WO2023030517A1

WO2023030517A1 - Kras g12c inhibitors and uses thereof

Info

Publication number: WO2023030517A1
Application number: PCT/CN2022/116994
Authority: WO
Inventors: Zheng Wang; Ding Zhou; Ziqiang CHENG
Original assignee: Suzhou Zanrong Pharma Limited
Priority date: 2021-09-06
Filing date: 2022-09-05
Publication date: 2023-03-09
Also published as: CN117222654A

Abstract

Provided are novel compounds useful as KRAS G12C inhibitors, as well as pharmaceutical compositions comprising these compounds and methods of treatment by administration of these compounds or the pharmaceutical compositions.

Description

KRAS G12C INHIBITORS AND USES THEREOF

FIELD OF THE DISCLOSURE

The present disclosure generally relates to novel compounds useful as inhibitors of the KRAS G12C, 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) ) . K-RAS 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 KRAS proteins, while GAPs act to accelerate intrinsic GTP hydrolysis, converting KRAS 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.

KRAS mutations are present in up to 25%of cancers, the oncogenic variants have different prevalence rates in different cancers. The G12C mutation, one of the most common KRAS mutations, is present in an estimated around 14%of lung adenocarcinomas and in 3%of colon adenocarcinomas. According to the American Cancer Society, around 200,000 patients are diagnosed each year with lung adenocarcinomas. That puts the KRAS-G12C population in the USA at 14,000–28,000 patients per year. In the case of KRAS-G12C-positive colorectal cancer (CRC) , closer to 3,000 patients are diagnosed each year. KRAS-G12C accounts for over 40%of all KRAS mutations, and has therefore been a key target for cancer drug developers. G12C is a single point mutation with a glycine-to-cysteine substitution at codon 12. The presence of cysteine at position 12 in KRAS-G12C protects bound GTP from the rapid regulated hydrolysis catalyzed by GTPase activating protein (GAP) family proteins, resulting in overall pathway activation (Victoria Dunnett-Kane, et al. Cancers (Basel) 2021 Jan; 13 (1) : 151) .

The brain is a common site for metastasis in NSCLC patients, present in 25-30%of patients at diagnosis and the majority (40-50%) of patients will develop brain metastases during the course of their disease (Timothy G. et al. Transl Lung Cancer Res 2013; 2 (4) : 273-283) . The prevalence of brain metastasis (BM) was high in patients with KRAS-G12C NSCLC; 28 %of patients had BM at diagnosis, and 40 %of patients developed BM during follow up (W. Cui, et al. Lung Cancer 146 (2020) 310–317) . The incidence of BM from CRC ranges from 0.6 to 3.2 %. Metastatic spread in CRC is thought to progress sequentially in many patients, from liver to lung and then to bone and brain as late sites of involvement. Strikingly, nearly two-thirds of the brain metastases identified occurred in RAS mutant mCRC and patients with KRAS-G12C-mutant mCRC have shorter overall survival (OS) than patients with other KRAS-mutant cancers (Sophie Müller. et al. Cancers 2021, 13, 900) .

Incidence of brain metastases is increasing due to both improved diagnostic techniques and increased cancer patient survival through advanced systemic treatments. Brain metastases from solid extracranial tumors is now estimated to be ～10 times higher than for primary malignant brain tumors (Kromer, C. et al. J. Neurooncol. 134, 55–64 (2017) ) .

Treatment options with lung cancer or colon adenocarcinomas brain metastases are limited and include local treatment (surgical resection, whole-brain radiation therapy (WBRT) , stereotactic radiosurgery (SRS) ) and systemic treatment (chemotherapy and targeted therapy) . Local treatments are to reduce symptoms (palliative) but cause serious side effects (neurological damage, “tumor spill” , cognitive deterioration) . Big problem for systemic treating brain metastases is that systemic drugs are unable to penetrate the blood-brain barrier (BBB) . Moreover, many small targeted agents are substrates of active efflux pumps in the BBB, such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) , which prevent the entry of these agents into the interstitial space of the brain (Riccardo Soffietti, et al. Nature Reviews Neurology volume 16, pages 557–574 (2020) ) .

The research community has put tremendous effort into developing drugs to target KRAS mutations but, until recently, there’s not been much success leading to KRAS being deemed “undruggable” . Two primary reasons have been proposed: First, RAS has a picomolar affinity for guanine nucleotide, while the cellular concentration of guanine nucleotides is in the millimolar range making it unfavorable for the binding of nucleotide analogs; second, outside of the nucleotide binding pocket RAS appears to lack deep pockets amenable to the binding of small molecules. Attempts to directly target KRAS have been hindered by its structure: KRAS presents a smooth surface with no deep hydrophobic pockets that would allow tight binding. Consequently, past efforts have shifted focus to other targets. More recently, efforts with the development of several small molecule inhibitors of KRAS-G12C have been more fruitful. ARS-1620 was the first G12C specific inhibitor able to demonstrate in vivo efficacy, and since then several other related compounds with increased biological activity have been produced, the earliest of which to enter the clinic are Adagrasib (MRTX849) and Sotorasib (AMG-510) (Janes, M.R. et al. Cell, 172, 578–589. e17 (2018) ; Canon, J. et al. Nature, 575, 217–223 (2019) ; Hallin, J. et al. Cancer Discov., 10, 54–71 (2020) ) . These compounds rely on mutant cysteine for binding, disrupting Switch-I/II and converting KRAS preference from GTP to GDP, thus holding KRAS in the inactive GDP bound state (Ostrem, J.M. et al. Nat. Cell Biol. 503, 548–551 (2013) ) . In fact, KRAS G12C appears to retain a near wild-type level of GTPase activity and undergoes nucleotide cycling in the cell. G12C inhibitors act by preventing further nucleotide exchange, thus “trapping” the protein in a state of inactivity (Janes, M.R. et al. Cell, 172, 578–589. e17 (2018) ) . The intrinsic GTPase activity of KRAS-G12C accounts not only for the efficacy of direct inactive-state inhibitors, but also widens the possibility of effective upstream targeting in G12C-mutant cancers. Brain metastases from solid extracranial tumors represent an unmet need of increasing relevance as their incidence is rising considerably. The field of targeted therapies and immunotherapy in brain metastases is rapidly expanding.

In conclusion, KRAS-G12C variants are most commonly found in non-small cell lung cancer and colorectal cancer (CRC) . NSCLC is the most common cause of BM and the development of BM in CRC is associated the KRAS-G12C mutation. KRAS-G12C is one of the most common driver oncoproteins and is dependent on nucleotide exchange for activation and susceptible to drugs that block this process. Inactive state-selective inhibitors disrupt the cycle and trap KRAS-G12C in its GDP-bound state to suppress tumor growth in cancer patients.

Therefore, there is need to develop new KRAS-G12C-selective inhibitors that demonstrate sufficient efficacy for targeting KRAS-G12C, in particular new KRAS-G12C-selective inhibitors that are BBB penetrable and thus promising for treating patients of KRAS-G12C lung cancer and colorectal cancer, particularly those with brain metastasis.

SUMMARY OF THE DISCLOSURE

Disclosed herein are novel compounds that are capable of inhibiting KRAS G12C proteins. As a result, the compounds of the present disclosure are useful in the treatment of KRAS G12C-associated diseases such as cancers.

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

or a pharmaceutically acceptable salt thereof,

wherein

is a single bond or double bond;

G is C (R ^a) or N;

Z is

or

R ^a is absent, hydrogen, deuterium, cyano, halogen, alkyl, haloalkyl, heteroalkyl, hydroxyalkyl, or -C (O) N (R ^c) ₂;

each R ^b is independently hydrogen, deuterium, halogen, cyano, alkyl, alkoxy, heteroalkyl, cycloalkyl, or heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxyl, halogen, -NR ^cR ^d, and heterocyclyl optionally substituted with one or more groups selected from hydroxyl, halogen, cyano and amino;

each R ^c is independently hydrogen, alkyl, alkenyl, alkynyl or haloalkyl;

R ^d is selected from the group consisting of alkyl optionally substituted with heteroaryl or -N (R ^c) ₂, haloalkyl, -C (O) N (R ^c) ₂, - (CH ₂) _nNHC (O) -alkyl, heterocyclyl, and heteroaryl, wherein the heterocyclyl and heteroaryl is optionally substituted with one or more groups independently selected from halogen, hydroxyl, amino, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, heteroalkyl, hydroxyalkyl, -O-haloalkyl and –S-haloalkyl;

W is CR ^e or N;

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

Q is CR ^f or N;

R ^f is –Y- (CH ₂) _m-T-R ^g, wherein - (CH ₂) _m-is optionally substituted with hydroxyl, halogen, cyano or amino;

Y is selected from a bond, -O-, -S-, -N (R ^c) -, or alkynyl;

T is selected from 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 oxo, hydroxyl, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl;

R ^g is selected from the group consisting of hydrogen, hydroxyl, halogen, -OR ^c, -N (R ^c) ₂, -N (R ^c) SO ₂-alkyl, alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -COOH, -CH ₂OC (O) -heterocyclyl, -NHC (=NH) NH ₂, -C (O) N (R ^c) ₂, - (CH ₂OR ^c) (CH ₂) _pOR ^c, and -N (R ^c) C (O) -aryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R’, and the aryl portion in -N (R ^c) C (O) -aryl and the heterocyclyl portion in -CH ₂OC (O) -heterocyclyl is optionally substituted with one or more R”;

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

each R” is independently selected from oxo, hydroxyl, halogen, alkyl, heteroalkyl, hydroxyalkyl, haloalkyl, alkoxy, -E-phenyl, -E-phenylSO ₂F, -N (R ^c) 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;

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

each of R ^1a, R ^1b, R ^2a, R ^2b, R ^3a, R ^3b, and R ⁴ is independently selected from absent, hydrogen, oxo, hydroxyl, halogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, -C (O) OR ^c, -C (O) N (R ^c) ₂, -N (R ^c) 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 ^c, or -N (R ^c) ₂, or -SO ₂ (R ^c) ; or

two of R ^1a, R ^1b, R ^2a, R ^2b, R ^3a, R ^3b, and R ⁴ together with the carbon atom (s) they are attached form alkyl, alkenyl, cycloalkyl or heterocyclyl, said alkyl, cycloalkyl or heterocyclyl are optionally substituted with one or more groups independently selected from cyano, halogen, hydroxyl, amino, alkoxy, alkyl, alkenyl, or alkynyl;

L ¹ is a bond, - [C (R ^h) ₂] _u-*, - [C (R ^h) ₂] _u-C (O) -*or –N (R ^c) C (O) -*, wherein *denotes a point of attachment of L ¹ to L ²;

L ² is a bond, -O-, -N (R ⁱ) -, or -S (O) _v-;

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

R ⁱ is selected from absent, hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, or -C (O) -heterocyclyl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl and cycloalkyl are optionally substituted with one or more R”’, and the heterocyclyl portion in -C (O) -heterocyclyl is optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, alkyl and -N (R ^c) ₂;

or R ^h and R ⁱ together with the carbon atom and nitrogen atom they are attached respectively form a heterocyclyl or heteroaryl optionally substituted with one or more groups independently selected from cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, hydroxyalkyl, alkyl or -alkyl-N (R ^c) ₂;

each R”’ is independently selected from -N (R ^c) ₂, hetercyclyl optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, or alkyl;

L ³ is a bond, -C (O) -, or alkyl;

R ⁵ is hydrogen, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R ^j;

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

n is 0, 1 or 2;

m is an integer from 0 to 4;

p is an integer from 0 to 2;

r is 1 or 2;

u is an integer from 0 to 4;

v is an integer from 0 to 2;

provided that

when one of

is a double bond, then the other

is a single bond;

when

is a triple bond, then R ^a is absent, R ^b is present and r is 1;

or when

is a double bond, then R ^a is present, R ^b is present and r is 2, or R ^a and R ^b and the carbon atom to which they are attached form cycloalkyl optionally substituted with one or more R ^e.

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

or a pharmaceutically acceptable salt thereof,

wherein ring A is a heterocyclyl or heteroaryl optionally substituted with one or more groups independently selected from cyano, halogen, hydroxyl, amino, alkyl, alkoxy, haloalkyl, hydroxyalkyl, or -alkyl-N (R ^c) ₂.

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 G12C 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 G12C-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 G12C 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 (Ia) , Formula (Ib) , Formula (Ic) 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, that is substituted by one or more cyano groups, as defined above.

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

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

or a pharmaceutically acceptable salt thereof,

wherein

is a single bond or double bond;

G is C (R ^a) or N;

Z is

or

each R ^b is independently hydrogen, deuterium, halogen, cyano, alkyl, alkoxy, heteroalkyl, cycloalkyl, or heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxyl, halogen, -NR ^cR ^d, and heterocyclyl optionally substituted with one or more groups selected from hydroxyl, halogen, cyano and amino;

each R ^c is independently hydrogen, alkyl, alkenyl, alkynyl or haloalkyl;

W is CR ^e or N;

Q is CR ^f or N;

Y is selected from a bond, -O-, -S-, -N (R ^c) -, or alkynyl;

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

each of R ^1a, R ^1b, R ^2a, R ^2b, R ^3a, R ^3b, and R ⁴ is independently selected from absent, hydrogen, oxo, hydroxyl, halogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, -C (O) OR ^c, -C (O) N (R ^c) ₂, -N (R ^c) 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 ^c, -N (R ^c) ₂, or -SO ₂ (R ^c) ; or

L ² is a bond, -O-, -N (R ⁱ) -, or -S (O) _v-;

L ³ is a bond, -C (O) -, or alkyl;

n is 0, 1 or 2;

m is an integer from 0 to 4;

p is an integer from 0 to 2;

r is 1 or 2;

u is an integer from 0 to 4;

v is an integer from 0 to 2;

provided that

when one of

is a double bond, then the other

is a single bond;

when

is a triple bond, then R ^a is absent, R ^b is present and r is 1;

or when

In some embodiments, both

are single bond, G is C (R ^a) , and R ^a is hydrogen.

In some embodiments, one

is a single bond, the other

is a double bond, G is C (R ^a) , and R ^a is absent.

In some embodiments, both

are single bond, and G is N.

In some embodiments, Z is -N-C (O) -C (R ^a) =C (R ^b) _r.

In some embodiments, Z is -N-SO ₂C (R ^a) =C (R ^b) _r.

In certain embodiments, R ^a is hydrogen, deuterium, cyano, halogen, or alkyl.

In certain embodiments, R ^a is hydrogen, one R ^b is hydrogen, the other R ^b is selected from the group consisting of hydrogen, alkyl, heteroalkyl, haloalkyl, heteroaryl, -alkyl-NR ^cR ^d, cycloalkyl, and -alkyl-heterocyclyl, wherein the heterocyclyl in -alkyl-heterocyclyl is optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano or amino.

In certain embodiments, R ^a and the two R ^b are deuterium.

In certain embodiments, R ^a is halogen, and the two R ^b are hydrogen.

In some embodiments, Z is

In certain embodiments, R ^b is hydrogen or -alkyl-NR ^cR ^d.

In some embodiments, Z is

In certain embodiments, R ^a is hydrogen, and R ^b is hydrogen.

In some embodiments, W is N.

In some embodiments, W is CR ^e.

In certain embodiments, R ^e is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -OR ^c, alkyl, alkenyl, and alkynyl, wherein alkyl, alkenyl, and alkynyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxyl, halogen, cyano, -OR ^c, and -N (R ^c) ₂.

In certain embodiments, R ^e is selected from the group consisting of halogen, hydrogen, halogen, hydroxyl, cyano, methoxy or ethynyl.

In some embodiments, Q is N.

In some embodiments, Q is CR ^f, and R ^f is –Y- (CH ₂) _m-T-R ^g.

In some embodiments, Y is a bond, -O-or -S-.

In some embodiments, Y is -N (R ^c) -.

In some embodiments, Y is alkynyl. In certain embodiments, Y is C _2-6 alkynyl, C _2-5 alkynyl, C _2-4 alkynyl or C _2-3 alkynyl. In certain embodiments, Y is ethynyl.

In some embodiments, m is 0.

In some embodiments, m is 1, 2, or 3.

In some embodiments, T is a bond.

In some embodiments, T is a heterocyclyl optionally substituted with one or more groups independently selected from oxo, hydroxyl, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl.

In certain embodiments, T is a heterocyclyl selected from the group consisting of:

each of which is optionally substituted with one or more groups independently selected from oxo, hydroxyl, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl.

In some embodiments, Y is a bond, and T is a bond. In certain embodiments, Y is a bond, m is 0, and T is a bond.

In some embodiments, Y is a bond, and T is heterocyclyl optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl. In certain embodiments, Y is a bond, m is 0, and T is heterocyclyl optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl.

In some embodiments, Y is -O-or -S-, and T is a bond or heterocyclyl optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl. In certain embodiments, Y is -O-or -S-, m is 1, 2 or 3, and T is a bond or heterocyclyl optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl.

In some embodiments, Y is -N (R ^c) -, and T is a bond. In certain embodiments, Y is -N (R ^c) -, m is 1 or 2, and T is a bond.

In some embodiments, Y is alkynyl, and T is a bond or heterocyclyl optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl. In certain embodiments, Y is alkynyl, m is 0 or 1, and T is a bond or heterocyclyl optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl.

In some embodiments, R ^g is selected from the group consisting of hydrogen, hydroxyl, halogen, alkyl, -N (R ^c) ₂, or -OR ^c.

In certain embodiments, R ^g is hydrogen, hydroxyl or halogen.

In certain embodiments, R ^g is alkyl. In certain embodiments, R ^g is C _1-6 alkyl, C _1-5 alkyl, C _1-4 alkyl, or C _1-3 alkyl. In certain embodiments, R ^g is alkyl, ethyl, or isopropyl.

In certain embodiments, R ^g is -N (R ^c) ₂, wherein each R ^c is independently C _1-6 alkyl, C _1-5 alkyl, C _1-4 alkyl, or C _1-3 alkyl. In certain embodiments, each R ^c is methyl.

In certain embodiments, R ^g is -OR ^c, wherein R ^c is C _1-6 alkyl, C _1-5 alkyl, C _1-4 alkyl, or C _1-3 alkyl. In certain embodiments, R ^c is methyl.

In some embodiments, Y is a bond, -O-, -S-or alkynyl, T is heterocyclyl optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl, and R ^g is hydrogen, halogen, alkyl, -N (R ^c) ₂, or -OR ^c.

In some embodiments, Y is a bond, -O-, -S-, -N (R ^c) or alkynyl, T is a bond, and R ^g is -N (R ^c) ₂.

In some embodiments, each of R ^1a, R ^1b, R ^2a, R ^2b, R ^3a, R ^3b, and R ⁴ is independently selected from hydrogen, alkyl or heteroalkyl, wherein the alkyl and heteroaryl are optionally substituted with one or more groups independently selected from cyano, hydroxyl, halogen, -OR ^c, -N (R ^c) ₂, or -SO ₂ (R ^c) .

In certain embodiments, each of R ^1a, R ^1b, R ^2a, R ^2b, R ^3a, R ^3b, and R ⁴ is independently selected from hydrogen.

In certain embodiments, one of R ^1a, R ^1b, R ^2a, R ^2b, R ^3a, R ^3b, and R ⁴ is C _1-6 alkyl, C _1-5 alkyl, C _1-4 alkyl, or C _1-3 alkyl, and the others are hydrogen. In certain embodiments, one of R ^1a, R ^1b, R ^2a, R ^2b, R ^3a, R ^3b, and R ⁴ is methyl, the others are hydrogen.

In certain embodiments, one of R ^1a, R ^1b, R ^2a, R ^2b, R ^3a, R ^3b, and R ⁴ is C _1-6 cyanoalkyl, C _1-5 cyanoalkyl, C _1-4 cyanoalkyl, or C _1-3 cyanoalkyl, and the others are hydrogen. In certain embodiments, one of R ^1a, R ^1b, R ^2a, R ^2b, R ^3a, R ^3b, and R ⁴ is –CH ₂CN, the others are hydrogen.

In certain embodiments, one of R ^1a, R ^1b, R ^2a, R ^2b, R ^3a, R ^3b, and R ⁴ is C _1-6 haloalkyl, C _1-5 haloalkyl, C _1-4 haloalkyl, or C _1-3 haloalkyl, and the others are hydrogen. In certain embodiments, one of R ^1a, R ^1b, R ^2a, R ^2b, R ^3a, R ^3b, and R ⁴ is –CH ₂F, the others are hydrogen.

In certain embodiments, one of R ^1a, R ^1b, R ^2a, R ^2b, R ^3a, R ^3b, and R ⁴ is C _2-6 heteroalkyl, C _2-5 heteroalkyl, C _2-4 heteroalkyl, or C _2-3 heteroalkyl, and the others are hydrogen. In certain embodiments, one of R ^1a, R ^1b, R ^2a, R ^2b, R ^3a, R ^3b, and R ⁴ is –CH ₂OCH ₃, the others are hydrogen.

In certain embodiments, one of R ^1a, R ^1b, R ^2a, R ^2b, R ^3a, R ^3b, and R ⁴ is -C _1-6 alkyl-SO ₂CH ₃, -C _1-5 alkyl-SO ₂CH ₃, -C _1-4 alkyl-SO ₂CH ₃, -C _1-3 alkyl-SO ₂CH ₃, or -C _1-2 alkyl-SO ₂CH ₃, and the others are hydrogen. In certain embodiments, one of R ^1a, R ^1b, R ^2a, R ^2b, R ^3a, R ^3b, and R ⁴ is –CH ₂SO ₂CH ₃, the others are hydrogen.

In some embodiments, two of R ^1a, R ^1b, R ^2a, R ^2b, R ^3a, R ^3b, and R ⁴ together with the carbon atom (s) they are attached form an alkyl.

In certain embodiments, R ^1a and R ^3a together with the carbon atoms they are attached form propyl or butyl.

In certain embodiments, R ^1a and R ⁴ together with the carbon atoms they are attached form propyl or butyl.

In certain embodiments, R ^2a and R ^3a together with the carbon atoms they are attached form propyl or butyl.

In some embodiments, two of R ^1a, R ^1b, R ^2a, R ^2b, R ^3a, R ^3b, and R ⁴ together with the carbon atom (s) they are attached form an alkenyl.

In certain embodiments, R ^1a and R ^3a together with the carbon atoms they are attached form butenyl.

In certain embodiments, R ^1a and R ⁴ together with the carbon atoms they are attached form butenyl.

In certain embodiments, R ^2a and R ^3a together with the carbon atoms they are attached form butenyl.

In some embodiments, two of R ^1a, R ^1b, R ^2a, R ^2b, R ^3a, R ^3b, and R ⁴ together with the carbon atom (s) they are attached form a cycloalkyl or heterocyclyl.

In certain embodiments, R ^1a and R ^1b together with the carbon atom they both are attached form C _3-6 cycloalkyl or C _3-6 heterocyclyl.

In certain embodiments, R ^2a and R ^2b together with the carbon atom they both are attached form C _3-6 cycloalkyl or C _3-6 heterocyclyl.

In certain embodiments, R ^3a and R ^3b together with the carbon atom they both are attached form C _3-6 cycloalkyl or C _3-6 heterocyclyl.

In certain embodiments, R ^1a and R ^2a together with the carbon atom they both are attached form C _3-6 cycloalkyl or C _3-6 heterocyclyl.

In certain embodiments, R ^3a and R ⁴ together with the carbon atom they both are attached form C _3-6 cycloalkyl or C _3-6 heterocyclyl.

In some embodiments, L ¹ is a bond.

In some embodiments, L ¹ is - [C (R ^h) ₂] _u-*. In certain embodiments, L ¹ is - [C (R ^h) ₂] _u-*, R ^h is hydrogen, and u is 0, 1, 2 or 3.

In some embodiments, L ¹ is - [C (R ^h) ₂] _u-C (O) -*. In certain embodiments, L ¹ is - [C (R ^h) ₂] _u-C (O) -*, R ^h is hydrogen, and u is 0, 1, 2 or 3.

In some embodiments, L ¹ is –N (R ^c) C (O) -*. In certain embodiments, L ¹ is –N (R ^c) C (O) -*, and R ^c is hydrogen.

In some embodiments, L ¹ is -S (O) _v-.

In some embodiments, L ² is a bond.

In some embodiments, L ² is -O-.

In some embodiments, L ² is -N (R ⁱ) -. In certain embodiments, L ² is -N (R ⁱ) -, R ⁱ is hydrogen, alkyl, or -C (O) -heterocyclyl, wherein the alkyl is optionally substituted with one or more R”’, and the heterocyclyl portion in -C (O) -heterocyclyl is optionally substituted with one or more groups independently selected from alkyl or -N (R ^c) ₂.

In some embodiments, L ¹ is - [C (R ^h) ₂] _u-*, L ² is -N (R ⁱ) -, u is 1, and R ^h and R ⁱ together with the carbon atom and nitrogen atom they are attached respectively form a heteroaryl optionally substituted with one or more groups independently selected from cyano, halogen, hydroxyl, haloalkyl, hydroxyalkyl, alkyl or -alkyl-N (R ^c) ₂.

In certain embodiments, L ¹ is - [C (R ^h) ₂] _u-*, L ² is -N (R ⁱ) -, u is 1, and R ^h and R ⁱ together with the carbon atom and nitrogen atom they are attached respectively form triazolyl or imidazolyl, each optionally substituted with one or more groups independently selected from cyano, halogen, hydroxyl, haloalkyl, hydroxyalkyl, alkyl or -alkyl-N (R ^c) ₂.

In some embodiments, L ¹ is - [C (R ^h) ₂] _u-C (O) -*, L ² is -N (R ⁱ) -, and u is 0.

In some embodiments, L ³ is a bond.

In some embodiments, L ³ is -C (O) -.

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

In some embodiments, R ⁵ is aryl optionally substituted with one or more R ^j. In certain embodiments, R ⁵ is C _5-12 aryl, C _5-11 aryl, C _5-10 aryl, C _5-9 aryl, C _5-8 aryl or C _5- ₇ aryl, each of which is optionally substituted with one or more R ^j. In certain embodiments, R ⁵ is phenyl, naphthyl or 2, 3-dihydro-1H-indenyl, each of which is optionally substituted with one or more R ^j. In certain embodiments, R ^j is hydroxyl, halogen, amino, alkyl, alkynyl, haloalkyl or cycloalkyl.

In some embodiments, R ⁵ is heteroaryl optionally substituted with one or more R ^j. In certain embodiments, R ⁵ is C _5-12 heteroaryl, C _5-11 heteroaryl, C _5-10 heteroaryl, C _5-9 heteroaryl, C _5-8 heteroaryl or C _5-7 heteroaryl, each of which is optionally substituted with one or more R ^j. In certain embodiments, R ⁵ is pyridyl, quinolinyl, isoquinolinyl, indazolyl, or benzo [b] thiophenyl, each of which is optionally substituted with one or more R ^j. In certain embodiments, R ^j is hydroxyl, halogen, amino, alkyl or alkynyl.

In a further aspect, the present disclosure provides a compound having having Formula (Ia) , Formula (Ib) or Formula (Ic) :

or a pharmaceutically acceptable salt thereof,

wherein

In certain embodiments, both

are single bond.

