CN117222646A - KRAS G12C inhibitors and uses thereof - Google Patents

Abstract

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

Description

KRAS G12C inhibitors and uses thereof

Technical Field

The present disclosure relates generally to novel compounds useful as KRAS G12C inhibitors, pharmaceutical compositions comprising these compounds and methods of treatment by administration of these compounds or the pharmaceutical compositions.

Background

RAS is one of the most well known proto-oncogenes. Its gain of function mutation occurs in about 30% of human cancers. KRAS (Kirsten rat sarcoma virus oncogene homolog), the most common mutant RAS isoform, has been extensively studied over the past few years. KRAS and highly related NRAS and HRAS gtpases hydrolyze Guanosine Triphosphate (GTP) to Guanosine Diphosphate (GDP). It controls a variety of cellular functions by cycling between an active GTP-binding conformation and an inactive GDP-binding conformation (Hobbs, G.A. et al, J.Cell Sci.) "129, 1287-1292, (2016)).

KRAS is an important Oncogene that has been shown to drive tumorigenesis (G G Jinesh et al, oncogene, volume 37, pages 839-846 (2018)). K-RAS also regulates many genetic regulatory mechanisms and forms a large tumorigenic network. The KRAS gene encodes a 21 kDa protein, referred to as KRAS, which is part of the RAS/MAPK pathway. KRAS protein is a GTPase enzyme, meaning that it binds with high affinity to the guanosine nucleotides GDP and guanosine-triphosphate (GTP) and hydrolyzes GTP to GDP (Dhirendra K.Simanshu et al, cell (Cell) 29, 2017, 6, 170 (1): 17-33). The GDP/GTP cycle is tightly regulated by a variety of families of multi-domain proteins: guanosine nucleotide exchange factors (GEFs) and Gtpase Activating Proteins (GAPs). GEF stimulates dissociation and subsequent GTP association of GDP, thereby activating KRAS protein, whereas GAP accelerates intrinsic GTP hydrolysis, thereby converting KRAS into its inactive state (Dhirendra k.simansu et al, cell 2017, month 6, 29; 170 (1): 17-33). The GTP-bound form of KRAS is considered to be the active form and downstream signal effectors bind specifically to the GTP-bound form of KRAS. When KRAS protein binds to GDP, the protein is turned off (inactivated) and no signal is relayed to the nucleus.

KRAS mutations are present in up to 25% of cancers, with oncogenic variants having different prevalence in different cancers. As one of the most common KRAS mutations, the G12C mutation is present in an estimated about 14% of lung adenocarcinomas and 3% of colon adenocarcinomas. According to the american cancer society (American Cancer Society) data, about 200,000 patients are diagnosed with lung adenocarcinoma each year. This has resulted in 14,000-28,000 patients in the KRAS-G12C population annually in the united states. In the case of KRAS-G12C positive colorectal cancer (CRC), nearly 3,000 patients are diagnosed each year. KRAS-G12C accounts for more than 40% of all KRAS mutations, and thus has 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 the bound GTP from rapid regulatory hydrolysis catalyzed by GTPase Activating Protein (GAP) family proteins, resulting in overall pathway activation (Victoria Dunnett-Kane et al Cancer (Cancer) Basel 2021 month 1; 13 (1): 151).

Brain is a common site of metastasis in NSCLC patients, 25% -30% of which appear at diagnosis, and most (40-50%) of which develop brain metastasis during their course (Timothy G et al, study of transformed lung cancer (Transl Lung Cancer Res) 2013;2 (4): 273-283). Patients with KRAS-G12C NSCLC have a high prevalence of Brain Metastases (BM); 28% of patients have BM at diagnosis and 40% of patients have BM during follow-up (W.Cui et al, lung Cancer 146 (2020) 310-317). The incidence of BM in CRC is in the range of 0.6% to 3.2%. In many patients, metastatic spread of CRC is thought to progress sequentially, from liver to lung, and then to bone and brain as late affected sites. Remarkably, nearly two-thirds of brain metastases were identified to occur in RAS mutant mCRC, and the total survival (OS) of patients with KRAS-G12C mutant mCRC was shorter than that of patients with other KRAS mutant cancers (Sophie muller et al, cancer 2021,13,900).

The incidence of brain metastases is increasing due to improvements in diagnostic techniques and increased survival in cancer patients through advanced systemic treatment. It is estimated that the brain metastasis rate of the extracranial solid tumor is now about 10 times that of the primary malignant brain tumor (Kromer, c. Et al, journal of neurooncology (j. Neuroobol.)) 134,55-64 (2017)).

Treatment options for lung cancer or colon adenocarcinoma brain metastases are limited and include topical treatments (surgical excision, whole Brain Radiation Therapy (WBRT), stereotactic Radiosurgery (SRS) and systemic treatments (chemotherapy and targeted therapies), which are intended to alleviate symptoms (palliative), but can cause serious side effects (nerve damage, "tumor leakage", cognitive deterioration.) the big problem of systemic treatment of brain metastases is that systemic drugs cannot penetrate the blood-brain barrier (BBB). Furthermore, many small targeted drugs are substrates of active efflux pumps in the BBB, such as P-glycoprotein (P-gp) and breast cancer drug resistance protein (BCRP), which prevent these agents from entering the brain interstitial space (Riccardo Soffietti et al, natural review neurology (Nature Reviews Neurology), volume 16, pages 557-574 (2020)).

The research community has made great efforts in developing drugs that target KRAS mutations, but until recently, has not been successful enough, resulting in KRAS being considered "drug-free". Two main reasons are proposed: first, RAS has picomolar affinity for guanine nucleotides, whereas cell concentrations of guanine nucleotides are in the millimolar range, which is detrimental to the binding of nucleotide analogs; second, outside the nucleotide binding pocket, RAS appears to lack a deep pocket suitable for small molecule binding. Attempts to directly target KRAS have been hampered by their structure: KRAS presents a smooth surface without deep hydrophobic pockets that can tightly bind. Thus, past efforts have shifted emphasis to other targets. Recently, development of several small molecule inhibitors of KRAS-G12C has achieved greater success. ARS-1620 was the first G12C-specific inhibitor to demonstrate efficacy in vivo, and since then several other related compounds with enhanced biological activity have been produced, of which Adraganib (MRTX 849) and Sotorasib (AMG-510) (Janes, M.R. et al, cells (Cell), 172,578-589.e17 (2018), canon, J. Et al, nature, 575,217-223 (2019), hallin, J. Et al, cancer discovery (Cancer discover), 10,54-71 (2020)), were the earliest to enter the clinic. These compounds rely on mutant cysteines to bind, disrupt switch-I// II, and convert KRAS preference from GTP to GDP, thus placing KRAS in an inactive GDP-binding state (Ostrem, j.m. et al, nature cell biology (Nature cell biol.)) 503,548-551 (2013). Indeed, KRAS G12C appears to retain near wild-type gtpase activity levels and undergo nucleotide cycling in cells. The role of the G12C inhibitor is to prevent further nucleotide exchange, thus "trapping" the protein in an inactive state (Janes, M.R. et al, cell 172,578-589.E17 (2018)). The inherent gtpase activity of KRAS-G12C not only demonstrates the efficacy of direct inactive status inhibitors, but also broadens the possibility of effective upstream targeting in G12C mutant cancers. Brain metastases of extracranial solid tumors show increased related unmet needs, as their incidence is greatly rising. The fields of targeted therapies and immunotherapy for brain metastasis are rapidly expanding.

In summary, 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 with KRAS-G12C mutations. KRAS-G12C is one of the most common driving oncoproteins and relies on nucleotide exchange for activation and is sensitive to drugs that block this process. The inactive state selective inhibitor disrupts the circulation and traps KRAS-G12C in its GDP-binding state to inhibit tumor growth in cancer patients.

Therefore, there is a need to develop new KRAS-G12C selective inhibitors that demonstrate sufficient efficacy for targeting KRAS-G12C, in particular new KRAS-G12C selective inhibitors with BBB penetration, and thus are promising for the treatment of KRAS-G12C lung cancer and colorectal cancer patients, especially brain metastasis patients.

Disclosure of Invention

Disclosed herein are novel compounds capable of inhibiting KRAS G12C protein. Thus, the compounds of the present disclosure are useful for treating KRAS G12C-related diseases, such as cancer.

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

or a pharmaceutically acceptable salt thereof,

wherein the method comprises the steps of

Ring a is heterocyclyl or heteroaryl;

u is C (R) ^a ) Or N;

g is N-C (O) -C (R) ^a )C(R ^b ) _r Or N-SO ₂ C(R ^a )C(R ^b ) _r ；

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

Each R ^b Independently is hydrogen, deuterium, halogen, cyano, alkyl, alkoxy, heteroalkyl, or heteroaryl, wherein the alkyl, the heteroalkyl, and the heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of: hydroxy, halogen, -NR ^c R ^d And heterocyclyl optionally substituted with one or more groups independently selected from hydroxy, halogen, cyano, and amino;

each R ^c Independently hydrogen, deuterium, alkyl, alkenyl, alkynyl or haloalkyl;

R ^d selected from the group consisting of: optionally heteroaryl or N (R) ^c ) ₂ Substituted alkyl, haloalkyl, -C (O) N (R) ^c ) ₂ 、-(CH ₂ ) _n NHC (O) -alkyl, heterocyclyl, and heteroaryl, wherein the heterocyclyl and heteroaryl are optionally substituted with one or more groups independently selected from: halogen, hydroxy, amino, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, heteroalkyl, hydroxyalkyl, -O-haloalkyl and-S-haloalkyl；

W is C (R) ^e ) Or N;

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

Each R is independently selected from the group consisting of: oxo, hydroxy, halogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, -C (O) OR ^c 、-C(O)N(R ^c ) ₂ 、-N(R ^c ) ₂ And heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, and said heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of: cyano, hydroxy, halogen, -OR ^c or-N (R) ^c ) ₂ ；

Ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted with one or more R ^f Substitution;

each R ^f Independently selected from the group consisting of: oxo, hydroxy, halo, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of: hydroxy, halogen, cyano, -OR ^c 、-N(R ^c ) ₂ And heteroaryl;

t is O or S;

y is aryl or heteroaryl, each of which is optionally substituted with one or more R ^f Substitution;

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

q is- (CH) ₂ ) _m V-, wherein- (CH) ₂ ) _m -optionally substituted with hydroxy, halogen, cyano or amino;

V is selected from bond, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally substituted with one or more groups independently selected from: hydroxy, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl;

z is selected from the group consisting of: hydrogen, hydroxy, halogen, -N (R) ^c ) ₂ Alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -COOH, -NHC (=nh) NH ₂ 、-C(O)N(R ^c ) ₂ 、-OR ^c 、-(CH ₂ OR ^c )(CH ₂ ) _p OR ^c 、-N(R ^c ) C (O) -aryl, -N (R) ^c ) C (O) -heterocyclyl, -C (O) N (R) ^c ) -heterocyclyl and- (CH) ₂ ) _p -heterocyclyl, wherein said cycloalkyl, said heterocyclyl, said aryl and said heteroaryl are optionally substituted with one or more R ^g Substituted, and-N (R) ^c ) Aryl moieties in C (O) -aryl and- (CH) ₂ ) _p The heterocyclyl moiety in the heterocyclyl is optionally substituted with one or more R ^h Substitution;

each R ^g Independently selected from hydroxy, halogen, -C (O) H, alkyl, alkoxy, haloalkyl, hydroxyalkyl, or-N (R) ^c ) ₂ ；

Each R ^h Independently selected from oxo, hydroxy, halogen, alkyl, heteroalkyl, hydroxyalkyl, haloalkyl, alkoxy, -M-phenyl, -M-phenylSO ₂ F、-N(R ^c ) ₂ 、-SO ₂ F. -C (O) (alkyl) or-C (O) (haloalkyl), wherein said alkyl, said heteroalkyl, said hydroxyalkyl, said haloalkyl and said alkoxy are optionally substituted with one or more groups independently selected from aryl, heteroaryl or t-butyldimethylsilyloxy;

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

l is-L ¹ -L ² -L ³ -；

L ¹ And L ³ Independently selected from the group consisting of: bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, -N (R) ⁱ ) -alkyl-,-alkyl-N (R) ⁱ )-、-S(O) _n -alkyl-, -alkyl-S (O) _n -, -alkyl-C (=o) -, -C (=o) -alkyl-, -N (R) ⁱ ) C (=o) -alkyl-, -C (=o) N (R ⁱ ) -alkyl-and-alkyl-C (=o) N (R ⁱ ) -, wherein the alkyl, the alkenyl, the alkynyl, the heteroalkyl, the heteroalkenyl, the heteroalkynyl, and-N (R ⁱ ) -alkyl-, -alkyl-N (R) ⁱ )-、-S(O) _n -alkyl-, -alkyl-S (O) _n -, -alkyl-C (=o) -, -C (=o) -alkyl-, -N (R) ⁱ ) C (=o) -alkyl-, -C (=o) N (R ⁱ ) -alkyl-and-alkyl-C (=o) N (R ⁱ ) The alkyl moiety in (E) is optionally substituted with one or more R ^j Substitution;

R ⁱ selected from the group consisting of: hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, the heteroalkyl, the cycloalkyl, the heterocyclyl, the aryl, and the heteroaryl are optionally substituted with one or more groups independently selected from hydroxy, halogen, cyano, amino, or alkyl;

R ^j selected from hydroxy, halogen, cyano, amino, or alkyl optionally substituted with one or more groups independently selected from: halogen, hydroxy, cyano, cycloalkyl, heterocyclyl or-N (R) ^c ) ₂ Wherein the heterocyclyl is optionally substituted with one or more groups selected from: hydroxy, halogen, cyano, amino, alkyl or-N (R) ^c ) ₂ ；

L ² Selected from the group consisting of: bond, -O-, -S-, -N (R) ⁱ )-、-S(O) _n -、-S-S-、-S(O) _n -N(R ⁱ )-、-N(R ⁱ )-S(O) _n -、-C(＝O)-、-C(＝S)-、-C(＝O)N(R ⁱ )-、-C(＝S)N(R ⁱ )-、-N(R ⁱ )C(＝O)-、-N(R ⁱ )C(＝S)-、-OC(＝O)O-、-C(＝O)N(R ⁱ )-S(O) _n -、-S(O) _n -N(R ⁱ )C(＝O)-、-N(R ⁱ )C(＝O)-N(R ⁱ )-、-N(R ⁱ )-S(O) _n -N(R ⁱ ) -, cycloalkyl, heterocyclyl, aryl and heteroaryl;

m is an integer from 0 to 3;

p is an integer from 0 to 4;

n is an integer from 0 to 2;

r is 1 or 2;

provided that it is

When (when)When it is a triple bond, then R ^a Absent, R ^b Exists and r is 1;

or whenWhen it is a double bond, then R ^a In presence of R ^b Exists and R is 2, or R ^a And R is ^b And the carbon atoms to which they are attached form a chain optionally substituted with one or more R ^e Substituted cycloalkyl groups.

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

or a pharmaceutically acceptable salt thereof,

wherein R is ¹ Is hydrogen, hydroxy, halogen, cyano, alkyl or alkynyl, wherein said alkyl and said alkynyl are optionally substituted with one or more groups independently selected from hydroxy, halogen and cyano.

In another aspect, the present disclosure provides a pharmaceutical composition comprising a 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 of inhibiting KRas G12C activity in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

In a further aspect, the present disclosure provides a method of treating KRas G12C-related cancer, comprising administering to a subject in need thereof an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

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

(a) Knowing 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 a pharmaceutical composition of the present disclosure.

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

Detailed Description

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 disclosure will be described in conjunction with the enumerated embodiments, it will be understood that the embodiments are not intended to limit the 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 appended claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein that can 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 of a departure or conflict between one or more of the incorporated references and similar materials (including but not limited to the defined terms, term usage, described techniques, etc.) and the present application, the present disclosure controls. All references, patents, patent applications cited in this disclosure are hereby incorporated by reference in their entirety.

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

Definition of the definition

The definition of specific functional groups and chemical terms is described in more detail below. For purposes of this disclosure, chemical elements are identified according to the periodic Table of elements (Periodic Table of the Elements), CAS version, handbook of physics and chemistry (Handbook of Chemistry and Physics), 75 th edition, inner cover, and specific functional groups are generally defined as described herein. In addition, the general principles of organic chemistry and specific functional moieties and reactivities are described in the following documents: organic chemistry (Organic Chemistry), thomas Sorrell, 2 nd edition, sossary science book Press (University Science Books, sausalito), 2006; smith and March, march higher organic chemistry (March's Advanced Organic Chemistry), 6 th edition, john Wiley father-child publishing company (John Wiley & Sons, inc., new York), 2007; larock, complex organic transformations (Comprehensive Organic Transformations), 3 rd edition, VCH Press, inc. (VCH Publishers, inc., new York), 2018; carruther, some modern methods of organic synthesis (Some Modern Methods of Organic Synthesis), 4 th edition, cambridge university Press, cambridge (Cambridge University Press, cambridge), 2004; each of these documents is incorporated by reference in its entirety.

Throughout this disclosure, linking substituents are described. It is particularly desirable that each linking substituent includes both the forward and reverse forms of the linking substituent. For example, -NR (CR ' R ") -includes both-NR (CR ' R") -and- (CR ' R ") NR-. In the case where a linking group is explicitly required for a structure, the Markush variable (Markush variable) listed for the group is understood to be the linking group. For example, if the structure requires a linking group and the markush group definition of the variables lists "alkyl", it is understood that "alkyl" means a linking alkylene.

Where a bond to a substituent is shown intersecting a bond connecting two atoms in a ring, such substituent may be bonded to any atom in the ring. Where substituents are listed, but it is not specified through which atom such substituent is bonded to the remainder of a given formula compound, such substituent may be bonded through any atom in this formula. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

As used herein, for convenience, a dash "-" is used in front of or at the end of a chemical group to indicate the point of attachment of a substituent. For example, -OH is attached through a carbon atom; chemical groups may be delineated by one or more dashes or without losing their ordinary meaning. Wavy lines drawn through lines in the structure indicate the point of attachment of the group. The order in which chemical groups are written or named does not indicate or imply a direction unless chemical or structural requirements. As used herein, the solid line from the center of the ring indicates that the point of attachment of the substituent on the ring can be at any ring atom. Where substituents are listed, but it is not specified through which atom such substituent is bonded to the remainder of a given formula compound, such substituent may be bonded through any atom in this formula. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

In any variable (e.g., R ⁱ ) When a compound occurs more than one time in any component or formula, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if the display group is 0 to 2R ⁱ Partially substituted, then the radicals may optionally be substituted by up to two R ⁱ Partially substituted, and R ⁱ Each at each occurrence is independently selected from R ⁱ Is defined in (a). Moreover, combinations of substituents and/or variables are permissible 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 compounds of formula (I), formula (Ia), formula (Ib), and specific compounds disclosed herein.

As used herein, the term "C _i-j "indicates a range of the number of carbon atoms, where i and j are integers, and the range of the number of carbon atoms includes the endpoints (i.e., i and j) and each integer point therebetween, and where j is greater than i. For example, C _1-6 A range of one to six carbon atoms is indicated, 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 carbon atoms, in particular 1 to 10 carbon atoms, in particular 1 to 8 carbon atoms, in particular 1 to 6 carbon atoms, in particular 1 to 5 carbon atoms, in particular 1 to 4 carbon atoms, in particular 1 to 3 carbon atoms or in particular 1 to 2 carbon atoms.

As used herein, the term "alkyl", whether used as part of another term or independently, refers to a saturated straight or branched chain hydrocarbon group that may optionally be independently substituted with one or more substituents described below. The term "C _i-j Alkyl "refers to an alkyl group having i to j carbon atoms. In some embodiments, the alkyl group comprises 1 to 10 carbon atoms. In some embodiments, the alkyl group comprises 1 to 9 carbon atoms. In some embodiments, the alkyl group comprises 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. "C _1-10 Examples of alkyl "include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. "C _1-6 Examples of alkyl "are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-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, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl, and the like.

As used herein, the term "alkenyl", whether used as part of another term or independently, refers to a straight or branched chain hydrocarbon group having at least one carbon-carbon double bond that may be optionally independently substituted with one or more substituents described herein and includes groups having a "cis" orientation and a "trans" orientation or alternatively an "E" orientation and a "Z" orientation. In some embodiments, alkenyl groups include 2 to 12 carbon atoms. In some embodiments, alkenyl groups include 2 to 11 carbon atoms. In some embodiments, alkenyl groups include 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 include 2 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (ethylene or vinyl), propenyl (allyl), butenyl, pentenyl, 1-methyl-2-buten-1-yl, 5-hexenyl, and the like.

