomyoma, fibroma, lipoma and teratoma;

(ii) Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma) , alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;

(iii) Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma) , stomach (carcinoma, lymphoma, leiomyosarcoma) , pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma) , small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma) , large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma) ;

(iv) Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma) , lymphoma, leukemia) , bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma) , prostate (adenocarcinoma, sarcoma) , testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma) ;

(v) Liver: hepatoma (hepatocellular carcinoma) , cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;

(vi) Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma) , fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma) , multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses) , benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors;

(vii) Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans) , meninges (meningioma, meningiosarcoma, gliomatosis) , brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma) , glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors) , spinal cord neurofibroma, meningioma, glioma, sarcoma) ;

(viii) Gynecological: uterus (endometrial 'carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma) , granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma) , vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma) , vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma) , fallopian tubes (carcinoma) ;

(ix) Hematologic: blood (myeloid leukemia (acute and chronic) , acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome) , Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma) ;

(x) Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and

(xi) Adrenal glands: neuroblastoma.
The method of claim 52, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer.
A method for treating cancer in a subject in need thereof, the method comprising (a) acquiring the knowledge that the cancer is associated with a KRas G12D mutation; and (b) administering to the subject an effective amount of a compound of any one of claims 1-48 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 49.
The method of any one of claims 50-54, wherein the administering is conducted via a route selected from the group consisting of parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, intracerebrospinal, intrasynovial, intrathecal administration, intramuscular injection, intravitreous injection, intravenous injection, intra-arterial injection, oral, buccal, sublingual, transdermal, topical, intratracheal, intrarectal, subcutaneous, and topical administration.
The method of any one of claims 50-55, wherein the compound is administered simultaneously, separately or sequentially with one or more additional therapeutic agents.
The method of claim 56, wherein the one or more additional therapeutic agents are selected from an anti-PD-1 or PD-L1 antagonist, an MEK inhibitor, a CDK4/CDK6 inhibitor, an EGFR inhibitor, ERK inhibitor, a SHP2 inhibitor, a platinum agent or pemetrexed.
Use of the compound of any one of claims 1-48 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 49 in the manufacture of a medicament for treating cancer.
A compound of any one of claims 1-48 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 49, for use in the treatment of cancer.