In certain embodiments, Q is CR ^f.

In certain embodiments, Q is N.

In certain embodiments, L ³ is a bond.

In certain embodiments, R ⁵ is aryl or heteroaryl, each optionally substituted with one or more R ^j.

In certain embodiments, R ⁵ is selected from the group consisting of phenyl, naphthyl, 2, 3-dihydro-1H-indenyl, pyridinyl, quinolinyl, isoquinolinyl, indazolyl, and benzo [b] thiophenyl, each of which is optionally substituted with one or more R ^j.

In certain embodiments, u is 0 or 1.

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 G12C 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 G12C 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 G12C 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 G12C-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.

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 or colorectal cancer, in particular, non-small cell lung cancer or colorectal cancer with brain metastasis.

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 or PD-L1 antagonist, an MEK inhibitor, a CDK4/CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, a SHP2 inhibitor, a SOS1 inhibitor, a mTOR inhibitor, a VEGFR inhibitor, EGFR antibody, 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 G12C 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 G12C 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

Step 1:

The starting material of Formula (Ia’_1) is commercially available.Compound of Formular (Ia’_2) may be prepared by the Curtius rearrangement reaction with a compound of Formula (Ia’_1) in the presence of diphenyl phosphorazidate (DPPA) under standard conditions.

Step 2:

Compound of Formula (Ia’_3) may be prepared by the removing the Boc protective group of Compound of Formula (Ia’_2) with acid (e.g, TFA) under standard condition.

Step 3:

Compound of Formula (Ia’_5) may be prepared by the cyclization of a compound of Formula (Ia’_3) with Compound of Formula (Ia’_4) under standard conditions.

Step 4:

Compound of Formula (Ia’_6) may be prepared by the nitration reaction of a compound of Formula (Ia’_5) with nitric acid under standard conditions.

Step 5:

Compound of Formula (Ia’_7) may be prepared by the chlorination reaction of a compound of Formula (Ia’_6) with chloride reagents (e.g, POCl ₃) in the presence of base (e.g, DIPEA) under standard conditions.

Step 6:

Compound of Formula (Ia’_9) may be prepared by the substitution reaction with a compound of Formula (Ia’_7) and a compound of Formula (Ia’_8) in the presence of base (e.g, DIPEA, NaHCO ₃) under standard conditions.

Step 7:

Compound of Formula (Ia’_10) may be prepared by the reduction of a compound of Formula (Ia’_9) , followed by intramolecular cyclization under standard reduction conditions (e.g, Fe/NH ₄Cl) .

Step 8:

Compound of Formula (Ia’_11) may be prepared by the methylation reaction of a compound of Formula (Ia’_10) with methylation reagents (e.g, MeI) under standard conditions.

Step 9:

Compound of Formula (Ia’) may be prepared by the Suzuki coupling reaction of a compound of Formular (Ia’_11) with a compound of Formula (Ia’_12) in the presence of Palladium catalyst (e.g, PddppfCl ₂) and base (e.g, Na ₂CO ₃) under standard conditions.

Example 1

2- (10-acryloyl-3- (8-chloronaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

Step 1. methyl 5- (2- (tert-butoxy) -1-cyano-2-oxoethyl) pyrazine-2-carboxylate

A solution of tert-butyl 2-cyanoacetate (25 g, 177.09 mmol) and t-BuOK (19.87 g, 177.09 mmol) in THF (800 mL) was stirred at r. t for 0.5h, then methyl 5-chloropyrazine-2-carboxylate (20.37 g, 118.06 mmol) was added. The reaction mixture was reflux overnight. Then the reaction mixture was cooled to room temperature and filtered to afford the desired product (25 g, 76.36%) . LC/MS (ESI) m/z: 278 (M+H) ⁺.

Step 2. methyl 5- (cyanomethyl) pyrazine-2-carboxylate

A solution of methyl 5- (2- (tert-butoxy) -1-cyano-2-oxoethyl) pyrazine-2-carboxylate (24 g, 86.55 mmol) and PTSA (14.9 g, 86.55 mmol) in toluene (800 mL) was heated at 110 ℃ for 3h. Then the reaction mixture was concentrated and the residue was dissolved in H ₂O (200 mL) . The resulting solution was extracted with EA twice. The combined organic layers were washed with sat. NaHCO ₃, dried over Na ₂SO ₄ and concentrated. The residue was purified by column chromatography (eluted by PE/EA = 5/1) to afford the desired product (9.5 g, 61.95%) . LC/MS (ESI) m/z: 178 (M+H) ⁺.

Step 3. 1- (tert-butyl) 2-methyl 5- (cyanomethyl) -5, 6-dihydropyrazine-1, 2 (4H) -dicarboxylate

To a solution of methyl 5- (cyanomethyl) pyrazine-2-carboxylate (9.5 g, 53.62 mmol) and Boc ₂O (17.2 mL, 80.44 mmol) in ethyl acetate (500 mL) was added Pd/C (4 g, 10%Pd on carbon) and the reaction was stirred at 50℃ overnight at the atmosphere of H ₂ under general pressure. The mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography to afford the title compound (12 g, 79.55%) . LC/MS (ESI) m/z: 282 (M+H) ⁺.

Step 4. 1- (tert-butyl) 2-methyl 5- (cyanomethyl) piperazine-1, 2-dicarboxylate

To a solution of 1- (tert-butyl) 2-methyl 5- (cyanomethyl) -5, 6-dihydropyrazine-1, 2 (4H) -dicarboxylate (10 g, 35.55 mmol) in MeOH (100 mL) were added AcOH (20 mL) and NaBH ₃CN (4.47 g, 71.09 mmol) and the reaction mixture was stirred at 30℃ overnight. The reaction mixture was quenched with sat. NaHCO ₃ and extracted with EA twice. The combined organic layers were washed with brine, dried and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford the title compound (8 g, 79.43%) . LC/MS (ESI) m/z: 284 (M+H) ⁺.

Step 5. 1- (tert-butyl) 2-methyl 5- (cyanomethyl) -4- (4-methoxybenzyl) piperazine-1, 2-dicarboxylate

To a solution of 1- (tert-butyl) 2-methyl 5- (cyanomethyl) piperazine-1, 2-dicarboxylate (67 g, 211.12 mmol) and 4-methoxybenzaldehyde (56.4 mL, 464.47 mmol) in DCM (1200 mL) and AcOH (12.09 mL, 211.12 mmol) was added NaBH ₃CN (116.34 g, 548.92 mmol) at 0℃ and the reaction was stirred at 30℃overnight. The reaction mixture was quenched with sat. NaHCO ₃ and extracted with DCM twice. The combined organic layers were washed with brine, dried and concentrated in vacuo. The residue was purified by silica column chromatography eluting with DCM in petroleum ether (0～25%) to afford 1- (tert-butyl) 2-methyl 5- (cyanomethyl) -4- (4-methoxybenzyl) piperazine-1, 2-dicarboxylate (20 g, 21.65%) . LC/MS (ESI) m/z: 418 (M+H) ⁺.

Step 6. tert-butyl (2-chloro-3-fluoropyridin-4-yl) carbamate

A solution of 2-chloro-3-fluoroisonicotinic acid (180 g, 1 mol) and t-BuOH (1300 mL) in Toluene (1300 mL) was added TEA (428 mL) . The mixture was stirred at 110℃ for 0.5h, then DPPA (332 mL) was added dropwise to the mixture after the mixture was cooled. The reaction mixture stirred at 110℃ for 6 h. Then the reaction mixture was concentrated, and diluted with water, extracted with EA. The combined organic was washed with brine, dried Na ₂SO ₄, concentrated and to afford desired product (193 g, 76%) .

MS Calcd: 246.06, MS (ESI) : 247.0 [M+H] ⁺.

Step 7. 2-chloro-3-fluoropyridin-4-amine

A solution of tert-butyl (2-chloro-3-fluoropyridin-4-yl) carbamate (193 g, 0.78 mol) in dioxane/HCl (1 L) was stirred at room temperature overnight. Then the reaction mixture was concentrated and the residue was dissolved in water (2000 ml) , extracted with MTBE (1000 ml) once which was dropped, then sat. NaHCO ₃ aqueous (200 mL) was added until PH>7, extracted with EA (1500 ml x3) . The combined organic layers were washed with sat. NaCl, dried over Na ₂SO ₄ and concentrated and to afford the desired product (93 g, 81%) .

MS (ESI) : 147 [M+H] ⁺.

¹H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J = 5.4 Hz, 1H) , 6.73 –6.65 (m, 1H) , 6.58 (s, 2H) .

Step 8: 5- ( ( (2-chloro-3-fluoropyridin-4-yl) amino) methylene) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione

To a solution of 2-chloro-3-fluoropyridin-4-amine (29 g, 198.6 mmol) in Trimethyl Orthoformate (200 mL) was stirred at 80℃ for 2 hours. The mixture was added 2, 5-dimethoxyaniline (28.6 g, 198.6 mmol) . The reaction was stirred at 80℃for 16 hours. The mixture was cooled to room temperature and diluted with 5% EtOAc/hexane (300 mL) , and was filtered to give the desired product (48 g, yield: 80.7%) , which was used to next step without further purification.

MS (ESI) : 301 [M+H] ⁺.

¹H NMR (400 MHz, CDCl ₃) δ 11.42 (d, J = 12.8 Hz, 1H) , 8.60 (d, J = 13.2 Hz, 1H) , 8.24 (d, J = 5.6 Hz, 1H) , 7.27 (d, J = 10.4 Hz, 1H) , 1.77 (s, 6H) .

Step 9: 7-chloro-8-fluoro-1, 6-naphthyridin-4-ol

To a solution of Phenyl ether (450 mL) was heated at 210℃. 5- ( ( (2-chloro-3-fluoropyridin-4-yl) amino) methylene) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione (48 g, 160 mmol) was added to the reaction. The mixture was stirred at 210℃ for 0.3 hour. The reaction was cooled to room temperature and wash with hexane. The mixture was filtered out and the residue was purified by silica gel column (DCM: MeOH=30: 1) to give the desired product (13.5 g, yield: 42.4%) .

MS (ESI) : 199.1 [M+H] ⁺.

¹H NMR (400 MHz, DMSO-d ₆) δ 12.39 (s, 1H) , 8.84 (s, 1H) , 7.95 (d, J = 7.2 Hz, 1H) , 6.23 (d, J = 7.6 Hz, 1H) .

Step 10: 7-chloro-8-fluoro-3-nitro-1, 6-naphthyridin-4-ol

To a solution of 7-chloro-8-fluoro-1, 6-naphthyridin-4-ol (13.5g, 67.8 mmol) in H ₂SO ₄ (90 mL) was added HNO ₃ (30 mL) at room temperature. The mixture was stirred at 80℃ for 2 hours. The reaction mixture was quenched with ice water and pH was adjusted to about 7 with solid NaOH. The reaction was extracted with EA (600 mL x2) . The combined organic layers were washed with brine (400 mL x 2) , dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the desired product (13.2 g, yield: 79.7%) . which was used to next step without further purification.

MS Calcd: 242.98, MS (ESI) : 244.0 [M+H] ⁺.

Step 11: 4, 7-dichloro-8-fluoro-3-nitro-1, 6-naphthyridine

To a solution of 7-chloro-8-fluoro-3-nitro-1, 6-naphthyridin-4-ol (13.2 g, 54.2 mmol) in POCl ₃ (130 mL) were added DIEA (21 g, 0.1622 mmol) , the mixture was stirred at 105℃ for 16 hours. The mixture was concentrated under reduced pressured. The residue was diluted with ice water (200 ml) and 1M NaOH (aq) was added until PH> 7 (kept below 5℃) , then extracted with EtOAc (200 ml x 2) , the combined organic layers were washed with brine (200 mL x 2) , dried over anhydrous Na ₂SO ₄. After filtration, the filtrate was concentrated under reduced pressure to give the desired product (13.5 g, yield: 93.7%) which was used to next step without further purification.

MS Calcd: 260.95, MS (ESI) : 262.0 [M+H] ⁺.

¹H NMR (400 MHz, CDCl ₃) δ 9.48 (s, 2H) .

Step 12: methyl 1- (7-chloro-8-fluoro-3-nitro-1, 6-naphthyridin-4-yl) -5- (cyanomethyl) -4- (4-methoxybenzyl) piperazine-2-carboxylate

To a solution of 4, 7-dichloro-8-fluoro-3-nitro-1, 6-naphthyridine (2.61 g, 10 mmol) in CH ₃CN (30 mL) were added methyl 5- (cyanomethyl) -4- (4-methoxybenzyl) piperazine-2-carboxylate (3.03g, 10 mmol) and NaHCO ₃ (1.68 g, 20 mmol) . The reaction was stirred at 55℃ for 16 hours. The reaction was concentrated under reduced pressure to give the residue. The residue was purified by silica gel column (EA: PE = 1: 3) to give the desired product (2.27 g, yield: 43%) . MS Calcd: 528.1, MS (ESI) : 529.2 [M+H] ⁺.

Step 13: 2- (3-chloro-4-fluoro-10- (4-methoxybenzyl) -8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

To a mixture of methyl 1- (7-chloro-8-fluoro-3-nitro-1, 6-naphthyridin-4-yl) -5- (cyanomethyl) -4- (4-methoxybenzyl) piperazine-2-carboxylate (3.7g, 7 mmol) in EtOH (60 mL) and saturated ammonium chloride aqueous solution (60 mL) was added ferrous powder (2.0 g, 35 mmol) at room temperature, then the reaction was heated to 80℃ and stirred for 16 hours under nitrogen atmosphere. Filter the reaction solution while it was hot, water (100 ml) was added to the filtrate, and extracted with EtOAc (200 ml x 3) , the combined extracts were washed with water and brine, dried over Na ₂SO ₄, filtered, concentrated under reduced pressure and the residue was purified by SGC (EA: PE=1: 3) to afford title product (1.1g, yield: 43%) .

MS Calcd: 466.1, MS (ESI) : 467.2 [M+H] ⁺.

Step 14: 2- (3-chloro-4-fluoro-10- (4-methoxybenzyl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

To a solution of 2- (3-chloro-4-fluoro-10- (4-methoxybenzyl) -8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile (1.1 g, 2.36 mmol) in DMF (15 mL) was added Cs ₂CO ₃ (1.53 g, 4.72 mmol) and MeI (503 mg, 3.54 mmol) in turn under nitrogen atmosphere at room temperature, then the reaction was stirred for 2 hours under nitrogen atmosphere at room temperature. Water (100 ml) was added, stirred for 20 minutes at room temperature, filtered, the solid was washed was water and dried under reduced pressure to afford title product (880 mg, yield: 78%) .

MS Calcd: 480.2, MS (ESI) : 481.2 [M+H] ⁺.

Step 15: 2- (3- (8-chloronaphthalen-1-yl) -4-fluoro-10- (4-methoxybenzyl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

To a solution of 2- (10- (4-methoxybenzyl) -7-methyl-6- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -8-oxo-2, 3, 4, 7, 8, 8a, 9, 10, 11, 12-decahydro-1H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 7] naphthyridin-11-yl) acetonitrile (240 mg, 0.5 mmol) , 2- (8-chloronaphthalen-1-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (288 mg,1 mmol) and K ₂CO ₃ (207 mg, 1.5 mmol) in dioxane (4 mL) and H ₂O (1 ml ) was added Pd (PPh ₃) ₄ (58 mg, 0.05 mmol) under nitrogen atmosphere at room temperature, then the reaction was heated to 100℃ and stirred for 16 hours under nitrogen atmosphere. After cooling to rt, water (5 ml) was added, extracted with EtOAc (10 ml x3) , the combined extracts were washed with water and brine, dried over Na ₂SO ₄, filtered, the filtrate was concentrated under reduced pressure. The residue was purified by TLC (PE: EtOAc=1: 1) to afford title product (180 mg crude, yield: 29.7%) . MS Calcd: 606.2, MS (ESI) : 607.2 [M+H] ⁺.

Step 16: 2- (3- (8-chloronaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

To a solution of 2- (3- (8-chloronaphthalen-1-yl) -4-fluoro-10- (4-methoxybenzyl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile (180 mg, ～50%purity, 0.15 mmol) in TFA (10 mL) was added methyl (phenyl) sulfane (0.1 ml) . The mixture was stirred at 50℃ for 3 h under N ₂ atmosphere. The reaction mixture was concentrated to give residue. The residue was quenched with water and pH was adjusted to about 7 with solid NaHCO ₃. The reaction was extracted with EA (30 mL x3) . The combined organic layers were washed with brine (20 mL x2) , dried over anhydrous Na ₂SO ₄. After filtration, the filtrate was concentrated purified by TLC (DCM: MeOH=10: 1) to give the desired product (120 mg, yield: 83.3%) . MS Calcd: 486.1, MS (ESI) : 487.2 [M+H] ⁺.

Step 12: 2- (10-acryloyl-3- (8-chloronaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

To a solution of 2- (3- (8-chloronaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile (120 mg, 0.173 mmol) in DCM (5 mL) was added acryloyl chloride (32 mg, 0.36 mmol) and TEA (54 mg, 0.54 mmol) dropwise at 0℃. The mixture was stirred for 1 hours at 0℃. The reaction was concentrated under reduced pressure (below 20℃) and the residue was purified by pre-HPLC (0.05%formic acid in water/MeCN) to afford two isomers (Example 1A: 2.7 mg/Example 1B: 16.5 mg)

Example 1A: MS Calcd: 540.2, MS (ESI) : 541.3 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD) δ 9.31 (s, 1H) , 8.70 (s, 1H) , 8.07 (d, J = 8.0 Hz, 1H) , 7.92 (d, J = 8.0 Hz, 1H) , 7.63 -7.61 (m, 2H) , 7.53-7.51 (m, 1H) , 7.45 –7.43 (m, 1H) , 6.88 –6.82 (m, 1H) , 6.25 (d, J = 16.8 Hz, 1H) , 5.80 (d, J = 10.8 Hz, 1H) , 4.50 –4.41 (m, 4H) , 3.58 –3.55 (m, 2H) , 3.48 (s, 3H) , 2.88 –2.85 (m, 2H) .

Example 1B: MS Calcd: 540.2, MS (ESI) : 541.3 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD) δ 9.49 (s, 1H) , 9.05 (m, 1H) , 8.18 (d, J = 8.0 Hz, 1H) , 8.05 (d, J = 8.0 Hz, 1H) , 7.74 -7.70 (m, 2H) , 7.63-7.61 (m, 1H) , 7.56-7.53 (m, 1H) , 7.13 –7.10 (m, 1H) , 6.33 (d, J = 16.8 Hz, 1H) , 5.88 (d, J = 10.4 Hz, 1H) , 4.98 –4.96 (m, 2H) , 4.17 -4.06 (m, 1H) , 4.03 -3.99 (m, 1H) , 3.90 -3.81 (m, 1H) , 3.79-3.71 (m, 1H) , 3.61 (s, 3H) .

Example 2

2- (10-acryloyl-4-fluoro-3- (2-fluoro-6-hydroxyphenyl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

Step 1: 2- (4-fluoro-3- (2-fluoro-6-hydroxyphenyl) -10- (4-methoxybenzyl) -7- methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

To a solution of 2- (3-chloro-4-fluoro-10- (4-methoxybenzyl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile (240 mg, 0.27 mmol) , (2-fluoro-6-hydroxyphenyl) boronic acid (314 mg,1 mmol) and K ₂CO ₃ (207 mg, 1.5 mmol) in dioxane (4 mL) and H ₂O (1 ml) was added Ruphos-G2-Pd (39 mg, 0.05 mmol) under nitrogen atmosphere at room temperature, then the reaction was heated to 100℃ and stirred for 2 hours under nitrogen atmosphere. After cooling to rt, water (5 ml) was added, extracted with EtOAc (10 ml x3) , the combined extracts were washed with water and brine, dried over Na ₂SO ₄, filtered, the filtrate was concentrated under reduced pressure. The residue was purified by TLC (PE: EtOAc=1: 1) to afford title product (200 mg, yield: 61.9%) .

MS (ESI) : 557.2 [M+H] ⁺.

Step 2: 2- (4-fluoro-3- (2-fluoro-6-hydroxyphenyl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

To a solution of 2- (4-fluoro-3- (2-fluoro-6-hydroxyphenyl) -10- (4-methoxybenzyl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile (180 mg, 0.32 mmol) in TFA (10 mL) was added methyl (phenyl) sulfane (0.1 ml) . The mixture was stirred at 50℃ for 3 h under N ₂ atmosphere. The reaction mixture was concentrated to give residue. The residue was quenched with water and pH was adjusted to about 7 with solid NaHCO ₃. The reaction was extracted with EA (30 mL x3) . The combined organic layers were washed with brine (20 mL x2) , dried over anhydrous Na ₂SO ₄. After filtration, the filtrate was concentrated purified by TLC (DCM: MeOH=8: 1) to give the desired product (120 mg, yield: 85.6%) .

MS (ESI) : 437.2 [M+H] ⁺.

Step 3: 2- (10-acryloyl-11- (cyanomethyl) -4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-3-yl) -3-fluorophenyl acrylate

To a solution of 2- (4-fluoro-3- (2-fluoro-6-hydroxyphenyl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile (110 mg, 0.20 mmol) in DCM (5 mL) was added acryloyl chloride (38 mg, 0.42 mmol) and TEA (60 mg, 0.60 mmol) dropwise at 0℃. The mixture was stirred for 1 hours at 0℃. The reaction was concentrated under reduced pressure (below 20℃) and the residue was used for next step directly without further purification (140 mg crude, yield: 100%)

MS (ESI) : 545.3 [M+H] ⁺.

Step 4: 2- (10-acryloyl-4-fluoro-3- (2-fluoro-6-hydroxyphenyl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

To a solution of 2- (10-acryloyl-11- (cyanomethyl) -4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-3-yl) -3-fluorophenyl acrylate (140 mg crude, 0.20 mmol) in THF (4 mL) and H ₂O (1 ml) was added LiOH. H ₂O (21 mg, 0.5 mmol) . The mixture was stirred at rt for 3 h. The mixture was concentrated under reduced pressure (below 20℃) and the residue was purified by pre-HPLC (0.05%formic acid in water/MeCN) to afford 2 isomers [Example 2A: 5.6mg, Example 2B: 6.7mg]

Example 2A: MS (ESI) : 491.3 [M+H] ⁺. ¹H NMR (400 MHz, MeOD) δ 9.33 (s, 1H) , 8.93 (s, 1H) , 7.38-7.35 (m, 1H) , 7.00-7.02 (m, 1H) , 6.84-6.75 (m, 2H) , 6.76 (d, J = 8.4 Hz, 1H) , 5.90 (d, J = 10.8 Hz, 1H) , 4.59 -4.40 (m, 3H) , 4.22-4.18 (m, 1H) , 3.61 (s, 3H) , 3.34 -3.30 (m, 2H) , 2.94-2.93 (m, 2H)

Example 2B: MS (ESI) : 491.3 [M+H] ⁺. ¹H NMR (400 MHz, MeOD) δ 9.45 (s, 1H) , 9.09 (s, 1H) , 7.37-7.33 (m, 1H) , 7.18-7.11 (m, 1H) , 6.85-6.75 (m, 2H) , 6.30 (d, J = 16.8 Hz, 1H) , 5.88 (d, J = 12.0 Hz, 1H) , 5.03 -4.87 (m, 2H) , 4.09 -4.02 (m, 1H) , 3.99-3.97 (m, 1H) , 3.77-3.74 (m, 1H) , 3.61 (s, 3H) , 3.54 -3.50 (m, 1H) , 3.36-3.32 (m, 2H)

Example 3

2- (10-acryloyl-4-fluoro-3- (3-hydroxynaphthalen-1-yl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

Step 1: 2- (4-fluoro-10- (4-methoxybenzyl) -3- (3- (methoxy methoxy) naphthalen-1-yl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

To a solution of 2- (10- (4-methoxybenzyl) -7-methyl-6- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -8-oxo-2, 3, 4, 7, 8, 8a, 9, 10, 11, 12-decahydro-1H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 7] naphthyridin-11-yl) acetonitrile (240 mg, 0.5 mmol) , 2- (3- (methoxymethoxy) naphthalen-1-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (314 mg, 1 mmol) and K ₂CO ₃ (207 mg, 1.5 mmol) in dioxane (4 mL) and H ₂O (1 ml) was added Pd (PPh ₃) ₄ (58 mg, 0.05 mmol) under nitrogen atmosphere at room temperature, then the reaction was heated to 100℃ and stirred for 16 hours under nitrogen atmosphere. After cooling to rt, water (5 ml) was added, extracted with EtOAc (10 ml x3) , the combined extracts were washed with water and brine, dried over Na ₂SO ₄, filtered, the filtrate was concentrated under reduced pressure. The residue was purified by TLC (PE: EtOAc=1: 1) to afford title product (200 mg, yield: 63.3%) .

MS (ESI) : 633.3 [M+H] ⁺.

Step 2: 2- (4-fluoro-3- (3-hydroxynaphthalen-1-yl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

To a solution of 2- (4-fluoro-10- (4-methoxybenzyl) -3- (3- (methoxymethoxy) naphthalen-1-yl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile (180 mg, 0.28 mmol) in TFA (10 mL) was added methyl (phenyl) sulfane (0.1 ml) . The mixture was stirred at 50℃ for 3 h under N ₂ atmosphere. The reaction mixture was concentrated to give residue. The residue was quenched with water and pH was adjusted to about 7 with solid NaHCO ₃. The reaction was extracted with EA (30 mL x3) . The combined organic layers were washed with brine (20 mL x2) , dried over anhydrous Na ₂SO ₄. After filtration, the filtrate was concentrated purified by TLC (DCM: MeOH=10: 1) to give the desired product (110 mg, yield: 84.6%) .

MS (ESI) : 469.3 [M+H] ⁺.

Step 3: 4- (10-acryloyl-11- (cyanomethyl) -4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-3-yl) naphthalen-2-yl acrylate

To a solution of 2- (4-fluoro-3- (3-hydroxynaphthalen-1-yl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile (100 mg, 0.173 mmol) in DCM (5 mL) was added acryloyl chloride (32 mg, 0.36 mmol) and TEA (54 mg, 0.54 mmol) dropwise at 0℃. The mixture was stirred for 1 hours at 0℃. The reaction was concentrated under reduced pressure (below 20℃) and the residue was used for next step directly without further purification (120 mg crude, yield: 100%) .

MS (ESI) : 577.4 [M+H] ⁺.

Step4: 2- (10-acryloyl-4-fluoro-3- (3-hydroxynaphthalen-1-yl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

To a solution of 4- (10-acryloyl-11- (cyanomethyl) -4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-3-yl) naphthalen-2-yl acrylate (120 mg crude, 0.173 mmol) in THF (4 mL) and H ₂O (1 ml) was added LiOH·H ₂O (21 mg, 0.5 mmol) . The mixture was stirred at rt for 3 h. The mixture was concentrated under reduced pressure (below 20℃) and the residue was purified by pre-HPLC (0.05%formic acid in water/MeCN) to afford 2 isomers [Example 3A: 6.5mg, Example 3B: 35.8 mg] .