As used herein, the term "alkynyl", whether used as part of another term or independently, refers to a straight or branched chain hydrocarbon group having at least one carbon-carbon triple bond that may be optionally independently substituted with one or more substituents described herein. In some embodiments, alkenyl groups include 2 to 12 carbon atoms. In some embodiments, alkynyl groups include 2 to 11 carbon atoms. In some embodiments, alkynyl groups include 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 include 2 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and the like.

As used herein, the term "alkoxy group", whether used as part of another term or 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 portion of the alkoxy group has i to j carbon atoms. In some embodiments, the alkoxy group comprises 1 to 10 carbon atoms. In some embodiments, the alkoxy group comprises 1 to 9 carbon atoms. In some embodiments, the alkoxy group comprises 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. "C _1-6 Examples of alkoxy groups "include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, neopentyloxy, n-hexyloxy, and the like.

As used herein, the term "amino" refers to-NH ₂ A group. The amino group 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 used as part of another term or independently, refers to mono-and polycyclic ring systems having a total of from 5 to 20 ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system comprises from 3 to 12 ring members. Examples of "aryl" include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, and the like, which may bear one or more substituents. As used herein, the term "aryl" also includes groups in which an aromatic ring is fused to one or more additional rings. In the case of a polycyclic system, only one ring need be aromatic (e.g., 2, 3-indoline), but all rings may be aromatic (e.g., quinoline). The second ring may also be fused or bridged. Examples of polycyclic aryl groups include, but are not limited to, benzofuranyl, indanyl, phthalimidyl, naphthalimidyl, phenanthridinyl, tetrahydronaphthyl, and the like. Aryl groups may 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 "cycloalkyl", whether used as part of another term or independently, refers to monovalent non-aromatic saturated or partially unsaturated monocyclic and polycyclic systems wherein all ring atoms are carbon and the system includes at least three ring-forming carbon atoms. In some embodiments, cycloalkyl groups may include 3 to 12 ring carbon atoms, 3 to 10 ring carbon atoms, 3 to 9 ring carbon atoms, 3 to 8 ring carbon atoms, 3 to 7 ring carbon atoms, 3 to 6 ring carbon atoms, 3 to 5 ring carbon atoms, 4 to 12 ring carbon atoms, 4 to 10 ring carbon atoms, 4 to 9 ring carbon atoms, 4 to 8 ring carbon atoms, 4 to 7 ring carbon atoms, 4 to 6 ring carbon atoms, 4 to 5 ring carbon atoms. Cycloalkyl groups may be saturated or partially unsaturated. Cycloalkyl groups may be substituted. In some embodiments, cycloalkyl groups may be saturated cyclic alkyl groups. In some embodiments, cycloalkyl groups may be partially unsaturated cyclic alkyl groups that include at least one double or triple bond in their ring system. In some embodiments, cycloalkyl groups may be monocyclic or polycyclic. Fused, spiro, and bridged ring systems are also included within the scope of this definition. Examples of monocyclic cycloalkyl groups 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 groups include, but are not limited to, adamantyl, norbornyl, fluorenyl, spiro-pentadienyl, spiro [3.6] -decyl, bicyclo [1, 1] pentenyl, bicyclo [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 bromoo), and iodine (or iodoo).

As used herein, the term "haloalkyl" refers to an alkyl group as defined above substituted with one or more halogens as defined above. Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, trichloromethyl, 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 as well as any quaternized form of basic nitrogen (including N-oxides).

As used herein, the term "heteroalkyl" refers to an alkyl group having at least one of its carbon atoms replaced with a heteroatom selected from N, O or S. Heteroalkyl groups may be carbon or heteroatom radicals (i.e., heteroatoms may be present in the middle or at the ends of the group) and may optionally be independently substituted with one or more substituents described herein. The term "heteroalkyl" encompasses both alkoxy and heteroalkoxy.

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

As used herein, the term "heteroalkynyl" refers to an alkynyl group having at least one of its carbon atoms replaced with a heteroatom selected from N, O or S. Heteroalkynyl groups may be carbon radicals or heteroatom radicals (i.e., a heteroatom may occur in the middle or at the ends of a group) and may optionally be independently substituted with one or more substituents described herein.

As used herein, the term "heteroaryl", whether used as part of another term or independently, refers to an aryl group having one or more heteroatoms in addition to carbon atoms. Heteroaryl groups may be monocyclic. Examples of monocyclic heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, benzofuranyl, and pteridinyl. Heteroaryl also includes polycyclic groups in which the heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclic rings, wherein the linking group or point of attachment is on the heteroaromatic ring. Examples of polycyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, benzothienyl, benzofuranyl, benzo [1,3] dioxolyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, 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 carbocyclic 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 independently substituted with one or more substituents. In some embodiments, the heterocyclyl is a saturated heterocyclyl. In some embodiments, a heterocyclyl is a partially unsaturated heterocyclyl having one or more double bonds in its ring system. In some embodiments, the heterocyclyl may include any oxidized form of carbon, nitrogen or sulfur and any quaternized form of basic nitrogen. "heterocyclyl" also includes groups in which the heterocyclyl is fused to a saturated, partially unsaturated, or fully unsaturated (i.e., aromatic) carbocyclic or heterocyclic ring. The heterocyclic group may be carbon-linked or nitrogen-linked, where possible. In some embodiments, the heterocycle is carbon-linked. In some embodiments, the heterocycle is nitrogen-linked. For example, the groups derived from pyrrole may be pyrrol-1-yl (nitrogen-linked) or pyrrol-3-yl (carbon-linked). Further, the 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. Fused, spiro, and bridged ring systems are also included within the scope of this definition. Examples of monocyclic heterocyclyl groups include, but are not limited to, oxetanyl, 1-dioxothietanylpyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, piperidinyl, piperazinyl, piperidinyl, morpholinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyridonyl, pyrimidinonyl, pyrazinonyl, pyrimidinonyl, pyridazinonyl, pyrrolidinyl, triazinonyl, and the like. Examples of fused heterocyclic groups include, but are not limited to, phenyl condensed rings or pyridyl condensed rings, such as quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, quinolizinyl, quinazolinyl, azaindolizinyl, pteridinyl, chroenyl, isochroenyl, 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, and the like. Examples of spiroheterocyclyl groups include, but are not limited to, spiropyranyl, spirooxazinyl, and the like. Examples of bridged heterocyclyl groups include, but are not limited to, morphinan, hexamethylenetetramine, 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" refers to-OH.

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

As used herein, the term "oxo" refers to an =o substituent.

As used herein, the term "partially unsaturated" refers to a group 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", means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. It is to be understood that "substitution" or "substitution by … …" includes implicit preconditions that such substitution is consistent with the permissible valence of the substituted atom, and that the substitution results in a stable or chemically feasible compound, e.g., a compound that does not spontaneously undergo transformations such as rearrangement, cyclization, elimination, and the like. Unless otherwise indicated, an "optionally substituted" group may have the appropriate substituent at each substitutable position of the group, and where more than one position in any given structure may be substituted with more than one substituent selected from the specified group, the substituents may be the same or different at each position. It will be appreciated by those skilled in the art that the substituents themselves may be substituted, if appropriate. Unless specifically stated as "unsubstituted", references to chemical moieties herein are to be understood as including substituted variants. For example, reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants.

Compounds of formula (I)

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

or a pharmaceutically acceptable salt thereof,

wherein the method comprises the steps of

Ring a is heterocyclyl or heteroaryl;

u is C (R) ^a ) Or N;

g is N-C (O) -C (R) ^a )C(R ^b ) _r Or N-SO ₂ C(R ^a )C(R ^b ) _r ；

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

Each R ^b Independently is hydrogen, deuterium, halogen, cyano, alkyl, alkoxy, heteroalkyl, or heteroaryl, wherein the alkyl, the heteroalkyl, and the heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of: hydroxy, halogen, -NR ^c R ^d And heterocyclyl optionally substituted with one or more groups independently selected from hydroxy, halogen, cyano, and amino;

each R ^c Independently hydrogen, deuterium, alkyl, alkenyl, alkynyl or haloalkyl;

R ^d selected from the group consisting of: optionally heteroaryl or-N (R) ^c ) ₂ Substituted alkyl, haloalkyl, -C (O) N (R) ^c ) ₂ 、-(CH ₂ ) _n NHC (O) -alkyl, heterocyclyl, and heteroaryl, wherein the heterocyclyl and heteroaryl are optionally substituted with one or more groups independently selected from: halo, hydroxy, amino, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, heteroalkyl, hydroxyalkyl, -O-haloalkyl, and-S-haloalkyl;

W is C (R) ^e ) Or N;

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

Each R is independently selected from the group consisting of: oxo, hydroxy, halogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, -C (O) OR ^c 、-C(O)N(R ^c ) ₂ 、-N(R ^c ) ₂ And heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, and said heteroaryl are optionally independently selected from one or more ofThe following groups are substituted: cyano, hydroxy, halogen, -OR ^c or-N (R) ^c ) ₂ ；

Ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted with one or more R ^f Substitution;

each R ^f Independently selected from the group consisting of: oxo, hydroxy, halo, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of: hydroxy, halogen, cyano, -OR ^c 、-N(R ^c ) ₂ And heteroaryl;

t is O or S;

y is aryl or heteroaryl, each of which is optionally substituted with one or more R ^f Substitution;

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

q is- (CH) ₂ ) _m V-, wherein- (CH) ₂ ) _m -optionally substituted with hydroxy, halogen, cyano or amino;

v is selected from bond, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally substituted with one or more groups independently selected from: hydroxy, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl;

z is selected from the group consisting of: hydrogen, hydroxy, halogen, -N (R) ^c ) ₂ Alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -COOH, -NHC (=nh) NH ₂ 、-C(O)N(R ^c ) ₂ 、-OR ^c 、-(CH ₂ OR ^c )(CH ₂ ) _p OR ^c 、-N(R ^c ) C (O) -aryl, -N (R) ^c ) C (O) -heterocyclyl, -C (O) N (R) ^c ) -heterocyclyl and- (CH) ₂ ) _p -a heterocyclyl group, wherein said cycloalkyl group, said heterocyclyl group, saidAryl and said heteroaryl are optionally substituted with one or more R ^g Substituted, and-N (R) ^c ) Aryl moieties in C (O) -aryl and- (CH) ₂ ) _p The heterocyclyl moiety in the heterocyclyl is optionally substituted with one or more R ^h Substitution;

each R ^g Independently selected from hydroxy, halogen, -C (O) H, alkyl, alkoxy, haloalkyl, hydroxyalkyl, or-N (R) ^c ) ₂ ；

Each R ^h Independently selected from oxo, hydroxy, halogen, alkyl, heteroalkyl, hydroxyalkyl, haloalkyl, alkoxy, -M-phenyl, -M-phenylSO ₂ F、-N(R ^c ) ₂ 、-SO ₂ F. -C (O) (alkyl) or-C (O) (haloalkyl), wherein said alkyl, said heteroalkyl, said hydroxyalkyl, said haloalkyl and said alkoxy are optionally substituted with one or more groups independently selected from aryl, heteroaryl or t-butyldimethylsilyloxy;

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

l is-L ¹ -L ² -L ³ -；

L ¹ And L ³ Independently selected from the group consisting of: bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, -N (R) ⁱ ) -alkyl-, -alkyl-N (R) ⁱ )-、-S(O) _n -alkyl-, -alkyl-S (O) _n -, -alkyl-C (=o) -, -C (=o) -alkyl-, -N (R) ⁱ ) C (=o) -alkyl-, -C (=o) N (R ⁱ ) -alkyl-and-alkyl-C (=o) N (R ⁱ ) -, wherein the alkyl, the alkenyl, the alkynyl, the heteroalkyl, the heteroalkenyl, the heteroalkynyl, and-N (R ⁱ ) -alkyl-, -alkyl-N (R) ⁱ )-、-S(O) _n -alkyl-, -alkyl-S (O) _n -, -alkyl-C (=o) -, -C (=o) -alkyl-, -N (R) ⁱ ) C (=o) -alkyl-, -C (=o) N (R ⁱ ) -alkyl-and-alkyl-C (=o) N (R ⁱ ) The alkyl moiety in (E) is optionally substituted with one or more R ^j Substitution;

R ⁱ Selected from the group consisting of: hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl and heteroarylAryl, wherein the alkyl, the heteroalkyl, the cycloalkyl, the heterocyclyl, the aryl, and the heteroaryl are optionally substituted with one or more groups independently selected from hydroxy, halogen, cyano, amino, or alkyl;

R ^j selected from hydroxy, halogen, cyano, amino, or alkyl optionally substituted with one or more groups independently selected from: halogen, hydroxy, cyano, cycloalkyl, heterocyclyl or-N (R) ^c ) ₂ Wherein the heterocyclyl is optionally substituted with one or more groups selected from: hydroxy, halogen, cyano, amino, alkyl or-N (R) ^c ) ₂ ；

L ² Selected from the group consisting of: bond, -O-, -S-, -N (R) ⁱ )-、-S(O) _n -、-S-S-、-S(O) _n -N(R ⁱ )-、-N(R ⁱ )-S(O) _n -、-C(＝O)-、-C(＝S)-、-C(＝O)N(R ⁱ )-、-C(＝S)N(R ⁱ )-、-N(R ⁱ )C(＝O)-、-N(R ⁱ )C(＝S)-、-OC(＝O)O-、-C(＝O)N(R ⁱ )-S(O) _n -、-S(O) _n -N(R ⁱ )C(＝O)-、-N(R ⁱ )C(＝O)-N(R ⁱ )-、-N(R ⁱ )-S(O) _n -N(R ⁱ ) -, cycloalkyl, heterocyclyl, aryl and heteroaryl;

m is an integer from 0 to 3;

p is an integer from 0 to 4;

n is an integer from 0 to 2;

r is 1 or 2;

provided that it is

When (when)When it is a triple bond, then R ^a Absent, R ^b Exists and r is 1;

or whenWhen it is a double bond, then R ^a In presence of R ^b Exists and R is 2, or R ^a And R is ^b And to their useThe attached carbon atoms forming a ring optionally substituted with one or more R ^e Substituted cycloalkyl groups.

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

In some embodiments, G is N-SO ₂ C(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, an R ^b Is hydrogen, another R ^b Selected from the group consisting of: hydrogen, alkyl, heteroalkyl, haloalkyl, heteroaryl, -alkyl-NR ^c R ^d And-alkyl-heterocyclyl, wherein the heterocyclyl in the-alkyl-heterocyclyl is optionally substituted with one or more groups independently selected from hydroxy, halogen, cyano or amino.

In certain embodiments, R ^a And two R ^b Is deuterium.

In certain embodiments, R ^a Is halogen, and two R ^b Is hydrogen.

In some embodiments, G is N-C (O) -C≡C (R) ^b ) _r 。

In some embodiments, G is N-SO ₂ C≡C(R ^b ) _r 。

In certain embodiments, R ^b Is hydrogen or-alkyl-NR ^c R ^d 。

In some embodiments, U is N.

In some embodiments, U is C (R ^a ). In certain embodiments, R ^a Is hydrogen.

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

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

In some embodiments, ring a is a bridged heterocyclyl. In certain embodiments, ring a is a 6-to 12-membered bridged heterocyclyl. In certain embodiments, ring a is a 6-to 10-membered bridged heterocyclyl. In certain embodiments, ring a is an 8-to 10-membered bridged heterocyclyl.

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

wherein the method comprises the steps ofRepresents a single bond or a double bond.

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

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

wherein s is an integer of 0 to 3, and q is an integer of 1 to 4.

In certain embodiments, ring a is

In some embodiments, ring a is heteroaryl.

In some embodiments, W is N.

In one placeIn some embodiments, W is C (R ^e ). In certain embodiments, R ^e Is hydrogen, hydroxy, halogen, cyano or C _1-6 An alkyl group.

In some embodiments, ring B is optionally substituted with one or two R ^f Substituted cycloalkyl groups. In certain embodiments, ring B is optionally substituted with one or more R ^f Substituted C _5-12 Cycloalkyl groups. In certain embodiments, ring B is optionally substituted with one or more R ^f Substituted C _5-10 Cycloalkyl groups. In certain embodiments, ring B is optionally substituted with one or more R ^f Substituted C _5-8 Cycloalkyl groups. In certain embodiments, ring B is optionally substituted with one or more R ^f Substituted C _5-7 Cycloalkyl groups. In certain embodiments, ring B is optionally substituted with one or more R ^f Substituted C _5-6 Cycloalkyl groups.

In some embodiments, ring B is optionally substituted with one or two R ^f Substituted heterocyclyl groups. In certain embodiments, ring B is optionally substituted with one or more R ^f Substituted 5-to 12-membered heterocyclyl. In certain embodiments, ring B is optionally substituted with one or more R ^f Substituted 5-to 10-membered heterocyclyl. In certain embodiments, ring B is optionally substituted with one or more R ^f Substituted 5-to 8-membered heterocyclyl. In certain embodiments, ring B is optionally substituted with one or more R ^f Substituted 5-to 7-membered heterocyclyl. In certain embodiments, ring B is optionally substituted with one or more R ^f Substituted 5-to 6-membered heterocyclyl.

In certain embodiments, ring B is piperidinyl or 1,2,3, 6-tetrahydropyridinyl, each of which is optionally substituted with one or more R independently selected from oxo, alkyl, alkynyl, heteroalkyl, or cyano ^f Wherein said alkyl, said alkynyl, said heteroalkyl are optionally substituted with one OR more substituents selected from cyano, halogen, -OR ^c 、-N(R ^c ) ₂ Or heteroaryl, wherein R is ^c Is hydrogen or alkyl.

In some embodiments, ring B is optionally substituted with one or two R ^f Substituted aryl. In certain embodiments, ring B is optionally substituted with one or more R ^f Substituted C _5-12 Aryl groups. In certain embodiments, ring B is optionally substituted with one or more R ^f Substituted C _5-10 Aryl groups. In certain embodiments, ring B is optionally substituted with one or more R ^f Substituted C _5-8 Aryl groups. In certain embodiments, ring B is optionally substituted with one or more R ^f Substituted C _5-7 Aryl groups. In certain embodiments, ring B is optionally substituted with one or more R ^f Substituted C _5-6 Aryl groups.

In certain embodiments, ring B is optionally substituted with one or more R independently selected from amino, hydroxy, halo, or haloalkyl ^f A substituted phenyl group.

In some embodiments, ring B is optionally substituted with one or two R ^f Substituted heteroaryl groups. In certain embodiments, ring B is optionally substituted with one or more R ^f Substituted 5-to 12-membered heteroaryl. In certain embodiments, ring B is optionally substituted with one or more R ^f Substituted 5-to 10-membered heteroaryl. In certain embodiments, ring B is optionally substituted with one or more R ^f Substituted 5-to 8-membered heteroaryl. In certain embodiments, ring B is optionally substituted with one or more R ^f Substituted 5-to 7-membered heteroaryl. In certain embodiments, ring B is optionally substituted with one or more R ^f Substituted 5-to 6-membered heteroaryl.

In certain embodiments, ring B is optionally substituted with one or more R independently selected from amino, hydroxy, halo, or haloalkyl ^f Substituted pyridinyl or pyrimidinyl.

In some embodiments, T is O.

In some embodiments, T is S.

In some embodiments, Y is optionally substituted with one or two R ^f Substituted aryl. In certain embodiments, Y is optionally substituted with one or more R ^f Substituted C _5-12 Aryl groups. In certain embodiments, Y is optionally substituted with one or more R ^f Substitution ofC of (2) _5-11 Aryl groups. In certain embodiments, Y is optionally substituted with one or more R ^f Substituted C _5-10 Aryl groups. In certain embodiments, Y is optionally substituted with one or more R ^f Substituted C _5-8 Aryl groups. In certain embodiments, Y is optionally substituted with one or more R ^f Substituted C _5-7 Aryl groups. In certain embodiments, Y is optionally substituted with one or more R ^f Substituted C _5-6 Aryl groups.

In certain embodiments, Y is phenyl or naphthyl, each of which is optionally substituted with one or more R ^j And (3) substitution.

In certain embodiments, R ^f Is hydroxy, halogen, amino, alkyl, alkenyl, alkynyl, haloalkyl, haloalkynyl or cycloalkyl.

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

In certain embodiments, Y is selected from benzothienyl, benzimidazolyl, quinazolinyl, benzotriazolyl, thienyl, thienopyridinyl, isoquinolinyl, indolyl, or indazolyl, each of which is optionally substituted with one or more R ^f And (3) substitution.

In certain embodiments, R ^f Is hydroxy, halogen, amino, alkyl, alkenyl, alkynyl, haloalkyl, haloalkynyl or heteroaryl.

In some embodiments, E is-O-.

In some embodiments, E is-S-.

In some embodiments, E is-N (R ^c ) -, wherein R is ^c Is hydrogen or alkyl.

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

In some embodiments, V is a bond.

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

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

each of which is optionally substituted with one or more groups independently selected from the group consisting of: oxo, hydroxy, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl.