Example 3A: MS (ESI) : 523.3 [M+H] ⁺. ¹H NMR (400 MHz, MeOD) δ 9.26 (s, 1H) , δ 8.23 (s, 1H) , 7.66 (d, J = 8.4 Hz, 1H) , 7.43 (d, J = 8.4 Hz 1H) , 7.33 –7.31 (m, 1H) , 7.19 –7.12 (m, 3H) , 7.10 –6.86 (m, 1H) , 6.23 (d, J = 16.8 Hz , 1H) , 5.77 (d, J = 12 Hz, 1H) , 4.80 –4.71 (m, 1H) , 4.38 –4.26 (m, 3H) , 4.14 –4.11 (m, 1H) , 3.34 (s, 3H) , 3.25 –3.20 (m, 2H) , 2.82 (d, J = 5.2 Hz, 1H)

Example 3B: MS (ESI) : 523.3 [M+H] ⁺. ¹H NMR (400 MHz, MeOD) δ 9.26 (s, 1H) , δ 8.23 (s, 1H) , 7.65 (d, J = 8.4 Hz, 1H) , 7.44 (d, J = 8.4 Hz 1H) , 7.34 –7.32 (m, 1H) , 7.18 –7.12 (m, 3H) , 7.09 –6.86 (m, 1H) , 6.22 (d, J = 16.8 Hz , 1H) , 5.78 (d, J = 12 Hz, 1H) , 4.38 –4.26 (m, 3H) , 4.14 –4.11 (m, 1H) , 3.34 (s, 3H) , 3.25 –3.20 (m, 2H) , 2.82 (m, 2H) .

Example 4

2- (10-acryloyl-4-fluoro-7-methyl-3- (8-methylnaphthalen-1-yl) -8-oxo-8, 8a, 9, 10, 11,12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

Step 1: 2- (4-fluoro-10- (4-methoxybenzyl) -7-methyl-3- (8-methylnaphthalen-1-yl) -8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

To a solution of 2- (10- (4-methoxybenzyl) -7-methyl-6- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -8-oxo -2, 3, 4, 7, 8, 8a, 9, 10, 11, 12-decahydro-1H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 7] naphthyridin-11-yl) acetonitrile (240 mg, 0.5 mmol) , 4, 4, 5, 5-tetramethyl-2- (8-methylnaphthalen-1-yl) -1, 3, 2-dioxaborolane (268 mg,1 mmol) and K ₂CO ₃ (207 mg, 1.5 mmol) in dioxane (4 mL) and H ₂O (1 ml) was added Pd (PPh ₃) ₄ (58 mg, 0.05 mmol) under nitrogen atmosphere at room temperature, then the mixture was heated to 100℃ and stirred for 16 hours under nitrogen atmosphere. After cooling to rt, the mixture was diluted with water and extracted with EtOAc (50 ml x3) . The combined extracts were washed with water and brine, dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by pre-TLC (PE: EtOAc=1: 1) to afford title product (120 mg, yield: 41%) .

MS (ESI) : 587.3 [M+H] ⁺.

Step 2: 2- (4-fluoro-7-methyl-3- (8-methylnaphthalen-1-yl) -8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

To a solution of 2- (3- (8-chloronaphthalen-1-yl) -4-fluoro-10- (4-methoxybenzyl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile (120 mg, 0.25 mmol) in TFA (4 mL) was added thioanisole (0.1 ml) . The mixture was stirred at 50℃ for 3 h under N ₂ atmosphere. The reaction mixture was concentrated to give a residue. The residue was quenched with water and pH was adjusted to about 7 with solid NaHCO ₃. The mixture was extracted with EA (30 mL x3) . The combined organic layers were washed with brine (20 mL x2) , dried over anhydrous Na ₂SO ₄. After filtration, the filtrate was concentrated and the residue was purified by pre-TLC (DCM: MeOH=10: 1) to give the desired product (80 mg, yield: 80%) .

MS (ESI) : 467.1 [M+H] ⁺.

Step 3: 2- (10-acryloyl-4-fluoro-7-methyl-3- (8-methylnaphthalen-1-yl) -8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

To a solution of 2- (4-fluoro-7-methyl-3- (8-methylnaphthalen-1-yl) -8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile (80 mg, 0.17 mmol) in DCM (5 mL) was added acryloyl chloride (32 mg, 0.36 mmol) and TEA (54 mg, 0.54 mmol) dropwise at 0℃. The mixture was stirred for 1 hours at 0℃. The reaction miture was concentrated under reduced pressure (below 20 ℃) and the residue was purified by pre-HPLC (0.05%formic acid in water/MeCN) to afford title product (Example 4A: 1.9 mg; Example 4B: 2.1 mg, yield: 4.5%) .

Example 4A: MS Calcd: 520.2, MS (ESI) : 521.2 [M+H] ⁺. ¹H NMR (400 MHz, CDCl ₃) δ 9.27 (s, 1H) , 8.94 (s, 1H) , 8.00 (d, J = 8.5 Hz, 1H) , 7.83 (d, J = 8.3 Hz, 1H) , 7.60 –7.53 (m, 1H) , 7.53 –7.44 (m, 1H) , 7.44 –7.38 (m, 1H) , 7.29 –7.26 (m, 1H) , 6.75 (dd, J = 16.7, 10.5 Hz, 1H) , 6.45 (d, J = 17.1 Hz, 1H) , 5.88 (d, J = 10.6 Hz, 1H) , 4.90 (br s, 1H) , 4.54 –4.26 (m, 3H) , 4.26 –4.05 (m, 2H) , 3.63 (s, 3H) , 2.92 –2.71 (m, 2H) , 2.00 (d, J = 3.5 Hz, 3H) .

Example 4B: MS Calcd: 520.2, MS (ESI) : 521.2 [M+H] ⁺. ¹H NMR (400 MHz, CDCl ₃) δ 9.47 (s, 1H) , 9.01 (s, 1H) , 8.00 (d, J = 8.2 Hz, 1H) , 7.83 (d, J = 8.0 Hz, 1H) , 7.59 –7.53 (m, 1H) , 7.53 –7.44 (m, 1H) , 7.42 (t, J = 7.5 Hz, 1H) , 7.27 –7.25 (m, 1H) , 7.05 –6.92 (m, 1H) , 6.42 (d, J = 16.8 Hz, 1H) , 5.89 (d, J = 10.6 Hz, 1H) , 5.11 –4.88 (m, 2H) , 3.87 –3.83 (m, 3H) , 3.61 (s, 3H) , 3.49 –3.46 (m, 1H) , 3.26 –3.24 (m, 1H) , 2.94 –2.90 (m, 1H) , 1.99 (d, J = 6.4 Hz, 3H) .

Example 5

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

Step1: 2- (3-chloro-4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

To a solution of 2- (3-chloro-4-fluoro-10- (4-methoxybenzyl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin- 11-yl) acetonitrile (500 mg, 1.04 mmol) in TFA (10 mL) was added thioanisole (1 drop) . The mixture was stirred at 50℃ for 2 h under N ₂ atmosphere. The reaction mixture was concentrated. The residue was quenched with water and pH was adjusted to about 7 with solid NaHCO ₃. The mixture was extracted with EtOAc (30 mL x3) . The combined organic layers were washed with brine (30 mL x 3) , dried over anhydrous Na ₂SO ₄. After filtration, the filtrate was concentrated to give the desired product (380 mg, crude) , which was used to next step without further purification.

MS (ESI) : 361.1 [M+H] ⁺.

Step 2: 2- (10-acryloyl-3-chloro-4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

To a solution of 2- (3-chloro-4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile (380 mg, 1.05 mmol) in DCM (10 mL) was added acryloyl chloride (190 mg, 2.1 mmol) and TEA (318 mg, 3.15 mmol) dropwise at 0℃. The mixture was stirred for 1 hours at rt. The reaction was quenched with H ₂O (15 mL) and extracted with DCM (15 mL x3) . The combined organic layers were washed with brine (15 mL x2) , dried over anhydrous Na ₂SO ₄. After filtration, the filtrate was concentrated and the crude was purified by pre-TLC (PE: EA=3: 1) to give the desired product (310 mg, yield: 71%) .

MS (ESI) : 415.1 [M+H] ⁺.

¹H NMR (400 MHz, CDCl ₃) δ 9.18 (s, 1H) , 8.97 (s, 1H) , 7.04 –6.70 (m, 1H) , 6.47 –6.38 (m, 1H) , 5.88 (dd, J = 10.6, 1.6 Hz, 1H) , 5.07 –4.84 (m, 2H) , 4.27 –4.07 (m, 1H) , 3.93 –3.87 (m, 1H) , 3.76 –3.66 (m, 1H) , 3.61 (s, 3H) , 3.52 –3.39 (m, 1H) , 3.33 –3.23 (m, 1H) , 2.94 –2.83 (m, 1H) .

Step 3: t 2- (10-acryloyl-4-fluoro-7-methyl-8-oxo-3- (8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

To a solution of 2- (10-acryloyl-3-chloro-4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile (150 mg, 0.36 mmol) , triisopropyl ( (8- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) silane (314 mg, 0.72 mmol) in dioxane (10 mL) and water (2 mmol) were added Pd (dtbpf) Cl ₂ (24 mg, 0.036 mmol) , K ₃PO ₄ (229 mg, 1.08 mmol) . The reaction mixture was stirred for 16 hours at 100℃ under nitrogen atmosphere. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x3) . The combined organic layers were washed with brine (30 mL x 3) , dried over anhydrous Na ₂SO ₄. After filtration, the filtrate was concentrated and the crude was purified by pre-TLC (PE: EA=3: 1) to give the desired product (48 mg, yield: 20%) .

MS (ESI) : 687.4 [M+H] ⁺.

Step 4: 2- (10-acryloyl-3- (8-ethynylnaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

To a solution of 2- (10-acryloyl-4-fluoro-7-methyl-8-oxo-3- (8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile (40 mg, 0.058 mmol) in DMF (5 mL) was added CsF (26 mg, 0.174 mmol) . The reaction mixture was stirred for 16 hours at rt. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x3) . The combined organic layers were washed with brine (30 mL x 3) , dried over anhydrous Na ₂SO ₄. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by pre-HPLC (0.05%NH ₄OH in water/MeCN) to afford title product (5 mg, yield: 16%) .

MS (ESI) : 531.2 [M+H] ⁺.

¹H NMR (400 MHz, CD ₃OD) δ 9.39 (d, J = 9.6 Hz, 1H) , 9.08 (d, J = 6.4 Hz, 1H) , 8.15 –8.04 (m, 2H) , 7.77 –7.60 (m, 3H) , 7.55 –7.48 (m, 1H) , 7.19 –7.08 (m, 1H) , 6.29 (d, J = 17.0 Hz, 1H) , 5.87 (d, J = 12.1 Hz, 1H) , 5.05 (s, 1H) , 4.95 (d, J =14.6 Hz, 1H) , 4.08 (br s, 1H) , 4.01 –3.92 (m, 1H) , 3.79 –3.69 (m, 1H) , 3.60 (s, 3H) , 3.54 –3.33 (m, 3H) .

Example 6

2- (10-acryloyl-3- (8-ethynyl-3-hydroxynaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

Step 1: tert-butyldimethyl ( (4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5- ( (triisopropylsilyl) ethynyl) naphthalen-2-yl) oxy) silane

A solution of 3- ( (tert-butyldimethylsilyl) oxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl trifluoromethanesulfonate (1.5 g, 2.559 mmol) , Bis (pinacolato) diboron (1.95g, 7.677 mmol) , AcOK (750 mg, 7.677 mmol) and Pd (dppf) Cl ₂ (372 mg, 0.510 mmol) in toluene (50 mL) was stirred overnight at 110℃ under N ₂ atmosphere. The reaction mixture was cooled to rt, diluted with water (200 mL) . The mixture was extracted with EtOAc (100 mL x3) . The combined organic layers were washed with brine (50 mL x 2) , dried over anhydrous Na ₂SO ₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, elute with PE /EA (50: 1) to afford the desired product (412 mg, yield: 28%) .

¹H NMR (400 MHz, DMSO-d6) δ 7.66 (d, J = 8.1 Hz, 1H) , 7.43 (d, J = 6.8 Hz, 1H) , 7.25 (m, 1H) , 7.20 –7.14 (m, 1H) , 6.99 (d, J = 2.5 Hz, 1H) , 1.12 (s, 12H) , 0.94 –0.86 (m, 21H) , 0.77 (s, 9H) , 0.03 (s, 6H) .

Step 2: 2- (10-acryloyl-4-fluoro-3- (3-hydroxy-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11- yl) acetonitrile

A solution of 2- (10-acryloyl-3-chloro-4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile (80 mg, 0.192 mmol) , tert-butyldimethyl ( (4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5- ( (triisopropylsilyl) ethynyl) naphthalen-2-yl) oxy) silane (216 mg, 0.384 mmol) , K ₃PO ₄ (120 mg, 0.576 mmol) and Pd (dtbpf) Cl ₂ (12 mg, 0.019 mmol) in 1, 4-dioxane (5 mL) and H ₂O (1 mL) was stirred overnight at 90℃ under N ₂ atmosphere. The reaction mixture was cooled to rt, diluted with water (40 mL) . The mixture was extracted with EtOAc (20 mL x3) . The combined organic layers were washed with brine (30 mL x 2) , dried over anhydrous Na ₂SO ₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, elute with PE /EA (1: 5) to afford the desired product (30 mg, yield: 22%) .

MS (ESI) : 703.3 [M+H] ⁺.

Step 4: 2- (10-acryloyl-3- (8-ethynyl-3-hydroxynaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

To a solution of 2- (10-acryloyl-4-fluoro-3- (3-hydroxy-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile (27 mg, 0.038 mmol) in DMF (1.5 mL) was added CsF (29mg, 0.192 mmol) . The reaction mixture was stirred for 3 hours at rt. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x3) . The combined organic layers were washed with brine (30 mL x 3) , dried over anhydrous Na ₂SO ₄. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by pre-HPLC (0.05%NH4OH in water/MeCN) to afford title product (5.38 mg, yield: 25%) .

MS (ESI) : 547.3 [M+H] ⁺.

¹H NMR (400 MHz, MeOD) δ 9.33 (d, J = 7.6 Hz, 1H) , 9.06 (d, J = 5.3 Hz, 1H) , 7.73 –7.57 (m, 1H) , 7.32 –7.27 (m, 1H) , 7.27 –7.22 (m, 1H) , 7.17 –7.14 (m, 2H) , 7.13 –7.10 (m, 1H) , 6.28 (d, J = 16.9 Hz, 1H) , 5.86 (d, J = 11.0 Hz, 1H) , 5.06 (s, 1H) , 4.94 (m, 2H) , 4.13 –4.03 (m, 1H) , 4.02 –3.90 (m, 1H) , 3.76 –3.66 (m, 1H) , 3.59 (s, 3H) , 3.50 –3.40 (m, 2H) , 3.36 –3.33 (m, 1H) .

Example 7

Step 1. 1-bromo-8-chloro-3- (methoxy methoxy) naphthalene

To a solution of 4-bromo-5-chloronaphthalen-2-ol (400 mg, 1.56 mmol) in DCM (10 mL) was added DIEA (410 mg, 3.15 mmol) and MOMBr (390 mg, 3.15 mmol) at 0℃ under N ₂ atmosphere. The mixture was stirred at 0℃ for 2h. After diluting with water, the mixture was extracted with DCM. The combined organics was washed with brine, dried over Na ₂SO ₄. After concentration, the crude was purified by pre-TLC to afford desired product (400 mg, yield: 85%) . ¹H NMR (400 MHz, DMSO-d6) δ 7.92 (dd, J = 8.3, 1.0 Hz, 1H) , 7.75 (d, J = 2.6 Hz, 1H) , 7.64 –7.58 (m, 2H) , 7.50 –7.44 (m, 1H) , 5.35 (s, 2H) , 3.43 (s, 3H) .

Step 2. 2- (8-chloro-3- (methoxymethoxy) naphthalen-1-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane

To a solution of 1-bromo-8-chloro-3- (methoxy methoxy) naphthalene (400 mg, 1.3 mmol) , 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (660 mg, 2.6 mmol) and KOAc (254mg, 2.6 mmol) in DMF (6 mL) was added Pd (dppf) Cl ₂ (95 mg, 0.13 mmol) under nitrogen atmosphere at room temperature, then the reaction mixture was stirred at 90℃ for 24 hours under nitrogen atmosphere. Water (30 ml) was added and the mixture was extracted with EtOAc (20 ml x3) . The combined extracts were washed with water and brine, dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by pre-TLC (PE: EtOAc=30: 1) to afford title product (330 mg, yield: 70%) . ¹H NMR (400 MHz, DMSO-d6) δ 7.85 (dd, J = 8.2, 1.0 Hz, 1H) , 7.57 –7.51 (m, 2H) , 7.49 –7.42 (m, 1H) , 7.27 (d, J = 2.5 Hz, 1H) , 5.35 (s, 2H) , 3.43 (s, 3H) , 1.37 (s, 12H) .

Step 3: 2- (3- (8-chloro-3- (methoxymethoxy) naphthalen-1-yl) -4-fluoro-10- (4-methoxybenzyl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

To a solution of 2- (10- (4-methoxybenzyl) -7-methyl-6- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -8-oxo -2, 3, 4, 7, 8, 8a, 9, 10, 11, 12-decahydro-1H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 7] naphthyridin-11-yl) acetonitrile (240 mg, 0.5 mmol) , 2- (8-chloro-3- (methoxymethoxy) naphthalen-1-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (330 mg, 0.94 mmol) and K ₂CO ₃ (207 mg, 1.5 mmol) in dioxane (4 mL) and H ₂O (1 ml) was added Pd-Ruphos-G4 (50 mg, 0.05 mmol) under nitrogen atmosphere at room temperature, then the mixture was heated to 100℃ and stirred for 16 hours under nitrogen atmosphere. After cooling to rt, the mixture was diluted with water and extracted with EtOAc (40 ml x3) . The combined extracts were washed with water and brine, dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by pre-TLC (PE: EtOAc=1: 1) to afford title product (200 mg, yield: 60%) .

MS (ESI) : 667.1 [M+H] ⁺.

Step 4: 2- (3- (8-chloro-3-hydroxynaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

To a solution of 2- (3- (8-chloronaphthalen-1-yl) -4-fluoro-10- (4-methoxybenzyl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile (200 mg, 0.3 mmol) in TFA (4 mL) was added thioanisole (0.1 ml) . The mixture was stirred at 50℃ for 3 h under N ₂ atmosphere. The reaction mixture was concentrated to give residue. The residue was quenched with water and pH was adjusted to about 7 with solid NaHCO ₃. The mixture was extracted with EA (30 mL x3) . The combined organic layers were washed with brine (40 mL x2) , dried over anhydrous Na ₂SO ₄. After filtration, the filtrate was concentrated and the crude was purified by pre-TLC (DCM: MeOH=10: 1) to give the desired product (105 mg, yield: 70%) .

MS (ESI) : 503.2 [M+H] ⁺.

¹H NMR (400 MHz, CDCl ₃) δ 9.40 (d, J = 6.3 Hz, 1H) , 9.04 (s, 1H) , 7.75 –7.66 (m, 1H) , 7.39 –7.34 (m, 2H) , 7.34 –7.31 (m, 1H) , 7.21 (d, J = 2.7 Hz, 1H) , 4.11 (d, J = 13.6 Hz, 1H) , 3.67 –3.55 (m, 4H) , 3.52 –3.44 (m, 2H) , 3.35 (d, J = 13.2 Hz, 1H) , 2.72 –2.57 (m, 1H) , 2.57 –2.44 (m, 2H) .

Step 5: 4- (10-acryloyl-11- (cyanomethyl) -4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-3-yl) -5-chloronaphthalen-2-yl acrylate

To a solution of 2- (3- (8-chloro-3-hydroxynaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile (100 mg, 0.2 mmol) in DCM (5 mL) was added acryloyl chloride (54 mg, 0.60 mmol) and TEA (60 mg, 0.60 mmol) dropwise at 0℃. The mixture was stirred for 1 hours at 0℃. The mixture was concentrated under reduced pressure to afford crude title product, which was used for next step directly.

MS (ESI) : 611.1 [M+H] ⁺.

Step 6: 2- (10-acryloyl-3- (8-chloro-3-hydroxynaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

To a solution of 4- (10-acryloyl-11- (cyanomethyl) -4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-3-yl) -5-chloronaphthalen-2-yl acrylate (150 mg crude, 0.20 mmol) in THF (4 mL) and H ₂O (1 mL) was added LiOH·H ₂O (21 mg, 0.5 mmol) . The mixture was stirred at rt for 3 h. The mixture was concentrated under reduced pressure (below 20℃) and the residue was purified by pre-HPLC (0.05%formic acid in water/MeCN) to afford title product (Example 7A: 1.5 mg/Example 7B: : 4.6 mg, Yield: 5.4%for two steps) .

Example 7A: MS Calcd: 556.1, MS (ESI) : 557.1 [M+H] ⁺. ¹H NMR (400 MHz, CDCl ₃) δ 9.25 –9.12 (m, 1H) , 8.90 (s, 1H) , 7.66 –7.64 (m, 1H) , 7.35 –7.29 (m, 2H) , 7.25 –7.13 (m, 2H) , 6.79 –6.65 (m, 1H) , 6.42 (d, J = 16.2 Hz, 1H) , 5.93 –5.80 (m, 1H) , 5.00 –4.74 (m, 1H) , 4.44 –4.20 (m, 2H) , 4.24 –4.00 (m, 2H) , 3.84 –3.80 (m, 1H) , 3.60 (s, 3H) , 2.97 –2.60 (m, 2H) .

Example 7B: ¹H NMR (400 MHz, CDCl ₃) δ 9.46 –9.22 (m, 1H) , 9.06 –8.84 (m, 1H) , 7.61 –7.58 (m, 1H) , 7.28 –7.26 (m, 1H) , 7.24 –7.03 (m, 3H) , 6.99 –6.87 (m, 1H) , 6.39 (d, J = 9.1.0 Hz, 1H) , 5.92 –5.80 (m, 1H) , 5.00 –4.71 (m, 2H) , 3.93 –3.65 (m, 2H) , 3.62 –3.31 (m, 4H) , 3.24 –3.22 (m, 2H) , 2.85 –2.81 (m, 1H) .

Example 8

2- (10-acryloyl-3- (8-chloro-7-fluoronaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

Step 1. 5-chloro-6-fluoro-1, 4-dihydro-1, 4-epoxynaphthalene

To a mixture of l-bromo-3-chloro-2, 4-difluorobenzene (25 g, 110 mmol) and furan (15 g, 220 mmol) in toluene (250 ml) at -15℃ was added n-BuLi (2.50 M, 52.8 mL, 132 mmol) dropwise over 0.5 hour. The mixture was allowed to warm to room temperature and stirring continued for 12 h. Subsequently, the mixture was quenched with water (200 ml) and was filtered. The organic layer was collected and the aqueous layer was extracted with ethyl acetate (200 ml*2) . The combined organic layer was dried over and Na ₂SO ₄ and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (PE: EA=10: 1) to afford 5-chloro-6-fluoro-1, 4-dihydro-1, 4-epoxynaphthalene (8.1 g, 37%yield) .

¹H NMR (400 MHz, CDCl ₃) δ 7.09 (d, J = 5.2 Hz, 2H) , 7.06 –7.01 (m, 1H) , 6.73 (dd, J = 9.5, 7.7 Hz, 1H) , 5.88 (s, 1H) , 5.74 (s, 1H) .

Step 2. 8-chloro-7-fluoronaphthalen-1-ol

A mixture of 5-chloro-6-fluoro-1, 4-dihydro-1, 4-epoxynaphthalene (15 g, 76.3 mmol, ) in concentrated hydrochloric acid (34 g, 931 mmol) and ethyl alcohol (110 ml) was heated at 80℃ with stirring for 6 h. Subsequently, the reaction mixture was concentrated under vacuum. The residue was adjusted to pH ～ 7 with saturated aq NaHCO ₃ and then extracted with ethyl acetate (250 mL*2) . The combined organic layer was dried over and Na ₂SO ₄ and filtered. The filtrate was concentrated under vacuum. The residue was triturated with petroleum ether (500 mL) , and then filtered, the filter cake was dried under vacuum to afford the desired product (13 g, 86 %yield) . ¹H NMR (400 MHz, CDCl ₃) δ 7.89 (s, 1H) , 7.73 (dd, J = 9.1, 5.5 Hz, 1H) , 7.42 –7.33 (m, 2H) , 7.27 (t, J = 7.8 Hz, 1H) , 7.09 –7.04 (m, 1H) .

Step 3: 8-chloro-7-fluoronaphthalen-1-yl trifluoromethanesulfonate

A mixture of 8-chloro-7-fluoronaphthalen-l-ol (13 g, 66.1 mmol) , DIEA (51.3 g, 396.6 mmol) , 4 A MS (120 g) in dichloromethane (150 ml) was stirred for 10 minutes at 20 ℃. To this suspension cooled to -40 ℃ was added trifluoromethanesulfonic anhydride (24.2 g, 85.9 mmol) dropwise. After 20 minutes the reaction mixture was diluted with water (150 mL) and the organic layer was collected. The aqueous layer was then extracted with ethyl acetate (150 mL x 2) . The combined organic layer was dried over and Na ₂SO ₄ and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (PE: EA = 10: 1) to afford the desired product (18.5 g, 85 %yield) . ¹H NMR (400 MHz, CDCl ₃) δ 7.88 (dd, J = 8.1, 0.9 Hz, 1H) , 7.83 (dd, J = 9.0, 5.3 Hz, 1H) , 7.58 (d, J = 7.7 Hz, 1H) , 7.50 (t, J = 8.0 Hz, 1H) , 7.42 (t, J = 8.7 Hz, 1H) .

Step 4: 2- (8-chloro-7-fluoronaphthalen-1-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane

A mixture of 8-chloro-7-fluoronaphthalen-l-yl trifluoromethanesulfonate (13.3 g, 40.5 mmol) , (PinB) ₂ (20.6 g, 81 mmol) , KOAc (19.9 g, 202.5 mmol) and Pd(dppf) Cl ₂ (2.96 g, 4.05 mmol) in DMF (150 mL) was purged with nitrogen and then the mixture was stirred at 80℃ for 12 h. The mixture was cooled to room temperature and was diluted with ethyl acetate (150 mL) and water (150 mL) . The organic layer was separated and the aqueous layer was extracted with ethyl acetate (150 mL*2) . The combined organic layer was washed with brine (150 mL) , dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under vacuum. The residue was purified by column chromatography (PE: EA = 10: 1) to afford the desired product (9.6 g, 74%yield) . ¹H NMR (400 MHz, CDCl ₃) δ 7.85 (d, J = 8.2 Hz, 1H) , 7.75 (dd, J = 9.0, 5.5 Hz, 1H) , 7.70 (d, J = 6.8 Hz, 1H) , 7.50 –7.43 (m, 1H) , 7.32 (t, J = 8.7 Hz, 1H) , 1.45 (s, 6H) , 1.26 (s, 6H) .