In some embodiments, Z is selected from hydrogen, hydroxy, halo, alkyl, haloalkyl, -N (R ^c ) ₂ 、-N(R ^c ) C (O) -heterocyclyl or-C (O) N (R) ^c ) -heterocyclyl, wherein-N (R ^c ) C (O) -heterocyclyl and-C (O) N (R) ^c ) The heterocyclyl moiety in the heterocyclyl is optionally substituted with one or more R ^h And (3) substitution. In certain embodiments, R ^h Is alkyl or-N (R) ^c ) ₂ 。

In some embodiments, V is a bond, and Z is hydrogen, -N (R ^c ) C (O) -heterocyclyl or-C (O) N (R) ^c ) -heterocyclyl, wherein-N (R ^c ) C (O) -heterocyclyl and-C (O) N (R) ^c ) The heterocyclyl moiety in the heterocyclyl is optionally substituted with one or more R ^h And (3) substitution.

In some embodiments, V is heterocyclyl optionally substituted with one or more groups independently selected from: oxo, hydroxy, halogen, cyano, aminoAlkyl, hydroxyalkyl or heteroaryl, and Z is selected from hydrogen, hydroxy, halogen, alkyl, haloalkyl or-N (R ^c ) ₂ 。

In some embodiments, L is-L ¹ -L ² -L ³ -，L ¹ And L ³ Independently selected from the group consisting of bond, alkyl, -N (R) ⁱ ) -alkyl-, -alkyl-N (R) ⁱ )-、-S(O) _n -alkyl-, -alkyl-S (O) _n -, -alkyl-C (=o) -, -C (=o) -alkyl-, -N (R) ⁱ ) C (=o) -alkyl-, -C (=o) N (R ⁱ ) -alkyl-or-alkyl-C (=o) N (R ⁱ ) -, wherein the alkyl group and-N (R ⁱ ) -alkyl-, -alkyl-N (R) ⁱ )-、-S(O) _n -alkyl-, -alkyl-S (O) _n -, -alkyl-C (=o) -, -C (=o) -alkyl-, -N (R) ⁱ ) C (=o) -alkyl-, -C (=o) N (R ⁱ ) -alkyl-and-alkyl-C (=o) N (R ⁱ ) The alkyl moiety in (E) is optionally substituted with one or more R ^j And (3) substitution.

In certain embodiments, L is-L ¹ -L ² -L ³ -，L ¹ And L ³ Independently selected from the group consisting of bond, alkyl, -N (R) ⁱ ) -alkyl-, -alkyl-N (R) ⁱ )-、-S(O) _n -alkyl-, -alkyl-S (O) _n -, -alkyl-C (=o) -, -C (=o) -alkyl-, -N (R) ⁱ ) C (=o) -alkyl-, -C (=o) N (R ⁱ ) -alkyl-or-alkyl-C (=o) N (R ⁱ ) -, wherein the alkyl or-N (R ⁱ ) -alkyl-, -alkyl-N (R) ⁱ )-、-S(O) _n -alkyl-, -alkyl-S (O) _n -, -alkyl-C (=o) -, -C (=o) -alkyl-, -N (R) ⁱ ) C (=o) -alkyl-, -C (=o) N (R ⁱ ) -alkyl-and-alkyl-C (=o) N (R ⁱ ) The alkyl moiety in is optionally substituted with one or more R ^j Substituted- (CH) ₂ ) _t -, and t is an integer from 0 to 10.

In certain embodiments, R ^j Selected from hydrogen or alkyl optionally substituted with one or more groups independently selected from: halogen, -N (R) ^c ) ₂ Or optionally one or more groups selected from alkyl or-N (R ^c ) ₂ A heterocyclic group substituted with a group of (a).

In some embodiments, L is-L ¹ -L ² -L ³ -，L ¹ And L ³ Independently selected from alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl, each of which is optionally substituted with one or more R ^j And (3) substitution.

In certain embodiments, L is-L ¹ -L ² -L ³ -，L ¹ And L ³ Independently selected from L ¹ And L ³ Independently selected from- (CH) ₂ ) _u CH＝CH(CH ₂ ) _v -、-(CH ₂ ) _u CH≡CH(CH ₂ ) _v -、-O(CH ₂ ) _t -、-(CH ₂ ) _t O-、-S(CH ₂ ) _t -、-(CH ₂ ) _t S-、-O(CH ₂ ) _u CH＝CH(CH ₂ ) _v -、-(CH ₂ ) _u CH＝CH(CH ₂ ) _v O-、-O(CH ₂ ) _u CH≡CH(CH ₂ ) _v -、-(CH ₂ ) _u CH≡CH(CH ₂ ) _v O-,-S(CH ₂ ) _u CH＝CH(CH ₂ ) _v -、-(CH ₂ ) _u CH＝CH(CH ₂ ) _v S-、-S(CH ₂ ) _u CH≡CH(CH ₂ ) _v -、-(CH ₂ ) _u CH≡CH(CH ₂ ) _v S-、-O(CH ₂ ) _u CH＝CH(CH ₂ ) _v S-、-S(CH ₂ ) _u CH＝CH(CH ₂ ) _v O-、-O(CH ₂ ) _u CH≡CH(CH ₂ ) _v S-or-S (CH) ₂ ) _u CH≡CH(CH ₂ ) _v O-, each of which is optionally substituted with one or more R ^j Substitution, wherein u and v are independently integers from 0 to 10.

In certain embodiments, R ^j Selected from hydrogen or alkyl optionally substituted with one or more groups independently selected from: halogen, -N (R) ^c ) ₂ Or optionally one or more groups selected from alkyl or-N (R ^c ) ₂ A heterocyclic group substituted with a group of (a).

In some embodiments, L is-L ¹ -L ² -L ³ -，L ² Selected from-O-, -N (R) ⁱ )-、-S(O) _n -、-C(＝O)N(R ⁱ ) -or-N (R) ⁱ )C(＝O)-。

In some embodiments, L is-L ¹ -L ² -L ³ -，L ¹ Is alkyl, heteroalkyl or-S (O) _n -alkyl-, L ² is-C (=O) -, and L ³ Is a key.

In some embodiments, L is-L ¹ -L ² -L ³ -，L ¹ Is a bond, alkyl, heteroalkyl, or-N (R) ⁱ ) -alkyl-, L ² is-O-, -S-or-N (R) ⁱ ) -, and L ³ Is a bond, alkyl, alkenyl or heteroalkyl.

In some embodiments, L is-L ¹ -L ² -L ³ -，L ¹ Is a bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl or-S (O) _n -alkyl-, L ² is-S (O) _n -or-S-S-, and L ³ Is a bond, alkyl, alkenyl, alkynyl or heteroalkyl.

In some embodiments, L is-L ¹ -L ² -L ³ -，L ¹ Is a bond, alkyl, alkenyl, heteroalkyl, -N (R) ⁱ ) -alkyl-, -N (R) ⁱ ) C (=o) -alkyl-or-C (=o) N (R ⁱ ) -alkyl-, L ² is-S (O) _n -N(R ⁱ )-、-N(R ⁱ )-S(O) _n -、-C(＝O)N(R ⁱ )-、-C(＝S)N(R ⁱ )-、-N(R ⁱ )C(＝O)-、-N(R ⁱ )C(＝S)-、-OC(＝O)O-、-C(＝O)N(R ⁱ )-S(O) _n -、-S(O) _n -N(R ⁱ )C(＝O)-、-N(R ⁱ )C(＝O)-N(R ⁱ ) -or-N (R) ⁱ )-S(O) _n -N(R ⁱ ) -, and L ³ Is a bond, alkyl, alkenyl or-alkyl-S (O) _n -。

In some embodiments, L is selected from the group consisting of-CH ₂ C(＝O)N(R ⁱ )CH ₂ -、-C(＝O)N(R ⁱ )(CH ₂ ) ₂ -、-CH ₂ N(R ⁱ )C(O)CH ₂ -、-CH ₂ CH ₂ N(R ⁱ )C(O)-、-CH ₂ CH ₂ N(R ⁱ )CH ₂ -、-CH ₂ N(R ⁱ )CH ₂ CH ₂ -、-CH ₂ OCH ₂ CH ₂ -or-CH ₂ CH ₂ OCH ₂ -, each of which is optionally substituted with one or more R ^j And (3) substitution.

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

or a pharmaceutically acceptable salt thereof,

wherein R is ¹ Is hydrogen, hydroxy, halogen, cyano, alkyl or alkynyl, wherein said alkyl and said alkynyl are optionally substituted with one or more groups independently selected from hydroxy, halogen and cyano.

In some embodiments, E is O or S.

In some embodiments, L is selected from the group consisting of-CH ₂ C(＝O)N(R ⁱ )CH ₂ -、-C(＝O)N(R ⁱ )(CH ₂ ) ₂ -、-CH ₂ N(R ⁱ )C(O)CH ₂ -、-CH ₂ CH ₂ N(R ⁱ )C(O)-、-CH ₂ CH ₂ N(R ⁱ )CH ₂ -、-CH ₂ N(R ⁱ )CH ₂ CH ₂ -、-CH ₂ OCH ₂ CH ₂ -or-CH ₂ CH ₂ OCH ₂ -, each of which is optionally substituted with one or more R ^j And (3) substitution.

In some embodiments, E is O or S, and L is selected from the group consisting of-CH ₂ C(＝O)N(R ⁱ )CH ₂ -、-C(＝O)N(R ⁱ )(CH ₂ ) ₂ -、-CH ₂ N(R ⁱ )C(O)CH ₂ -、-CH ₂ CH ₂ N(R ⁱ )C(O)-、-CH ₂ CH ₂ N(R ⁱ )CH ₂ -、-CH ₂ N(R ⁱ )CH ₂ CH ₂ -、-CH ₂ OCH ₂ CH ₂ -or-CH ₂ CH ₂ OCH ₂ -, each of which is optionally substituted with one or more R ^j And (3) substitution.

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

1- (8- ((dimethylamino) methyl) -3- (naphthalen-1-yl) -1,2,3,4,8,9,10,11,12,13 a,14,16, 17-decatetrahydro-15H-6, 19- (aminosubunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7] diazacyclotetradec-15-yl) prop-2-en-1-one

1- (8- ((dimethylamino) methyl) -3- (naphthalen-1-yl) -1,2,3,4,8,9,10,11,12,13,14,15 a,16,18, 19-hexadeca-17H-6, 21- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7] diazepan-17-yl) prop-2-en-1-one

1- (8- ((dimethylamino) methyl) -3- (naphthalen-1-yl) -1,2,3,4,8,9,10,13 a,14,16, 17-dodecahydro-15H-6, 19- (aminosubunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7] diaza-tetradec-1-yl) prop-2-en-1-one

1- (8- ((dimethylamino) methyl) -3- (naphthalen-1-yl) -1,2,3,4,8,9,10,11,12,15 a,16,18, 19-decatetrahydro-17H-6, 21- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7] diazacyclohexadec-17-yl) prop-2-en-1-one

9-propenoyl-4- ((dimethylamino) methyl) -16- (naphthalen-1-yl) -5,6,8,9,10,11,14,15,16,17-decahydro-2, 13- (aminosubunit) -8, 12-methylenepyrido [3,4-d ] [1] oxa [3,7,10,13] tetraazacyclopentadec-7 (4H) -one

1- (4- ((dimethylamino) methyl) -17- (naphthalen-1-yl) -4,5,8,9,11,12,15,16,17,18-decahydro-10H-2, 14- (aminosubunit) -9, 13-methylenepyrido [3,4-d ] [1] oxa [3,7,10] triazacyclo hexadec-10-yl) prop-2-en-1-one

1- (4- ((dimethylamino) methyl) -17- (naphthalen-1-yl) -4,5,6,7,8,9,11,12,15,16,17,18-dodecahydro-10H-2, 14- (aminosubunit) -9, 13-methylenepyrido [3,4-d ] [1] oxa [3,7,10] triazacyclo hexadecan-10-yl) prop-2-en-1-one

1- (4- ((dimethylamino) methyl) -18- (naphthalen-1-yl) -5,6,9,10,12,13,16,17,18,19-decahydro-2, 15- (aminosubunit) -10, 14-methylenepyrido [3,4-d ] [1] oxa [3,7,10] triazacyclo heptadec-in-11 (4H) -yl) prop-2-en-1-one

1- (4- ((dimethylamino) methyl) -18- (naphthalen-1-yl) -5,6,7,8,9,10,12,13,16,17,18,19-dodecahydro-2, 15- (aminosubunit) -10, 14-methylenepyrido [3,4-d ] [1] oxa [3,7,10] triazacyclo heptadec-no-11 (4H) -yl) prop-2-en-1-one 14-propenoyl-8- ((dimethylamino) methyl) -3- (naphthalen-1-yl) -1,2,3,4,9,10,12 a,13,14,15, 16-dodecahydro-6, 18- (aminosubunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazacyclo trideca-11 (8H) -one (isomer 1)

1- (8- ((dimethylamino) methyl) -3- (naphthalen-1-yl) -1,2,3,4,8,9,10,11,13a,14,16, 17-dodecahydro-6, 19- (aminosubunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1,10] dioxa [3,7] diazacyclotetradec-15 (13H) -yl) prop-2-en-1-one 1- (4- ((dimethylamino) methyl) -18- (naphthalen-1-yl) -4,5,6,7,9,10,12,13,16,17,18,19-dodecahydro-11H-2, 15- (aminosubunit) -10, 14-methylenepyrido [3,4-d ] [1,13] dioxa [3,7,10] triazacyclohexadec [3, 10] prop-2-en-1-one

15-propenoyl-8- ((dimethylamino) methyl) -10-methyl-3- (naphthalen-1-yl) -1,2,3,4,9,10,13 a,14,15,16, 17-dodecahydro-8H-6, 19- (aminosubunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,12] triazacyclotetradec-11 (12H) -one

1- (3- (8-chloronaphthalen-1-yl) -8- ((dimethylamino) methyl) -1,2,3,4,8,9,10,11,12,13,14,15 a,16,18, 19-hexadeca hydro-17H-6, 21- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7] diazacyclohexadec-17-yl) prop-2-en-1-one

15-propenoyl-3- (8-chloronaphthalen-1-yl) -8- ((dimethylamino) methyl) -1,2,3,4,8,9,10,11,13 a,14,15,16, 17-decatetrahydro-12H-6, 19- (aminosubunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazacyclotetradec-n-12-one

14-propenoyl-3- (8-chloronaphthalen-1-yl) -8- ((dimethylamino) methyl) -10-methyl-1, 2,3,4,9,10,12 a,13,14,15, 16-dodecahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecano-11 (8H) -one

14-propenoyl-3- (8-chloronaphthalen-1-yl) -8- ((dimethylamino) methyl) -10-methyl-1, 2,3,4,9,10,12 a,13,14,15, 16-dodecahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecano-11 (8H) -one

16-propenoyl-3- (8-chloronaphthalen-1-yl) -8- ((dimethylamino) methyl) -1,2,3,4,9,10,11,12,14 a,15,16,17, 18-decatetrahydro-6, 20- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazacyclopentadec-3 (8H) -one

15-propenoyl-8- ((dimethylamino) methyl) -3- (naphthalen-1-yl) -1,2,3,4,9,10,13 a,14,15,16, 17-dodecahydro-8H-6, 19- (aminosubunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,12] triazacyclotetradecan-11 (12H) -one

11-propenoyl-18- (8-chloronaphthalen-1-yl) -4- ((dimethylamino) methyl) -8-methyl-5,6,8,9,10,11,12,13,16,17,18,19-dodecahydro-2, 15- (aminosubunit) -10, 14-methylenepyrido [3,4-d ] [1] oxa [3,7,10,13] tetraazacyclo heptadecan-7 (4H) -one

15-propenoyl-3- (8-chloronaphthalen-1-yl) -8- ((dimethylamino) methyl) -1,2,3,4,9,10,13 a,14,15,16, 17-dodecahydro-8H-6, 19- (aminosubunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,10] triazacyclotetradec-11 (12H) -one

2- (14-propenoyl-8- ((dimethylamino) methyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecan-e-15-yl) acetonitrile

14-propenoyl-8- ((dimethylamino) methyl) -10, 15-dimethyl-3- (naphthalen-1-yl) -1,2,3,4,9,10,12 a,13,14,15, 16-dodecahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-11 (8H) -ketoformate salt

2- (16-propenoyl-8- ((dimethylamino) methyl) -12-methyl-3- (naphthalen-1-yl) -13-oxo-1, 2,3,4,8,9,10,11,12,13,14 a,15,16,17, 18-hexadeca hydro-6, 20- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazacyclopentadec-17-yl) acetonitrile

14-propenoyl-8- ((dimethylamino) methyl) -15-methyl-3- (naphthalen-1-yl) -1,2,3,4,9,10,12 a,13,14,15, 16-dodecahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecan-11 (8H) -one

2- (14-propenoyl-10-methyl-3- (naphthalen-1-yl) -11-oxo-8- (2- (pyrrolidin-1-yl) ethyl) -1,2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridec-15-yl) acetonitrile

2- (15-propenoyl-8- ((dimethylamino) methyl) -11-methyl-3- (naphthalen-1-yl) -12-oxo-1, 2,3,4,9,10,11,12,13 a,14,15,16, 17-decahydro-8H-6, 19- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazacyclotetradec-n-16-yl) acetonitrile

2- (14-propenoyl-8- (2- (dimethylamino) ethyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecan-15-yl) acetonitrile

2- ((8R, 12aR, 15S) -14-propenoyl-8- ((dimethylamino) methyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecan-15-yl) acetonitrile

2- (14-propenoyl-10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecan-15-yl) acetonitrile

2- (14-propenoyl-10-methyl-3- (naphthalen-1-yl) -11-oxo-8- (piperidin-1-ylmethyl) -1,2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridec-e-yl-2-15-yl) acetonitrile

2- ((8S, 12aR, 15S) -14-propenoyl-8- ((dimethylamino) methyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecan-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecan-en-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-10-methyl-11-oxo-3-phenyl-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((8R, 12aS, 15R) -14-propenoyl-8- ((dimethylamino) methyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecan-15-yl) acetonitrile

2- ((12 aS, 15R) -14-propenoyl-10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecan-en-15-yl) acetonitrile

2- (14-propenoyl-8- ((dimethylamino) methyl) -11-methyl-3- (naphthalen-1-yl) -12-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,10] triazatridec-n-15-yl) acetonitrile

2- (14-propenoyl-11-methyl-3- (naphthalen-1-yl) -12-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,10] triazatridecan-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-10- (4- (dimethylamino) butyl) -3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecan-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-10-methyl-3- (naphthalen-1-yl) -11-oxo-9- (pyrrolidin-1-ylmethyl) -1,2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridec- -c-n-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-10-methyl-3- (naphthalen-1-yl) -11-oxo-9- (piperidin-1-ylmethyl) -1,2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridec- -c-n-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-10-methyl-9- ((4-methylpiperazin-1-yl) methyl) -3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-9- ((3- (dimethylamino) azetidin-1-yl) methyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-9- ((4- (dimethylamino) piperidin-1-yl) methyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-10-methyl-3- (naphthalen-1-yl) -1,2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridec-en-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-11-methyl-3- (naphthalen-1-yl) -1,2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminosubunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,10] triazatridec- -2-yl) acetonitrile

2- (14-propenoyl-10-methyl-9- (2-morpholinoethyl) -3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridec- -c-n-15-yl) acetonitrile

2- (14-propenoyl-10-methyl-3- (naphthalen-1-yl) -11-oxo-9- (2- (piperidin-1-yl) ethyl) -1,2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridec-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-9- ((dimethylamino) methyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridec-en-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-9- (azetidin-1-ylmethyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-n-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-10- (2- (4-methylpiperazin-1-yl) ethyl) -3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-n-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-10- (2- (1-methylpiperidin-4-yl) ethyl) -3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridec-n-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-10- (3- (4-methylpiperazin-1-yl) propyl) -3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-n-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-10- (3- (1-methylpiperidin-4-yl) propyl) -3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridec-n-15-yl) acetonitrile

2- ((12 aS, 15R) -14-propenoyl-10-methyl-3- (naphthalen-1-yl) -11-oxo-8- (piperidin-1-ylmethyl) -1,2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridec- -c-in-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-3- (8-chloronaphthalen-1-yl) -10-methyl-11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminosubunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-n-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-9- (2- (dimethylamino) ethyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-n-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-10-methyl-3- (naphthalen-1-yl) -11-oxo-8- (2- (piperidin-1-yl) ethyl) -1,2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridec-en-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-8- (2- (dimethylamino) ethyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridec- -c-n-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-10-methyl-8- (2- (1-methylpiperidin-4-yl) ethyl) -3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-8- ((4- (dimethylamino) piperidin-1-yl) methyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecan-in-15-yl) acetonitrile

2- (14-propenoyl-9- (2- (4- (dimethylamino) piperidin-1-yl) ethyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridec- -c-n-15-yl) acetonitrile