Step 5: 2- (3- (8-chloro-7-fluoronaphthalen-1-yl) -4-fluoro-10- (4-methoxybenzyl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

To a solution of 2- (10- (4-methoxybenzyl) -7-methyl-6- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -8-oxo -2, 3, 4, 7, 8, 8a, 9, 10, 11, 12-decahydro-1H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 7] naphthyridin-11-yl) acetonitrile (480 mg, 1.0 mmol) , 2- (8-chloro-7-fluoronaphthalen-1-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (610 mg, 2 mmol) and K ₂CO ₃ (414 mg, 3.0 mmol) in dioxane (8 mL) and H ₂O (2 ml ) was added RuPhos-Pd-G4 (85 mg, 0.1 mmol) under nitrogen atmosphere at room temperature, then the reaction was heated to 100 ℃ and stirred for 16 hours under nitrogen atmosphere. After cooling, water (40 ml) was added and the mixture was extracted with EtOAc (50 ml x3) . The combined extracts were washed with water and brine, dried over Na ₂SO ₄, filtered, the filtrate was concentrated under reduced pressure. The residue was purified by pre-TLC (PE: EtOAc=1: 1) to afford title product (240 mg, yield: 38.4%) . MS (ESI) : 625.2 [M+H] ⁺.

Step 6: 2- (3- (8-chloro-7-fluoronaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

To a solution of 2- (3- (8-chloro-7-fluoronaphthalen-1-yl) -4-fluoro-10- (4-methoxybenzyl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile (240 mg, 0.38 mmol) in TFA 6 mL) was added methyl (phenyl) sulfane (0.2 ml) . The mixture was stirred at 50℃ for 3 h under N ₂ atmosphere. The reaction mixture was concentrate. The residue was diluted with water and pH was adjusted to about 7 with solid NaHCO ₃. The mixture was extracted with EA (30 mL x3) . The combined organic layers were washed with brine (20 mL x2) , dried over anhydrous Na ₂SO ₄. After filtration, the filtrate was concentrated and purified by pre-TLC (DCM: MeOH=10: 1) to give the desired product (155 mg, yield: 80 %) . MS (ESI) : 505.1 [M+H] ⁺. ¹H NMR (400 MHz, CDCl ₃) δ 9.36 (d, J = 10.2 Hz, 1H) , 8.98 (d, J = 7.4 Hz, 1H) , 8.02 (d, J =7.8 Hz, 1H) , 7.91 (dd, J = 9.0, 5.5 Hz, 1H) , 7.71 –7.56 (m, 2H) , 7.44 –7.36 (m, 1H) , 3.87 –3.72 (m, 2H) , 3.64 (s, 3H) , 3.59 –3.50 (m, 2H) , 3.50 –3.34 (m, 2H) , 3.29 –3.11 (m, 1H) , 3.05 –2.87 (m, 1H) .

Step 7: 2- (10-acryloyl-3- (8-chloro-7-fluoronaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

To a solution of 2- (3- (8-chloro-7-fluoronaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile (70 mg, 0.139 mmol) in DCM (3 mL) at 0℃ was added TEA (30 mg, 0.3 mmol) , and the mixture was stirred for 5 minutes at 0℃ before acryloyl chloride (25 mg, 0.28 mmol) was added. The resulted mixture was stirred for 30 minutes at 0℃. Then the reaction was concentrated under reduced pressure (below 20℃) and the residue was purified by pre-HPLC (0.05%formic acid in water/MeCN) to afford two isomers (Example 8A: 5.5 mg/Example 8B: 22.9 mg) . MS Calcd: 558.1, MS (ESI) : 559.1 [M+H] ⁺.

Example 8A: ¹H NMR (400 MHz, CDCl ₃) δ 9.49 –9.24 (m, 1H) , 8.93 (s, 1H) , 8.03 (d, J = 8.0 Hz, 1H) , 7.91 (dd, J = 9.2, 5.5 Hz, 1H) , 7.78 –7.56 (m, 2H) , 7.42 (t, J = 8.8 Hz, 1H) , 6.85 –6.69 (m, 1H) , 6.44 (d, J = 16.8 Hz, 1H) , 5.88 (d, J = 10.5 Hz, 1H) , 4.88 –4.80 (m, 1H) , 4.61 –3.90 (m, 5H) , 3.62 (s, 3H) , 3.07 –2.68 (m, 2H) .

Example 8B: ¹H NMR (400 MHz, CDCl ₃) δ 9.49 (s, 1H) , 8.99 (d, J = 13.5 Hz, 1H) , 8.02 (d, J = 7.6 Hz, 1H) , 7.91 (dd, J = 9.0, 5.5 Hz, 1H) , 7.74 –7.57 (m, 2H) , 7.45 –7.36 (m, 1H) , 7.06 –6.92 (m, 1H) , 6.42 (d, J = 16.9 Hz, 1H) , 5.99 –5.74 (m, 1H) , 5.13 –4.90 (m, 2H) , 4.08 –3.89 (m, 2H) , 3.87 –3.71 (m, 1H) , 3.61 –3.56 (m, 4H) , 3.37 –3.21 (m, 1H) , 2.95 (d, J = 13.3 Hz, 1H) .

Example 22

2- (10-acryloyl-3- (3-chloro-2- (trifluoromethyl) phenyl) -4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

Step 1. 2- (3- (3-chloro-2- (trifluoromethyl) phenyl) -4-fluoro-10- (4-methoxybenzyl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

To a solution of 2- (3-chloro-4-fluoro-10- (4-methoxybenzyl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile (240 mg, 0.5 mmol) and 2- (3-chloro-2- (trifluoromethyl) phenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (306 mg, 1.0 mmol) in dioxane/H ₂O (5 mL/1mL) was added K ₂CO ₃ (207 mg, 1.5 mmol) and Pd (PPh ₃) ₄ (116 mg, 0.1 mmol) . The mixture was stirred at 100℃ under N ₂ atmosphere for 16 h. Then the reaction mixture was concentrated, and diluted with water, extracted with EA. The combined organic was washed with brine, dried Na ₂SO ₄, concentrated and purified by pre-TLC to afford desired product (269 mg, crude) .

MS (ESI) : 625.1 [M+H] ⁺.

Step 2. 2- (3- (3-chloro-2- (trifluoromethyl) phenyl) -4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

To a solution of 2- (3- (3-chloro-2- (trifluoromethyl) phenyl) -4-fluoro-10- (4-methoxybenzyl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile2- (3- (3-chloro-2- (trifluoromethyl) phenyl) -4-fluoro-10- (4-methoxybenzyl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile (269 mg, crude) in TFA (5 mL) was added PhSMe (0.1 mL) . The reaction mixture was stirred at 50℃ for 3h. Then the reaction mixture was concentrated and the residue was adjusted to PH>7 with sat. NaHCO ₃ aqueous. The resulting solution was extracted with EA. The combined organic layers were washed with sat. NaCl, dried over Na ₂SO ₄ and concentrated. The crude was purified by pre-TLC to afford the desired product (116 mg, yield: 46%, 2 steps) .

MS (ESI) : 505.1 [M+H] ⁺.

Step 3. 2- (10-acryloyl-3- (3-chloro-2- (trifluoromethyl) phenyl) -4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

To a solution of 2- (3- (3-chloro-2- (trifluoromethyl) phenyl) -4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3- c] [1, 6] naphthyridin-11-yl) acetonitrile (90 mg, 0.178 mmol) in DCM (5 mL) at 0℃was added TEA (40 mg, 0.4 mmol) and acryloyl chloride (20 mg, 0.22 mmol) . Then the reaction mixture was stirred at 0℃ under N ₂ atmosphere for 0.5 hours. The reaction was concentrated under reduced pressure and the residue was purified by pre-HPLC (0.05%formic acid in water/MeCN) to afford two isomers (Example 22A: 10 mg/Example 22B: 20 mg) .

MS (ESI) : 559.2 [M+H] ⁺.

Example 22A: ¹H NMR (400 MHz, CDCl ₃) δ 9.20 (s, 1H) , 8.92 (s, 1H) , 7.68 (d, J = 8.1 Hz, 1H) , 7.59 (t, J = 7.9 Hz, 1H) , 7.41 (d, J = 7.5 Hz, 1H) , 6.75 (dd, J = 16.7, 10.6 Hz, 1H) , 6.45 (d, J = 16.7 Hz, 1H) , 5.88 (d, J = 11.5 Hz, 1H) , 4.90 (br s, 1H) , 4.55 –4.23 (m, 3H) , 4.24 –4.02 (m, 2H) , 3.62 (s, 3H) , 3.10 –2.63 (m, 2H) .

Example 22B: ¹H NMR (400 MHz, CDCl ₃) δ 9.41 (s, 1H) , 9.00 (s, 1H) , 7.69 (d, J = 8.0 Hz, 1H) , 7.59 (t, J = 7.4 Hz, 1H) , 7.41 (s, 1H) , 6.98 (dd, J = 16.3, 10.7 Hz, 1H) , 6.42 (d, J = 16.7 Hz, 1H) , 5.89 (d, J = 10.8 Hz, 1H) , 5.16 –4.84 (m, 2H) , 4.04 –3.69 (m, 3H) , 3.61 (s, 3H) , 3.59 –3.40 (m, 1H) , 3.37 –3.20 (m, 1H) , 3.01 –2.82 (m, 1H) .

The following compounds were prepared according to the above described methods using different starting materials.

Compound 10A

¹H NMR (400 MHz, MeOD) δ 9.39 (s, 1H) , 8.94 (s, 1H) , 8.03 (dd, J = 21.4, 7.9 Hz, 2H) , 7.70 –7.63 (m, 3H) , 7.55 (t, J = 7.4 Hz, 1H) , 7.47 (t, J = 7.6 Hz, 1H) , 6.97 (dd, J = 16.8, 10.7 Hz, 1H) , 6.34 (d, J = 16.5 Hz, 1H) , 5.88 (d, J = 10.8 Hz, 1H) , 4.60 –4.44 (m, 2H) , 4.39-4.36 (m, 2H) , 4.27 –4.18 (m, 1H) , 3.76 –3.62 (m, 1H) , 3.60 (s, 3H) , 2.92 (d, J = 5.9 Hz, 2H) .

Compound 10B

¹H NMR (400 MHz, DMSO-d ₆) δ 9.49 (s, 1H) , 9.22 (s, 1H) , 8.09 (dd, J = 16.6, 7.9 Hz, 2H) , 7.74 –7.66 (m, 3H) , 7.59 (t, J = 7.5 Hz, 1H) , 7.54 –7.48 (m, 1H) , 7.07 (dd, J = 16.8, 10.6 Hz, 1H) , 6.20 (dd, J = 16.8, 2.2 Hz, 1H) , 5.87 –5.72 (m, 1H) , 4.96 –4.77 (m, 2H) , 4.13 –4.05 (m, 1H) , 3.90 –3.60 (m, 2H) , 3.53 (s, 3H) , 3.48 – 3.41 (m, 1H) , 3.40 –3.34 (m, 2H) .

Compound 11

¹H NMR (400 MHz, DMSO) δ 10.02 (s, 1H) , 8.70 (s, 1H) , 8.47 (d, J = 8.1 Hz, 1H) , 8.16 (dd, J = 9.0, 5.0 Hz, 1H) , 8.04 (d, J = 8.1 Hz, 1H) , 7.74 (t, J = 7.8 Hz, 1H) , 7.57 (dd, J = 12.2, 9.1 Hz, 1H) , 7.02 (d, J = 17.3 Hz, 1H) , 6.21 –6.15 (m, 1H) , 5.81 (d, J = 12.2 Hz, 1H) , 4.71 (d, J = 15.6 Hz, 2H) , 3.96 (s, 1H) , 3.55 (s, 3H) , 2.75 (d, J = 13.6 Hz, 2H) , 2.69 –2.66 (m, 1H) , 2.42 (dd, J = 12.0, 2.6 Hz, 2H) , 2.33 (s, 1H) .

Compound 146

¹H NMR (400 MHz, MeOD) δ 9.48 (s, 1H) , 9.09 (s, 1H) , 7.72 (dd, J = 7.9, 1.0 Hz, 1H) , 7.42 (d, J = 6.6 Hz, 1H) , 7.30 (t, J = 7.7 Hz, 1H) , 7.22 –6.63 (m, 1H) , 6.26 (d, J = 17.5 Hz, 1H) , 5.82 (d, J = 10.6 Hz, 1H) , 4.61 –4.35 (m, 5H) , 4.03 (s, 1H) , 3.84 (d, J = 17.0 Hz, 1H) , 3.66 (s, 1H) , 3.59 (s, 3H) , 3.41 (s, 1H) .

Compound 148A

¹H NMR (400 MHz, CD ₃OD) δ 9.37 (s, 1H) , 8.88 (s, 1H) , 8.06 (d, J = 7.9 Hz, 1H) , 7.88 (d, J = 8.3 Hz, 1H) , 7.62 –7.58 (m, 1H) , 7.54 –7.42 (m, 2H) , 7.31 (d, J = 5.8 Hz, 1H) , 7.02 –6.91 (m, 1H) , 6.34 (d, J = 17.4 Hz, 1H) , 5.88 (d, J = 12.0 Hz, 1H) , 4.62 –4.53 (m, 1H) , 4.52 –4.44 (m, 2H) , 4.44 –4.31 (m, 2H) , 3.59 (d, J = 2.5 Hz, 3H) , 3.51 –3.42 (m, 1H) , 3.02 –2.89 (m, 2H) .

Compound 149A

¹H NMR (400 MHz, MeOD) δ 9.34 (d, J = 3.8 Hz, 1H) , 8.95 (s, 1H) , 8.06 (dd, J = 7.4, 2.1 Hz, 1H) , 7.93 (dd, J = 9.0, 5.8 Hz, 1H) , 7.62 –7.52 (m, 2H) , 7.36 (t, J = 9.2 Hz, 1H) , 6.96 (ddd, J = 16.8, 10.7, 2.0 Hz, 1H) , 6.34 (d, J = 15.9 Hz, 1H) , 5.87 (d, J = 12.3 Hz, 1H) , 4.82 –4.06 (m, 6H) , 3.61 (t, J = 4.1 Hz, 3H) , 3.04 –2.76 (m, 2H) , 1.83 (dd, J = 5.1, 2.5 Hz, 3H) .

Compound 149B

¹H NMR (400 MHz, MeOD) δ 9.46 (d, J = 3.8 Hz, 1H) , 9.14 (d, J = 28.5 Hz, 1H) , 8.07 (dd, J = 6.0, 4.0 Hz, 1H) , 7.93 (dd, J = 9.0, 5.9 Hz, 1H) , 7.62 –7.50 (m, 2H) , 7.36 (t, J = 9.3 Hz, 1H) , 7.12 (dd, J = 16.3, 10.7 Hz, 1H) , 6.28 (dd, J = 16.9, 1.7 Hz, 1H) , 5.86 (d, J = 12.3 Hz, 1H) , 5.03 –4.91 (m, 2H) , 4.81 (s, 1H) , 4.07 (s, 1H) , 4.02 –3.91 (m, 1H) , 3.83 –3.70 (m, 1H) , 3.62 –3.44 (m, 4H) , 3.38 –3.33 (m, 2H) , 3.28 –3.24 (m, 1H) , 1.82 (d, J = 1.9 Hz, 3H) .

Compound 151A

¹H NMR (400 MHz, MeOD) δ 9.34 (d, J = 5.4 Hz, 1H) , 8.16 –8.08 (m, 1H) , 7.95 –7.87 (m, 1H) , 7.77 –7.65 (m, 2H) , 7.58 –7.48 (m, 1H) , 6.97 (dd, J = 16.8, 10.7 Hz, 1H) , 6.34 (d, J = 17.1 Hz, 1H) , 5.88 (d, J = 10.9 Hz, 1H) , 4.63 –4.15 (m, 6H) , 3.60 (s, 3H) , 3.03 –2.83 (m, 2H) .

Compound 151B

¹H NMR (400 MHz, MeOD) δ 9.46 (s, 1H) , 9.10 (d, J = 4.9 Hz, 1H) , 8.20 –8.05 (m, 1H) , 7.99 –7.84 (m, 1H) , 7.79 –7.65 (m, 2H) , 7.59 –7.46 (m, 1H) , 7.23 – 7.04 (m, 1H) , 6.29 (d, J = 16.7 Hz, 1H) , 5.87 (d, J = 11.9 Hz, 1H) , 5.12 –4.91 (m, 2H) , 4.09 (s, 1H) , 4.04 –3.93 (m, 1H) , 3.86 –3.68 (m, 1H) , 3.61 (s, 3H) , 3.57 –3.43 (m, 1H) , 3.41 –3.34 (m, 2H) .

Compound 169

¹H NMR (400 MHz, DMSO-d ₆) δ 9.73 –9.53 (m, 1H) , 9.31 –9.19 (m, 1H) , 8.29 –8.19 (m, 1H) , 8.19 –8.09 (m, 1H) , 7.83 –7.71 (m, 1H) , 7.71 –7.57 (m, 1H) , 7.56 –7.43 (m, 1H) , 7.12 –6.83 (m, 1H) , 6.16 (d, J = 17.0 Hz, 1H) , 5.77 (d, J = 10.1 Hz, 1H) , 5.00 –4.67 (m, 1H) , 4.44 (d, J = 11.5 Hz, 1H) , 4.23 –4.03 (m, 1H) , 3.63 (d, J = 12.3 Hz, 1H) , 3.53 (s, 3H) , 3.29 –2.83 (m, 2H) , 1.11 –0.92 (m, 3H) .

Compound 174A

¹H NMR (400 MHz, CDCl ₃) δ 9.21 (s, 1H) , 8.91 (s, 1H) , 7.33 (d, J = 7.3 Hz, 1H) , 7.26 (d, J = 14.9 Hz, 1H) , 7.13 (d, J = 7.4 Hz, 1H) , 6.75 (dd, J = 16.7, 10.6 Hz, 1H) , 6.45 (dd, J = 16.7, 1.4 Hz, 1H) , 5.88 (dd, J = 10.6, 1.5 Hz, 1H) , 4.92 (s, 1H) , 4.43 (s, 2H) , 4.29 (dd, J = 13.9, 5.4 Hz, 1H) , 4.22 –4.04 (m, 2H) , 3.62 (s, 3H) , 3.05 –2.88 (m, 2H) , 2.87 (d, J = 7.1 Hz, 1H) , 2.76 (dd, J = 17.1, 3.6 Hz, 1H) , 1.90 (t, J = 7.2 Hz, 2H) , 1.14 (s, 3H) , 1.01 (s, 3H) .

Compound 174B

¹H NMR (400 MHz, CDCl ₃) δ 9.41 (s, 1H) , 8.99 (s, 1H) , 7.33 (d, J = 7.4 Hz, 1H) , 7.26 (d, J = 14.9 Hz, 1H) , 7.10 (d, J = 7.4 Hz, 1H) , 7.04 –6.91 (m, 1H) , 6.42 (dd, J = 16.8, 1.4 Hz, 1H) , 5.98 –5.78 (m, 1H) , 5.18 –4.83 (m, 2H) , 3.86 (d, J = 9.4 Hz, 2H) , 3.74 (d, J = 12.3 Hz, 1H) , 3.61 (s, 3H) , 3.47 (d, J = 9.0 Hz, 1H) , 3.28 (dd, J = 16.8, 7.5 Hz, 1H) , 2.97 (dd, J = 15.4, 6.1 Hz, 3H) , 1.90 (t, J = 7.2 Hz, 2H) , 1.10 (s, 3H) , 1.03 (s, 3H) .

Compound 175

¹H NMR (400 MHz, MeOD) δ 9.43 (d, J = 6.7 Hz, 1H) , 9.09 (s, 1H) , 8.14 –8.10 (m, 1H) , 8.07 (d, J = 8.3 Hz, 1H) , 7.76 –7.61 (m, 3H) , 7.56 –7.49 (m, 1H) , 7.14 (dd, J = 16.8, 10.7 Hz, 1H) , 6.26 (d, J = 17.0 Hz, 1H) , 5.82 (d, J = 10.6 Hz, 1H) , 4.99 –4.88 (m, 1H) , 4.63 –4.39 (m, 1H) , 4.10 (d, J = 41.8 Hz, 1H) , 3.84 (d, J = 12.2 Hz, 1H) , 3.65 (s, 1H) , 3.60 (s, 3H) , 3.45 (d, J = 23.8 Hz, 1H) , 3.22 –3.01 (m, 1H) , 2.89 (d, J = 51.8 Hz, 1H) .

Compound 176A

¹H NMR (400 MHz, MeOD) δ 9.27 (d, J = 9.1 Hz, 1H) , 8.92 (d, J = 2.7 Hz, 1H) , 8.13 (t, J = 7.7 Hz, 2H) , 7.74 –7.66 (m, 2H) , 7.45 (t, J = 9.0 Hz, 1H) , 6.95 – 6.85 (m, 1H) , 6.32 (d, J = 18.4 Hz, 1H) , 5.84 (d, J = 10.6 Hz, 1H) , 4.71 –4.62 (m, 1H) , 4.58 (s, 2H) , 4.39 –4.32 (m, 2H) , 4.03 –3.90 (m, 1H) , 3.61 (s, 3H) , 3.48 (d, J =1.9 Hz, 1H) , 3.15 (d, J = 15.5 Hz, 1H) , 1.35 (d, J = 15.6 Hz, 1H) , 1.23 (s, 3H) .

Compound 176B

¹H NMR (400 MHz, MeOD) δ 9.40 (d, J = 7.1 Hz, 1H) , 9.07 (d, J = 3.3 Hz, 1H) , 8.13 (t, J = 7.7 Hz, 2H) , 7.74 –7.66 (m, 2H) , 7.45 (t, J = 8.9 Hz, 1H) , 7.12 (dd, J = 16.9, 10.5 Hz, 1H) , 6.80 (s, 1H) , 6.24 (d, J = 16.7 Hz, 1H) , 5.81 (d, J = 10.1 Hz, 1H) , 5.38 (d, J = 14.8 Hz, 1H) , 4.54 (d, J = 30.1 Hz, 1H) , 4.08 (s, 1H) , 3.98 (d, J = 13.9 Hz, 1H) , 3.60 (s, 3H) , 3.45 (dd, J = 60.4, 35.7 Hz, 3H) , 3.15 (s, 1H) , 1.61 (t, J =16.1 Hz, 3H) .

Compound 177

¹H NMR (400 MHz, MeOD) δ 9.44 (d, J = 6.6 Hz, 1H) , 9.10 (s, 1H) , 8.14 (dd, J = 12.5, 5.1 Hz, 2H) , 7.75 –7.67 (m, 2H) , 7.45 (t, J = 8.3 Hz, 1H) , 7.21 –6.63 (m, 1H) , 6.26 (d, J = 16.9 Hz, 1H) , 5.83 (d, J = 11.3 Hz, 1H) , 4.93 (d, J = 13.1 Hz, 1H) , 4.49 (s, 1H) , 4.05 (s, 1H) , 3.84 (d, J = 10.1 Hz, 1H) , 3.67 (s, 1H) , 3.60 (s, 3H) , 3.45 (d, J = 22.1 Hz, 1H) , 3.15 (s, 2H) .

Compound 180

¹H NMR (400 MHz, CDCl ₃) δ 10.08 (s, 1H) , 9.47 (s, 1H) , 9.15-9.13 (m, 1H) , 7.35 (dd, J = 15.3, 8.1 Hz, 1H) , 7.19 –6.97 (m, 1H) , 6.94 –6.70 (m, 2H) , 6.16 (d, J =16.6 Hz, 1H) , 5.76 (d, J = 8.9 Hz, 1H) , 4.74 (d, J = 14.6 Hz, 1H) , 4.31 (d, J = 11.9 Hz, 1H) , 4.10-4.05 (m, 1H) , 3.79 –3.56 (m, 2H) , 3.51 (s, 3H) , 3.01-2.97 (m, 1H) , 2.72- 2.67 (m, 1H) .

Compound 181

¹H NMR (400 MHz, MeOD) δ 9.55 (s, 1H) , 9.14 (s, 1H) , 8.13 (d, J = 7.8 Hz, 1H) , 8.04 (d, J = 8.2 Hz, 1H) , 7.69 –7.62 (m, 1H) , 7.62 –7.52 (m, 2H) , 7.52 –7.46 (m, 1H) , 7.22 –6.69 (m, 1H) , 6.28 (d, J = 16.6 Hz, 1H) , 5.95 –5.59 (m, 2H) , 5.15 –4.90 (m, 1H) , 4.60 –4.36 (m, 1H) , 4.22 –4.01 (m, 1H) , 3.91 –3.80 (m, 1H) , 3.75 –3.66 (m, 1H) , 3.62 (s, 3H) , 3.51 –3.40 (m, 1H) , 3.27 –3.11 (m, 1H) , 3.03 –2.75 (m, 2H) .

Compound 182

¹H NMR (400 MHz, MeOD) δ 9.49 –9.31 (m, 1H) , 9.07 (s, 1H) , 7.82 (d, J =8.3 Hz, 1H) , 7.49 (d, J = 7.1 Hz, 1H) , 7.43 –7.36 (m, 1H) , 7.37 –7.30 (m, 1H) , 7.28 –7.02 (m, 2H) , 6.26 (d, J = 17.0 Hz, 1H) , 5.82 (d, J = 10.6 Hz, 1H) , 4.97 –4.87 (m, 2H) , 4.49 (d, J = 12.5 Hz, 1H) , 4.02 (d, J = 11.0 Hz, 1H) , 3.82 (d, J = 10.9 Hz, 1H) , 3.63 (s, 1H) , 3.58 (s, 3H) , 3.47 –3.32 (m, 1H) , 3.13 (dd, J = 21.5, 11.3 Hz, 1H) .

Compound 183

¹H NMR (400 MHz, MeOD) δ 9.42 (d, J = 8.8 Hz, 1H) , 9.09 (s, 1H) , 7.87 (dd, J = 8.9, 5.8 Hz, 1H) , 7.44 –7.03 (m, 4H) , 6.26 (d, J = 16.9 Hz, 1H) , 5.82 (d, J =10.5 Hz, 1H) , 4.92 (d, J = 14.9 Hz, 1H) , 4.50 (d, J = 13.7 Hz, 1H) , 4.03 (d, J = 7.5 Hz, 1H) , 3.83 (d, J = 11.0 Hz, 1H) , 3.69 (d, J = 33.2 Hz, 1H) , 3.59 (s, 3H) , 3.49 –3.34 (m, 1H) , 3.22 –3.01 (m, 2H) .

Compound 185A

¹H NMR (400 MHz, MeOD) δ 9.49 –9.45 (m, 1H) , 8.99 (s, 1H) , 8.24 (d, J =8.7 Hz, 1H) , 8.09 (d, J = 8.4 Hz, 1H) , 7.91 (d, J = 8.4 Hz, 1H) , 7.66 (t, J = 7.5 Hz, 1H) , 7.52 (t, J = 7.5 Hz, 1H) , 7.47 –7.40 (m, 1H) , 7.00 (dd, J = 16.8, 10.9 Hz, 1H) , 6.69 (td, J = 54.8, 7.5 Hz, 1H) , 6.37 (d, J = 16.8 Hz, 1H) , 5.90 (d, J = 11.1 Hz, 1H) , 4.96 –4.86 (m, 1H) , 4.66 –4.47 (m, 2H) , 4.46 –4.37 (m, 2H) , 4.35 –4.24 (m, 1H) , 3.63 (s, 3H) , 2.96 (d, J = 4.9 Hz, 2H) .

Compound 185B

¹H NMR (400 MHz, MeOD) δ 9.60 –9.54 (m, 1H) , 9.13 (d, J = 4.6 Hz, 1H) , 8.24 (d, J = 8.5 Hz, 1H) , 8.09 (dd, J = 8.2, 3.9 Hz, 1H) , 7.91 (dd, J = 8.7, 4.7 Hz, 1H) , 7.70 –7.63 (m, 1H) , 7.54 –7.44 (m, 1H) , 7.42 –7.34 (m, 1H) , 7.15 (dd, J = 16.5, 11.2 Hz, 1H) , 6.67 (td, J = 55.0, 7.0 Hz, 1H) , 6.31 (d, J = 16.8 Hz, 1H) , 5.89 (d, J = 10.7 Hz, 1H) , 5.05 –4.92 (m, 2H) , 4.13 –3.95 (m, 2H) , 3.86 –3.77 (m, 1H) , 3.63 (s, 3H) , 3.57 –3.45 (m, 1H) , 3.45 –3.36 (m, 2H) .

Compound 186A

¹H NMR (400 MHz, CD ₃OD) δ 9.41 (s, 1H) , 8.95 (s, 1H) , 7.98 (d, J = 8.2 Hz, 1H) , 7.76 –7.67 (m, 2H) , 7.61 –7.52 (m, 2H) , 7.44 (t, J = 7.2 Hz, 1H) , 6.97 (dd, J = 16.8, 10.7 Hz, 1H) , 6.34 (d, J = 16.9 Hz, 1H) , 5.88 (dd, J = 10.7, 1.4 Hz, 1H) , 4.86 (s, 1H) , 4.60 –4.44 (m, 2H) , 4.43 –4.32 (m, 2H) , 4.30 –4.19 (m, 1H) , 3.60 (s, 3H) , 2.92 (d, J = 5.7 Hz, 2H) .

Compound 186B

¹H NMR (400 MHz, CD ₃OD) δ 9.53 (s, 1H) , 9.10 (s, 1H) , 7.98 (d, J = 8.3 Hz, 1H) , 7.74 (dd, J = 9.6, 2.3 Hz, 1H) , 7.68 (d, J = 8.6 Hz, 1H) , 7.61 –7.50 (m, 2H) , 7.44 (t, J = 7.6 Hz, 1H) , 7.13 (dd, J = 16.8, 10.7 Hz, 1H) , 6.29 (d, J = 16.7 Hz, 1H) , 5.87 (d, J = 10.7 Hz, 1H) , 5.08 –4.91 (m, 2H) , 4.13 –3.94 (m, 2H) , 3.79 (dd, J = 12.6, 4.2 Hz, 1H) , 3.61 (s, 3H) , 3.55 –3.47 (m, 1H) , 3.35 (d, J = 6.8 Hz, 2H) .

Compound 187A

¹H NMR (400 MHz, CD ₃OD) δ 9.52 (s, 1H) , 8.78 (s, 1H) , 8.29 (s, 1H) , 8.13 (d, J = 8.1 Hz, 1H) , 7.88 (s, 1H) , 7.82 (d, J = 8.5 Hz, 1H) , 7.70 –7.58 (m, 2H) , 7.11 (t, J = 56.0 Hz, 1H) , 7.01 –6.88 (m, 1H) , 6.36 (d, J = 16.6 Hz, 1H) , 5.90 (d, J = 10.8 Hz, 1H) , 4.91-4.85 (m, 2H) , 4.66 –4.40 (m, 4H) , 3.58 (s, 3H) , 2.99-2.95 (m, 2H) .

Compound 187B

¹H NMR (400 MHz, CD ₃OD) δ 9.55 (s, 1H) , 9.07 (s, 1H) , 8.26 (s, 1H) , 8.12 (d, J = 8.0 Hz, 1H) , 7.83 (s, 1H) , 7.74 (d, J = 8.3 Hz, 1H) , 7.65 (t, J = 7.5 Hz, 1H) , 7.59-7.54 (m, 1H) , 7.17-7.14 (m, 1H) , 7.06 (t, J = 56.0 Hz, 1H) , 6.29 (d, J = 16.7 Hz, 1H) , 5.87 (d, J = 11.2 Hz, 1H) , 5.17 –4.93 (m, 4H) , 4.13 (s, 1H) , 4.01 (d, J = 14.1 Hz, 1H) , 3.87 (d, J = 8.5 Hz, 1H) , 3.65-3.62 (m, 1H) , 3.60 (s, 3H) .

Example 23

2- (3- (8-chloronaphthalen-1-yl) -4-fluoro-10- (2-fluoroacryloyl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

Step 1. 2- (3- (8-chloronaphthalen-1-yl) -4-fluoro-10- (2-fluoroacryloyl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

To a solution of 2- (3- (8-chloronaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile (120 mg, 0.173 mmol) and 2-fluoroacrylic acid (32 mg, 0.36 mmol) in DMF (5 mL) was added HATU (136 mg, 0.36 mmol) and TEA (54 mg, 0.54 mmol) 0℃. The mixture was stirred for 2 hours from 0℃ to room temperature. After diluting with water, the mixture was extracted with EtOAc. The combined organics were washed with water and brine, dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by pre-HPLC (0.05%formic acid in water/MeCN) to afford title product (Example 23A: 2.1 mg/Example 23B: 5.1 mg)

Example 23A: MS (ESI) : 559.2 [M+H] ⁺. ¹H NMR (400 MHz, CDCl ₃) δ 9.41 –9.27 (m, 1H) , 8.95 (s, 1H) , 8.05 (d, J = 6.7 Hz, 1H) , 7.91 (d, J = 8.1 Hz, 1H) , 7.71 –7.64 (m, 2H) , 7.56 (d, J = 7.2 Hz, 1H) , 7.45 (t, J = 7.7 Hz, 1H) , 5.63 –5.45 (m, 1H) , 5.37 –5.29 (m, 1H) , 4.83 –4.80 (m, 1H) , 4.59 –4.54 (m, 1H) , 4.29 –4.25 (m, 2H) , 4.27 –3.98 (m, 2H) , 3.62 (s, 3H) , 3.09 –2.90 (m, 2H) .

Example 23B: MS (ESI) : 559.2 [M+H] ⁺. ¹H NMR (400 MHz, CDCl ₃) δ 9.39 (d, J = 12.3 Hz, 1H) , 9.01 (d, J = 6.1 Hz, 1H) , 8.06 –8.00 (m, 1H) , 7.91 (dd, J = 8.2, 1.1 Hz, 1H) , 7.67 –7.57 (m, 2H) , 7.56 –7.51 (m, 1H) , 7.47 –7.40 (m, 1H) , 5.68 – 5.48 (m, 1H) , 5.42 –5.32 (m, 1H) , 5.19 –4.88 (m, 2H) , 4.07 –3.78 (m, 2H) , 3.65 –3.62 (m, 1H) , 3.61 (s, 3H) , 3.57 –3.30 (m, 1H) , 3.29 –3.14 (m, 1H) , 3.14 –3.00 (m, 1H) .

Example 24

2- (3- (8-chloro-7-fluoronaphthalen-1-yl) -4-fluoro-10- (2-fluoroacryloyl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

Step 1. 2- (3- (8-chloro-7-fluoronaphthalen-1-yl) -4-fluoro-10- (2-fluoroacryloyl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

To a solution of 2- (3- (8-chloro-7-fluoronaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3- c] [1, 6] naphthyridin-11-yl) acetonitrile (100 mg, 0.198 mmol) in DCM (4 mL) was added TEA (70 mg, 0.69 mmol) and 2-fluoroacrylic acid (35.6 mg, 0.396 mmol) , HATU (113 mg, 0.30 mmol) in turn at 0℃. The mixture was stirred for 1 hours at 0℃. The reaction was concentrated under reduced pressure (below 20℃) and the residue was purified by pre-HPLC (0.05%formic acid in water/MeCN) to afford two isomers (Example 24A: 3.0 mg/Example 24B: 22.3mg) . MS (ESI) : 577.1 [M+H] ⁺.

Example 24A: ¹H NMR (400 MHz, CDCl ₃) δ 9.22 (d, J = 14.4 Hz, 1H) , 8.95 (s, 1H) , 8.06 –7.98 (m, 1H) , 7.91 (dd, J = 8.9, 5.4 Hz, 1H) , 7.66 (dd, J = 29.9, 6.9 Hz, 2H) , 7.41 (t, J = 8.3 Hz, 1H) , 5.53 (d, J = 47.4 Hz, 1H) , 5.39 –5.27 (m, 1H) , 4.73 (d, J = 98.5 Hz, 2H) , 4.06 (dd, J = 143.0, 73.9 Hz, 4H) , 3.65 (d, J = 13.5 Hz, 3H) , 3.13 –2.71 (m, 2H) .

Example 24B: ¹H NMR (400 MHz, CDCl ₃) δ 9.22 (d, J = 14.4 Hz, 1H) , 8.95 (s, 1H) , 8.06 –7.98 (m, 1H) , 7.91 (dd, J = 8.9, 5.4 Hz, 1H) , 7.66 (dd, J = 29.9, 6.9 Hz, 2H) , 7.41 (t, J = 8.3 Hz, 1H) , 5.53 (d, J = 47.4 Hz, 1H) , 5.39 –5.27 (m, 1H) , 4.73 (d, J = 98.5 Hz, 2H) , 4.06 (dd, J = 143.0, 73.9 Hz, 4H) , 3.65 (d, J = 13.5 Hz, 3H) , 3.13 –2.71 (m, 2H) .

Example 25

2- (3- (8-chloro-7-fluoronaphthalen-1-yl) -10- (4- (dimethylamino) but-2-enoyl) -4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

Step 1. 2- (3- (8-chloro-7-fluoronaphthalen-1-yl) -10- (4- (dimethylamino) but-2-enoyl) -4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

To a solution of 2- (3- (8-chloro-7-fluoronaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile (70 mg, 0.139 mmol) in DMA (3 mL) was added SOCl ₂ (33 mg, 0.278 mmol) and (E) -4- (dimethylamino) but-2-enoic acid (46 mg, 0.278 mmol) in turn at 0℃. The mixture was stirred for 1 hours at 0℃. The reaction was concentrated under reduced pressure (below 20℃) and the residue was purified by pre-HPLC (0.05%formic acid in water/MeCN) to afford two isomers (Example 25A: 4.4 mg/Example 25B: 17.3 mg) . MS (ESI) : 616.1 [M+H] ⁺.

Example 25A: ¹H NMR (400 MHz, CDCl ₃) δ 9.25 (d, J = 14.8 Hz, 1H) , 8.92 (s, 1H) , 8.01 (d, J = 7.8 Hz, 1H) , 7.95 –7.84 (m, 1H) , 7.65 (dt, J = 15.1, 7.4 Hz, 2H) , 7.40 (d, J = 3.0 Hz, 1H) , 6.93 (s, 2H) , 4.90 (s, 1H) , 4.55 –3.98 (m, 4H) , 3.67 –3.58 (m, 3H) , 3.53 (s, 1H) , 3.16 –2.82 (m, 2H) , 2.81 –2.62 (m, 3H) , 2.58 (s, 4H) .

Example 25B: ¹H NMR (400 MHz, CDCl ₃) δ 9.22 (d, J = 14.4 Hz, 1H) , 8.95 (s, 1H) , 8.06 –7.98 (m, 1H) , 7.91 (dd, J = 8.9, 5.4 Hz, 1H) , 7.66 (dd, J = 29.9, 6.9 Hz, 2H) , 7.41 (t, J = 8.3 Hz, 1H) , 5.53 (d, J = 47.4 Hz, 1H) , 5.39 –5.27 (m, 1H) , 4.73 (d, J = 98.5 Hz, 2H) , 4.06 (dd, J = 143.0, 73.9 Hz, 4H) , 3.65 (d, J = 13.5 Hz, 3H) , 3.13 –2.71 (m, 2H) .

Example 26

(S) -3- (8-chloro-7-fluoronaphthalen-1-yl) -10- (4- (dimethylamino) but-2-enoyl) -4-fluoro-7-methyl-9, 10, 11, 12-tetrahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-8 (8aH) -one

Step 1. 1- (tert-butyl) 3-methyl (S) -4- (7-chloro-8-fluoro-3-nitro-1, 6-naphthyridin-4-yl) piperazine-1, 3-dicarboxylate

At 0℃, to a solution of 4, 7-dichloro-8-fluoro-3-nitro-1, 6-naphthyridine (2 g, 7.63 mmol) and DIPEA (3.74 mL, 22.89 mmol) in dioxane (30 mL) was added 1- (tert-butyl) 3-methyl (S) -piperazine-1, 3-dicarboxylate (1.86 g, 7.63 mmol) , then the reaction mixture was stirred at 50℃ overnight. The reaction mixture was diluted with water and extracted with EA twice. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by silica gel column chromatography eluting with 0%to 30%ethyl acetate in petroleum ether to afford 1- (tert-butyl) 3-methyl (S) -4- (7-chloro-8-fluoro-3-nitro-1, 6-naphthyridin-4-yl) piperazine-1, 3-dicarboxylate (1.6 g, 44.61%) . LC/MS ESI (m/z) : 470 [M+H] ⁺.

Step 2. tert-butyl (S) -3-chloro-4-fluoro-8-oxo-7, 8, 8a, 9, 11, 12-hexahydro-10H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridine-10-carboxylate

To a solution of 1- (tert-butyl) 3-methyl (S) -4- (7-chloro-8-fluoro-3-nitro-1, 6-naphthyridin-4-yl) piperazine-1, 3-dicarboxylate (1.6 g, 3.41 mmol) in EtOH (50 mL) and water (10 mL) were added Fe (1.9 g, 34.05 mmol) and NH ₄Cl (3.6 g, 68.11 mmol) . The reaction mixture was stirred at 80℃ for 3hrs. Then the mixture was filtered and the solvent was removed from the liquid phase. The residue was diluted with water, extracted with EA twice. The combined organic layers were washed with water and brine, dried and concentrated to give tert-butyl (S) -3-chloro-4-fluoro-8-oxo-7, 8, 8a, 9, 11, 12-hexahydro-10H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridine-10-carboxylate (1.3 g, 93.61%) . LC/MS ESI (m/z) : 408 [M+H] ⁺.

Step 3. tert-butyl (S) -3-chloro-4-fluoro-7-methyl-8-oxo-7, 8, 8a, 9, 11, 12-hexahydro-10H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridine-10-carboxylate

To a solution of ert-butyl (S) -3-chloro-4-fluoro-8-oxo-7, 8, 8a, 9, 11, 12-hexahydro-10H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridine-10-carboxylate (1.3 g, 3.19 mmol) and Cs ₂CO ₃ (3.1 g, 9.57 mmol) in DMF (20 mL) was added CH ₃I (1.13 g, 7.97 mmol) , then the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water, extracted with EA twice. The combined organic layers were washed with water and brine, dried and concentrated to afford tert-butyl (S) -3-chloro-4-fluoro-7-methyl-8-oxo-7, 8, 8a, 9, 11, 12-hexahydro-10H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridine-10-carboxylate (1.0 g, 74.37%) . LC/MS ESI (m/z) : 422 [M+H] ⁺

Step 4. tert-butyl (S) -3- (8-chloro-7-fluoronaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-7, 8, 8a, 9, 11, 12-hexahydro-10H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridine-10-carboxylate

To a solution of tert-butyl (S) -3-chloro-4-fluoro-7-methyl-8-oxo-7, 8, 8a, 9, 11, 12-hexahydro-10H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridine-10-carboxylate (240 mg, 0.57 mmol) , K ₂CO ₃ (236 mg, 1.71 mmol) and 2- (8-chloro-7-fluoronaphthalen-1-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (349 mg, 1.14 mmol) in dioxane (5 mL) and H ₂O (1 mL) was added RuPhos-Pd-G ₄ (50 mg, 0.06 mmol) . Then the mixture was stirred at 100℃ overnight under N ₂. The reaction was diluted with ice-water and then extracted with EA twice. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by silica gel column chromatography eluting with 0%to 50%ethyl acetate in petroleum ether to afford the title compound tert-butyl (S) -3- (8-chloro-7-fluoronaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-7, 8, 8a, 9, 11, 12-hexahydro-10H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridine-10-carboxylate (120 mg, 37.27%) . LC/MS ESI (m/z) : 566 [M+H] ⁺.

Step 5. (S) -3- (8-chloro-7-fluoronaphthalen-1-yl) -4-fluoro-7-methyl-9, 10, 11, 12-tetrahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-8 (8aH) -one

To a solution of tert-butyl (S) -3- (8-chloro-7-fluoronaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-7, 8, 8a, 9, 11, 12-hexahydro-10H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridine-10-carboxylate (120 mg, 0.21 mmol) in dioxane (5 mL) was added HCl/dioxane (4M, 5 mL) . The reaction mixture was stirred at room temperature for 2hrs. The mixture was concentrated to give the title compound (S) -3- (8-chloro-7-fluoronaphthalen-1-yl) -4-fluoro-7-methyl-9, 10, 11, 12-tetrahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-8 (8aH) -one (HCl salt, 85 mg, 79.87%) . LC/MS ESI (m/z) : 466 [M+H] ⁺.

Step 6. (S) -3- (8-chloro-7-fluoronaphthalen-1-yl) -10- (4- (dimethylamino) but-2-enoyl) -4-fluoro-7-methyl-9, 10, 11, 12-tetrahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-8 (8aH) -one

To a suspension of (S) -3- (8-chloronaphthalen-1-yl) -4-fluoro-7-methyl-9, 10, 11, 12-tetrahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-8 (8aH) -one (HCl salt, 65 mg, 0.13 mmol) and DIPEA (0.06 mL, 0.39 mmol) in DMF (5 mL) under nitrogen were added HATU (99 mg, 0.26 mmol) and (E) -4- (dimethylamino) but-2-enoic acid (34 mg, 0.26 mmol) . The reaction mixture was stirred at 60℃ overnight. The mixture was quenched with water, extracted with EA twice. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by silica column (0%to 20%methanol in dichloromethane) to give crude product which was further purified by prep-HPLC to give title product (12.9 mg, 17.23%) .

LC/MS ESI (m/z) : 577 [M+H] ⁺.

¹H NMR (400 MHz, MeOD) δ 9.48 (s, 1H) , 9.12 (s, 1H) , 8.20 –8.05 (m, 2H) , 7.76 –7.63 (m, 2H) , 7.54 (t, J = 8.6 Hz, 1H) , 7.15 (d, J = 14.8 Hz, 1H) , 6.77 (s, 1H) , 4.60 –4.49 (m, 2H) , 4.06 (s, 1H) , 3.87 (d, J = 12.3 Hz, 1H) , 3.68 (s, 2H) , 3.59 (s, 3H) , 3.11 (d, J = 14.7 Hz, 1H) , 2.63 (d, J = 59.8 Hz, 6H) , 2.15 (dd, J = 38.9, 31.3 Hz, 2H) .

Example 36

2- (3- (8-chloronaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-10- (3- (pyridin-2-yl) acryloyl) -8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

Step 1. 2- (3- (8-chloronaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-10- (3- (pyridin-2-yl) acryloyl) -8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile

To a solution of 2- (3- (8-chloronaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) acetonitrile (100 mg, 0.20 mmol) in DMA (3 mL) was added SOCl ₂ (47.6 mg, 0.4 mmol) and (E) -3- (pyridin-2-yl) acrylic acid (59.6 mg, 0.4 mmol) in turn at 0℃. The mixture was stirred for 2 hours at 0℃. The reaction was concentrated under reduced pressure (below 20℃) and the residue was purified by pre-HPLC (0.05% formic acid in water/MeCN) to afford title product (17.1 mg) .

MS (ESI) : 518.3 [M+H] ⁺.

¹H NMR (400 MHz, CDCl ₃) δ 9.43 (d, J = 13.5 Hz, 1H) , 9.01 (s, 1H) , 8.72 (s, 1H) , 8.04 (s, 1H) , 7.91 (d, J = 7.4 Hz, 1H) , 7.84 (s, 2H) , 7.74 (s, 1H) , 7.65 (d, J =6.8 Hz, 2H) , 7.55 (d, J = 7.5 Hz, 2H) , 7.44 (dd, J = 7.9, 3.8 Hz, 2H) , 5.23 (d, J = 32.4 Hz, 2H) , 3.93 (s, 2H) , 3.74 (d, J = 44.8 Hz, 1H) , 3.61 (s, 3H) , 3.33 (dd, J = 36.1, 27.1 Hz, 2H) , 3.01 (s, 1H) .

Compound 28A

¹H NMR (400 MHz, CD ₃OD) δ 9.46 –9.33 (m, 1H) , 9.17 –9.02 (m, 1H) , 8.14 (d, J = 8.1 Hz, 1H) , 8.02 (d, J = 8.1 Hz, 1H) , 7.79 –7.63 (m, 2H) , 7.63 –7.54 (m, 2H) , 7.53-7.48 (m, 1H) , 7.12 –6.82 (m, 1H) , 5.26 –4.97 (m, 2H) , 4.81 –4.42 (m, 2H) , 4.11 –3.88 (m, 2H) , 3.82 –3.62 (m, 1H) , 3.60 (d, J = 4.1 Hz, 3H) , 3.43 –3.33 (m, 2H) , 3.28 –3.10 (m, 1H) .

Compound 29A

¹H NMR (400 MHz, CD ₃OD) δ 9.41 (d, J = 3.5 Hz, 1H) , 9.09 (d, J = 4.9 Hz, 1H) , 8.15 (d, J = 7.8 Hz, 1H) , 8.02 (d, J = 8.2 Hz, 1H) , 7.74 –7.64 (m, 2H) , 7.64 – 7.56 (m, 2H) , 7.54 –7.48 (m, 1H) , 6.16 (d, J = 6.1 Hz, 1H) , 5.03 –4.93 (m, 1H) , 4.83 –4.76 (m, 1H) , 4.62 –4.54 (m, 1H) , 4.09 –4.03 (m, 1H) , 3.95 –3.87 (m, 1H) , 3.85 –3.69 (m, 2H) , 3.67 (s, 3H) , 3.64 –3.62 (m, 1H) , 3.62 (s, 3H) , 3.56 –3.39 (m, 2H) .

Compound 51A

¹H NMR (400 MHz, CDCl ₃) δ 9.00 (s, 1H) , 8.62 (s, 1H) , 7.93-7.91 (m, 1H) , 7.81 (d, J = 8.1 Hz, 1H) , 7.60 –7.50 (m, 2H) , 7.46 (d, J = 7.1 Hz, 1H) , 7.35-7.32 (m, 1H) , 6.62 –6.52 (m, 1H) , 6.36 (d, J = 16.4 Hz, 1H) , 5.79 (d, J = 9.7 Hz, 1H) , 5.25 – 4.62 (m, 1H) , 4.50 –4.01 (m, 1H) , 3.95 –3.47 (m, 4H) , 3.24 –3.11 (m, 2H) , 3.07 (s, 3H) , 2.75 –2.44 (m, 2H) .

Compound 51B

¹H NMR (400 MHz, CDCl ₃) δ 9.17 (s, 1H) , 8.83 (s, 1H) , 8.00 (s, 1H) , 7.87 (d, J = 7.5 Hz, 1H) , 7.61-7.57 (m, 2H) , 7.51 (s, 1H) , 7.40 (s, 1H) , 6.61-6.59 (m, 1H) , 6.43 (d, J = 16.2 Hz, 1H) , 5.87 (d, J = 10.0 Hz, 1H) , 5.31 –4.74 (m, 1H) , 4.62 –3.99 (m, 1H) , 3.99 –3.62 (m, 2H) , 3.59 –3.29 (m, 4H) , 3.20 (s, 3H) , 3.15 –3.05 (m, 2H) .

Compound 52

¹H NMR (400 MHz, CD3OD) δ 9.24 (s, 1H) , 8.75 (s, 1H) , 8.13 (d, J = 8.2 Hz, 1H) , 8.01 (d, J = 8.1 Hz, 1H) , 7.72 –7.61 (m, 2H) , 7.56 (t, J = 6.5 Hz, 1H) , 7.49-7.45 (m, 1H) , 6.89 –6.80 (m, 1H) , 6.32 (d, J = 16.7 Hz, 1H) , 5.87 (d, J = 10.6 Hz, 1H) , 5.19 –4.99 (m, 1H) , 4.40 (d, J = 9.7 Hz, 2H) , 4.21 –3.78 (m, 2H) , 3.76 –3.61 (m, 1H) , 3.60 –3.44 (m, 2H) , 3.42 –3.33 (m, 2H) .

Compound 65

¹H NMR (400 MHz, MeOD) δ 9.46 –9.27 (m, 1H) , 9.21 –8.96 (m, 1H) , 8.15 (d, J = 8.0 Hz, 1H) , 8.03 (d, J = 7.9 Hz, 1H) , 7.65 (ddd, J = 20.9, 10.9, 5.4 Hz, 3H) , 7.51 (t, J = 7.9 Hz, 1H) , 7.19 –6.84 (m, 1H) , 6.30 (t, J = 19.6 Hz, 1H) , 5.86 (d, J = 10.7 Hz, 1H) , 4.36 (d, J = 27.7 Hz, 2H) , 4.08 (s, 2H) , 3.68 (d, J = 23.7 Hz, 1H) , 3.49 (d, J = 9.9 Hz, 1H) , 3.40 (s, 2H) , 2.70 (s, 2H) , 2.38 –2.30 (m, 6H) , 2.19 (t, J = 7.5 Hz, 1H) , 2.03 (s, 2H) .

Compound 70

¹H NMR (400 MHz, MeOD) δ 9.35 (dd, J = 50.6, 4.6 Hz, 1H) , 9.23 –8.99 (m, 1H) , 8.15 (d, J = 8.0 Hz, 1H) , 8.02 (d, J = 8.1 Hz, 1H) , 7.72 –7.57 (m, 3H) , 7.51 (t, J = 7.8 Hz, 1H) , 7.04 (ddd, J = 67.8, 16.7, 10.5 Hz, 1H) , 6.31 (t, J = 20.3 Hz, 1H) , 5.87 (d, J = 10.9 Hz, 1H) , 4.25 (d, J = 6.3 Hz, 2H) , 4.09 (s, 1H) , 3.97 (dd, J = 19.3, 9.0 Hz, 1H) , 3.83 –3.73 (m, 1H) , 3.54 (d, J = 8.2 Hz, 1H) , 3.38 –3.33 (m, 2H) , 2.44 (dd, J = 20.4, 14.4 Hz, 2H) , 2.28 (d, J = 16.5 Hz, 6H) , 2.23 –2.14 (m, 1H) , 2.04 –1.87 (m, 3H) .