2- (14-propenoyl-10-methyl-9- (2- (4-methylpiperazin-1-yl) ethyl) -3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridec-15-yl) acetonitrile

2- (14-propenoyl-9- (2- (3- (dimethylamino) azetidin-1-yl) ethyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecan-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-10-methyl-8- ((1-methylpyrrolidin-2-yl) methyl) -3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecen-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-9- (2- (dimethylamino) ethyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-n-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-3- (8-chloronaphthalen-1-yl) -10-methyl-11-oxo-9- (piperidin-1-ylmethyl) -1,2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecan-in-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-3- (8-chloronaphthalen-1-yl) -10-methyl-11-oxo-8- (2- (pyrrolidin-1-yl) ethyl) -1,2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecan-15-yl) acetonitrile

2- ((8R, 12aR, 15S) -14-propenoyl-3- (8-chloronaphthalen-1-yl) -8- ((dimethylamino) methyl) -10-methyl-11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-10-methyl-8- ((4-methylpiperazin-1-yl) methyl) -3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecan-in-15-yl) acetonitrile

2- (14-propenoyl-9- (2- (azetidin-1-yl) ethyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridec-n-15-yl) acetonitrile

2- (14-propenoyl-10-methyl-3- (naphthalen-1-yl) -11-oxo-9- (2- (pyrrolidin-1-yl) ethyl) -1,2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridec-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-10-methyl-3- (naphthalen-1-yl) -11-oxo-8- (pyrrolidin-1-ylmethyl) -1,2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridec- -in-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-10-methyl-3- (naphthalen-1-yl) -11-oxo-8- (2- (pyrrolidin-1-yl) ethyl) -1,2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecan-in-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-3- (8-chloronaphthalen-1-yl) -10- (2- (4-methylpiperazin-1-yl) ethyl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-3- (8-chloronaphthalen-1-yl) -10-methyl-8- (1-methylpyrrolidin-2-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoylidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((8R, 12aR, 15S) -14-propenoyl-8- ((dimethylamino) methyl) -10-methyl-3- (8-methylnaphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((8 r,12ar,15 s) -14-propenoyl-3- (8-chloro-3-hydroxynaphthalen-1-yl) -8- ((dimethylamino) methyl) -10-methyl-11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((8R, 12aR, 15S) -14-propenoyl-8- ((dimethylamino) methyl) -3- (8-ethynylnaphthalen-1-yl) -10-methyl-11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((8 r,12ar,15 s) -14-propenoyl-3- (8-chloro-7-fluoronaphthalen-1-yl) -8- ((dimethylamino) methyl) -10-methyl-11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((8R, 12aR, 15S) -14-propenoyl-3- (5-chloroisoquinolin-4-yl) -8- ((dimethylamino) methyl) -10-methyl-11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-n-15-yl) acetonitrile

2- ((8 r,12ar,15 s) -14-propenoyl-8- ((dimethylamino) methyl) -3- (7-fluoro-8-methylnaphthalen-1-yl) -10-methyl-11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((8 r,12ar,15 s) -14-propenoyl-8- ((dimethylamino) methyl) -3- (8-ethynyl-7-fluoronaphthalen-1-yl) -10-methyl-11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((8R, 12aR, 15S) -14-propenoyl-8- ((dimethylamino) methyl) -10-methyl-3- (5-methylisoquinolin-4-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-n-15-yl) acetonitrile

2- ((8R, 12aR, 15S) -14-propenoyl-3- (5-chloro-6-fluoroisoquinolin-4-yl) -8- ((dimethylamino) methyl) -10-methyl-11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((8R, 12aR, 15S) -14-propenoyl-3- (5-chloroquinolin-4-yl) -8- ((dimethylamino) methyl) -10-methyl-11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoylidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-3- (8-chloronaphthalen-1-yl) -10-methyl-11-oxo-8- (tetrahydro-1H-pyrrolizin-7 a (5H) -yl) -1,2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((12 aR, 15S) -3- (8-chloronaphthalen-1-yl) -14- (2-fluoroacryloyl) -10-methyl-11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((8R, 12aR, 15S) -3- (8-chloronaphthalen-1-yl) -8- ((dimethylamino) methyl) -14- (2-fluoroacryloyl) -10-methyl-11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-n-15-yl) acetonitrile

3-propenoyl-15-chloro-13-fluoro-14- (2-fluoro-6-methoxyphenyl) -2, 6-dimethyl-2, 3, 4a,6,7,8, 9-octahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,10] triazatridecan-5 (1H) -one

3-propenoyl-15-chloro-13-fluoro-14- (2-fluoro-6-hydroxyphenyl) -2, 7-dimethyl-1, 2,3, 4a,5,8, 9-octahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatridecan-6 (7H) -one

3-propenoyl-15-chloro-13-fluoro-14- (2-fluoro-6-hydroxyphenyl) -2, 6-dimethyl-2, 3, 4a,6,7,8, 9-octahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,10] triazatridecan-5 (1H) -one

3-propenoyl-15-chloro-13-fluoro-14- (2-fluoro-6-hydroxyphenyl) -2-methyl-1, 2,3, 4a,5,8, 9-octahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatridecan-6 (7H) -one

3-propenoyl-15-chloro-13-fluoro-14- (2-fluoro-6-hydroxyphenyl) -2-methyl-2, 3, 4a,6,7,8, 9-octahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,10] triazatrideca-5 (1H) -one

3-propenoyl-15-chloro-9- ((dimethylamino) methyl) -13-fluoro-14- (2-fluoro-6-methoxyphenyl) -2, 7-dimethyl-1, 2,3, 4a,5,8, 9-octahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatrideca-6 (7H) -one

2- (3-propenoyl-15-chloro-13-fluoro-14- (2-fluoro-6-methoxyphenyl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatrideca-2-yl) acetonitrile

2- (3-propenoyl-15-chloro-9- ((dimethylamino) methyl) -13-fluoro-14- (2-fluoro-6-methoxyphenyl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (amino subunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatrideca-2-yl) acetonitrile

2- (3-propenoyl-15-chloro-13-fluoro-14- (2-fluoro-6-hydroxyphenyl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatrideca-2-yl) acetonitrile

2- (3-propenoyl-15-chloro-13-fluoro-14- (2-fluoro-6-methoxyphenyl) -6-methyl-5-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,10] triazatrideca-2-yl) acetonitrile

2- ((2 s,4 ar) -3-propenoyl-15-chloro-13-fluoro-14- (2-fluoro-6-hydroxyphenyl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatrideca-2-yl) acetonitrile

2- (3-propenoyl-15-chloro-9- ((dimethylamino) methyl) -13-fluoro-14- (2-fluoro-6-methoxyphenyl) -6-methyl-5-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (amino subunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,10] triazatrideca-2-yl) acetonitrile

3-propenoyl-15-chloro-9- ((dimethylamino) methyl) -13-fluoro-14- (2-fluoro-6-methoxyphenyl) -2, 6-dimethyl-2, 3, 4a,6,7,8, 9-octahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,10] triazatrideca-5 (1H) -one

2- (14-propenoyl-4-fluoro-10-methyl-3- (naphthalen-1-yl) -11-oxo-8, 9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminosubunit) pyrazino [1,2-g ] pyrido [4,3-d ] [1] oxa [3,7,11] triazatridecan-15-yl) acetonitrile

2- (14-propenoyl-4-fluoro-11-methyl-3- (naphthalen-1-yl) -12-oxo-8, 9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [4,3-d ] [1] oxa [3,7,10] triazatrideca-15-yl) acetonitrile

2- (14-propenoyl-8- ((dimethylamino) methyl) -4-fluoro-11-methyl-3- (naphthalen-1-yl) -12-oxo-8, 9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [4,3-d ] [1] oxa [3,7,10] triazatridecan-15-yl) acetonitrile

2- (14-propenoyl-8- ((dimethylamino) methyl) -4-fluoro-10-methyl-3- (naphthalen-1-yl) -11-oxo-8, 9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [4,3-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((2 s,4 ar) -3-propenoyl-15-chloro-13-fluoro-14- (2-fluoro-6-methoxyphenyl) -7-methyl-6-oxo-9- (2- (piperidin-1-yl) ethyl) -1,2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminoiden) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatrideca-n-2-yl) acetonitrile

2- ((2 s,4 ar) -3-propenoyl-13-fluoro-14- (2-fluoro-6-hydroxyphenyl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminoiden) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatridecan-2-yl) acetonitrile

2- (3-propenoyl-15-chloro-13-fluoro-14- (3-hydroxyphenyl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminoidene) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatridec-n-2-yl) acetonitrile

2- ((2 s,4 ar) -3-propenoyl-15-chloro-13-fluoro-14- (2-hydroxyphenyl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminoiden) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatridecan-2-yl) acetonitrile

2- ((2 s,4 ar) -3-propenoyl-15-chloro-13-fluoro-14- (2-fluoro-6-methoxyphenyl) -7-methyl-6-oxo-8- (2- (piperidin-1-yl) ethyl) -1,2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminoiden) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatrideca-n-2-yl) acetonitrile

2- ((2 s,4 ar) -3-propenoyl-15-chloro-13-fluoro-14- (2-fluoro-6-methoxyphenyl) -7-methyl-6-oxo-8- (2- (piperidin-1-yl) ethyl) -1,2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminoiden) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatrideca-n-2-yl) acetonitrile

2- ((2 s,4 ar) -3-propenoyl-15-chloro-13-fluoro-14- (2-fluorophenyl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminoiden) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatridecan-2-yl) acetonitrile

2- ((2 s,4 ar) -3-propenoyl-15-chloro-13-fluoro-14- (2-fluoro-5-hydroxyphenyl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatrideca-2-yl) acetonitrile

2- (3-propenoyl-15-chloro-13-fluoro-14- (6-hydroxynaphthalen-1-yl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatrideca-2-yl) acetonitrile

2- ((2 s,4 ar) -3-propenoyl-15-chloro-13-fluoro-14- (1H-indazol-7-yl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (amino subunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatrideca-2-yl) acetonitrile

2- ((2 s,4 ar) -3-propenoyl-14- (1H-benzo [ d ] imidazol-7-yl) -15-chloro-13-fluoro-7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminoiden) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatrideca-2-yl) acetonitrile

2- ((2 s,4 ar) -3-propenoyl-15-chloro-13-fluoro-14- (7-hydroxynaphthalen-1-yl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminoiden) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatridec-2-yl) acetonitrile

2- ((2 s,4 ar) -3-propenoyl-15-chloro-13-fluoro-14- (3-hydroxynaphthalen-1-yl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminoiden) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatridec-2-yl) acetonitrile

2- ((2 s,4 ar) -3-propenoyl-15-chloro-13-fluoro-14- (2-fluoro-6-hydroxyphenyl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatrideca-2-yl) acetonitrile

2- ((2 s,4 ar) -3-propenoyl-15-chloro-13-fluoro-7-methyl-14- (8-methylnaphthalen-1-yl) -6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminoiden) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatridec-2-yl) acetonitrile

2- ((2 s,4 ar) -3-propenoyl-15-chloro-14- (8-chloro-7-fluoronaphthalen-1-yl) -13-fluoro-7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminoiden) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatrideca-2-yl) acetonitrile

2- ((8S, 12aR, 15S) -14-propenoyl-3- (8-chloronaphthalen-1-yl) -8- ((dimethylamino) methyl) -10-methyl-11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((2 s,4 ar) -3-propenoyl-15-chloro-14- (8-chloro-7-fluoronaphthalen-1-yl) -13-fluoro-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminoiden) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatrideca-2-yl) acetonitrile

2- ((8 r,12ar,15 s) -14-propenoyl-3- (8-chloro-7-fluoronaphthalen-1-yl) -10-methyl-11-oxo-8- (pyrrolidin-1-ylmethyl) -1,2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((2 s,4ar,9 r) -3-propenoyl-15-chloro-14- (8-chloro-7-fluoronaphthalen-1-yl) -9- ((dimethylamino) methyl) -13-fluoro-7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminoiden) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatridec-2-yl) acetonitrile

2- ((8S, 12aR, 15S) -14-propenoyl-3- (8-chloro-7-fluoronaphthalen-1-yl) -8- ((dimethylamino) methyl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((8 r,12ar,15 s) -14-propenoyl-3- (8-chloro-7-fluoronaphthalen-1-yl) -8- ((dimethylamino) methyl) -4-fluoro-10-methyl-11-oxo-8, 9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [4,3-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((8S, 12aR, 15S) -14-propenoyl-3- (8-chloro-7-fluoronaphthalen-1-yl) -8- ((dimethylamino) methyl) -4-fluoro-11-oxo-8, 9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [4,3-d ] [1] oxa [3,7,11] triazatridec- -in-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-3- (8-chloronaphthalen-1-yl) -4-fluoro-10-methyl-11-oxo-8, 9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [4,3-d ] [1] oxa [3,7,11] triazatridecan-in-15-yl) acetonitrile and

2- ((2 s,4 ar) -3-propenoyl-15-chloro-14- (8-chloronaphthalen-1-yl) -13-fluoro-7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminoiden) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatrideca-2-yl) acetonitrile

Or a pharmaceutically acceptable salt thereof.

Table 1 below illustrates exemplary compounds of the present disclosure.

TABLE 1

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

As used herein, the term "prodrug" refers to a compound or a pharmaceutically acceptable salt thereof that upon metabolism under physiological conditions or conversion by solvolysis yields the desired active compound. Prodrugs include, but are not limited to, esters, amides, carbamates, carbonates, ureides, solvates or hydrates of the active compounds. Typically, prodrugs are 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 metabolism, the ester groups are cleaved to yield the active drug. In addition, some prodrugs are enzymatically activated to produce the active compound or compounds that produce the active compound upon further chemical reaction. The prodrug may be developed from a prodrug form to an active form in a single step, or may have one or more intermediate forms that may or may not be active themselves. The preparation and use of prodrugs is discussed in the following references: higuchi and v.stilla, "Pro-drug as novel delivery system (Pro-drugs as Novel Delivery Systems)", volume 14 of the a.c.s. seminar Series (a.c. symposium Series), bioreversible carrier in drug design (Bioreversible Carriers in Drug Design), editors Edward b.roche, american pharmaceutical society (American Pharmaceutical Association) and pegamon Press, 1987. Prodrug: challenge and return (Prodrugs: challenges and Rewards), editorial V.Stella, R.Borchardt, M.Hageman, R.Oliyai, H.Maag, J.Tilley, new York Springs Press (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 a compound that exerts a pharmacological effect but breaks down into inactive metabolite degradants such that the activity time is limited. See, for example, "soft drugs: principles and methods of safe drug design (Soft drugs: principles and methods for the design of safe drugs) ", nicholas Bodor, drug research review (Medicinal Research Reviews), volume 4, stage 4, 449-469,1984, which references are hereby incorporated by reference in their entirety.

As used herein, the term "metabolite", e.g., an active metabolite, overlaps with the prodrug as described above. Such metabolites are therefore pharmacologically active compounds, or compounds that are further metabolized to pharmacologically active compounds, which are derivatives produced by metabolic processes in the subject. For example, such metabolites may result from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound or salt or prodrug. Wherein the active metabolite is such a pharmacologically active derivative compound. For prodrugs, the prodrug compounds are generally inactive or less active than the metabolite. For active metabolites, the parent compound may be an active compound or may be an inactive prodrug.

Prodrugs and active metabolites may be identified using conventional techniques known in the art. See, for example, bertolini et al, 1997, journal of pharmaceutical chemistry (J Med Chem) 40:2011-2016; shan et al, J.Pharm.Sci.86:756-757; bagshawe,1995, drug development study (drug Dev Res) 34:220-230; wermuth, supra.

As used herein, the term "pharmaceutically acceptable" means that the substance or composition is chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the subject being treated.

As used herein, unless otherwise indicated, the term "pharmaceutically acceptable salt" includes salts that retain the biological effectiveness of the free acids and bases of the indicated compounds and are not biologically or otherwise undesirable. Contemplated pharmaceutically acceptable salt forms include, but are not limited to, mono-, di-, tri-, tetra-salts, and the like. The pharmaceutically acceptable salts are non-toxic in the amount and concentration in which they are administered. The preparation of such salts may facilitate pharmacological use by altering the physical properties of the compound without impeding its performance in terms of its physiology. Useful alterations in physical properties include lowering the melting point to facilitate transmucosal administration and increasing the solubility to facilitate administration of higher concentrations of the drug.

Pharmaceutically acceptable salts include acid addition salts, such as acid addition salts including: sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, mesylate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinic acid salts. 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.

When an acidic functional group such as carboxylic acid or phenol is present, pharmaceutically acceptable salts also include base addition salts, such as base addition salts including: benzathine (benzathine), chloroprocaine (chloroprocaine), choline, diethanolamine, ethanolamine, tert-butylamine, ethylenediamine, meglumine, procaine (procaine), aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamines and zinc. See, for example, remington's Pharmaceutical Sciences, 19 th edition, mark publication company, mack Publishing co., easton, PA, volume 2, page 1457, 1995; manual of pharmaceutical salts: properties, selection and Use (Handbook of Pharmaceutical Salts: properties, selection, and Use), stahl and Wermuth, wiley-VCH Press of Wei Yinhai M, germany (Wiley-VCH, weinheim, germany), 2002. Such salts may be prepared using the appropriate corresponding base.

Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the free base form of the compound may be dissolved in a suitable solvent (e.g., an aqueous or water-alcohol solution including a suitable acid) and then isolated by evaporation of 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, treating the free base with the following acid: inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, and the like; pyranosyl acids such as glucuronic acid or galacturonic acid; alpha-hydroxy acids such as citric acid or tartaric acid; amino acids such as aspartic acid or glutamic acid; aromatic acids such as benzoic acid or cinnamic acid; sulfonic acids such as p-toluenesulfonic acid or ethanesulfonic acid; etc.

Similarly, if the particular compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treating 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 amino acids derived from, for example, L-glycine, L-lysine and L-arginine; ammonia, primary, secondary and tertiary amines; organic salts of 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 the present disclosure may exist in unsolvated forms, solvated forms (e.g., hydrated forms), and solid forms (e.g., crystalline or polycrystalline forms), and that the present disclosure is intended to cover all such forms.

As used herein, the term "solvate" or "solvated form" refers to a solvent addition form that includes a stoichiometric or non-stoichiometric amount of solvent. Some compounds have a solvent fraction that captures a fixed molar ratio in the crystalline solid stateA child, thereby forming a solvate trend. If the solvent is water, the solvate formed is a hydrate, and if the solvent is an alcohol, the solvate formed is an alkoxide (alcoholate). The hydrate is produced by maintaining one or more water molecules with water as H ₂ One molecule of the substance in the molecular state of O. 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 "crystalline form," "polymorphic form," and "polymorph" are used interchangeably and refer to a crystalline structure of a compound (or a salt or solvate thereof) that can crystallize in a different crystal packing arrangement, all of which have the same elemental composition. Different crystal forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors may dominate one crystal form. Polymorphs of a compound 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 atoms include atoms having the same atomic number but different mass numbers. For example, unless otherwise indicated, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, or iodine in a compound of the present disclosure is meant to also include isotopes thereof, such as, but not limited to ¹ H、 ² H、 ³ H、 ¹¹ C、 ¹² C、 ¹³ C、 ¹⁴ C、 ¹⁴ N、 ¹⁵ N、 ¹⁶ O、 ¹⁷ O、 ¹⁸ O、 ³¹ P、 ³² P、 ³² S、 ³³ S、 ³⁴ S、 ³⁶ S、 ¹⁷ F、 ¹⁸ F、 ¹⁹ F、 ³⁵ Cl、 ³⁷ Cl、 ⁷⁹ Br、 ⁸¹ Br、 ¹²⁴ I、 ¹²⁷ I and ¹³¹ I. in some embodiments, the hydrogen comprises protium, deuterium, and tritium. In some embodiments, the carbon packageScraper ¹² C and C ¹³ C。

Those skilled in the art will appreciate that the compounds of the present disclosure may exist in different tautomeric forms, and that all such forms are contemplated as falling within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can be converted to each other by a low energy barrier. The existence and concentration of the isomeric forms will depend on the environment in which the compound is located and may vary depending, for example, on whether the compound is solid or in an organic or aqueous solution. For example, proton tautomers (also known as proton-metamorphosing tautomers) include interconversions by proton transfer, such as keto-enol, amide-imide, lactam-lactam, imine-enamine isomerisation, and cyclic forms where a proton may occupy two or more positions of a heterocyclic ring system. Valence tautomers include interconversions by recombination of some of the bond-forming electrons. Tautomers may be in equilibrium or sterically locked into one form by appropriate substitution. Unless otherwise indicated, compounds of the present disclosure identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms.

Synthesis of Compounds

The compounds provided herein may be prepared using any known organic synthesis technique and may be synthesized according to any of a number of possible synthetic routes.