Compound 71

¹H NMR (400 MHz, MeOD) δ 9.41 (d, J = 4.3 Hz, 1H) , 9.15 (d, J = 6.6 Hz, 1H) , 8.15 (d, J = 8.2 Hz, 1H) , 8.03 (d, J = 7.1 Hz, 1H) , 7.72 –7.59 (m, 3H) , 7.51 (t, J = 7.8 Hz, 1H) , 7.12 (dd, J = 16.7, 10.7 Hz, 1H) , 6.29 (d, J = 16.8 Hz, 1H) , 5.87 (d, J =10.8 Hz, 1H) , 4.27 (s, 2H) , 4.10 (s, 1H) , 4.02 –3.95 (m, 1H) , 3.81 (dd, J = 12.8, 8.0 Hz, 1H) , 3.46 (d, J = 9.1 Hz, 1H) , 3.35 (d, J = 6.0 Hz, 2H) , 2.62 (s, 6H) , 2.01 (dd, J =14.8, 7.0 Hz, 4H) , 1.83 (s, 4H) .

Compound 144

¹H NMR (400 MHz, CD ₃OD) δ 9.18 (d, J = 37.9 Hz, 1H) , 8.84 (s, 1H) , 8.44 (s, 1H) , 8.12 (d, J = 8.1 Hz, 1H) , 8.01-7.98 (m, 1H) , 7.66-7.62 (m, 2H) , 7.60 –7.54 (m, 1H) , 7.51 –7.42 (m, 1H) , 6.95 –6.77 (m, 2H) , 5.33 –4.92 (m, 1H) , 4.83 –4.64 (m, 2H) , 4.32 –4.03 (m, 1H) , 4.02 –3.82 (m, 1H) , 3.82 –3.64 (m, 2H) , 3.63 –3.58 (m, 1H) , 3.57 (s, 2H) , 3.50 –3.39 (m, 2H) , 3.22 (s, 3H) , 2.60 (s, 6H) .

Compound 147A

¹H NMR (400 MHz, MeOD) δ 9.38 (s, 1H) , 8.95 (s, 1H) , 8.03 (dd, J = 21.3, 7.8 Hz, 2H) , 7.70 –7.67 (m, 2H) , 7.64 (d, J = 7.2 Hz, 1H) , 7.55 (t, J = 7.4 Hz, 1H) , 7.49 –7.44 (m, 1H) , 5.58 –5.34 (m, 2H) , 4.93 –4.88 (m, 1H) , 4.57 –4.49 (m, 1H) , 4.45 –4.36 (m, 2H) , 4.36 –4.17 (m, 2H) , 3.60 (s, 3H) , 3.02 –2.91 (m, 2H) .

Compound 147B

¹H NMR (400 MHz, DMSO) δ 9.49 (s, 1H) , 9.22 (s, 1H) , 8.09 (dd, J = 17.2, 7.4 Hz, 2H) , 7.75 –7.70 (m, 2H) , 7.68 (d, J = 6.9 Hz, 1H) , 7.59 (t, J = 7.1 Hz, 1H) , 7.52 (t, J = 7.4 Hz, 1H) , 5.54 –5.29 (m, 2H) , 4.93 –4.73 (m, 2H) , 4.14 –3.94 (m, 2H) , 3.72 –3.64 (m, 1H) , 3.63 –3.55 (m, 2H) , 3.54 (s, 3H) , 3.44 –3.37 (m, 1H) .

Compound 150A

¹H NMR (400 MHz, CDCl ₃) δ 9.51 –9.20 (m, 1H) , 8.99 (d, J = 30.1 Hz, 1H) , 8.00 –7.93 (m, 1H) , 7.82 (dd, J = 8.9, 5.9 Hz, 1H) , 7.62 –7.49 (m, 2H) , 7.31 (t, J = 9.1 Hz, 1H) , 5.65 –5.45 (m, 1H) , 5.34 (ddd, J = 16.7, 12.0, 3.6 Hz, 1H) , 5.17 –4.78 (m, 1H) , 4.69 –4.53 (m, 1H) , 4.30 –4.12 (m, 2H) , 4.10 –3.81 (m, 1H) , 3.63 (s, 3H) , 3.32 –2.72 (m, 2H) , 1.90 –1.82 (m, 3H) .

Compound 150B

¹H NMR (400 MHz, CDCl ₃) δ 9.42 (d, J = 5.7 Hz, 1H) , 9.03 (s, 1H) , 8.01 –7.93 (m, 1H) , 7.82 (dd, J = 8.6, 5.9 Hz, 1H) , 7.60 –7.49 (m, 2H) , 7.31 (dd, J = 11.8, 6.6 Hz, 1H) , 5.57 (dd, J = 47.0, 3.7 Hz, 1H) , 5.43 –5.30 (m, 1H) , 5.03 (d, J = 50.7 Hz, 2H) , 4.05 –3.65 (m, 3H) , 3.62 (s, 3H) , 3.46 (d, J = 36.6 Hz, 1H) , 3.23 (dd, J = 16.7, 7.1 Hz, 1H) , 3.05 (d, J = 5.4 Hz, 1H) , 1.90 –1.81 (m, 3H) .

Compound 152A

¹H NMR (400 MHz, MeOD) δ 9.33 (d, J = 4.4 Hz, 1H) , 8.96 (s, 1H) , 8.12 (d, J = 7.4 Hz, 1H) , 7.98 –7.84 (m, 1H) , 7.78 –7.64 (m, 2H) , 7.60 –7.46 (m, 1H) , 5.67 –5.29 (m, 2H) , 5.05 –4.87 (m, 1H) , 4.66 –4.47 (m, 1H) , 4.49 –4.28 (m, 3H) , 4.27 –4.14 (m, 1H) , 3.60 (s, 3H) , 3.18 –2.77 (m, 2H) .

Compound 152B

¹H NMR (400 MHz, MeOD) δ 9.43 (s, 1H) , 9.12 (s, 1H) , 8.13 (d, J = 7.4 Hz, 1H) , 7.90 (ddd, J = 9.0, 4.9, 1.6 Hz, 1H) , 7.78 –7.64 (m, 2H) , 7.61 –7.47 (m, 1H) , 5.57 –5.32 (m, 2H) , 5.09 –4.93 (m, 1H) , 4.17 –4.00 (m, 2H) , 3.83 –3.70 (m, 1H) , 3.61 (s, 3H) , 3.53 –3.42 (m, 1H) , 3.38 –3.34 (m, 1H) .

Compound 154A

¹H NMR (400 MHz, DMSO) δ 9.37 (d, J = 8.6 Hz, 1H) , 9.31 (s, 1H) , 9.01 (d, J = 3.0 Hz, 1H) , 8.32 (dd, J = 7.1, 2.4 Hz, 2H) , 7.86 –7.78 (m, 2H) , 5.51 (d, J = 2.8 Hz, 1H) , 5.47 –5.37 (m, 1H) , 4.90 –4.83 (m, 1H) , 4.50 –4.34 (m, 2H) , 4.28 (s, 1H) , 4.16 –4.08 (m, 2H) , 3.51 (d, J = 3.2 Hz, 3H) , 3.08 –3.01 (m, 1H) , 2.95 (s, 1H) , 2.00 (dd, J = 14.4, 6.7 Hz, 1H) , 1.87 (d, J = 5.9 Hz, 3H) .

Compound 154B

P2: ¹H NMR (400 MHz, DMSO) δ 9.42 (d, J = 7.2 Hz, 1H) , 9.32 (s, 1H) , 9.23 (s, 1H) , 8.36 –8.30 (m, 2H) , 7.87 –7.79 (m, 2H) , 5.52 –5.30 (m, 2H) , 4.93 – 4.70 (m, 2H) , 4.15 –3.98 (m, 2H) , 3.59 (s, 3H) , 3.53 (s, 3H) , 2.00 (dd, J = 14.1, 6.5 Hz, 1H) , 1.86 (s, 3H) .

Compound 155A

P1: ¹H NMR (400 MHz, DMSO) δ 9.20 (dd, J = 206.3, 8.5 Hz, 1H) , 8.58 –8.15 (m, 2H) , 7.68 (ddt, J = 25.1, 20.3, 7.3 Hz, 2H) , 7.21 (s, 1H) , 6.67 (s, 1H) , 5.82 (s, 1H) , 5.44 –5.16 (m, 3H) , 4.82 –4.63 (m, 1H) , 4.27 (d, J = 16.0 Hz, 1H) , 3.45 (d, J =12.9 Hz, 2H) , 2.87 –2.54 (m, 2H) , 2.04 –1.92 (m, 3H) , 1.75 –1.32 (m, 4H) .

Compound 155B

P2: ¹H NMR (400 MHz, MeOD) δ 9.53 –9.51 (m, 1H) , 9.14 –9.10 (m, 1H) , 8.14 –8.04 (m, 1H) , 7.68 –7.47 (m, 2H) , 5.34 (t, J = 4.7 Hz, 2H) , 4.05 (d, J = 12.6 Hz, 1H) , 3.82 (d, J = 3.7 Hz, 1H) , 3.61 (s, 2H) , 3.48 (dt, J = 4.2, 1.3 Hz, 1H) , 3.13 (dt, J = 3.5, 1.7 Hz, 1H) , 2.59 (d, J = 0.5 Hz, 1H) , 2.21 –2.16 (m, 3H) , 2.06 –1.99 (m, 4H) , 1.60 (dd, J = 11.2, 4.6 Hz, 3H) .

Compound 156A

¹H NMR (400 MHz, DMSO) δ 9.46 –9.27 (m, 2H) , 8.98 (s, 1H) , 7.50 –7.35 (m, 1H) , 7.28 (dd, J = 10.1, 8.1 Hz, 2H) , 5.57 –5.33 (m, 2H) , 4.84 (dd, J = 21.0, 10.4 Hz, 1H) , 4.53 –4.00 (m, 5H) , 3.51 (s, 3H) , 3.12 –3.00 (m, 1H) , 2.91 (dd, J = 17.3, 6.4 Hz, 1H) , 1.84 (d, J = 5.1 Hz, 1H) , 0.64 –0.53 (m, 2H) , 0.29 (d, J = 4.0 Hz, 2H) .

Compound 156B

¹H NMR (400 MHz, DMSO) δ 9.40 (s, 3H) , 9.19 (s, 1H) , 7.42 (dd, J = 13.4, 7.8 Hz, 1H) , 7.29 (dd, J = 12.6, 5.7 Hz, 2H) , 5.56 –5.27 (m, 2H) , 5.02 –4.62 (m, 2H) , 4.17 –3.90 (m, 2H) , 3.57 (s, 1H) , 3.51 (s, 4H) , 3.25 –3.12 (m, 2H) , 1.92 –1.78 (m, 1H) , 0.60 (d, J = 8.2 Hz, 2H) , 0.29 (d, J = 4.2 Hz, 2H) .

Compound 157A

¹H NMR (400 MHz, MeOD) δ 9.51 –9.36 (m, 1H) , 8.97 (s, 1H) , 8.51 (d, J =8.5 Hz, 1H) , 8.28 (d, J = 6.2 Hz, 1H) , 8.10 (d, 1H) , 7.92 (d, 1H) , 7.62 (d, J = 6.3 Hz, 1H) , 5.47 –5.30 (m, 2H) , 4.46 –4.36 (m, 2H) , 4.23 (dd, J = 14.1, 6.6 Hz, 1H) , 3.61 (s, 4H) , 3.05 (s, 3H) , 3.01 –2.86 (m, 2H) , 2.23 (dd, J = 26.3, 6.3 Hz, 1H) , 2.02 (d, J =8.7 Hz, 1H) , 0.89 (d, J = 7.2 Hz, 1H) .

Compound 157B

¹H NMR (400 MHz, MeOD) δ 9.51 (d, J = 11.9 Hz, 1H) , 9.13 (s, 1H) , 8.43 (dd, J = 48.4, 7.1 Hz, 1H) , 8.20 (dd, J = 51.8, 7.2 Hz, 1H) , 8.07 –7.83 (m, 2H) , 7.80 –7.51 (m, 1H) , 5.51 –5.24 (m, 2H) , 4.48 –4.28 (m, 1H) , 4.06 (s, 1H) , 3.78 (s, 1H) , 3.64 (s, 3H) , 3.48 (s, 2H) , 3.03 (s, 3H) , 2.36 –2.15 (m, 2H) , 0.90 (s, 1H) .

Compound 158

¹H NMR (400 MHz, MeOD) δ 9.36 (d, J = 39.4 Hz, 1H) , 9.03 (d, J = 67.7 Hz, 1H) , 7.81 (td, J = 8.0, 5.5 Hz, 1H) , 7.57 –7.47 (m, 1H) , 7.40 (d, J = 7.7 Hz, 1H) , 5.55 –5.28 (m, 2H) , 4.98 (dd, J = 18.7, 12.9 Hz, 2H) , 4.54 (d, J = 29.7 Hz, 1H) , 4.39 –4.01 (m, 2H) , 3.74 (d, J = 17.5 Hz, 1H) , 3.59 (s, 3H) , 3.39 (dd, J = 43.1, 15.1 Hz, 2H) .

Compound 159A

¹H NMR (400 MHz, MeOD) δ 9.49 (s, 1H) , 9.41 (dd, J = 40.6, 2.9 Hz, 1H) , 9.02 (t, J = 34.4 Hz, 1H) , 8.58 (d, J = 22.1 Hz, 1H) , 8.34 –8.19 (m, 1H) , 7.91 (dd, J =7.5, 1.1 Hz, 1H) , 7.75 (td, J = 7.9, 2.0 Hz, 1H) , 5.61 –5.26 (m, 2H) , 4.65 –4.11 (m, 4H) , 3.61 (d, J = 3.5 Hz, 3H) , 3.35 (s, 2H) , 3.13 –2.80 (m, 2H) .

Compound 159B

¹H NMR (400 MHz, MeOD) δ 9.52 –9.43 (m, 2H) , 9.13 (s, 1H) , 8.55 (d, J =25.7 Hz, 1H) , 8.28 (d, J = 8.1 Hz, 1H) , 7.90 (t, J = 7.1 Hz, 1H) , 7.75 (td, J = 7.9, 1.7 Hz, 1H) , 5.52 –5.34 (m, 2H) , 4.99 (s, 1H) , 4.05 (d, J = 5.8 Hz, 2H) , 3.78 (s, 1H) , 3.60 (s, 3H) , 3.40 (d, J = 38.0 Hz, 4H) .

Compound 160A

¹H NMR (400 MHz, MeOD) δ 9.48 (d, J = 1.9 Hz, 1H) , 9.38 (s, 1H) , 9.14 (s, 1H) , 8.41 (d, J = 18.2 Hz, 1H) , 8.13 (d, J = 7.7 Hz, 1H) , 7.71 –7.61 (m, 2H) , 5.55 –5.33 (m, 2H) , 4.95 (s, 1H) , 4.06 (s, 2H) , 3.78 (s, 1H) , 3.61 (s, 3H) , 3.40 (d, J = 62.7 Hz, 4H) , 2.02 (s, 3H) .

Compound 160B

¹H NMR (400 MHz, MeOD) δ 9.38 (d, J = 5.0 Hz, 2H) , 8.97 (d, J = 1.7 Hz, 1H) , 8.42 (d, J = 20.2 Hz, 1H) , 8.13 (d, J = 8.0 Hz, 1H) , 7.71 –7.60 (m, 2H) , 5.43 (ddd, J = 32.8, 21.4, 4.0 Hz, 2H) , 4.89 (dd, J = 11.7, 5.5 Hz, 1H) , 4.52 (d, J = 13.3 Hz, 1H) , 4.41 (dt, J = 9.3, 5.9 Hz, 3H) , 4.29 –4.17 (m, 1H) , 3.61 (d, J = 2.0 Hz, 3H) , 2.96 (dtd, J = 24.7, 17.2, 6.1 Hz, 2H) , 2.03 (d, J = 7.0 Hz, 3H) .

Compound 161A

¹H NMR (400 MHz, CDCl ₃) δ 9.44 –9.26 (m, 1H) , 9.00 –8.76 (m, 1H) , 7.82 (d, J = 8.3 Hz, 1H) , 7.69 –7.58 (m, 1H) , 7.56 –7.48 (m, 1H) , 6.42 –6.17 (m, 1H) , 5.69 –5.27 (m, 2H) , 5.17 –5.03 (m, 1H) , 4.85 –4.56 (m, 2H) , 4.49 –3.80 (m, 1H) , 3.69 –3.55 (m, 3H) , 3.43 (s, 1H) , 2.68 (s, 2H) .

Compound 161B

¹H NMR (400 MHz, CDCl ₃) δ 9.49 –9.12 (m, 1H) , 9.08 –8.86 (m, 1H) , 7.82 (d, J = 7.3 Hz, 1H) , 7.63 (t, J = 7.5 Hz, 1H) , 7.54 –7.43 (m, 1H) , 5.74 –5.24 (m, 2H) , 4.94 –4.54 (m, 2H) , 4.35 –4.10 (m, 2H) , 4.00 (s, 1H) , 3.86 –3.54 (m, 5H) , 3.43 (s, 2H) , 3.31 –2.69 (m, 2H) .

Compound 162A

¹H NMR (400 MHz, CDCl ₃) δ 9.23 (s, 1H) , 8.96 (s, 1H) , 8.02 –7.95 (m, 1H) , 7.87 –7.79 (m, 1H) , 7.55 –7.43 (m, 2H) , 7.37 –7.29 (m, 1H) , 5.64 –5.28 (m, 2H) , 4.84 (s, 1H) , 4.64 –4.54 (m, 1H) , 4.33 –3.98 (m, 4H) , 3.66 –3.63 (m, 3H) , 2.96 –2.74 (m, 2H) , 2.61 –2.48 (m, 1H) , 2.28 –2.09 (m, 1H) , 0.81 (t, J = 7.4 Hz, 3H) .

Compound 162B

¹H NMR (400 MHz, CDCl ₃) δ 9.42 (s, 1H) , 9.04 (s, 1H) , 7.99 (d, J = 7.8 Hz, 1H) , 7.83 (dd, J = 8.9, 5.9 Hz, 1H) , 7.57 –7.43 (m, 2H) , 7.32 (t, J = 9.3 Hz, 1H) , 5.67 –5.34 (m, 2H) , 5.04 (d, J = 56.0 Hz, 2H) , 3.95 –3.42 (m, 7H) , 3.26 –3.01 (m, 2H) , 2.52 (s, 1H) , 2.17 (s, 1H) , 0.88 –0.73 (m, 4H) .

Compound 163

¹H NMR (400 MHz, MeOD) δ 9.19 (d, J = 5.4 Hz, 1H) , 8.86 (s, 1H) , 8.03 (d, J = 8.1 Hz, 1H) , 7.91 (dd, J = 8.9, 6.0 Hz, 1H) , 7.56 –7.28 (m, 3H) , 5.41 (dd, J = 27.9, 3.8 Hz, 1H) , 5.33 (s, 1H) , 3.74 (dd, J = 20.0, 11.2 Hz, 4H) , 3.53 (d, J = 9.4 Hz, 1H) , 3.49 –3.31 (m, 4H) , 3.29 –3.04 (m, 4H) , 2.50 (dt, J = 14.2, 7.7 Hz, 1H) , 2.22 –2.08 (m, 1H) , 0.74 (td, J = 7.4, 4.3 Hz, 3H) .

Compound 164A

¹H NMR (400 MHz, MeOD) δ 9.32 (d, J = 5.7 Hz, 1H) , 8.92 (d, J = 1.5 Hz, 1H) , 8.15 (dd, J = 7.5, 2.0 Hz, 1H) , 8.07 (dd, J = 8.1, 5.6 Hz, 1H) , 7.77 –7.62 (m, 2H) , 7.51 (t, J = 8.8 Hz, 1H) , 6.80 (dd, J = 11.0, 3.3 Hz, 1H) , 4.62 –4.30 (m, 5H) , 4.21 (ddd, J = 19.6, 14.0, 5.7 Hz, 1H) , 3.58 (d, J = 5.2 Hz, 3H) , 2.92 (dtd, J = 24.5, 17.3, 6.1 Hz, 2H) , 2.13 –1.93 (m, 1H) , 1.35 –1.24 (m, 2H) , 1.09 –0.89 (m, 2H) .

Compound 164B

¹H NMR (400 MHz, MeOD) δ 9.40 (d, J = 5.6 Hz, 1H) , 9.10 (d, J = 5.0 Hz, 1H) , 8.25 –8.13 (m, 1H) , 8.08 (dd, J = 9.1, 5.6 Hz, 1H) , 7.72 –7.62 (m, 2H) , 7.52 (t, J = 8.8 Hz, 1H) , 6.70 (dd, J = 11.0, 5.6 Hz, 1H) , 4.04 (d, J = 7.1 Hz, 2H) , 3.60 (s, 4H) , 3.42 (dd, J = 31.6, 13.3 Hz, 5H) , 2.10 (dd, J = 7.2, 3.5 Hz, 1H) , 1.38 –1.21 (m, 2H) , 1.01 (dd, J = 7.4, 4.2 Hz, 2H) .

Compound 165A

¹HNMR (400 MHz, MeOD) δ 9.31 (dd, J = 10.9, 3.9 Hz, 1H) , 8.94 (d, J =12.9 Hz, 1H) , 8.16 (d, J = 2.0 Hz, 1H) , 8.11 –8.05 (m, 1H) , 7.71 (dd, J = 14.0, 6.0 Hz, 2H) , 7.53 (td, J = 8.9, 2.5 Hz, 1H) , 4.84 –4.62 (m, 2H) , 4.60 –4.49 (m, 1H) , 4.48 –4.17 (m, 3H) , 3.62 –3.59 (m, 3H) , 3.08 –2.74 (m, 2H) , 2.12 (d, J = 2.7 Hz, 3H) .

Compound 165B

¹H NMR (400 MHz, CDCl ₃) δ 9.42 (d, J = 8.8 Hz, 1H) , 9.03 (dd, J = 10.0, 4.8 Hz, 1H) , 8.01 (dd, J = 7.3, 2.0 Hz, 1H) , 7.94 –7.77 (m, 1H) , 7.72 –7.54 (m, 2H) , 7.39 (t, J = 8.7 Hz, 1H) , 5.07 –4.95 (m, 1H) , 3.97 –3.79 (m, 2H) , 3.76 –3.65 (m, 1H) , 3.61 (s, 3H) , 3.49 –3.33 (m, 1H) , 3.23 (ddd, J = 33.7, 16.5, 10.4 Hz, 2H) , 3.09 –2.84 (m, 1H) , 2.15 (s, 3H) .

Compound 166A

¹H NMR (400 MHz, MeOD) δ 9.31 (d, J = 6.2 Hz, 1H) , 8.93 (s, 1H) , 8.21 –8.11 (m, 1H) , 8.11 –8.03 (m, 1H) , 7.77 –7.63 (m, 2H) , 7.52 (td, J = 8.9, 2.3 Hz, 1H) , 6.72 (dd, J = 14.8, 1.5 Hz, 1H) , 6.42 (dd, J = 14.9, 10.1 Hz, 1H) , 4.42 (dd, J = 87.5, 53.3 Hz, 6H) , 3.60 (d, J = 3.8 Hz, 3H) , 3.07 –2.74 (m, 2H) , 1.83 –1.70 (m, 1H) , 0.99 (dd, J = 10.6, 5.0 Hz, 2H) , 0.67 (d, J = 4.2 Hz, 2H) .

Compound 166B

¹HNMR (400 MHz, MeOD) δ 9.43 (d, J = 3.8 Hz, 1H) , 9.07 (d, J = 5.6 Hz, 1H) , 8.15 (dd, J = 10.0, 2.4 Hz, 1H) , 8.10 –8.05 (m, 1H) , 7.72 –7.63 (m, 2H) , 7.51 (t, J = 8.9 Hz, 1H) , 6.87 (d, J = 15.0 Hz, 1H) , 6.37 (dd, J = 14.8, 10.1 Hz, 1H) , 4.95 (d, J = 11.1 Hz, 2H) , 4.58 (s, 1H) , 4.04 (s, 1H) , 3.91 (s, 1H) , 3.67 (s, 1H) , 3.59 (s, 3H) , 3.54 –3.34 (m, 2H) , 1.75 (s, 1H) , 0.99 (d, J = 6.9 Hz, 2H) , 0.67 (s, 2H) .

Compound 167A

¹H NMR (400 MHz, CDCl ₃) δ 9.19 (d, J = 3.8 Hz, 1H) , 8.95 (s, 1H) , 8.02 (d, J = 9.1 Hz, 1H) , 7.91 (dd, J = 9.0, 5.6 Hz, 1H) , 7.63 (t, J = 6.5 Hz, 2H) , 7.41 (td, J =8.7, 3.3 Hz, 1H) , 6.70 –6.53 (m, 1H) , 6.45 (dd, J = 16.4, 9.2 Hz, 1H) , 6.12 (dd, J = 14.3, 9.7 Hz, 1H) , 4.57 (d, J = 35.9 Hz, 1H) , 4.31 (dd, J = 15.1, 7.9 Hz, 1H) , 4.22 –4.14 (m, 1H) , 4.13 –3.98 (m, 2H) , 3.86 (dd, J = 21.4, 13.0 Hz, 1H) , 3.62 (s, 3H) , 3.01 –2.61 (m, 2H) .

Compound 167B

¹HNMR (400 MHz, CDCl ₃) δ 9.46 (d, J = 3.7 Hz, 1H) , 9.06 (d, J = 3.2 Hz, 1H) , 8.02 (d, J = 8.0 Hz, 1H) , 7.91 (dd, J = 9.0, 5.5 Hz, 1H) , 7.64 (dd, J = 15.8, 6.9 Hz, 2H) , 7.40 (t, J = 8.7 Hz, 1H) , 6.75 –6.65 (m, 1H) , 6.36 (d, J = 16.5 Hz, 1H) , 6.06 (dd, J = 9.9, 2.1 Hz, 1H) , 4.69 (t, J = 13.2 Hz, 1H) , 4.26 (s, 1H) , 3.77 (d, J = 24.0 Hz, 1H) , 3.66 (d, J = 4.6 Hz, 3H) , 3.64 –3.56 (m, 2H) , 3.56 –3.42 (m, 1H) , 3.19 –2.97 (m, 2H) .

Compound 168A

¹H NMR (400 MHz, CD ₃OD) δ 9.33 (d, J = 32.6 Hz, 1H) , 8.84 (d, J = 15.7 Hz, 1H) , 8.09 (dd, J = 20.5, 8.1 Hz, 2H) , 7.76 –7.67 (m, 2H) , 7.67 –7.61 (m, 1H) , 7.53 (td, J = 8.0, 3.0 Hz, 1H) , 6.05 (d, J = 6.9 Hz, 1H) , 5.43 –5.37 (m, 1H) , 5.28 – 5.03 (m, 2H) , 4.84 –4.71 (m, 2H) , 4.56 –4.42 (m, 1H) , 3.57 (d, J = 5.1 Hz, 3H) , 3.52 –3.37 (m, 1H) , 3.05 –2.93 (m, 1H) , 2.87 –2.56 (m, 2H) .

Compound 168B

¹H NMR (400 MHz, CD ₃OD) δ 9.37 (d, J = 10.1 Hz, 1H) , 9.10 (d, J = 5.5 Hz, 1H) , 8.09 (dd, J = 19.9, 8.0 Hz, 2H) , 7.77 –7.59 (m, 3H) , 7.57 –7.45 (m, 1H) , 5.54 –5.31 (m, 2H) , 5.10 –4.87 (m, 2H) , 4.24 –3.92 (m, 2H) , 3.81 –3.64 (m, 1H) , 3.60 (s, 3H) , 3.56 –3.37 (m, 2H) , 3.36 –3.32 (m, 1H) , 2.99 –2.72 (m, 1H) .