The reactions for preparing the compounds of the present disclosure may be carried out in suitable solvents that may be readily selected by those skilled in the art of organic synthesis. Suitable solvents may be substantially unreactive with the starting materials (reactants), intermediates or products at the temperature at which the reaction is carried out, for example, a temperature which may range from the freezing temperature of the solvent to the boiling temperature of the solvent. A given reaction may be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, the appropriate solvent for the particular reaction step may be selected by one skilled in the art.

The preparation of the compounds of the present disclosure may 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 of skill in the art. The chemistry of protecting groups can be found, for example, in the following references: T.W.Greene and P.G.M.Wuts protecting group in organic Synthesis (Protective Groups in Organic Synthesis), 3 rd edition, john wili's father-son publishing company, N.Y. (1999); kocienski, protecting group (Protecting Groups), qiao Zhitai m press (Georg Thieme Verlag), 2003; and Peter g.m.wuts, greene's Protective Groups in Organic Synthesis, 5 th edition, wili publishing (Wiley), 2014, incorporated herein by reference in its entirety.

The reaction may be monitored according to any suitable method known in the art. For example, the radiation may be detected by, for example, nuclear magnetic resonance spectroscopy (e.g., ¹ h or ¹³ C) The product formation is monitored by spectroscopic means such as infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatographic methods such as High Performance Liquid Chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS), or Thin Layer Chromatography (TLC). The compounds can be purified by a variety of methods including High Performance Liquid Chromatography (HPLC) ("Preparative LC-MS Purification: improved Compound Specific Method Optimization) improved compound specific method optimization" Karl F.Blom, brian Glass, richard Sparks, andrew P.combos J.Combined chemistry (J.combi.chem.)) "2004,6 (6), 874-883, which is incorporated herein by reference in its entirety) and normal phase silica gel chromatography.

Use of compounds

In one aspect, the present disclosure provides compounds capable of inhibiting KRAS proteins, particularly KRAS G12C proteins.

As used herein, the term "therapy" is intended to have its normal meaning, i.e., treating a disease so as to completely or partially alleviate one, some or all of its symptoms, or correct or compensate for an underlying pathology, thereby achieving a beneficial or desired clinical outcome. For the purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilization of disease state (i.e., not worsening), delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. "therapy" may also mean an increase in survival compared to the expected survival in the absence of receiving therapy. The condition requiring therapy includes a condition that has suffered from a condition or disorder, a condition that is susceptible to suffering from a condition or disorder, or a condition that is to be prevented from a condition or disorder. The term "therapy" also encompasses prophylaxis unless there is a specific indication to the contrary. The terms "therapeutic" and "therapeutically" should be interpreted in a corresponding manner.

As used herein, the term "prevention" is intended to have its normal meaning and includes primary prevention for preventing the development of a disease and secondary prevention in which the disease has progressed and the patient is temporarily or permanently protected from exacerbation or worsening of the disease or suffering from new symptoms associated with the disease.

The term "treatment" is used synonymously with "therapy". Similarly, the term "treatment" may be regarded as "application of therapy", wherein "therapy" is as defined herein.

In a further aspect, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, for therapy, e.g., for therapy related to KRAS proteins, in particular KRAS G12C proteins.

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

In some embodiments, the cancer is mediated by KRAS proteins. In some embodiments, the cancer is mediated by KRAS G12C protein.

Pharmaceutical composition

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

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

As used herein, the term "pharmaceutical composition" refers to a formulation of the present disclosure including a molecule or compound in a form suitable for administration to a subject.

As used herein, the term "pharmaceutically acceptable excipient" means an excipient that can be used to prepare a pharmaceutical composition that is generally safe, non-toxic, and biologically and otherwise desirable, and includes excipients that are acceptable for veterinary use as well as for human pharmaceutical use. As used herein, "pharmaceutically acceptable excipients" includes one and more than one such excipient. The term "pharmaceutically acceptable excipient" also encompasses "pharmaceutically acceptable carrier" and "pharmaceutically acceptable diluent".

The particular excipients used will depend on the means and purpose for which the compounds of the present disclosure are applied. The solvent is generally selected based on solvents deemed safe by those skilled in the art to be administered to mammals, including humans. Generally, the safe solvent is a non-toxic aqueous solvent 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), and the like, and mixtures thereof.

In some embodiments, suitable excipients may include buffers, such as phosphates, citrates and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (e.g., octadecyldimethylbenzyl ammonium chloride, hexamethylammonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butanol or benzyl alcohol, alkyl parabens such as methyl or propyl parabens, catechol, resorcinol, cyclohexanol, 3-pentanol, and m-cresol); a low molecular weight (less than about 10 residues) polypeptide; proteins, such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers, e.g. polyvinylpyrrolidoneAn alkanone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrans; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions, such as sodium; metal complexes (e.g., zn protein complexes); and/or nonionic surfactants, e.g. TWEEN ^TM 、PLURONICS ^TM Or polyethylene glycol (PEG).

In some embodiments, suitable excipients may include one or more stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, fragrances, flavoring agents, and other known additives to provide an optimal presentation of a drug (i.e., a compound of the present disclosure or pharmaceutical composition thereof) or to aid in the manufacture of a pharmaceutical product (i.e., a drug). The active pharmaceutical ingredient may also be embedded in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or in macroemulsions, respectively, hydroxymethyl cellulose or gelatin microcapsules and poly- (methyl methacrylate) microcapsules. Such techniques are disclosed in the Remington's pharmaceutical sciences 16 th edition, osol, A. Edition (1980). A "liposome" is a vesicle comprising various types of lipids, phospholipids, and/or surfactants that can be used to deliver a drug (such as a compound disclosed herein and optionally a chemotherapeutic agent) to a mammal, including a human. The components of liposomes are typically arranged in bilayer form, similar to the lipid arrangement of biological membranes.

The pharmaceutical compositions provided herein may be in any form that allows for administration of the composition to a subject, including but not limited to humans, and allows for formulation of the composition to be compatible with the intended route of administration.

Various routes are contemplated for the pharmaceutical compositions provided herein, and thus the pharmaceutical compositions provided herein may be supplied in bulk or unit dosage forms depending on the intended route of administration. For example, for oral, buccal and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, soft capsules, and caplets may be acceptable as solid dosage forms, and emulsions, syrups, elixirs, suspensions, and solutions may be acceptable as liquid dosage forms. For injectable administration, emulsions and suspensions may be acceptable as liquid dosage forms, and powders suitable for reconstitution with a suitable solution may be acceptable as solid dosage forms. For inhaled administration, solutions, sprays, dry powders and aerosols may be acceptable dosage forms. For topical (including buccal and sublingual) or transdermal administration, powders, sprays, ointments, pastes, creams, lotions, gels, solutions and patches may be in acceptable dosage forms. For vaginal administration, pessaries, tampons, creams, gels, pastes, foams, and sprays can be in acceptable dosage forms.

The amount of active ingredient in a unit dosage form of the composition is a therapeutically effective amount and will vary depending upon the particular treatment involved. As used herein, the term "therapeutically effective amount" refers to the amount of a molecule, compound, or composition comprising the molecule or compound that treats, ameliorates, or prevents the identified disease or condition or exhibits a detectable therapeutic or inhibitory effect. The effect may be detected by any assay known in the art. The precise effective amount of the subject will depend on the weight, size and health of the subject; the nature and extent of the pathology; the rate of application; selecting a treatment or combination of treatments for administration; judgment of prescribing physician. The therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician.

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

In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of a tablet formulation. Pharmaceutically acceptable excipients suitable for tablet formulations include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate; granulating and disintegrating agents, such as corn starch or alginic acid; binders, such as starch; lubricants, such as magnesium stearate, stearic acid or talc; preservatives, such as ethyl or propyl parahydroxybenzoate; and antioxidants such as ascorbic acid. The tablet formulation may be uncoated or coated to regulate its disintegration and subsequent absorption of the active ingredient in the gastrointestinal tract, or to improve its 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 the form of hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin; or in the form of soft gelatin capsules wherein the active ingredient is mixed with water or an oil, for example peanut oil, liquid paraffin or olive oil.

In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of an aqueous suspension, which generally comprises the active ingredient in the form of a fine powder, and one or more suspending agents, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth, and gum acacia; dispersants or wetting agents, such as lecithin or condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate); or condensation products of ethylene oxide with long chain fatty alcohols, such as heptadecaethyleneoxy cetyl alcohol; or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, 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 suspension may also include one or more preservatives (e.g., ethyl or propyl parahydroxybenzoate), antioxidants (e.g., ascorbic acid), colorants, flavors, and/or sweeteners (e.g., sucrose, saccharin, or aspartame).

In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of an oily suspension, typically comprising the suspended active ingredient in a vegetable oil (such as peanut oil, castor oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). Oily suspensions may also contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweeteners (e.g., as set forth above) and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, for example olive oil or arachis oil; or mineral oils such as liquid paraffin; or a mixture of any of these oils. Suitable emulsifying agents may be, for example, naturally-occurring gums, such as acacia or tragacanth; naturally occurring phospholipids, such as soybean, lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate) and condensation products of the partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also include sweeteners, flavoring agents and preservatives.

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

In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of a 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. Such suspensions may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents as 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 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 are conventionally 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 find use in the preparation of injectables.

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

In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of aqueous and non-aqueous (e.g., in fluorocarbon propellants) aerosols comprising any suitable solvent and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers, and combinations thereof. The carrier and stabilizer will vary depending on the requirements of the particular compound, but typically includes nonionic surfactants (Tween, pluronic (Pluronic) or polyethylene glycol), innocuous proteins (such as 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 the form of a 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 be formulated, typically with 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 patches well known to those of ordinary skill in the art.

Pharmaceutically acceptable excipients and carriers, in addition to those representative dosage forms described above, are generally known to those skilled in the art and are therefore included in the present disclosure. Such excipients and carriers are described, for example, in the following references: ramington's pharmaceutical science (Remingtons Pharmaceutical Sciences), mark publishing company (Mack Pub.Co., new Jersey) (1991); leimngton: pharmaceutical science and practice (Remington: the Science and Practice of Pharmacy), editorial, university of philadelphia science (University of the Sciences in Philadelphia), 21 st edition, LWW (2005), which is incorporated herein by reference.

In some embodiments, the pharmaceutical compositions of the present disclosure may be formulated into a single dosage form. The amount of a compound provided herein in a single dosage form will vary depending upon the subject being treated and the particular mode of administration.

In some embodiments, the pharmaceutical compositions of the present disclosure may be formulated such that 0.001mg/kg body weight/day to 1000mg/kg body weight/day may be administered, for example, 0.01mg/kg body weight/day to 800mg/kg body weight/day, 0.01mg/kg body weight/day to 700mg/kg body weight/day, 0.01mg/kg body weight/day to 600mg/kg body weight/day, 0.01mg/kg body weight/day to 500mg/kg body weight/day, 0.01mg/kg body weight/day to 400mg/kg body weight/day, 0.01mg/kg body weight/day to 300mg/kg body weight/day, 0.1mg/kg body weight/day to 200mg/kg body weight/day, 0.1mg/kg body weight/day to 150mg/kg body weight/day, 0.1mg/kg body weight/day to 100mg/kg body weight/day 0.5mg/kg body weight/day to 100mg/kg body weight/day, 0.5mg/kg body weight/day to 80mg/kg body weight/day, 0.5mg/kg body weight/day to 60mg/kg body weight/day, 0.5mg/kg body weight/day to 50mg/kg body weight/day, 1mg/kg body weight/day to 45mg/kg body weight/day, 1mg/kg body weight/day to 40mg/kg body weight/day, 1mg/kg body weight/day to 35mg/kg body weight/day, 1mg/kg body weight/day to 30mg/kg body weight/day, A compound provided herein, or a pharmaceutically acceptable salt thereof, at a dose of 1mg/kg body weight/day to 25mg/kg body weight/day. In some cases, dosage levels below the lower limit of the aforementioned range may be more than adequate, while in other cases larger doses may be employed without causing any adverse side effects, provided that such larger doses are first divided into several small doses for administration throughout the day. For additional information on route of administration and dosage regimen, see, comprehensive pharmaceutical chemistry (Comprehensive Medicinal Chemistry), volume 5, chapter 25.3 (Corwin Hansch; editorial Committee chairman 1990), which is expressly incorporated herein by reference.

In some embodiments, the pharmaceutical compositions of the present disclosure may be formulated for short-acting, rapid-release, long-acting, and sustained-release. Thus, the pharmaceutical formulations of the present disclosure may also be formulated for controlled or slow release.

In a further aspect, there is also provided a veterinary composition comprising one or more molecules or compounds of the present disclosure, or a pharmaceutically acceptable salt 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 that are otherwise inert or acceptable in the veterinary field and compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route.

The pharmaceutical or veterinary composition may be packaged in various ways depending on the method used to administer the drug. For example, the article for dispensing may comprise a container containing the composition in a suitable 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 cans and the like. The container may also include a tamper evident assembly to prevent easy access to the contents of the package. In addition, the container has a label placed thereon describing the contents of the container. The tag may also include an appropriate warning. The compositions may also be packaged in unit-dose or multi-dose containers, such as sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, such as 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 a pharmaceutical composition comprising as a first active ingredient one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, and a second active ingredient.

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

Methods of treating diseases

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

In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof and the compositions provided herein may be used to treat KRAS G12C-associated cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof.

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

(i) Heart cancer: sarcomas (hemangiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma;

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

(iii) Gastrointestinal cancer: esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma), pancreatic cancer (ductal adenocarcinoma, insulinoma, glucagon tumor, gastrinoma, carcinoid tumor, schuvascular intestinal peptide tumor), small intestinal cancer (adenocarcinoma, lymphoma, carcinoid tumor, kaposi's sarcoma, smooth myoma, hemangioma, lipoma, neurofibroma, fibroma), large intestinal cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, smooth myoma);

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

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

(vi) Biliary tract cancer: gall bladder cancer, ampulla cancer, bile duct cancer; bone cancer: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, ewing's sarcoma, malignant lymphoma (reticulosarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondral tumor (bone exochondral osteowart), benign chondrioma, chondroblastoma, cartilage myxoid fibroma, osteoid osteoma and giant cell tumor;

(vii) Nervous system cancer: head bone cancer (osteoma, hemangioma, granuloma, xanthoma, malformed osteoma), meningioma (meningioma, glioblastoma), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma);

(viii) Gynecological cancer: uterine cancer (endometrial cancer (serous cyst adenocarcinoma, mucinous cyst adenocarcinoma, unclassified cancer), granulosa cell tumors, sertoli-Leydig cell tumor, asexual cell tumors, malignant teratomas), vulval cancer (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube cancer (carcinoma);

(ix) Blood cancer: hematological cancers (myelogenous leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphoblastic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma);

(x) Skin cancer: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, cutaneous fibroma, keloids, psoriasis; and

(xi) Adrenal cancer: neuroblastoma.

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

In certain embodiments, the cancers that may be treated with the compounds provided herein or pharmaceutically acceptable salts and compositions thereof are non-small cell lung cancer or colorectal cancer, particularly non-small cell lung cancer or colorectal cancer with brain metastases.

The concentration of administration and the route of administration of the subject will vary depending on the cancer to be treated. In certain embodiments, the administering is by a route selected from the group consisting of: parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, cerebrospinal, intrasynovial, intrathecal, intramuscular, intravitreal, intravenous, intraarterial, oral, buccal, sublingual, transdermal, topical, intratracheal, intrarectal, subcutaneous and topical administration.

The compounds, pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing such compounds and salts may also be co-administered with other anti-neoplastic compounds, such as chemotherapy, or in combination with other therapies, such as radiation or surgical intervention, as a pre-or post-operative aid.

In some embodiments, the compounds, pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising such compounds and salts may 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, a MEK inhibitor, a CDK4/CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, an SHP2 inhibitor, a SOS1 inhibitor, an mTOR inhibitor, a VEGFR inhibitor, an EGFR antibody, a platinum agent, or pemetrexed. In certain embodiments, the anti-PD-1 antagonist is selected from nivolumab (nivolumab), pembrolizumab (pembrolizumab), or AMB 404. In certain embodiments, the MEK inhibitor is Trametinib (Trametinib). In certain embodiments, the SHP2 inhibitor is RMC-4630.

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

(a) Knowing 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 or pharmaceutical composition thereof.

In another aspect, the present disclosure provides a method of inhibiting KRAS G12C activity in a subject in need thereof, the method comprising administering to the subject a compound of the present disclosure, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

Examples

The following examples are included for illustrative purposes. However, it should be understood that these examples are not limiting of the present disclosure and are intended only to demonstrate methods of practicing the present disclosure.

General synthetic pathway 1

Step 1:

the starting materials of formula (A1) wherein k is 0 or 1 are commercially available or can be prepared using conventional methods, for example as described in journal of organic chemistry (j.org.chem.) 2019,84,6040-6064.

The starting materials of formula (A2) are commercially available or can be prepared using conventional methods, for example as described in WO 2014015291 (A1).

The compound of formula (A3) may be prepared by subjecting the compound of formula (A1) to nucleophilic substitution reaction with the compound of formula (A2) under standard conditions in the presence of a base (e.g., DIPEA).

Step 2:

the compounds of formula (A4) may be prepared by removing the Boc protecting group of the compounds of formula (A3) with an acid (e.g., TFA) under standard conditions.

Step 3:

the compound of formula (A6) may be in the presence of a palladium catalyst (e.g., pd ₂ dba ₃ ) Ligand (e.g., ruphos) and base (e.g., cs ₂ CO ₃ ) Is prepared by subjecting a compound of formula (A4) to a buehwald coupling reaction with a compound of formula (A5) under standard conditions.

Step 4:

the compound of formula (A7) may be prepared by subjecting the compound of formula (A6) to hydrolysis reaction with a base (e.g., liOH) under standard conditions.

Step 5:

the compound of formula (A9) may be prepared by reacting a compound of formula (A7) with a compound of formula (A8) under standard conditions in the presence of a catalyst (e.g., EDCI, HOBt, HATU) and a base (e.g., DIPEA).

Step 6:

the compounds of formula (A10) may be in the presence of a palladium catalyst (e.g., pd (OAc) ₂ ) Ligand (e.g., BINAP) and base (e.g., cs ₂ CO ₃ ) Is prepared by subjecting a compound of formula (A9) to intramolecular buhelde coupling under standard conditions.

Step 7:

the compounds of formula (a 11) may be prepared by removing the PMB protecting group of the compounds of formula (a 10) with an acid (e.g., TFA) under standard conditions.

Step 8:

the compounds of formula (I) may be prepared by reacting a compound of formula (a 11) with acryloyl chloride and a base (e.g., triethylamine) under standard conditions.

General synthetic pathway 2

Step 1:

the compounds of formula (B2) may be in the presence of a palladium catalyst (e.g., pd (OAc) ₂ ) Ligand (e.g., BINAP) and base (e.g., cs ₂ CO ₃ ) Is prepared by subjecting a compound of formula (A6) wherein k is 0 or 1 to a buehwald coupling reaction with a compound of formula (B1) under standard conditions.

Step 2:

the compound of formula (B3) may be prepared by removing the Pht protecting group of the compound of formula (B2) with hydrazine hydrate under standard conditions.

Step 3:

the compound of formula (B4) may be in the presence of a base (e.g., DIPEA, K ₂ CO ₃ ) Is prepared by subjecting a compound of formula (B3) to nucleophilic substitution reaction with RX under standard conditions.

Step 4:

the compound of formula (B5) may be prepared by subjecting the compound of formula (B4) to hydrolysis reaction with a base (e.g., liOH) under standard conditions.

Step 5:

the compounds of formula (B6) may be prepared by subjecting the compounds of formula (B5) to a molecular lactam-forming reaction under standard conditions in the presence of a catalyst (e.g., EDCI, HOBt, HATU) and a base (e.g., DIPEA).

Step 6:

the compounds of formula (a 11) may be prepared by removal of the PMB protecting group of the compounds of formula (B6) with an acid (e.g., TFA) under standard conditions.

Step 7:

the compounds of formula (I) may be prepared by reacting a compound of formula (a 11) with acryloyl chloride and a base (e.g., triethylamine) under standard conditions.

Example 1:

1- {13- [ (dimethylamino) methyl ] -19- (naphthalen-1-yl) -14-oxa-2,5,16,19,23-pentaaza-tetracyclo [13.7.1.02,7.017,22] ditridec-1 (23), 15,17 (22) -trien-5-yl } prop-2-en-1-one (compound 1)

Step 1: 4-Benzylpiperazine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl piperazine-1-carboxylate (100 g,0.53 mol) and TEA (160 g,1.5 mol) in MeCN (1500 mL) was added BnBr (137 g,0.8 mol) at room temperature. The mixture was stirred at room temperature for 12 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified by a silica gel column (PE: ea=10:1) to give the desired product as a white solid (150 g, yield: 59%). MS (ESI): 277.0[ M+H ]] ⁺ 。

Step 2: 2-allyl-4-benzylpiperazine-1-carboxylic acid tert-butyl ester

To a 1000mL three-necked flask were added tert-butyl 4-benzylpiperazine-1-carboxylate (25 g,0.09 mol), TMEDA (25.4 g,0.21 mol) and Et ₂ O (500 mL). After cooling to-78 ℃, sec-BuLi (167 ml,1.3m solution in hexane, 0.22 mol) was added dropwise. After the addition was complete, the reaction mixture was heated to-10 ℃ and stirred for 1 hour. After cooling to-78 ℃, freshly prepared CuCN-2LiCl complex solution was added. The reaction mixture was stirred at-50℃for 30 min. The temperature was again cooled to-78 ℃ and allyl bromide (26.4 g,0.22 mol) and then stirred at-60℃for 1 hour. After stirring overnight at room temperature, the mixture was poured onto saturated NH ₄ In Cl solution and extracted with EA. The organic layer was washed with brine, dried over Na ₂ SO ₄ And (5) drying. After concentration, the residue was purified by a silica gel column (PE: ea=10:1) to give the desired product as a pale yellow oil. (27 g, yield: 94.4%).

¹ H NMR(400MHz,CDCl ₃ )δ7.37–7.22(m,5H),5.78–5.61(m,1H),5.06–4.86(m,2H),4.10(br s,1H),3.85(br s,1H),3.53(d,J＝13.2Hz,1H),3.37(d,J＝13.2Hz,1H),3.14–3.00(m,1H),2.87–2.64(m,2H),2.56–2.36(m,2H),2.09–1.99(m,2H),1.45(s,9H)。

Step 3: 2-allyl piperazine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 2-allyl-4-benzylpiperazine-1-carboxylate (30 g,94.9 mol) in DCE (600 mL) was added chloroethyl 1-chloroformate (40.4 g,284.8 mol) at 0deg.C, and the reaction mixture was stirred at 80deg.C for 2 hours. After cooling to room temperature and concentrating, the residue was purified by silica gel column chromatography eluting with (PE: ea=5:1) to give the compound 1- (tert-butyl) 4- (1-chloroethyl) 2-allylpiperazine-1, 4-dicarboxylic acid, which was diluted with MeOH (500 mL) and stirred at 60 ℃ for 1 hour. The mixture was concentrated under reduced pressure to give the title product (21 g, yield: 98%) as a yellow oil, which was used in the next step without further purification.

¹ H NMR(400MHz,CDCl3)δ5.84–5.60(m,1H),5.33(d,J＝13.2Hz,1H),5.14(d,J＝10.0Hz,1H),4.39(br s,1H),4.11–4.09(m,1H),3.43–3.31(m,3H),3.12–2.80(m,2H),2.67–2.66(m,2H),1.46(s,9H)。

Step 4: 2-allyl piperazine-1, 4-dicarboxylic acid 4-benzyl ester 1- (tert-butyl ester)

To tert-butyl 2-allylpiperazine-1-carboxylate (15 g,66.4 mol) at 0deg.C in EA (100 mL) and NaHCO ₃ To a solution of (saturated) (100 mL) was added CbzCl (17 g,99.6 mol) and the reaction mixture was warmed to room temperature for 2 hours. The reaction was extracted with EA. The organic layer was washed with brine and dried over Na2SO 4. After concentration, the residue was purified by a silica gel column (PE: ea=10:1) to give the desired product as a yellow oil. (17.3 g, yield: 73.6%). MS (ESI): 361.1[ M+H ]] ⁺ 。

Step 5: 3-allyl piperazine-1-carboxylic acid benzyl ester

To a solution of 4-benzyl 2-allylpiperazine-1, 4-dicarboxylate 1- (tert-butyl) ester (3.3 g,0.92 mol) in DCM (20 mL) was added TFA (20 mL) at 0deg.C and the reaction mixture was warmed to room temperature for 2 h. The mixture was concentrated under reduced pressure to give the title product (3.0 g, crude) as a yellow oil, which was used in the next step without further purification.

¹ H NMR(400MHz,CDCl3)δ7.48–7.29(m,5H),5.87–5.57(m,1H),5.18-5.15(m,4H),4.11(br s,2H),3.17(d,J＝11.0Hz,2H),2.99–2.78(m,3H),2.32(br s,2H)。

Step 6:4- (2-allyl-4- ((benzyloxy) carbonyl) piperazin-1-yl) -2-chloro-5, 8-dihydropyrido [3,4-d ] pyrimidine-7 (6H) -carboxylic acid tert-butyl ester

To a solution of benzyl 3-allylpiperazine-1-carboxylate (3 g,11.5 mol) in DMSO (30 mL) was added 2, 4-dichloro-5, 8-dihydropyrido [3,4-d ]]Pyrimidine-7 (6H) -carboxylic acid tert-butyl ester (3.8 g,12.7 mol) and DIEA (5.9 g,46.3 mmol) and the reaction mixture was stirred at 80℃for 16H. Will react with H ₂ O was diluted and extracted with EA. The organic layer was washed with brine and dried over Na2SO 4. In a concentrated stateAfter the shrinkage, the residue was purified by a silica gel column (PE: ea=3:1) to give the desired product as a brown solid. (2.5 g, yield: 41%).

LC-MS rt=2.357 minutes; MS calculated: 527.2, MS (ESI): 528.3[ M+H ]] ⁺ 。

¹ H NMR(400MHz,CDCl3)δ7.43–7.29(m,5H),5.67(br s,1H),5.19–5.13(m,2H),5.07(br s,2H),4.72–4.56(m,1H),4.40(d,J＝19.3Hz,1H),4.16(d,J＝12.6Hz,2H),3.85–3.65(m,2H),3.45–3.23(m,3H),3.21–2.90(m,2H),2.77–2.23(m,4H),1.48(s,9H)。

Step 7:1- (dimethylamino) hex-5-en-2-ol

To a solution of 2- (but-3-en-1-yl) oxaprozinane (10 g,10.2 mmol) in THF (100 mL) was added dimethylamine (60 mL) and the reaction mixture stirred at 50 ℃ for 2 hours. The reaction mixture was concentrated to give the desired product as a colorless oil. (6.4 g, yield: 44%).

¹ H NMR(400MHz,DMSO-d6)δ5.90–5.69(m,1H),5.12–4.90(m,2H),3.75–3.54(m,1H),3.46–3.19(m,1H),2.29(d,J＝12.1Hz,1H),2.26(s,6H),2.21(d,J＝7.2Hz,1H),2.19–2.11(m,2H),1.56–1.34(m,2H)。

Step 8:4- (2-allyl-4- ((benzyloxy) carbonyl) piperazin-1-yl) -2- ((1- (dimethylamino) hex-5-en-2-yl) oxy) -5, 8-dihydropyrido [3,4-d ] pyrimidine-7 (6H) -carboxylic acid tert-butyl ester

To 4- (2-allyl-4- ((benzyloxy) carbonyl) piperazin-1-yl) -2-chloro-5, 8-dihydropyrido [3,4-d ]]To a solution of pyrimidine-7 (6H) -carboxylic acid tert-butyl ester (2 g,3.8 mmol) in toluene (20 mL) was added Pd (OAc) ₂ (86mg，0.38mmol)、Cs ₂ CO ₃ (3.7 g,11.4 mmol), BINAP (236 mg,0.38 mmol) and 1- (dimethylamino) hexan-5-Alkenyl-2-alcohols (2.17 g,15.2 mmol). The reaction mixture was stirred at 100℃for 16 hours. Will react with H ₂ O was diluted and extracted with EA. The organic layer was washed with brine, dried over Na ₂ SO ₄ And (5) drying. After concentration, the residue was purified by a silica gel column (DMC: meoh=30:1) to give the desired product as a brown solid. (600 mg, yield: 25%).

LC-MS rt=1.350; MS calculated: 634.4, MS (ESI): 635.4[ M+H ]] ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ7.33–7.24(m,5H),5.81–5.68(m,1H),5.58(br s,1H),5.23(br s,1H),5.15–5.06(m,2H),4.96–4.83(m,3H),4.50(br s,1H),4.25(br s,1H),4.11–3.94(m,3H),3.75(br s,1H),3.58(br s,1H),3.31–3.15(m,2H),3.06(s,2H),2.53(d,J＝12.5Hz,2H),2.43–2.32(m,3H),2.20(s,6H),2.12–1.99(m,2H),1.84–1.70(m,2H),1.58(br s,2H),1.42(s,9H)。

Step 9: (9Z) -13- [ (dimethylamino) methyl]-14-oxa-2,5,16,19,23-pentaazatetracyclo [13.7.1.0 ^2,7 .0 ^17,22 ]Ditrideca-1 (23), 9,15,17 (22) -tetraene-5, 19-dicarboxylic acid 5-benzyl ester 19-tert-butyl ester

A solution of tert-butyl 4- (2-allyl-4- ((benzyloxy) carbonyl) piperazin-1-yl) -2- ((1- (dimethylamino) hex-5-en-2-yl) oxy) -5, 8-dihydropyrido [3,4-d ] pyrimidine-7 (6H) -carboxylate (250 mg,0.4 mmol) and Grubb's catalyst II (70 mg,0.08 mmol) in toluene (30 mL) was stirred at 100deg.C for 16 hours. After cooling to room temperature, the mixture was concentrated. The residue was purified by preparative TLC (silica gel, EA) to give a crude product, and the crude product was further purified by preparative HPLC (MeCN/water with 0.05% FA) to give the title product as a grey solid (42 mg, yield: 18%).

LC-MS rt=1.23 min; MS calculated: 606.4, MS (ESI): 607.5[ M+H ] ] ⁺ 。

Step 10: (9Z) -13- [ (dimethylamino) methyl]-14-oxa-2,5,1619, 23-pentaazatetracyclo [13.7.1.0 ] ^2,7 .0 ^17,22 ]Ditridecacarbon-1 (23), 9,15,17 (22) -tetraene-5-carboxylic acid benzyl ester

(9Z) -13- [ (dimethylamino) methyl]-14-oxa-2,5,16,19,23-pentaazatetracyclo [13.7.1.0 ^2,7 .0 ^17,22 ]A solution of ditridecarbon-1 (23), 9,15,17 (22) -tetraene-5, 19-dicarboxylic acid 5-benzyl ester 19-tert-butyl ester (220 mg,0.36 mmol) in TFA/DCM (v/v: 2/1,6 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give the title product (183 mg, yield: 100%) as a yellow oil, which was used in the next step without further purification.

LC-MS rt=0.79 min; MS calculated: 506.3, MS (ESI): 507.4[ M+H ]] ⁺ 。

Step 11: (9Z) -13- [ (dimethylamino) methyl]-19- (naphthalen-1-yl) -14-oxa-2,5,16,19,23-pentaazatetracyclo [13.7.1.0 ^2,7 .0 ^17,22 ]Ditridecacarbon-1 (23), 9,15,17 (22) -tetraene-5-carboxylic acid benzyl ester

(9Z) -13- [ (dimethylamino) methyl]-14-oxa-2,5,16,19,23-pentaazatetracyclo [13.7.1.0 ^2,7 .0 ^17,22 ]Ditridecacarbon-1 (23), benzyl 9,15,17 (22) -tetraene-5-carboxylate (150 mg,0.30 mmol), 1-bromonaphthalene (92 mg,0.45 mmol), ruphos-Pd (47 mg,0.06 mmol) and Cs ₂ CO ₃ A solution of (399mg, 1.20 mmol) in toluene (5 mL) was stirred at 100deg.C for 16 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (chromatography) (EA) to give the title product as a grey solid (103 mg, yield: 55%).

LC-MS rt=1.05 min; MS calculated: 632.3, ms observed: 633.3[ M+H ]] ⁺ 。

Step 12: methyl ({ [19- (naphthalen-1-yl) -14-oxa-2,5,16,19,23-pentaazatetracyclo [13.7.1.0 ] ^{2 ,7} .0 ^17,22 ]Ditridec-1 (23), 15,17 (22) -trien-13-yl]Methyl) amine

(9Z) -13- [ (dimethylamino) methyl]-19- (naphthalen-1-yl) -14-oxa-2,5,16,19,23-pentaazatetracyclo [13.7.1.0 ^2,7 .0 ^17,22 ]A solution of ditridecarboxylic acid-1 (23), benzyl 9,15,17 (22) -tetraene-5-carboxylate (100 mg,0.16 mmol) and Pd/C (10 mg, 10%) in MeOH (5 mL) in H ₂ Stirred at room temperature for 16 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the title product as a gray solid (55 mg, yield: 70%).

LC-MS rt=13.80 min; MS calculated: 500.3 ms observed: 501.3[ M+H ]] ⁺ 。

Step 13:1- {13- [ (dimethylamino) methyl ] -19- (naphthalen-1-yl) -14-oxa-2,5,16,19,23-pentaaza-tetracyclo [13.7.1.02,7.017,22] ditridec-1 (23), 15,17 (22) -trien-5-yl } prop-2-en-1-one

Dimethyl ({ [19- (naphthalen-1-yl) -14-oxa-2,5,16,19,23-pentaazatetracyclo [13.7.1.0 ] at 0deg.C under Ar ^2,7 .0 ^17,22 ]Ditridec-1 (23), 15,17 (22) -trien-13-yl]Methyl) amine (50 mg,0.1 mmol) and TEA (40 mg,0.4 mmol) were added dropwise to a stirred solution of acryloyl chloride (13 mg,0.15 mmol) in DCM (6 mL). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (ACN/water containing 0.05% FA) to give the title product (12 mg, yield: 22%).

LC-MS rt=1.13 min; MS calculated: 554.3, MS (ESI): 555.3[ M+H ]] ⁺ 。

¹ H NMR(400MHz,DMSO-d6)δ8.15(d,J＝7.8Hz,1H),7.93(d,J＝5.0Hz,1H),7.64(d,J＝7.8Hz,1H),7.59–7.50(m,2H),7.47(t,J＝8.0Hz,1H),7.22(d,J＝7.3Hz,1H),6.96–6.75(m,1H),6.26–6.12(m,1H),5.81–5.69(m,1H),5.37(br s,1H),5.16(br s,1H),4.43(br s,1H),4.14–3.85(m,4H),3.59–3.47(m,2H),3.26–3.06(m,2H),3.05–2.96(m,1H),2.84–2.62(m,4H),2.36–2.13(m,6H),2.02–1.66(m,4H),1.50–1.27(m,4H)。

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

Compound 2:

¹ H NMR(400MHz,DMSO-d6)δ8.32(s,2H,HCO ₂ H),8.19(s,1H),7.93(d,J＝5.4Hz,1H),7.64(d,J＝7.8Hz,1H),7.58–7.51(m,2H),7.47(t,J＝7.7Hz,1H),7.21(d,J＝7.3Hz,1H),6.93–6.75(m,1H),6.17(d,J＝13.8Hz,1H),5.74(d,J＝5.8Hz,1H),5.52–5.34(m,1H),4.41–4.01(m,6H),3.53–3.27(m,6H),3.15–3.05(m,2H),2.73–2.56(m,3H),2.41–2.31(m,1H),2.19(d,J＝7.3Hz,6H),1.92–1.63(m,2H),1.57–1.28(m,8H),1.16–0.89(m,2H)。

compound 3:

¹ H NMR(400MHz,CD ₃ OD)δ8.46(s,1H,HCO2H),8.23(d,J＝8.9Hz,1H),7.90–7.83(m,1H),7.62(d,J＝8.2Hz,1H),7.54–7.47(m,2H),7.44(t,J＝7.8Hz,1H),7.20(d,J＝7.2Hz,1H),6.92–6.78(m,1H),6.31(d,J＝16.7Hz,1H),5.90–5.72(m,2H),5.67(s,1H),5.45(br s,1H),4.99–4.89(m,1H),4.54–4.34(m,1H),4.28–4.04(m,5H),3.72–3.54(m,2H),3.b45–3.33(m,3H),3.21–3.07(m,2H),2.84–2.62(m,8H),2.48–2.44(m,1H),2.10–1.92(m,2H),1.69–1.66(m,1H)。

compound 4:

¹ H NMR(400MHz,CD ₃ OD)δ8.51(s,1H,HCO2H),8.31–8.20(m,1H),7.87(d,J＝7.2Hz,1H),7.61(d,J＝6.0Hz,1H),7.54–7.47(m,2H),7.43(t,J＝7.8Hz,1H),7.19(d,J＝7.1Hz,1H),6.93–6.71(m,1H),6.29(d,J＝16.4Hz,1H),5.87–5.77(m,1H),5.70–5.38(m,2H),5.34–5.15(m,1H),5.04–4.91(m,1H),4.74–4.38(m,1H),4.31–3.93(m,4H),3.80–3.51(m,2H),3.48–3.36(m,2H),3.15–2.94(m,2H),2.89–2.55(m,8H),2.47–1.17(m,9H)。

compound 7:

1H NMR(400MHz,CD ₃ OD)δ8.52(s,HCO2H,1H),8.29–8.22(m,1H),7.90–7.83(m,1H),7.61(d,J＝8.2Hz,1H),7.54–7.46(m,2H),7.44(t,J＝7.8Hz,1H),7.21(d,J＝7.4Hz,1H),6.80–6.74(m,1H),6.29–6,22(m,1H),5.82–5.80(m,1H),5.73–5.62(m,2H),4.97–4.93(m,1H),4.69–6.60(m,2H),4.37–4.34(m,1H),4.28–4.01(m,3H),3.71–3.69(m,1H),3.53–3.33(m,4H),3.23–2.86(m,6H),2.60–2.56(m,6H),1.97–1.70(m,2H)。

compound 8:

¹ H NMR(400MHz,CD ₃ OD)δ8.46(s,1H,HCO2H),8.24(d,J＝5.7Hz,1H),7.90–7.83(m,1H),7.61(d,J＝8.2Hz,1H),7.52–7.40(m,3H),7.20(d,J＝7.4Hz,1H),6.88–6.72(m,1H),6.30–6.19(m,1H),5.79(dt,J＝10.6,7.3Hz,1H),5.69(br s,1H),5.32(dd,J＝20.1,9.9Hz,1H),4.67–4.31(m,2H),4.31–4.17(m,2H),4.09–3.95(m,2H),3.73–3.65(m,1H),3.54–3.37(m,3H),3.19–3.06(m,2H),3.03–2.89(m,2H),2.88–2.79(m,6H),2.74–2.48(m,2H),2.39–2.14(m,1H),2.09–1.88(m,2H),1.80–1.59(m,2H),1.59–1.41(m,2H)。

compound 9:

¹ H NMR(400MHz,CD ₃ OD)δ8.47(s,1H),8.28–8.19(m,1H),7.87(d,J＝7.4Hz,1H),7.62(d,J＝7.9Hz,1H),7.53–7.47(m,2H),7.44(t,J＝7.9Hz,1H),7.19(t,J＝6.7Hz,1H),6.84–6.81(m,1H),6.26(dd,J＝16.6,4.5Hz,1H),5.81(t,J＝12.2Hz,1H),5.68–5.26(m,3H),4.96(s,1H),4.47(dd,J＝23.6,12.1Hz,2H),4.16(dt,J＝62.0,16.9Hz,3H),3.74–3.62(m,1H),3.45(d,J＝19.1Hz,2H),3.21–2.90(m,6H),2.77(br s,2H),2.73–2.56(m,6H),1.98–1.96(m,2H),1.74–1.70(m,2H)。

compound 10:

1H NMR(400MHz,CD ₃ OD)δ8.25(d,J＝8.4Hz,1H),7.89-7.83(m,1H),7.60(d,J＝8.4Hz,1H),7.53-7.46(m,2H),7.43(t,J＝8.0Hz,1H),7.21(d,J＝7.2Hz,1H),6.85-6.70(m,1H),6.28-6.19(m,1H),5.83-5.67(m,2H),5.13-5.04(m,1H),4.60-4.35(m,2H),4.26-4.18(m,1H),4.14-3.94(m,2H),3.70-3.63(m,1H),3.57-3.35(m,3H),3.19-3.06(m,1H),3.02-2.93(m,1H),2.67-2.58(m,2H),2.53-2.48(m,1H),2.67-2.58(m,2H),2.27(s,6H),2.07-1.97(m,1H),1.94-1.86(m,1H),1.83-1.74(m,1H),1.72-1.65(m,1H),1.62-1.53(m,2H),1.52-1.42(m,1H),1.40-1.24(m,2H),1.23-1.06(m,1H)。

compound 15:

¹ H NMR(400MHz,CD ₃ OD)δ7.90-7.83(m,1H),7.78-7.72(m,1H),7.61-7.49(m,2H),7.46-7.34(m,2H),6.87-6.77(m,1H),6.35-6.24(m,1H),5.90-5.67(m,2H),4.71-4.35(m,3H),4.25-4.15(m,1H),3.99-3.76(m,2H),3.75-3.50(m,5H),3.48-3.33(m,3H),2.99(s,6H),2.85-2.74(m,1H),1.86-1.45(m,12H),1.43-1.14(m,2H)。

example 2:

9-propenoyl-4- ((dimethylamino) methyl) -16- (naphthalen-1-yl) -5,6,8,9,10,11,14,15,16,17-decahydro-2, 13- (aminosubunit) -8, 12-methylenepyrido [3,4-d ] [1] oxa [3,7,10,13] tetraazacyclopentadec-7 (4H) -one (Compound 5)

Step 1: (Oxopropanan 2-ylmethyl) carbamic acid tert-butyl ester

To a solution of tert-butyl allylcarbamate (90 g,573 mmol) in DCM (600 mL) at 0deg.C was added m-CPBA (109 g, 6)32 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The mixture was quenched with NaOH (2N, 300 mL), washed with brine and water, and dried over anhydrous Na ₂ SO ₄ And (5) drying. After concentration, the crude title product (99 g) was obtained as a colorless oil, which was used in the next step without further purification.