Compound 170A

¹H NMR (400 MHz, CDCl ₃) δ 9.56 –9.24 (m, 1H) , 8.84 (s, 1H) , 7.63 (dd, J = 7.6, 1.2 Hz, 1H) , 7.54 (dd, 1H) , 7.43 –7.32 (m, 1H) , 6.41 (d, J = 3.9 Hz, 1H) , 6.17 (s, 1H) , 5.50 (dd, J = 47.4, 3.5 Hz, 1H) , 5.26 (s, 1H) , 5.10 (dd, J = 15.0, 3.5 Hz, 1H) , 4.83 –4.67 (m, 2H) , 4.58 (d, J = 8.5 Hz, 1H) , 3.61 (s, 3H) , 3.39 (s, 1H) , 2.67 (d, J =5.3 Hz, 2H) , 2.30 –2.13 (m, 1H) , 0.66 (d, J = 8.3 Hz, 2H) , 0.25 (s, 2H) .

Compound 170B

¹H NMR (400 MHz, CDCl ₃) δ 9.41 (s, 1H) , 9.01 (s, 1H) , 7.63 (dd, J = 7.7, 1.3 Hz, 1H) , 7.51 (dd, J = 8.5 Hz, 1H) , 7.41 –7.31 (m, 1H) , 5.57 (dd, J = 47.0, 3.7 Hz, 1H) , 5.37 (dd, J = 16.3, 3.6 Hz, 1H) , 5.06 (d, J = 58.6 Hz, 1H) , 3.86 (d, J = 3.4 Hz, 1H) , 3.69 (s, 1H) , 3.62 (s, 3H) , 3.42 (d, J = 29.1 Hz, 2H) , 3.24 (dd, J = 16.9, 7.3 Hz, 1H) , 3.08 (s, 1H) , 2.21 (dd, J = 8.1 Hz, 1H) , 1.38 –1.23 (m, 2H) , 0.64 (d, J = 7.1 Hz, 2H) , 0.25 (s, 2H) .

Compound 171A

¹H NMR (400 MHz, CDCl ₃) δ 9.24 (s, 1H) , 9.01 (t, J = 4.0 Hz, 1H) , 8.97 (s, 1H) , 8.12 (d, J = 8.3 Hz, 1H) , 7.66 (t, J = 7.7 Hz, 1H) , 7.43 –7.32 (m, 2H) , 5.54 (dd, J = 47.6, 3.5 Hz, 1H) , 5.33 (dd, J = 16.6, 3.7 Hz, 1H) , 4.85 (s, 1H) , 4.60 (d, J = 9.5 Hz, 1H) , 4.31 –4.15 (m, 3H) , 4.02 (dd, J = 26.4, 17.3 Hz, 1H) , 3.64 (s, 3H) , 2.98 – 2.71 (m, 2H) , 2.03 (d, J = 3.1 Hz, 3H) .

Compound 171B

¹HNMR (400 MHz, CDCl ₃) δ 9.44 (d, J = 3.4 Hz, 1H) , 9.04 (s, 1H) , 8.99 (dd, J = 12.6, 4.3 Hz, 1H) , 8.12 (dd, J = 8.3, 4.0 Hz, 1H) , 7.65 (t, J = 7.8 Hz, 1H) , 7.42 –7.30 (m, 2H) , 5.57 (dd, J = 47.0, 3.7 Hz, 1H) , 5.38 (d, J = 16.6 Hz, 1H) , 5.03 (d, J =51.2 Hz, 2H) , 3.85 (s, 2H) , 3.65 (s, 1H) , 3.63 (d, J = 2.8 Hz, 3H) , 3.51 –3.19 (m, 2H) , 3.01 (s, 1H) , 2.03 (d, J = 4.1 Hz, 3H) .

Compound 172A

¹H NMR (400 MHz, CDCl ₃) δ 9.46 (s, 1H) , 8.95 (d, J = 18.8 Hz, 1H) , 8.01 (d, J = 8.0 Hz, 1H) , 7.90 (dd, J = 9.0, 5.5 Hz, 1H) , 7.64 (dt, J = 26.7, 7.5 Hz, 2H) , 7.40 (t, J = 8.7 Hz, 1H) , 3.95 (dt, J = 7.4, 4.2 Hz, 1H) , 3.83 –3.72 (m, 1H) , 3.69 (dd, J = 6.0, 3.8 Hz, 1H) , 3.63 (t, J = 5.6 Hz, 3H) , 3.59 (dd, J = 8.0, 4.9 Hz, 2H) , 3.55 –3.50 (m, 1H) , 3.48 –3.38 (m, 1H) , 3.34 –3.17 (m, 2H) , 3.05 –2.89 (m, 1H) , 2.41 (d, J = 2.1 Hz, 1H) .

Compound 172B

¹H NMR (400 MHz, CDCl ₃) δ 9.43 (d, J = 9.8 Hz, 1H) , 9.03 (s, 1H) , 8.02 (dd, J = 8.0, 1.2 Hz, 1H) , 7.91 (dd, J = 9.0, 5.5 Hz, 1H) , 7.65 (dt, J = 15.1, 7.2 Hz, 2H) , 7.40 (t, J = 8.7 Hz, 1H) , 3.81 (d, J = 16.4 Hz, 1H) , 3.75 (t, J = 8.3 Hz, 2H) , 3.65 (dd, J = 7.7, 2.1 Hz, 3H) , 3.60 (dd, J = 8.8, 2.5 Hz, 2H) , 3.28 (ddd, J = 17.4, 10.0, 7.1 Hz, 2H) , 3.05 (dt, J = 39.8, 10.8 Hz, 1H) , 2.71 –2.62 (m, 1H) , 2.54 (dd, J = 27.6, 19.6 Hz, 1H) , 2.44 (dd, J = 5.4, 2.4 Hz, 1H) .

Compound 173

¹H NMR (400 MHz, DMSO) δ 9.37 (d, J = 14.3 Hz, 1H) , 8.93 (s, 1H) , 8.73 –8.31 (m, 1H) , 8.32 –8.13 (m, 2H) , 7.83 –7.39 (m, 3H) , 5.91 –5.76 (m, 1H) , 5.46 –5.12 (m, 3H) , 4.86 –4.32 (m, 3H) , 3.47 (d, J = 14.0 Hz, 3H) , 2.92 –2.66 (m, 2H) .

Compound 178

¹H NMR (400 MHz, MeOD) δ 9.44 (d, J = 6.1 Hz, 1H) , 9.15 (d, J = 4.5 Hz, 1H) , 8.17 –8.10 (m, 2H) , 7.75 –7.66 (m, 2H) , 7.45 (t, J = 8.5 Hz, 1H) , 7.27 –6.64 (m, 1H) , 6.25 (d, J = 16.9 Hz, 1H) , 5.82 (d, J = 11.0 Hz, 1H) , 4.93 (d, J = 13.0 Hz, 1H) , 4.62 –4.23 (m, 3H) , 4.04 (s, 1H) , 3.83 (d, J = 12.4 Hz, 1H) , 3.63 (s, 1H) , 3.39 (d, J = 11.1 Hz, 1H) , 3.19 (t, J = 27.0 Hz, 2H) , 2.71 (dd, J = 14.2, 7.7 Hz, 2H) , 2.35 (d, J = 17.6 Hz, 6H) .

Compound 179

¹H NMR (400 MHz, MeOD) δ 9.44 (d, J = 6.3 Hz, 1H) , 9.17 (s, 1H) , 8.14 (dd, J = 12.4, 5.1 Hz, 2H) , 7.74 –7.65 (m, 2H) , 7.45 (t, J = 8.5 Hz, 1H) , 7.20 –6.70 (m, 1H) , 6.26 (d, J = 16.8 Hz, 1H) , 5.82 (d, J = 11.9 Hz, 1H) , 4.94 (d, J = 14.0 Hz, 1H) , 4.52 (s, 1H) , 4.25 (d, J = 5.7 Hz, 2H) , 4.05 (s, 1H) , 3.83 (d, J = 13.6 Hz, 1H) , 3.68 (d, J = 10.9 Hz, 1H) , 3.48 (d, J = 1.6 Hz, 2H) , 3.14 (d, J = 12.3 Hz, 1H) , 2.53 (s, 2H) , 2.33 (d, J = 3.4 Hz, 6H) , 1.97 (d, J = 7.3 Hz, 2H) .

Compound 184A

¹H NMR (400 MHz, MeOD) δ 9.32 (d, J = 5.4 Hz, 1H) , 8.94 (s, 1H) , 8.17 (d, J = 9.5 Hz, 1H) , 8.14 –8.05 (m, 1H) , 7.77 –7.67 (m, 2H) , 7.53 (td, J = 8.9, 2.2 Hz, 1H) , 7.05 –6.83 (m, 2H) , 5.20 (dt, J = 12.9, 6.4 Hz, 1H) , 5.09 (d, J = 2.0 Hz, 1H) , 4.63 –4.29 (m, 5H) , 3.60 (d, J = 4.0 Hz, 3H) , 3.50 –3.40 (m, 1H) , 3.15 –2.78 (m, 2H) , 1.85 (dd, J = 12.7, 3.5 Hz, 2H) .

Compound 184B

¹H NMR (400 MHz, MeOD) δ 9.44 (d, J = 4.5 Hz, 1H) , 9.09 (d, J = 5.7 Hz, 1H) , 8.20 –8.14 (m, 1H) , 8.09 (dd, J = 9.1, 5.6 Hz, 1H) , 7.75 –7.63 (m, 2H) , 7.53 (t, J = 8.8 Hz, 1H) , 7.07 (d, J = 15.7 Hz, 1H) , 6.87 (dd, J = 38.1, 23.0 Hz, 1H) , 5.22 (d, J = 2.1 Hz, 1H) , 5.10 (s, 1H) , 5.02 (d, J = 4.7 Hz, 1H) , 4.94 (d, J = 14.8 Hz, 1H) , 4.86 (s, 2H) , 4.12 –4.05 (m, 1H) , 4.02 –3.93 (m, 1H) , 3.75 (ddd, J = 23.7, 12.5, 4.0 Hz, 1H) , 3.60 (s, 3H) , 3.37 (t, J = 7.0 Hz, 2H) .

Compound 188

¹H NMR (400 MHz, CDCl ₃) δ 9.46 (s, 1H) , 9.15 (s, 1H) , 8.42 (s, 1H) , 8.01 (dd, J = 14.1, 8.3 Hz, 2H) , 7.80 –7.45 (m, 4H) , 7.12 –6.94 (m, 1H) , 6.45 –6.28 (m, 1H) , 5.87 –5.73 (m, 1H) , 4.83 (d, J = 82.9 Hz, 1H) , 4.40 –4.08 (m, 2H) , 4.01 –3.66 (m, 2H) , 3.60 –3.46 (m, 1H) , 3.38 –3.13 (m, 2H) , 3.06 –2.92 (m, 1H) , 2.89 –2.80 (m, 1H) , 2.78 –2.63 (m, 6H) , 2.52 –2.34 (m, 2H) , 1.52 –1.32 (m, 2H) , 1.30 –1.20 (m, 1H) , 1.16 –1.04 (m, 1H) .

Example 145

10-acryloyl-3- (8-chloronaphthalen-1-yl) -4-fluoro-7-methyl-11- ( (methylsulfonyl) methyl) -9, 10, 11, 12-tetrahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-8 (8aH) -one

Step 1. 1-benzyl 4- (tert-butyl) 2-methyl (2S, 5R) -5- ( ( (methylsulfonyl) oxy) methyl) piperazine-1, 2, 4-tricarboxylate

To a stirred solution of 1-benzyl 4- (tert-butyl) 2-methyl (2S, 5R) -5- (hydroxymethyl) piperazine-1, 2, 4-tricarboxylate (660 mg, 1.62 mmol) in DCM (10 mL) was added TEA (491 mg, 4.85 mmol) and MsCl (278 mg, 2.42 mmol) at 0 ℃ under N ₂. The reaction was stirred at 0 ℃ for 1 h, then quenched with water (5 mL) and extracted with DCM (5 mL) . The organic phase was dried over anhydrous Na ₂SO ₄ and concentrated to give 1-benzyl 4- (tert-butyl) 2-methyl (2S, 5R) -5- ( ( (methylsulfonyl) oxy) methyl) piperazine-1, 2, 4-tricarboxylate (884 mg, crude) as a yellow oil. LC/MS (ESI) (m/z) : 487 [M+H] ⁺.

Step 2. 1-benzyl 4- (tert-butyl) 2-methyl (2S, 5R) -5- ( (methylthio) methyl) piperazine-1, 2, 4-tricarboxylate

To a solution of 1-benzyl 4- (tert-butyl) 2-methyl (2S, 5R) -5- ( ( (methylsulfonyl) oxy) methyl) piperazine-1, 2, 4-tricarboxylate (884 mg, crude) in DMF (5 mL) was added NaSMe (113 mg, 1.62 mmol) at r. t. The reaction was stirred at room temperature for 2 hours. The mixture was poured into water (20 mL) and extracted with EtOAc (10 mL x 3) . The combined organic phases were washed with brine (15 mL) , dried over anhydrous Na ₂SO ₄ and concentrated to dryness. The residue was purified by slica gel chromatography (PE: EA=2: 1) to give 1-benzyl 4- (tert-butyl) 2-methyl (2S, 5R) -5- ( (methylthio) methyl) piperazine-1, 2, 4-tricarboxylate (112 mg, 15.8%yield over 2 steps) as a yellow oil. LC/MS (ESI) (m/z) : 439 [M+H] ⁺.

Step 3. 1-benzyl 4- (tert-butyl) 2-methyl (2S, 5R) -5- ( (methylsulfonyl) methyl) piperazine-1, 2, 4-tricarboxylate

To a stirred solution of 1-benzyl 4- (tert-butyl) 2-methyl (2S, 5R) -5- ( (methylthio) methyl) piperazine-1, 2, 4-tricarboxylate (112 mg, 0.26 mmol) in DCM (10 mL) was added m-CPBA (130 mg, 0.64 mmol) at r. t. The reaction was stirred at room temperature for 1h. The reaction was washed with sat. NaHCO ₃ (15 mL) , dried over anhydrous Na ₂SO ₄ and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE: EA=1: 1) to give 1-benzyl 4- (tert-butyl) 2-methyl (2S, 5R) -5- ( (methylsulfonyl) methyl) piperazine-1, 2, 4-tricarboxylate (110 mg, 91.5%yield) as a yellow oil. LC/MS (ESI) (m/z) : 471 [M+H] ⁺

Step 4. 1- (tert-butyl) 3-methyl (3S, 6R) -6- ( (methylsulfonyl) methyl) piperazine-1, 3- dicarboxylate

To a solution of 1-benzyl 4- (tert-butyl) 2-methyl (2S, 5R) -5- ( (methylsulfonyl) methyl) piperazine-1, 2, 4-tricarboxylate (226 mg, 0.48 mmol) in MeOH (10 mL) was added Pd/C (30 mg, 10 wt%) at r. t. The mixture was stirred at room temperature for 1 hour under H ₂. The mixture was filtered and the filtrate was concentrated to dryness to give 1- (tert-butyl) 3-methyl (3S, 6R) -6- ( (methylsulfonyl) methyl) piperazine-1, 3-dicarboxylate (160 mg, 99.0%yield) as a yellow oil. LC/MS (ESI) (m/z) : 337 [M+H] ⁺

Step 5. 1- (tert-butyl) 3-methyl (3S, 6R) -4- (7-chloro-8-fluoro-3-nitro-1, 6-naphthyridin-4-yl) -6- ( (methylsulfonyl) methyl) piperazine-1, 3-dicarboxylate

To a stirred solution of 4, 7-dichloro-8-fluoro-3-nitro-1, 6-naphthyridine (187 mg, 0.71 mmol) and 1- (tert-butyl) 3-methyl (3S, 6R) -6- ( (methylsulfonyl) methyl) piperazine-1, 3-dicarboxylate (160 mg, 0.48 mmol) in dioxane (5mL) was added DIEA (184 mg, 1.43 mmol) . After stirring at 50 ℃ for 12 hours, the reaction mixture was diluted with EtOAc (15 mL) , washed with water (15 mL) , dried over anhydrous Na ₂SO ₄ and evaporated to dryness. The residue was purified by column chromatography on silica gel (PE: EtOAc = 2: 1) to give 1- (tert-butyl) 3-methyl (3S, 6R) -4- (7-chloro-8-fluoro-3-nitro-1, 6-naphthyridin-4-yl) -6- ( (methylsulfonyl) methyl) piperazine-1, 3-dicarboxylate (171 mg, 64.0%yield) as a yellow oil. LC/MS (ESI) (m/z) : 562 [M+H] ⁺

Step 6. tert-butyl (8aS, 11R) -3-chloro-4-fluoro-11- ( (methylsulfonyl) methyl) -8-oxo-7, 8, 8a, 9, 11, 12-hexahydro-10H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridine-10-carboxylate

A mixture of 1- (tert-butyl) 3-methyl (3S, 6R) -4- (7-chloro-8-fluoro-3-nitro-1, 6-naphthyridin-4-yl) -6- ( (methylsulfonyl) methyl) piperazine-1, 3-dicarboxylate (171 mg, 0.30 mmol) , iron powder (170 mg, 3.04 mmol) and NH ₄Cl (163 mg, 3.04 mmol) in EtOH (10 mL) and water (2 mL) was stirred at 80 ℃ for 4 hours. TLC (PE: EtOAc = 1: 1) indicated the reaction was complete. The reaction was filtered immediately and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE: EtOAc = 1: 1) to give tert-butyl (8aS, 11R) -3-chloro-4-fluoro-11- ( (methylsulfonyl) methyl) -8-oxo-7, 8, 8a, 9, 11, 12-hexahydro-10H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridine-10-carboxylate (143 mg, 94.0%yield) as a yellow oil. LC/MS (ESI) (m/z) : 500 [M+H] ⁺

Step 7. tert-butyl (2R, 4aS) -10-chloro-9-fluoro-6-methyl-2- ( (methylsulfonyl) methyl) -5-oxo-1, 2, 4, 4a, 5, 6-hexahydro-3H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] quinoline-3-carboxylate

To a solution of tert-butyl (8aS, 11R) -3-chloro-4-fluoro-11- ( (methylsulfonyl) methyl) -8-oxo-7, 8, 8a, 9, 11, 12-hexahydro-10H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridine-10-carboxylate (143 mg, 0.29 mmol) in DMF (5 mL) was added Cs ₂CO ₃ (280 mg, 0.86 mmol) and MeI (49 mg, 0.34 mmol) at 0 ℃. The reaction was stirred at 0 ℃ for 30 min. LCMS showed the reaction was complete. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (10 mL x 2) . The combined organic phases were washed with brine (20 mL) , dried over anhydrous Na ₂SO ₄ and concentrated to dryness. The residue was purified by column chromatography on silica gel (DCM: MeOH = 20 : 1) to give tert-butyl (2R, 4aS) -10-chloro-9-fluoro-6-methyl-2- ( (methylsulfonyl) methyl) -5-oxo-1, 2, 4, 4a, 5, 6-hexahydro-3H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] quinoline-3-carboxylate (125 mg, 85.0%yield) as a yellow solid. LC/MS (ESI) (m/z) : 513 [M+H] ⁺

Step 8. tert-butyl (8aS, 11R) -3- (8-chloronaphthalen-1-yl) -4-fluoro-7-methyl-11- ( (methylsulfonyl) methyl) -8-oxo-7, 8, 8a, 9, 11, 12-hexahydro-10H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridine-10-carboxylate

To a stirred solution of tert-butyl (2R, 4aS) -10-chloro-9-fluoro-6-methyl-2- ( (methylsulfonyl) methyl) -5-oxo-1, 2, 4, 4a, 5, 6-hexahydro-3H- pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] quinoline-3-carboxylate (120 mg, 0.23 mmol) and 2- (8-chloronaphthalen-1-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (101 mg, 0.35 mmol) in 1, 4-dioxane (10 mL) and water (2 mL) were added K ₂CO ₃ (97 mg, 0.70 mmol) and Ruphos Pd G4 (20 mg, 0.02 mmol) at r. t. The reaction was degassed under N ₂ atmosphere for three times and stirred at 100 ℃ for 18 hours. The reaction was cooled to r. t and filtered. The filtrate was diluted with EtOAc (15 mL) , washed with brine (15 mL) , dried over anhydrous Na ₂SO ₄ and concentrated to dryness. The residue was purified by prep-TLC (PE: EtOAc = 1: 1) to give tert-butyl (8aS, 11R) -3- (8-chloronaphthalen-1-yl) -4-fluoro-7-methyl-11- ( (methylsulfonyl) methyl) -8-oxo-7, 8, 8a, 9, 11, 12-hexahydro-10H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridine-10-carboxylate (40 mg, 26.8%yield ) as a yellow oil. LC/MS (ESI) (m/z) : 640 [M+H] ⁺

Step 9. (8aS, 11R) -3- (8-chloronaphthalen-1-yl) -4-fluoro-7-methyl-11- ( (methylsulfonyl) methyl) -9, 10, 11, 12-tetrahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-8 (8aH) -one

To a solution of tert-butyl (8aS, 11R) -3- (8-chloronaphthalen-1-yl) -4-fluoro-7-methyl-11- ( (methylsulfonyl) methyl) -8-oxo-7, 8, 8a, 9, 11, 12-hexahydro-10H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridine-10-carboxylate (20 mg, 0.03 mmol) in DCM (2 mL) was added TFA (0.5 mL) . The reaction was stirred at 25 ℃ for 2 hours. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to give (8aS, 11R) -3- (8-chloronaphthalen-1-yl) -4-fluoro-7-methyl-11- ( (methylsulfonyl) methyl) -9, 10, 11, 12-tetrahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-8 (8aH) -one (16 mg, 94.8 %yield) as a pink solid. LC/MS (ESI) (m/z) : 540 [M+H] ⁺.

Step 10. (8aS, 11R) -10-acryloyl-3- (8-chloronaphthalen-1-yl) -4-fluoro-7-methyl-11- ( (methylsulfonyl) methyl) -9, 10, 11, 12-tetrahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-8 (8aH) -one

To a solution of (8aS, 11R) -3- (8-chloronaphthalen-1-yl) -4-fluoro-7-methyl-11- ( (methylsulfonyl) methyl) -9, 10, 11, 12-tetrahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-8 (8aH) -one (16 mg, 0.03 mmol) and DIEA (12 mg, 0.09 mmol) in DCM (2 mL) was added a solution of acryloyl chloride (5 mg, 0.05 mmol) in DCM (0.5 mL) at 0 ℃ under N ₂. The reaction was quenched with water (10 mL) and extracted with EtOAc (10 mL) . The organic phase was dried over anhydrous Na ₂SO ₄ and concentrated to dryness. The residue was purified by prep-HPLC (Column: Gemini 5um C18 250*21.2mm; H ₂O (0.1%FA) /CH ₃CN) to give the desired product (5.4 mg, 30.7%yield) . LC/MS (ESI) (m/z) : 594.1 [M+H] ⁺.

¹H NMR (400 MHz, MeOD) δ 9.48 (d, J = 11.6 Hz, 1H) , 9.12 (s, 1H) , 8.14 (d, J = 7.3 Hz, 1H) , 8.02 (d, J = 7.2 Hz, 1H) , 7.74 –7.61 (m, 2H) , 7.60 –7.55 (m, 1H) , 7.50 (t, J = 7.8 Hz, 1H) , 7.09 (dd, J = 16.9, 10.8 Hz, 1H) , 6.25 (d, J = 17.0 Hz, 1H) , 5.84 (d, J = 10.7 Hz, 1H) , 5.41 –5.32 (m, 1H) , 4.58 (s, 1H) , 4.19 –3.82 (m, 4H) , 3.79 –3.69 (m, 1H) , 3.60 (s, 3H) , 3.29 –3.21 (m, 1H) , 3.14 (s, 3H) .

Example 153

(8aS, 11S) -10-acryloyl-3- (8-chloronaphthalen-1-yl) -11- ( (dimethylamino) methyl) -4-fluoro-7-methyl-9, 10, 11, 12-tetrahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-8 (8aH) -one

Step 1. methyl (2S, 5R) -5- (hydroxymethyl) -4- (4-methoxybenzyl) piperazine-2-carboxylate

To a solution of 1- (tert-butyl) 2-methyl (2S, 5R) -5- (hydroxymethyl) -4- (4-methoxybenzyl) piperazine-1, 2-dicarboxylate (1 g, 2.54 mmol) in dioxane (10 mL) was added HCl/dioxane (10 mL) . The reaction mixture was stirred at room temperature for 2hrs. The mixture was concentrated to give the title compound methyl (2S, 5R) -5- (hydroxymethyl) -4- (4-methoxybenzyl) piperazine-2-carboxylate (700 mg, 93.8%) as a white solid.

LC/MS ESI (m/z) : 295 [M+H] ⁺

Step 2. methyl (2S, 5R) -1- (7-chloro-8-fluoro-3-nitro-1, 6-naphthyridin-4-yl) -5- (hydroxymethyl) -4- (4-methoxybenzyl) piperazine-2-carboxylate

At 0℃, to a solution of 4, 7-dichloro-8-fluoro-3-nitro-1, 6-naphthyridine (623 mg, 2.38 mmol) and DIPEA (1.18 mL, 7.14 mmol) in dioxane (20 mL) was added methyl (2S, 5R) -5- (hydroxymethyl) -4- (4-methoxybenzyl) piperazine-2-carboxylate (700 mg, 2.38 mmol) , then the reaction mixture was stirred at 50 ℃ overnight. The reaction mixture was diluted with water, extracted with EA twice. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by silica gel column chromatography to afford methyl (2S, 5R) -1- (7-chloro-8-fluoro-3-nitro-1, 6-naphthyridin-4-yl) -5- (hydroxymethyl) -4- (4-methoxybenzyl) piperazine-2-carboxylate (900 mg, 72.8%) as a yellow oil.

LC/MS ESI (m/z) : 520 [M+H] ⁺

Step 3. (8aS, 11R) -3-chloro-4-fluoro-11- (hydroxymethyl) -10- (4-methoxybenzyl) -9, 10, 11, 12-tetrahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-8 (8aH) -one

To a solution of methyl (2S, 5R) -1- (7-chloro-8-fluoro-3-nitro-1, 6-naphthyridin-4-yl) -5- (hydroxymethyl) -4- (4-methoxybenzyl) piperazine-2-carboxylate (900 mg, 1.73 mmol) in EtOH (10 mL) and H ₂O (2 mL) were added Fe (967 mg, 17.31 mmol) and NH ₄Cl (1.8 g, 34.62 mmol) . The reaction mixture was stirred at 80℃ for 3hrs. Then the mixture was filtered and the solvent was removed from the liquid phase. The residue was diluted with water, extracted with EA twice. The combined organic layers were washed with water and brine, dried and concentrated to give (8aS, 11R) -3-chloro-4-fluoro-11- (hydroxymethyl) -10- (4-methoxybenzyl) -9, 10, 11, 12-tetrahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-8 (8aH) -one (750 mg, 94.6%) as a brown solid..

LC/MS ESI (m/z) : 458 [M+H] ⁺

Step 4. (8aS, 11R) -3-chloro-4-fluoro-11- (hydroxymethyl) -10- (4-methoxybenzyl) -7-methyl-9, 10, 11, 12-tetrahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-8 (8aH) -one

To a solution of (8aS, 11R) -3-chloro-4-fluoro-11- (hydroxymethyl) -10- (4-methoxybenzyl) -9, 10, 11, 12-tetrahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-8 (8aH) -one (700 mg, 1.53 mmol) and Cs ₂CO ₃ (1.5 g, 4.59 mmol) in DMF (20 mL) was added CH ₃I (542 mg, 3.82 mmol) , then the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water, extracted with EA twice. The combined organic layers were washed with water and brine, dried and concentrated to afford (8aS, 11R) -3-chloro-4-fluoro-11- (hydroxymethyl) -10- (4-methoxybenzyl) -7-methyl-9, 10, 11, 12-tetrahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-8 (8aH) -one (650 mg, 90.1%) as a brown solid.

LC/MS ESI (m/z) : 472 [M+H] ⁺

Step 5. (8aS, 11R) -3- (8-chloronaphthalen-1-yl) -4-fluoro-11- (hydroxymethyl) -10- (4-methoxybenzyl) -7-methyl-9, 10, 11, 12-tetrahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-8 (8aH) -one

To a solution of (8aS, 11R) -3-chloro-4-fluoro-11- (hydroxymethyl) -10- (4-methoxybenzyl) -7-methyl-9, 10, 11, 12-tetrahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-8 (8aH) -one (600 mg, 1.27 mmol) , K ₂CO ₃ (879 mg, 6.36 mmol) and 2- (8-chloronaphthalen-1-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (734 mg, 2.54 mmol) in dioxane (10 mL) and H ₂O (2 mL) was added RuPhos Pd G4 (15 mg, 0.02 mmol) , the mixture was stirred at 100℃ overnight under N ₂. The reaction was diluted with ice-water and then extracted with EA twice. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by silica gel column chromatography to give the title compound (8aS, 11R) -3- (8-chloronaphthalen-1-yl) -4-fluoro-11- (hydroxymethyl) -10- (4-methoxybenzyl) -7-methyl-9, 10, 11, 12-tetrahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-8 (8aH) -one (250 mg, 32.9%) as a yellow solid.

LC/MS ESI (m/z) : 598 [M+H] ⁺

Step 6. ( ( (8aS, 11R) -3- (8-chloronaphthalen-1-yl) -4-fluoro-10- (4-methoxybenzyl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) methyl methanesulfonate

To a solution of (8aS, 11R) -3- (8-chloronaphthalen-1-yl) -4-fluoro-11- (hydroxymethyl) -10- (4-methoxybenzyl) -7-methyl-9, 10, 11, 12-tetrahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-8 (8aH) -one (220 mg, 0.37 mmol) , DIPEA (0.18 mL, 1.10 mmol) in DCM (10 mL) was added MsCl (0.04 mL, 0.55 mmol) at 0℃. The reaction mixture was stirred at RT for 1 hour. The reaction mixture was quenched with aq. Na2CO3 and then extracted with EA twice. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by silica gel column chromatography to give the title compound ( ( (8aS, 11R) -3- (8-chloronaphthalen-1-yl) -4-fluoro-10- (4-methoxybenzyl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) methyl methanesulfonate (240 mg, 96.5%) as a yellow oil.

LC/MS ESI (m/z) : 676 [M+H] ⁺

Step 7. (8aS, 11S) -3- (8-chloronaphthalen-1-yl) -11- ( (dimethylamino) methyl) -4-fluoro-10- (4-methoxybenzyl) -7-methyl-9, 10, 11, 12-tetrahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-8 (8aH) -one

To a solution of ( ( (8aS, 11R) -3- (8-chloronaphthalen-1-yl) -4-fluoro-10- (4-methoxybenzyl) -7-methyl-8-oxo-8, 8a, 9, 10, 11, 12-hexahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-11-yl) methyl methanesulfonate (240 mg, 0.36 mmol) in THF (5 mL) was added Dimethylamine (～2.0 M in THF) (1.78 mL, 3.55 mmol) . The reaction mixture was stirred at 60℃ overnight. Then the mixture was filtered and the solvent was removed from the liquid phase. The residue was diluted with water, extracted with EA twice. The combined organic layers were washed with water and brine, dried and concentrated to give (8aS, 11S) -3- (8-chloronaphthalen-1-yl) -11- ( (dimethylamino) methyl) -4-fluoro-10- (4-methoxybenzyl) -7-methyl-9, 10, 11, 12-tetrahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-8 (8aH) -one (120 mg, 54.1%) as a brown solid.

LC/MS ESI (m/z) : 625 [M+H] ⁺

Step 8. (8aS, 11S) -3- (8-chloronaphthalen-1-yl) -11- ( (dimethylamino) methyl) -4-fluoro-7-methyl-9, 10, 11, 12-tetrahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-8 (8aH) -one

To a solution of (8aS, 11S) -3- (8-chloronaphthalen-1-yl) -11- ( (dimethylamino) methyl) -4-fluoro-10- (4-methoxybenzyl) -7-methyl-9, 10, 11, 12-tetrahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-8 (8aH) -one (40 mg, 0.06 mmol) in TFA (3 mL) was added thioanisole (0.07 mL, 0.59 mmol) . The reaction mixture was stirred at 40 ℃ for overnight. The mixture was poured slowly to ice-cooled sat. NaHCO ₃ with stirring for 30 min. The mixture was extracted with DCM twice. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by silica gel column chromatography to afford the title compound (8aS, 11S) -3- (8-chloronaphthalen-1-yl) -11- ( (dimethylamino) methyl) -4-fluoro-7-methyl-9, 10, 11, 12-tetrahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-8 (8aH) -one (35 mg, 88.4 %) as a yellow oil.

LC/MS ESI (m/z) : 505 [M+H] ⁺

Step 9. (8aS, 11S) -10-acryloyl-3- (8-chloronaphthalen-1-yl) -11- ( (dimethylamino) methyl) -4-fluoro-7-methyl-9, 10, 11, 12-tetrahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-8 (8aH) -one

To a suspension of (8aS, 11S) -3- (8-chloronaphthalen-1-yl) -11- ( (dimethylamino) methyl) -4-fluoro-7-methyl-9, 10, 11, 12-tetrahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-8 (8aH) -one (30 mg, 0.07 mmol) and DIPEA (0.03 mL, 0.15 mmol) in DCM (5 mL) under nitrogen at 0℃ was added acryloyl chloride (0.01 mL, 0.10 mmol) dropwise and reaction mixture stirred at 0℃. The reaction mixture was stirred at room temperature for 2 hrs. The mixture was quenched with water, extracted with EA twice. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by silica gel column chromatography to give crude product which was further purified by prep-HPLC to give (8aS, 11S) -10-acryloyl-3- (8-chloronaphthalen-1-yl) -11- ( (dimethylamino) methyl) -4-fluoro-7-methyl-9, 10, 11, 12-tetrahydro-7H-pyrazino [1', 2': 4, 5] pyrazino [2, 3-c] [1, 6] naphthyridin-8 (8aH) -one (5.3 mg, 13.8%) .

LC/MS ESI (m/z) : 559 [M+H] ⁺

¹H NMR (400 MHz, MeOD) δ 9.50 (t, J = 17.4 Hz, 1H) , 9.13 (d, J = 5.8 Hz, 1H) , 8.15 (d, J = 7.8 Hz, 1H) , 8.03 (d, J = 7.4 Hz, 1H) , 7.71 –7.58 (m, 3H) , 7.51 (t, J = 7.8 Hz, 1H) , 7.07 (dt, J = 137.6, 68.8 Hz, 1H) , 6.25 (dd, J = 16.9, 1.8 Hz, 1H) , 5.80 (t, J = 15.6 Hz, 1H) , 4.35 (d, J = 15.4 Hz, 1H) , 3.96 (dd, J = 11.1, 3.9 Hz, 1H) , 3.84 (d, J = 14.6 Hz, 1H) , 3.79 –3.63 (m, 2H) , 3.59 (d, J = 4.2 Hz, 3H) , 3.11 (ddd, J = 14.9, 11.8, 8.1 Hz, 2H) , 2.96 –2.82 (m, 1H) , 2.40 (t, J = 9.1 Hz, 6H) .

Biology assay

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

Phospho-ERK 1/2 assay in H358:

Allow H358 cell growth in a T75 flask in RPMI-1640 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%CO ₂ 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.

Table A shows the results of the exemplary compounds.

Table A

Example No.	H358 pERK IC ₅₀ (nM)
1A	6.2
1B	272
2A	977
3A	41
3B	964
4A	10
4B	249
5	166
6	29
7A	5.9
7B	255
8A	2.4
8B	196
10A	112
22A	10
22B	293
23A	311
24A	172
25A	15
25B	145
37A	101
51A	22
51B	570
52	532
65	67
70	32
71	255
146	292
148A	23
148B	394
149A	3.8

149B	897
150A	286
151A	4.8
152A	222
161B	971
162A	276
165A	74
167A	335
174A	17
174B	524
182	293
183	161
184A	11.8
185A	354
186A	280
187A	496

The compounds of the present disclosure show IC ₅₀ value of 0.5 to 10000 nM. Some compounds of the present disclosure show IC ₅₀ value of 1-5000 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.

KRAS (G12C) : SOS1 Nucleotide Exchange Assay

Thaw GDP loaded KRAS (G12C) and dilute GDP loaded KRAS (G12C) to 500 nM in RBD-RAS binding buffer. Prepare the master mixture (6 μl) : 96 wells × (1 μl diluted GDP loaded KRAS (G12C) , 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 thaw 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

H358 (ATCC CRL-5807) 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.

KRAS-G12C/cRAF Binding Assay

Thaw the frozen reagents on ice. Dilute the 500 X Tag2-KRAS-G12C protein stock solution (Cisbio, 63ADK000CB20PEG) and the 10 mM GTP (Sigma, V900868) stock solution with diluent buffer (Cisbio, 62DLBDDF) to prepare a working solution. Dilute the 100 X Anti-Tag1-Eu3+stock solution (Cisbio, 63ADK000CB20PEG) and 50 X anti-Tag2-XL665 (Cisbio, 63ADK000CB20PEG) stock solution with detection buffer (Cisbio, 62DB1FDG) to prepare a working solution. Dilute compounds in DMSO by hand for 10 points, 3 folds dilution. Then transfer 0.2 μL compounds to 384 assay plate by ECHO. Add 5 μL specified concentration of KRAS G12C&GTP to 384 assay plate, Centrifuge 1000 RPM for 1 min. Add 5 μL specified concentration of cRAF (Cisbio, 63ADK000CB20PEG) to the assay plate, centrifuge 1000 RPM for 1 min. Incubate at 25℃ for 15 min. Add 10 μL anti-Tag1-Eu and anti-Tag2-XL665 mixture to the assay plates. Centrifuge 1000 RPM for 1 min, incubate at 4℃ for 2h. Read the 665 /615 nm Ratio on Envision. Data analysis: A ratio (Ratio665nm/615nm) is calculated for each well. %Inhibition is calculated as follow:

%inhibition = 100- (Signal _cmpd-Signal _{Ave_PC}) / (Signal _{Ave_VC}-Signal _{Ave_PC}) ×100

Signal _{ave_pc}: The average ratio for the positive controls across the plate.

Signal _{ave_vc:} The average ratio for negative controls across the plate.

Calculate IC50 and Plot effect-dose curve of cmpds: Calculate IC50 by fitting % Inhibition values and log of compound concentrations to nonlinear regression (dose response –variable slope) with Graphpad 8.0.

Y=Bottom + (Top-Bottom) / (1+10^ ( (LogIC50-X) *HillSlope) )

X: log of Inhibitor concentration; Y: %Inhibition.

cRAF binding assay was carried out with the compounds of the present disclosure as well as Reference compound 1 AMG-510 (Sotorasib) . Table B shows the results of the exemplary compounds and Reference Compound 1.

Table B

Ex#	cRAF binding assay IC50 (nM)
Ref 1	2521
1A	48
25A	55

The compounds of the present disclosure show IC ₅₀ value of 0.5 to 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.

DMPK studies

DMPK studies were carried out with the compounds of the present disclosure as well as Reference compound 1 AMG-510 (Sotorasib) , and Reference compound 2 MRTX849 (Adagrasib) using the following assays: a) : MDCK-MDR1 Pgp assessment, and b) MDCK-BCRP BCRP assessment.

Assay a) : MDCK-MDR1 Pgp assessment

Efflux transport mediated by P-glycoprotein (Pgp) was assessed by MDCK-MDR1 cells. The final concentrations of test compounds and control compound were at 1 μM. The multi-well insert plate was incubated at 37 ℃ for 2 hours.

Assay b) : MDCK-BCRP BCRP assessment

Efflux transport mediated by Breast Cancer Resistance Protein (BCRP) was assessed by MDCK-BCRP cells. The final concentrations of test compounds and control compound were at 1 μM. The multi-well insert plate was incubated at 37 ℃for 1.5 hours.

Efflux ratio (ER) of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) reflects the potential of a compound to be pumped out of the brain by BBB efflux transporters. Substrates of P-gp and/or BCRP generally have brain penetration impairment.

From Table C, Ref compounds 1 and 2 are strong Pgp and/or BCRP substrates, which prevent the entry of these compounds into the interstitial space of the brain. In contrast, examples in Table C show great improvement towards efflux liabilities.

Table C

For the other Example compounds for which the results are not shown, all are expected to be comparable improvement towards Pgp and BCRP efflux liabilities. For some of the Example compounds, the results for Pgp ER, BCRP ER are comparable or even slightly better than those of the exemplary compounds in Table C.

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) :

or a pharmaceutically acceptable salt thereof,

wherein

is a single bond or double bond;

G is C (R ^a) or N;

Z is
or

R ^a is absent, hydrogen, deuterium, cyano, halogen, alkyl, haloalkyl, heteroalkyl, hydroxyalkyl, or -C (O) N (R ^c) ₂;

each R ^b is independently hydrogen, deuterium, halogen, cyano, alkyl, alkoxy, heteroalkyl, cycloalkyl, or heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of hydroxyl, halogen, -NR ^cR ^d, and heterocyclyl optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano and amino;

each R ^c is independently hydrogen, alkyl, alkenyl, alkynyl or haloalkyl;

R ^d is selected from the group consisting of alkyl optionally substituted with heteroaryl or -N (R ^c) ₂, haloalkyl, -C (O) N (R ^c) ₂, - (CH ₂) _nNHC (O) -alkyl, heterocyclyl, and heteroaryl, wherein the heterocyclyl and heteroaryl is optionally substituted with one or more groups independently selected from halogen, hydroxyl, amino, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, heteroalkyl, hydroxyalkyl, -O-haloalkyl and –S-haloalkyl;

W is CR ^e or N;

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

Q is CR ^f or N;

R ^f is –Y- (CH ₂) _m-T-R ^g, wherein - (CH ₂) _m-is optionally substituted with hydroxyl, halogen, cyano or amino;

Y is selected from a bond, -O-, -S-, -N (R ^c) -, or alkynyl;

T is selected from 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 oxo, hydroxyl, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl;

R ^g is selected from the group consisting of hydrogen, hydroxyl, halogen, -OR ^c, -N (R ^c) ₂, -N (R ^c) SO ₂-alkyl, alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -COOH, -CH ₂OC (O) -heterocyclyl, -NHC (=NH) NH ₂, -C (O) N (R ^c) ₂, - (CH ₂OR ^c) (CH ₂) _pOR ^c, and -N (R ^c) C (O) -aryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R’, and the aryl portion in -N (R ^c) C (O) -aryl and the heterocyclyl portion in -CH ₂OC (O) -heterocyclyl is optionally substituted with one or more R”;

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

each R” is independently selected from oxo, hydroxyl, halogen, alkyl, heteroalkyl, hydroxyalkyl, haloalkyl, alkoxy, -E-phenyl, -E-phenylSO ₂F, -N (R ^c) 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;

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

each of R ^1a, R ^1b, R ^2a, R ^2b, R ^3a, R ^3b, and R ⁴ is independently selected from absent, hydrogen, oxo, hydroxyl, halogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, -C (O) OR ^c, -C (O) N (R ^c) ₂, -N (R ^c) 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 ^c, -N (R ^c) ₂, or -SO ₂ (R ^c) ; or

two of R ^1a, R ^1b, R ^2a, R ^2b, R ^3a, R ^3b, and R ⁴ together with the carbon atom (s) they are attached form alkyl, alkenyl, cycloalkyl or heterocyclyl, said alkyl, cycloalkyl or heterocyclyl are optionally substituted with one or more groups independently selected from cyano, halogen, hydroxyl, amino, alkoxy, alkyl, alkenyl, or alkynyl;

L ¹ is a bond, - [C (R ^h) ₂] _u-*, - [C (R ^h) ₂] _u-C (O) -*or –N (R ^c) C (O) -*, wherein *denotes a point of attachment of L ¹ to L ²;

L ² is a bond, -O-, -N (R ⁱ) -, or -S (O) _v-;

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

R ⁱ is selected from absent, hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, or -C (O) -heterocyclyl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl and cycloalkyl are optionally substituted with one or more R”’ , and the heterocyclyl portion in -C (O) -heterocyclyl is optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, alkyl and -N (R ^c) ₂;

or R ^h and R ⁱ together with the carbon atom and nitrogen atom they are attached respectively form a heterocyclyl or heteroaryl optionally substituted with one or more groups independently selected from cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, hydroxyalkyl, alkyl or -alkyl-N (R ^c) ₂;

each R”’ is independently selected from -N (R ^c) ₂, hetercyclyl optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, or alkyl;

L ³ is a bond, -C (O) -, or alkyl;

R ⁵ is hydrogen, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R ^j;

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

n is 0, 1 or 2;

m is an integer from 0 to 4;

p is an integer from 0 to 2;

r is 1 or 2;

u is an integer from 0 to 4;

v is an integer from 0 to 2;

provided that

when one of
is a double bond, then the other
is a single bond;

when
is a triple bond, then R ^a is absent, R ^b is present and r is 1;

or when
is a double bond, then R ^a is present, R ^b is present and r is 2, or R ^a and R ^b and the carbon atom to which they are attached form cycloalkyl optionally substituted with one or more R ^e.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein both
are single bond, G is C (R ^a) , and R ^a is hydrogen.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein both
are single bond, and G is N.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Z is N-C (O) -C (R ^a) =C (R ^b) _r.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Z is N-SO ₂C (R ^a) =C (R ^b) _r.
The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ^a is hydrogen, deuterium, cyano, halogen, or alkyl.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Z is N-C (O) -C≡C (R ^b) _r.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Z is N-SO ₂C≡C (R ^b) _r.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Z is N-C (R ^a) ≡C (R ^b) _r.
The compound of any one of preceding claims, or a pharmaceutically acceptable salt thereof, wherein each R ^b is independently hydrogen, deuterium, alkyl, heteroalkyl, cycloalkyl, or heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of halogen, -NR ^cR ^d, and heterocyclyl optionally substituted with one or more groups selected from hydroxyl, halogen, cyano and amino.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein W is N.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein W is CR ^e.
The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein R ^e is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -OR ^c, alkyl, alkenyl, and alkynyl, wherein alkyl, alkenyl, and alkynyl are optionally substituted with one or more groups independently selected from the group consisting of hydroxyl, halogen, cyano, -OR ^c, and -N (R ^c) ₂.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Q is N.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Q is CR ^f, and R ^f is –Y- (CH ₂) _m-T-R ^g.
The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein Y is a bond, -O-or -S-.
The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein T is heterocyclyl optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl.
The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein Y is -N (R ^c) -.
The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein T is a bond.
The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein Y is alkynyl.
The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein T is a bond.
The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein T is a heterocyclyl optionally substituted with one or more groups independently selected from oxo, hydroxyl, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl.
The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein T is a heterocyclyl selected from the group consisting of:

each of which is optionally substituted with one or more groups independently selected from oxo, hydroxyl, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl.
The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein R ^g is selected from the group consisting of hydrogen, hydroxyl, halogen, alkyl, -N (R ^c) ₂, or -OR ^c.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each of R ^1a, R ^1b, R ^2a, R ^2b, R ^3a, R ^3b, and R ⁴ is independently selected from hydrogen, alkyl or heteroalkyl, wherein the alkyl and heteroaryl are optionally substituted with one or more groups independently selected from cyano, hydroxyl, halogen, -OR ^c, -N (R ^c) ₂, or -SO ₂ (R ^c) .
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein two of R ^1a, R ^1b, R ^2a, R ^2b, R ^3a, R ^3b, and R ⁴ together with the carbon atom (s) they are attached form an alkyl.
The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein R ^1a and R ^3a together with the carbon atoms they are attached form propyl or butyl.
The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein R ^1a and R ⁴ together with the carbon atoms they are attached form propyl or butyl.
The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein R ^2a and R ^3a together with the carbon atoms they are attached form propyl or butyl.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein two of R ^1a, R ^1b, R ^2a, R ^2b, R ^3a, R ^3b, and R ⁴ together with the carbon atom (s) they are attached form an alkenyl.
The compound of claim 30, or a pharmaceutically acceptable salt thereof, wherein R ^1a and R ^3a together with the carbon atoms they are attached form butenyl.
The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein R ^1a and R ⁴ together with the carbon atoms they are attached form butenyl.
The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein R ^2a and R ^3a together with the carbon atoms they are attached form butenyl.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein two of R ^1a, R ^1b, R ^2a, R ^2b, R ^3a, R ^3b, and R ⁴ together with the carbon atom (s) they are attached form a cycloalkyl or heterocyclyl.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R ^1a and R ^1b together with the carbon atom they both are attached form C _3-6 cycloalkyl or C _3-6 heterocyclyl.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R ^2a and R ^2b together with the carbon atom they both are attached form C _3-6 cycloalkyl or C _3-6 heterocyclyl.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R ^3a and R ^3b together with the carbon atom they both are attached form C _3-6 cycloalkyl or C _3-6 heterocyclyl.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R ^1a and R ^2a together with the carbon atom they both are attached form C _3-6 cycloalkyl or C _3-6 heterocyclyl.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R ^3a and R ⁴ together with the carbon atom they both are attached form C _3-6 cycloalkyl or C _3-6 heterocyclyl.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L ¹ is a bond.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L ¹ is - [C (R ^h) ₂] _u-*.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L ¹ is - [C (R ^h) ₂] _u-C (O) -*.
The compound of claim 41 or 42, or a pharmaceutically acceptable salt thereof, wherein R ^h is hydrogen, and u is 0, 1, 2 or 3.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L ¹ is –N (R ^c) C (O) -*.
The compound of claim 44, or a pharmaceutically acceptable salt thereof, wherein R ^c is hydrogen.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L ¹ is -S (O) _v-.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L ² is a bond.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L ² is -O-.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L ² is -N (R ⁱ) -.
The compound of claim 49, or a pharmaceutically acceptable salt thereof, wherein R ⁱ is hydrogen, alkyl, cycloalkyl, or -C (O) -heterocyclyl, wherein the alkyl and cycloalkyl are optionally substituted with one or more R”’ , and the heterocyclyl portion in -C (O) -heterocyclyl is optionally substituted with one or more groups independently selected from alkyl or -N (R ^c) ₂.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L ¹ is - [C (R ^h) ₂] _u-*, L ² is -N (R ⁱ) -, u is 1, and R ^h and R ⁱ together with the carbon atom and nitrogen atom they are attached respectively form a heteroaryl optionally substituted with one or more groups independently selected from cyano, halogen, hydroxyl, haloalkyl, hydroxyalkyl, alkyl or -alkyl-N (R ^c) ₂.
The compound of claim 51, or a pharmaceutically acceptable salt thereof, wherein the heteroaryl is triazolyl or imidazolyl.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L ³ is a bond.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L ³ is -C (O) -.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L ³ is alkyl.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is aryl optionally substituted with one or more R ^j.
The compound of claim 56, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is aryl selected from phenyl, naphthyl or 2, 3-dihydro-1H-indenyl, each of which is optionally substituted with one or more R ^j.
The compound of claim 57, or a pharmaceutically acceptable salt thereof, wherein R ^j is hydroxyl, halogen, amino, alkyl, alkynyl, haloalkyl or cycloalkyl.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is heteroaryl optionally substituted with one or more R ^j.
The compound of claim 59, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is heteroaryl selected from pyridinyl, quinolinyl, isoquinolinyl, indazolyl, or benzo [b] thiophenyl, each of which is optionally substituted with one or more R ^j.
The compound of claim 60, or a pharmaceutically acceptable salt thereof, wherein R ^j is hydroxyl, halogen, amino, alkyl or alkynyl.
The compound of claim 1, having Formula (Ia) , Formula (Ib) or Formula (Ic) :

or a pharmaceutically acceptable salt thereof,

wherein ring A is a heterocyclyl or heteroaryl optionally substituted with one or more groups independently selected from cyano, halogen, hydroxyl, amino, alkyl, alkoxy, haloalkyl, hydroxyalkyl, or -alkyl-N (R ^c) ₂.
The compound of claim 62, or a pharmaceutically acceptable salt thereof, wherein both
are single bond.
The compound of claim 62, or a pharmaceutically acceptable salt thereof, wherein Q is CR ^f.
The compound of claim 62, or a pharmaceutically acceptable salt thereof, wherein Q is N.
The compound of claim 62, or a pharmaceutically acceptable salt thereof, wherein L ³ is a bond.
The compound of any one of claims 62 to 66, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is aryl or heteroaryl, each optionally substituted with one or more R ^j.
The compound of claim 67, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is selected from the group consisting of phenyl, naphthyl, 2, 3-dihydro-1H-indenyl, pyridinyl, quinolinyl, isoquinolinyl, indazolyl, and benzo [b] thiophenyl, each of which is optionally substituted with one or more R ^j.
The compound of any one of claims 62 to 68, or a pharmaceutically acceptable salt thereof, wherein u is 0 or 1.
The compound of claim 1 selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition comprising the compound of any one of claims 1-70 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
A method for inhibiting KRas G12C activity in a subject in need thereof, comprising administering an effective amount of a compound of any one of claims 1-70 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 71 to the subject.
A method for treating a KRas G12C-associated cancer comprising administering an effective amount of a compound of any one of claims 1-70 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 71 to a subject in need thereof.
The method of claim 73, wherein the KRas G12C-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 74, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer.
The method of claim 75, wherein the cancer is with brain metastasis.
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 G12C mutation; and (b) administering to the subject an effective amount of a compound of any one of claims 1-70 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 71.
The method of any one of claims 72-77, 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 72-78, wherein the compound is administered simultaneously, separately or sequentially with one or more additional therapeutic agents.
The method of claim 79, 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 SOS1 inhibitor, a mTOR inhibitor, a VEGFR inhibitor, EGFR antibody, a platinum agent or pemetrexed.
Use of the compound of any one of claims 1-70 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 71 in the manufacture of a medicament for treating cancer.
A compound of any one of claims 1-70 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 71, for use in the treatment of cancer.