Step 2: (3- (dimethylamino) -2-hydroxypropyl) carbamic acid tert-butyl ester

To a solution of tert-butyl (oxaprop-2-ylmethyl) carbamate (96 g,557 mmol) in THF (200 mL) was added dimethylamine (40% in H) at room temperature ₂ O, 200 mL). The mixture was then heated to 80 ℃ and stirred for 6 hours. The reaction mixture was concentrated under reduced pressure to give the title product (120 g, yield: 99% for two steps) as a colorless oil, which was used in the next step without further purification.

LC-MS rt=1.11 min; MS calculated: 218.2, MS (ESI): 219.3[ M+H ]] ⁺ 。

Step 3: 1-amino-3- (dimethylamino) propan-2-ol TFA salt

A solution of tert-butyl (3- (dimethylamino) -2-hydroxypropyl) carbamate (120 g,550 mmol) and TFA (200 mL) in DCM (200 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title product (1170 g, yield: 99%) as a colorless oil, which was used in the next step without further purification.

Step 4:2- (3- (dimethylamino) -2-hydroxypropyl) isoindoline-1, 3-dione

A solution of 1-amino-3- (dimethylamino) propan-2-ol TFA salt (21 g,92 mmol) and isobenzofuran-1, 3-dione (6.8 g,46 mmol) in toluene (100 mL) was heated at 100deg.C for 5 hours. After cooling to room temperature, the reaction mixture was diluted with EA (200 mL) and washed with brine and water. The organic layer was concentrated and purified by column chromatography on silica gel using (DCM: meOH: et) ₃ N=20:1:1) to afford the desired product as a pale yellow solid (11 g, yield: 48%).

LC-MS [ mobile phase: from 95% water (0.1% FA) and 5% CH in 2.5 minutes ₃ CN (0.1% FA) to 5% water (0.1% FA) and 90% CH ₃ CN(0.1％ FA]Purity of: 85%; LC-MS rt=0.4 min; MS calculated: 248.1, MS (ESI): 249.1[ M+H ]] ⁺ 。

1H NMR(400MHz,CDCl3)δ7.83–7.80(m,2H),7.73–7.69(m,2H),4.35–4.29(m,1H),3.83–3.71(m,2H),3.05–2.91(m,2H),2.76(s,6H)。

Step 5: piperazine-1, 2, 4-tricarboxylic acid 1-benzyl 4- (tert-butyl) 2-methyl ester

To piperazine-1, 3-dicarboxylic acid 1- (tert-butyl) 3-methyl ester (20 g,81.87 mmol) in EtOAc/H ₂ NaHCO was added to the solution in O (v/v: 1/1, 400 mL) ₃ (20.6 g,245.6 mmol) followed by CbzCl (20.9 g,122.8 mmol) and the resulting mixture was stirred at room temperature for 16 hours. The mixture was extracted with EtOAc (200 ml x 3). The combined organic layers were washed with brine (150 ml x 3), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE: ea=10:1) to give the desired product as a white solid (28 g, yield: 90%).

LC-MS rt=0.34 min; MS calculated: 378.1, MS (ESI) m/z 401.4[ M+Na ]] ⁺ 。

¹ H NMR(400MHz,DMSO-d6)δ7.42–7.26(m,5H),5.14–5.05(m,2H),4.76–4.66(m,1H),4.35–4.31(m,1H),3.84–3.81(m,2H),3.65–3.62(m,3H),3.17(br s,2H),2.85–2.81(m,1H),1.37(s,9H)。

Step 6: piperazine-1, 2-dicarboxylic acid 1-benzyl 2-methyl ester TFA salt

A solution of 1-benzyl 4- (tert-butyl) 2-methyl piperazine-1, 2, 4-tricarboxylic acid ester (15 g,40.0 mmol) in TFA/DCM (v/v: 2/1, 300 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give the crude title product (15 g, yield: 100%) as a yellow oil, which was used in the next step without further purification.

LC-MS rt=0.63 min; MS calculated: 278.1, MS (ESI) m/z 279.2[ M+H ]] ⁺ 。

Step 7:4- (7- (tert-Butoxycarbonyl) -2-chloro-5, 6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazine-1, 2-dicarboxylic acid 1-benzyl ester 2-methyl ester

To a solution of piperazine-1, 2-dicarboxylic acid 1-benzyl ester 2-methyl ester TFA salt (9.2 g,21.2 mmol) and DIPEA (16.7 g,105.7 mmol) in DMSO (200 mL) was added 2, 4-dichloro-5, 8-dihydropyrido [3,4-d ]]Pyrimidine-7 (6H) -carboxylic acid tert-butyl ester (6.2 g,21.2 mmol). The mixture was stirred at 80℃for 16 hours. After cooling to room temperature, the mixture was diluted with water (300 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (200 ml x 3), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, purified with (PE: ea=3:1) to give the desired product as a pale yellow solid. (5.8 g, yield: 53%).

LC-MS rt=2.2 min; MS calculated: 545.2, MS (ESI) m/z 546.3[ M+H ]] ⁺ 。

¹ H NMR(400MHz,DMSO-d6)δ7.39–7.30(m,5H),5.20–5.03(m,2H),4.82(d,J＝16.3Hz,1H),4.45–4.37(m,3H),4.01–3.99(m,2H),3.61–3.56(m,4H),3.45–3.35(m,2H),3.30–3.04(m,2H),2.59(s,2H),1.44(s,9H)。

Step 8:4- (2-chloro-5, 6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazine-1, 2-dicarboxylic acid 1-benzyl ester 2-methyl ester

4- (7- (tert-Butoxycarbonyl) -2-chloro-5, 6,7, 8-tetrahydropyrido [3,4-d ]]A solution of 1-benzyl 2-methyl pyrimidine-4-yl-piperazine-1, 2-dicarboxylate (20 g,36.6 mmol) in TFA/DCM (v/v: 2/1, 300 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and taken up in saturated NaHCO ₃ And (5) neutralizing the solution. The resultant was extracted with EtOAc (200 ml x 3). The combined organic layers were washed with brine (200 ml x 3), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give the desired product as a yellow solid. (14 g, yield: 88%).

LC-MS rt=0.9 min; MS calculated: 445.1, MS (ESI) m/z 446.1[ M+H ]] ⁺ 。

Step 9:4- (2-chloro-7- (naphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazine-1, 2-dicarboxylic acid 1-benzyl ester 2-methyl ester

4- (2-chloro-5, 6,7, 8-tetrahydropyrido [3, 4-d)]Pyrimidine-4-yl) piperazine-1, 2-dicarboxylic acid 1-benzyl 2-methyl ester (21.4 g,48.0 mmol), 1-bromonaphthalene (40 g,192.0 mmol), ruphos-Pd (5.6 g,7.2 mmol) and Cs ₂ CO ₃ A mixture of (47 g,144.0 mmol) in toluene (300 mL) was stirred at 100deg.C for 16 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE: ea=6:1) to give the desired product as a yellow solid. (13 g, yield: 50%).

LC-MS rt=1.9 min; MS calculated: 571.2, MS (ESI) m/z 572.4[ M+H ]] ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ8.17(d,J＝5.0Hz,1H),7.90–7.83(m,1H),7.62(d,J＝8.1Hz,1H),7.53–7.48(m,2H),7.39–7.35(m,6H),7.12(d,J＝6.8Hz,1H),5.21–5.50(m,2H),4.87–4.84(m,1H),4.63–4.59(m,1H),4.33-4.28(m,3H),3.97–3.95(m,1H),3.65–3.63(m,3H),3.45–3.43(m,3H),3.24–3.20(m,2H),2.96-2.88(m,2H)。

Step 10:4- (2- ((1- (dimethylamino) -3- (1, 3-dioxoisoindolin-2-yl) propan-2-yl) oxy) -7- (naphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazine-1, 2-dicarboxylic acid 1-benzyl 2-methyl ester

4- (2-chloro-7- (naphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ]]Pyrimidine-4-yl) piperazine-1, 2-dicarboxylic acid 1-benzyl 2-methyl ester (292 mg,1.0 mmol), 2- (3- (dimethylamino) -2-hydroxypropyl) isoindoline-1, 3-dione (372 mg,1.5 mmol), pd (OAc) ₂ (22 mg,0.1 mmol), BINAP (124 mg,0.2 mmol) and Cs ₂ CO ₃ A solution of (977 mg,3.0 mmol) in toluene (5 mL) was stirred at 100deg.C for 1 hour. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (chromatography) (DCM/MeOH: 95/5) to give the title product as a grey solid (250 mg, yield: 32%).

LC-MS rt=2.0 min; MS calculated: 783.3, MS (ESI) m/z 784.4[ M+H ]] ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ8.19(s,2H),7.87(d,J＝7.7Hz,1H),7.81(s,2H),7.70(s,2H),7.61(d,J＝8.1Hz,1H),7.57–7.47(m,2H),7.46–7.35(m,5H),7.10(d,J＝7.2Hz,1H),5.98(s,1H),5.28–5.14(m,2H),4.99–4.81(m,1H),4.64–4.46(m,1H),4.27–3.95(m,6H),3.78–3.65(m,3H),3.60–3.45(m,2H),3.44–3.21(m,3H),3.20–3.11(m,1H),3.10–2.98(m,1H),2.90(br s,2H),2.73(s,6H)。

Step 11:4- (2- ((1-amino-3- (dimethylamino) propan-2-yl) oxy) -7- (naphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazine-1, 2-dicarboxylic acid 1-benzyl 2-methyl ester

4- (2- ((1- (dimethylamino) -3- (1, 3-dioxoisoindolin-2-yl) propan-2-yl) oxy) -7- (naphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3, 4-d)]Pyrimidine-4-yl) piperazine-1, 2-dicarboxylic acid 1-benzyl 2-methyl ester (200 mg,0.3 mmol) and NH ₂ NH ₂ .H ₂ A solution of O (128 mg,2.6 mmol) in EtOH (8 mL) was stirred at 45℃for 3 h. After cooling to room temperature Et ₂ O (10 mL) was added to the reaction mixture. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to give a product (160 mg, yield: 93%) as a yellow solid, which was used in the next step without further purification.

LC-MS rt=2.1 min; MS calculated: 653.3 MS (ESI) m/z 654.4[ M+H ]] ⁺ 。

¹ H NMR(400MHz,DMSO-d6)δ8.41(s,1H),8.17(s,1H),7.91(s,1H),7.64(t,J＝8.2Hz,1H),7.58–7.50(m,2H),7.48–7.45(m,1H),7.42–7.31(m,4H),7.21(t,J＝8.3Hz,1H),5.76(s,2H),5.24–4.97(m,3H),4.88–4.77(m,1H),4.52–4.22(m,1H),4.11–3.71(m,4H),3.68–3.47(m,3H),3.47–3.26(m,3H),3.25–2.96(m,3H),2.92–2.59(m,3H),2.46(s,2H),2.18(d,J＝6.8Hz,6H)。

Step 12:4- (2- ((1-amino-3- (dimethylamino) propan-2-yl) oxy) -7- (naphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -1- ((benzyloxy) carbonyl) piperazine-2-carboxylic acid

4- (2- ((1-amino-3- (dimethylamino) propan-2-yl) oxy) -7- (naphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3, 4-d)]Pyrimidine-4-yl) piperazine-1, 2-dicarboxylic acid 1-benzyl 2-methyl ester (180 mg,0.28 mmol) andLiOH (20 mg,0.83 mmol) in MeOH/THF/H ₂ The solution in O (v/v/v: 1/1,6 mL) was stirred at 60℃for 3 hours. The mixture was cooled to room temperature and concentrated. The residue was diluted with water and extracted with EA. By saturated KH ₂ PO ₄ The aqueous phase was adjusted to ph=6 and extracted with DCM (100 mL). The organic phase was washed with brine and dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give the title product (80 mg, yield: 46%) as a yellow oil, which was used in the next step without further purification.

LC-MS rt=1.4 min; MS calculated: 639.3 MS (ESI) m/z 640.4[ M+H ]] ⁺ 。

Step 13:4- ((dimethylamino) methyl) -16- (naphthalen-1-yl) -7-oxo-5,6,7,8,10,11,14,15,16,17-decahydro-2, 13- (aminosubunit) -8, 12-methylenepyrido [3,4-d ] [1] oxa [3,7,10,13] tetraazacyclopentadec-9 (4H) -carboxylic acid benzyl ester

A solution of 4- (2- ((1-amino-3- (dimethylamino) propan-2-yl) oxy) -7- (naphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -1- ((benzyloxy) carbonyl) piperazine-2-carboxylic acid (200 mg,0.32 mmol), HOBT (64 mg,0.46 mmol) and EDCI (90 mg,0.46 mmol) in DMF (10 mL) was stirred at room temperature for 4 hours. The mixture was concentrated and the residue was purified by preparative TLC (silica gel, EA) to give the crude product. The crude product was further purified by preparative HPLC (ACN/water containing 0.05% FA) to give the title product as a gray solid (19 mg, yield: 10%).

LC-MS rt=1.8 min; MS calculated: 621.3, MS (ESI) m/z 622.3[ M+H ]] ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ8.20(s,1H),7.88–7.82(m,1H),7.60(d,J＝8.1Hz,1H),7.54–7.46(m,2H),7.44–7.39(m,1H),7.35–7.30(m,5H),7.10(d,J＝7.5Hz,1H),5.41(br s,1H),5.24–5.08(m,2H),5.04(br s,1H),4.67–4.50(m,1H),4.38–4.31(m,1H),4.17–4.05(m,2H),3.75–3.60(m,2H),3.52–3.34(m,3H),3.32–3.24(m,2H),3.13(br s,3H),3.03–2.91(m,2H),2.77(s,6H),2.51(d,J＝14.1Hz,1H)。

Step 14:4- ((dimethylamino) methyl) -16- (naphthalen-1-yl) -5,6,8,9,10,11,14,15,16,17-decahydro-2, 13- (aminosubunit) -8, 12-methylenepyrido [3,4-d ] [1] oxa [3,7,10,13] tetraazacyclopentadec-7 (4H) -one

A solution of 4- ((dimethylamino) methyl) -16- (naphthalen-1-yl) -7-oxo-5,6,7,8,10,11,14,15,16,17-decahydro-2, 13- (aminoidene) -8, 12-methylenepyrido [3,4-d ] [1] oxa [3,7,10,13] tetraazacyclopentadec-9 (4H) -carboxylic acid benzyl ester (80 mg,0.129 mmol) and Pd/C (10%, 160mg, 200%), THF (5 mL) was stirred under hydrogen at room temperature for 2 days. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the title product (50 mg, yield: 79%) as a yellow oil, which was used in the next step without further purification.

LC-MS rt=0.4 min; MS calculated: 487.6, MS (ESI) m/z 488.3[ M+H ]] ⁺ 。

Step 15: 9-propenoyl-4- ((dimethylamino) methyl) -16- (naphthalen-1-yl) -5,6,8,9,10,11,14,15,16,17-decahydro-2, 13- (aminosubunit) -8, 12-methylenepyrido [3,4-d ] [1] oxa [3,7,10,13] tetraazacyclopentadec-7 (4H) -one

To a stirred solution of 4- ((dimethylamino) methyl) -16- (naphthalen-1-yl) -5,6,8,9,10,11,14,15,16,17-decahydro-2, 13- (aminoidene) -8, 12-methylenepyrido [3,4-d ] [1] oxa [3,7,10,13] tetraazapentadecan-o ne (48 mg,0.10 mmol) and TEA (12.5 mg,0.12 mmol) in DCM (6 mL) under Ar at 0 ℃ was added dropwise an acryloyl chloride solution (8.4 mg,0.092 mmol). The mixture was stirred at room temperature for 5 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (ACN/water containing 0.05% FA) to give the title product (4 mg, yield: 7%).

LC-MS rt=1.5 min; MS calculated: 541.3, MS (ESI) m/z 542.3[ M+H ]] ⁺ 。

¹ H NMR(400MHz,CD ₃ OD)δ8.49(s,HCO2H,2H),8.28–8.19(m,1H),7.86(d,J＝8.1Hz,1H),7.61(d,J＝8.1Hz,1H),7.53–7.35(m,3H),7.19(d,J＝7.4Hz,1H),6.83–6.47(m,1H),6.28–6.13(m,1H),5.77–5.75(m,1H),5.13–4.94(m,4H),4.35–4.20(m,2H),4.14–3.89(m,3H),3.76–3.65(m,2H),3.63–3.44(m,3H),3.20–3.10(m,2H),3.02(br s,1H),2.77(s,6H),2.59–2.55(m,1H)。

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

Compound 11a:

¹ H NMR(400MHz,DMSO-d6)δ8.18(d,J＝8.9Hz,1H),7.92(d,J＝8.0Hz,1H),7.68(s,1H),7.65(d,J＝8.2Hz,1H),7.58–7.51(m,1H),7.47(t,J＝7.8Hz,1H),7.22(d,J＝7.4Hz,1H),6.92–6.75(m,1H),6.18(d,J＝15.7Hz,1H),5.75–5.71(m,1H),5.39–5.36(m,1H),4.12–4.10(m,2H),4.03–4.00(m,1H),3.94–3.75(m,2H),3.75–3.59(m,2H),3.57–3.43(m,2H),3.31–3.03(m,3H),3.02–2.86(m,2H),2.77–2.75(m,1H),2.49–2.36(m,3H),2.13(s,6H),2.05–1.83(m,2H)。

compound 11b:

¹ H NMR(400MHz,DMSO-d6)δ8.18(d,J＝4.9Hz,1H),7.96–7.88(m,1H),7.74–7.60(m,2H),7.57–7.51(m,1H),7.51–7.42(m,1H),7.22(d,J＝7.2Hz,1H),6.85–6.81(m,1H),6.18(d,J＝16.3Hz,1H),5.82–5.69(m,1H),5.48–5.32(m,1H),4.12–4.09(m,2H),3.88–3.86(m,3H),3.75–3.57(m,3H),3.49–3.46(m,3H),2.91–2.89(m,3H),2.76–2.72(m,1H),2.48–2.36(m,3H),2.21(s,6H),2.08–1.90(m,2H)。

compound 11c:

¹ H NMR(400MHz,DMSO-d6)δ8.19(d,J＝6.2Hz,1H),7.96–7.89(m,1H),7.64(d,J＝8.2Hz,1H),7.58–7.50(m,2H),7.47(t,J＝7.8Hz,1H),7.31(dd,J＝8.7,3.6Hz,1H),7.23(d,J＝7.4Hz,1H),6.81–6.79(m,1H),6.14(d,J＝15.6Hz,1H),5.73(s,1H),4.10–4.08(m,2H),4.01–3.78(m,3H),3.78–3.59(m,3H),3.58–3.40(m,3H),3.12–2.84(m,3H),2.77(m,1H),2.48–2.38(m,3H),2.38–2.07(m,8H)。

example 3:

1- (8- ((dimethylamino) methyl) -3- (naphthalen-1-yl) -1,2,3,4,8,9,10,11,13a,14,16, 17-dodecahydro-6, 19- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1,10] dioxa [3,7] diazacyclotetradec-15 (13H) -yl) prop-2-en-1-one (Compound 12)

Step 1: piperazine-1, 2, 4-tricarboxylic acid 4-benzyl ester 1-tert-butyl ester 2-methyl ester

To piperazine-1, 2-dicarboxylic acid 1-tert-butyl 2-methyl ester (12.5 g,51.2 mmol) and NaHCO at 0deg.C ₃ A mixture of (8.6 g,102.3 mmol) in THF (100 mL) and water (100 mL) was added dropwise CbzCl (13.1 g,76.8 mmol) and the mixture was stirred at room temperature for 16 h. The mixture was extracted with EtOAc (2×100 ml) and the combined organic layers were washed with brine, over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (PE: etoac=5:1 to 3:1) to give 4-benzyl piperazine-1, 2, 4-tricarboxylic acid 1-tert-butyl 2-methyl ester (19 g,98% yield) as a colorless oil. MS (ESI) M/z 279 (M-100+H) ⁺ 。

Step 2: piperazine-1, 3-dicarboxylic acid 1-benzyl 3-methyl ester hydrochloride

A mixture of piperazine-1, 2, 4-tricarboxylic acid 4-benzyl ester 1-tert-butyl ester 2-methyl ester (12.0 g,31.7 mmol) in HCl/1, 4-dioxane (100 mL, 4M) was stirred at room temperature for 2 hours. The mixture was concentrated to dryness to give 1-benzyl piperazine-1, 3-dicarboxylate 3-methyl ester (10 g,100% yield) as a white solid, which was used in the next step without further purification. MS (ESI) M/z 278 (M+H) ⁺ 。

Step 3: 4-Benzylpiperazine-1, 3-dicarboxylic acid 1-benzyl 3-methyl ester

To a mixture of 4-benzyl 1-tert-butyl 2-methyl piperazine-1, 2, 4-tricarboxylic acid ester (10.0 g,35.9 mmol) and DIPEA (23.2 g,179.7 mmol) in THF (100 mL) was added BnBr (6.4 mL,53.9 mmol) dropwise at 0 ℃ and the mixture was stirred at room temperature for 16 hours. The reaction was quenched with ice water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to dryness. The residue was chromatographed on silica gel (PE: etoac=5:1 to 3:1) to give 1-benzyl 3-ester of 4-benzylpiperazine-1, 3-dicarboxylic acid as a colorless oil (11.0 g,83% yield). MS (ESI) M/z 369 (M+H) ⁺ 。

Step 4: 4-benzyl-3- (hydroxymethyl) piperazine-1-carboxylic acid benzyl ester

To a solution of 1-benzyl 3-methyl 4-benzylpiperazine-1, 3-dicarboxylate (11.0 g,29.9 mmol) in THF (100 mL) at 0deg.C was added LiBH dropwise ₄ (52.2 mL,104.5mmol,2M in THF). After addition, the mixture was stirred at 40 ℃ for 16 hours. The reaction mixture was treated with saturated NH ₄ The aqueous Cl solution was quenched and neutralized to pH about 7 with 1M aqueous HCl at 0deg.C. The mixture was extracted with EtOAc (3 x 70 ml) and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ Dried, filtered and concentrated to dryness. The residue was chromatographed on silica gel (DCM: meoh=50:1 to 30:1) to give benzyl 4-benzyl-3- (hydroxymethyl) piperazine-1-carboxylate (8.6 g,85% yield) as a colorless oil. MS (ESI) M/z 341 (M+H) ⁺ 。

Step 5: 4-benzyl-3- ((pent-4-en-1-yloxy) methyl) piperazine-1-carboxylic acid benzyl ester

To a mixture of benzyl 4-benzyl-3- (hydroxymethyl) piperazine-1-carboxylate (8.5 g,25.0 mmol) in toluene (50 mL) and aqueous NaOH (50 mL,50% w/w) was added 5-bromopent-1-ene (5.9 mL,50.0 mmol) and TBAB (0.8 g,2.5 mmol) at 0deg.C, and the mixture was stirred at room temperature for 16 hours. The mixture was extracted with EtOAc (2×80 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (PE: etoac=5:1 to 3:1) to give benzyl 4-benzyl-3- ((pent-4-en-1-yloxy) methyl) piperazine-1-carboxylate (7.5 g,74% yield) as a colorless oil. MS (ESI) M/z 409 (M+H) ⁺ 。

Step 6:3- ((pent-4-en-1-yloxy) methyl) piperazine-1-carboxylic acid benzyl ester

To a solution of benzyl 4-benzyl-3- ((pent-4-en-1-yloxy) methyl) piperazine-1-carboxylate (7.5 g,18.4 mmol) in DCE (80 mL) was added chloroethyl 1-chloroformate (6.0 mL,55.1 mmol) at 0deg.C, and the mixture was stirred at 70deg.C for 4 hours. The mixture was concentrated to dryness. The residue was dissolved in MeOH (70 mL) and the mixture was stirred at 60 ℃ for 1 hour. The resulting mixture was concentrated to dryness and the residue was purified by silica gel chromatography (DCM: meoh=30:1 to 20:1) to give benzyl 3- ((pent-4-en-1-yloxy) methyl) piperazine-1-carboxylate (5.0 g,86% yield) as a colorless oil. MS (ESI) M/z 319 (M+H) ⁺ 。

Step 7:4- (4- ((benzyloxy) carbonyl) -2- ((pent-4-en-1-yloxy) methyl) piperazin-1-yl) -2-chloro-5, 6-dihydropyrido [3,4-d ] pyrimidine-7 (8H) -carboxylic acid tert-butyl ester

To a solution of benzyl 3- ((pent-4-en-1-yloxy) methyl) piperazine-1-carboxylate (5.1 g,15.7 mmol) in DMSO (50 mL) was added DIPEA (2.03 g,15.7 mmol) followed by 2, 4-dichloro-5, 6-dihydropyrido [3,4-d ]]Pyrimidine-7 (8H) -carboxylic acid tert-butyl ester (4.8 g,15.7 mmol). The mixture was stirred at 80 ℃ for 16 hours, then quenched with water (150 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (PE: etoac=2:1) to give 4- (4- ((benzyloxy) carbonyl) -2- ((pent-4-en-1-yloxy) methyl) piperazin-1-yl) -2-chloro-5, 6-dihydropyrido [3,4-d ] as a yellow solid]Pyrimidine-7 (8H) -carboxylic acid tert-butyl ester (6.0 g,65% yield). MS (ESI) M/z 586 (M+H) ⁺ 。

Step 8:4- (4- ((benzyloxy) carbonyl) -2- ((3- (oxaprozin-2-yl) propoxy) methyl) piperazin-1-yl) -2-chloro-5, 6-dihydropyrido [3,4-d ] pyrimidine-7 (8H) -carboxylic acid tert-butyl ester

To 4- (4- ((benzyloxy) carbonyl) -2- ((pent-4-en-1-yloxy) methyl) piperazin-1-yl) -2-chloro-5, 6-dihydropyrido [3,4-d ] at 0 DEG C]To a solution of pyrimidine-7 (8H) -carboxylic acid tert-butyl ester (6 g,10.2 mmol) in DCM (60 mL) was added m-CPBA (3.5 g,20.5 mmol) and the mixture was stirred at room temperature for 16H. The mixture was treated with saturated NaHCO ₃ The aqueous solution (60 mL) was quenched and extracted with DCM (2X 50 mL). The combined organic phases were treated with saturated NaHCO ₃ Washing with aqueous solution and brine, washing with anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to dryness. Passing the residue throughSilica gel column chromatography (PE: etoac=3:1 to 1:1) purification to give 4- (4- ((benzyloxy) carbonyl) -2- ((3- (oxaprozin-2-yl) propoxy) methyl) piperazin-1-yl) -2-chloro-5, 6-dihydropyrido [3,4-d ] as a yellow solid ]Pyrimidine-7 (8H) -carboxylic acid tert-butyl ester (4.5 g,88% yield). MS (ESI) M/z 602 (M+H) ⁺ 。

Step 9:4- (2- (((5-azido-4-hydroxypentyl) oxy) methyl) -4- ((benzyloxy) carbonyl) piperazin-1-yl) -2-chloro-5, 8-dihydropyrido [3,4-d ] pyrimidine-7 (6H) -carboxylic acid tert-butyl ester

To 4- (4- ((benzyloxy) carbonyl) -2- ((3- (oxaprozin-2-yl) propoxy) methyl) piperazin-1-yl) -2-chloro-5, 6-dihydropyrido [3,4-d ]]Pyrimidine-7 (8H) -carboxylic acid tert-butyl ester (4.5 g,7.5 mmol) to a mixture of MeOH (40 mL) and water (10 mL) was added NH ₄ Cl (401 mg,7.5 mmol) and NaN ₃ (970 mg,14.9 mmol) and the mixture was stirred at 55deg.C for 16 hours. The mixture was diluted with water (20 mL) and extracted with DCM (3×50 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (DCM: meoh=30:1) to give 4- (2- (((5-azido-4-hydroxypentyloxy) methyl) -4- ((benzyloxy) carbonyl) piperazin-1-yl) -2-chloro-5, 8-dihydropyrido [3,4-d ] as a yellow solid]Pyrimidine-7 (6H) -carboxylic acid tert-butyl ester (3.0 g,62% yield). MS (ESI) M/z 645 (M+H) +.

Step 10:13- (azidomethyl) -9, 14-dioxa-2,5,16,19,23-pentaazatetracyclo [13.7.1.0 {2,7}.0 {17,22} ] ditridecac-1 (23), 15,17 (22) -triene-5, 19-dicarboxylic acid 5-benzyl ester 19-tert-butyl ester

At N ₂ To 4- (2- (((5-azido-4-hydroxypentyl) oxy) methyl) -4- ((benzyloxy) carbonyl) piperazin-1-yl) -2-chloro-5, 8-dihydropyrido [3,4-d ] under an atmosphere]Pyrimidine-7 (6H) -carboxylic acid tert-butyl ester (3 g,4.7 mmol) and Cs ₂ CO ₃ (3.0 g,9.3 mmol) Pd (OAc) was added to a mixture in toluene (240 mL) ₂ (210 mg,0.93 mmol) and BINAP (290 mg,0.47 mmol). The mixture is put under N ₂ Degassing three times under atmosphere and under N ₂ Stirring is carried out for 16 hours at 100℃under an atmosphere. The mixture was diluted with EtOAc (500 mL), washed with brine, and dried over Na ₂ SO ₄ Dried, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (eluting with DCM: meoh=50:1 to 30:1) to give 13- (azidomethyl) -9, 14-dioxa-2,5,16,19,23-pentaazatetracyclo [13.7.1.0 {2,7}.0 {17,22} ] as a yellow solid]Ditridec-1 (23), 15,17 (22) -triene-5, 19-dicarboxylic acid 5-benzyl ester 19-tert-butyl ester (1.3 g,46% yield). MS (ESI) M/z 609 (M+H) ⁺ 。

Step 11:13- (azidomethyl) -9, 14-dioxa-2,5,16,19,23-pentaazatetracyclo [13.7.1.0 {2,7}.0 {17,22} ] ditridecac-1 (23), 15,17 (22) -triene-5-carboxylic acid benzyl ester

To 13- (azidomethyl) -9, 14-dioxa-2,5,16,19,23-pentaazatetracyclo [13.7.1.0 {2,7}.0 {17,22} ]To a solution of ditridecarbon-1 (23), 15,17 (22) -triene-5, 19-dicarboxylic acid 5-benzyl ester 19-tert-butyl ester (1.3 g,2.14 mmol) in DCM (9 mL) was added TFA (3 mL), and the mixture was stirred at room temperature for 2 h. The mixture was treated with saturated NaHCO ₃ The aqueous solution was basified and extracted with DCM (2X 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ Drying and concentrating to dryness to give 13- (azidomethyl) -9, 14-dioxa-2,5,16,19,23-pentaazatetracyclo [13.7.1.0 {2,7}.0 {17,22} ] as a yellow solid]Ditridecacarbon-1 (23), 15,17 (22) -triene-5-carboxylic acid benzyl ester (0.9 g,83% yield), the product was used directly in the next step. MS (ESI) M/z 509 (M+H) ⁺ 。

Step 12:13- (azidomethyl) -19- (naphthalen-1-yl) -9, 14-dioxa-2,5,16,19,23-pentaazatetracyclo [13.7.1.0 {2,7}.0 {17,22} ] ditridecac-1 (23), 15,17 (22) -triene-5-carboxylic acid benzyl ester

At N ₂ In the atmosphere to 13- (azidomethyl) -9, 14-dioxa-2,5,16,19,23-pentaazatetracyclo [13.7.1.0 {2,7}.0 {17,22}]Ditridecacarbon-1 (23), 15,17 (22) -triene-5-carboxylic acid benzyl ester (0.9 g,1.77 mmol) and Cs ₂ CO ₃ (1.73G, 5.31 mmol) to a mixture of anhydrous 1, 4-dioxane (10 mL) was added 1-bromonaphthalene (1.0 mL,7.08 mmol), ruPhos Pd G2 (0.21G, 0.27 mmol). The mixture is put under N ₂ Degassing three times down, and under N ₂ Stirring is carried out for 16 hours at 80℃under an atmosphere. The mixture was diluted with water (10 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ Dried, and concentrated to dryness. The residue was purified by silica gel chromatography (eluting with PE: etoac=3:1 to 1:1) to give 13- (azidomethyl) -19- (naphthalen-1-yl) -9, 14-dioxa-2,5,16,19,23-pentaazatetracyclo [13.7.1.0 {2,7}.0 {17,22} ] as a yellow solid]Ditridecacarbon-1 (23), 15,17 (22) -triene-5-carboxylic acid benzyl ester (0.72 g,50% yield). MS (ESI) M/z 635 (M+H) ⁺ 。

Step 13:13- (aminomethyl) -19- (naphthalen-1-yl) -9, 14-dioxa-2,5,16,19,23-pentaazatetracyclo [13.7.1.0 {2,7}.0 {17,22} ] ditridecac-1 (23), 15,17 (22) -triene-5-carboxylic acid benzyl ester

To 13- (azidomethyl) -19- (naphthalen-1-yl) -9, 14-dioxa-2,5,16,19,23-pentaazatetracyclo [13.7.1.0 {2,7}.0 {17,22}]To a solution of ditridecarbon-1 (23), 15,17 (22) -trien-5-carboxylic acid benzyl ester (370 mg,0.58 mmol) in THF (5 mL) and water (1 mL) was added triphenylphosphine (306 mg,1.17 mmol), and the mixture was taken up in N ₂ Stirring is carried out for 4 hours at 50℃under an atmosphere. The resulting mixture was concentrated to dryness. The residue was purified by silica gel chromatography (eluting with DCM: meoh=20:1 to 10:1) to give To 13- (aminomethyl) -19- (naphthalen-1-yl) -9, 14-dioxa-2,5,16,19,23-pentaazatetracyclo [13.7.1.0 {2,7}.0 {17,22} ] as a yellow solid]Ditridecacarbon-1 (23), 15,17 (22) -triene-5-carboxylic acid benzyl ester (270 mg,76% yield). MS (ESI) M/z 609 (M+H) ⁺ 。

Step 14:13- [ (dimethylamino) methyl ] -19- (naphthalen-1-yl) -9, 14-dioxa-2,5,16,19,23-pentaazatetracyclo [13.7.1.0 {2,7}.0 {17,22} ] ditridecac-1 (23), 15,17 (22) -triene-5-carboxylic acid benzyl ester

To 13- (aminomethyl) -19- (naphthalen-1-yl) -9, 14-dioxa-2,5,16,19,23-pentaazatetracyclo [13.7.1.0 {2,7}.0 {17,22}, at 0 ]]To a solution of ditridecarbon-1 (23), 15,17 (22) -trien-5-carboxylic acid benzyl ester (270 mg,0.44 mmol) in DCE (5 mL) was added formaldehyde (67 mg,2.22 mmol), followed by the addition of sodium triacetoxyborohydride (281mg, 1.33 mmol) in portions and the mixture was stirred at room temperature for 16 hours. The reaction mixture was taken up with saturated NaHCO ₃ The aqueous solution was quenched and extracted with DCM (2X 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ Dried, and concentrated to dryness. The residue was purified by silica gel chromatography (eluting with DCM: meoh=20:1 to 10:1) to give 13- [ (dimethylamino) methyl as a yellow solid ]-19- (naphthalen-1-yl) -9, 14-dioxa-2,5,16,19,23-pentaazatetracyclo [13.7.1.0 {2,7}.0 {17,22}]Ditridecacarbon-1 (23), 15,17 (22) -triene-5-carboxylic acid benzyl ester (180 mg,64% yield). MS (ESI) M/z 637 (M+H) ⁺ 。

Step 15: dimethyl ({ [19- (naphthalen-1-yl) -9, 14-dioxa-2,5,16,19,23-pentaazatetracyclo [13.7.1.0 {2,7}.0 {17,22} ] ditridec-1 (23), 15,17 (22) -trien-13-yl ] methyl }) amine

To 13- [ (dimethylamino) methyl]-19- (naphthalen-1-yl) -9, 14-dioxa-2,5,16,19,23-pentaazatetracyclic[13.7.1.0^{2,7}.0^{17,22}]To a solution of ditridecarbon-1 (23), 15,17 (22) -triene-5-carboxylic acid benzyl ester (180 mg,0.28 mmol) in MeOH (5 mL) was added Pd/C (20 mg,10% wt). The mixture is put under N ₂ Degassing three times under atmosphere and under H ₂ Stirred under a balloon at room temperature for 3 hours. The mixture was filtered and the filtrate was concentrated to dryness to give dimethyl ({ [19- (naphthalen-1-yl) -9, 14-dioxa-2,5,16,19,23-pentaazatetracyclo [13.7.1.0 {2,7}.0 {17,22 }) as a yellow solid]Ditridec-1 (23), 15,17 (22) -trien-13-yl]Methyl) amine (90 mg,63% yield). MS (ESI) M/z 503 (M+H) ⁺ 。

Step 16:1- (8- ((dimethylamino) methyl) -3- (naphthalen-1-yl) -1,2,3,4,8,9,10,11,13a,14,16, 17-dodecahydro-6, 19- (aminosubunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1,10] dioxa [3,7] diazacyclotetradec-15 (13H) -yl) prop-2-en-1-one

To acrylic acid (13 mg,0.18 mmol) and Et ₃ N (0.05 mL,0.36 mmol) EDCI (52 mg,0.27 mmol) and HOBt (36 mg,0.27 mmol) were added to a mixture of DCM (3 mL), followed by dimethyl ({ [19- (naphthalen-1-yl) -9, 14-dioxa-2,5,16,19,23-pentaazatetracyclo [13.7.1.0 {2,7}.0 {17,22 })]Ditridec-1 (23), 15,17 (22) -trien-13-yl]Methyl) amine (90 mg,0.18 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM (10 mL), washed with water and brine, and dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (eluting with DCM: meoh=20:1 to 10:1) and further purified by preparative HPLC to give 1- {13- [ (dimethylamino) methyl]-19- (naphthalen-1-yl) -9, 14-dioxa-2,5,16,19,23-pentaazatetracyclo [13.7.1.0 {2,7}.0 {17,22}]Ditridecan-1 (23), 15,17 (22) -trien-5-yl } prop-2-en-1-one (compound 12a:3.1mg,3% yield and compound 12b:2.73mg,2% yield). MS (ESI) M/z 609 (M+H) ⁺ 。

Compound 12a: ¹ HNMR(400MHz,CD ₃ OD)δ8.26–8.20(m,1H),7.86(m,1H),7.61(m,1H),7.53–7.46(m,2H),7.45–7.40(m,1H),7.21(m,1H),6.83(s,1H),6.28(m,1H),5.81(m,1H),5.39(m 1H),4.56(m,1H),4.17(m,3H),4.01(m,1H),3.81(m,3H),3.70–3.62(m,2H),3.53(m,2H),3.40(m,1H),3.23(m,2H),2.95(m,3H),2.78(m,1H),2.51(s,6H),1.55(m,2H),1.30(m,2H)。

compound 12b: ¹ HNMR(400MHz,CDCl ₃ )δ8.23–8.15(m,1H),7.89–7.82(m,1H),7.60(m,1H),7.54–7.46(m,2H),7.42(m,1H),7.11(m,1H),6.58(m,1H),6.36(m,1H),5.79(m,1H),5.14(m,1H),4.62(m,1H),4.32(m,2H),4.16(m,2H),4.02(m,2H),3.69(m,1H),3.56–3.40(m,4H),3.13(m,4H),2.83(s,6H),2.66–2.50(m,2H),2.15(m,1H),1.42(m,2H),1.33(m,2H)。

the following compounds were prepared according to the above method using different starting materials.

Compound 13:

¹ HNMR(400MHz,CD ₃ OD)δ8.21(d,J＝5.7Hz,1H),7.86(s,1H),7.62(d,J＝8.0Hz,1H),7.51–7.47(m,2H),7.47–7.32(m,3H),7.21(t,J＝6.8Hz,1H),5.34(t,J＝4.7Hz,1H),4.58(s,1H),4.14(s,2H),3.87–3.79(m,1H),3.66(d,J＝18.2Hz,4H),3.46(d,J＝18.3Hz,4H),3.12–2.98(m,2H),2.90(d,J＝7.2Hz,6H),2.55(dd,J＝14.8,7.8Hz,2H),2.18(d,J＝7.7Hz,1H),2.06–1.97(m,3H),1.57(d,J＝23.6Hz,4H)。

example 4:

15-propenoyl-8- ((dimethylamino) methyl) -10-methyl-3- (naphthalen-1-yl) -1,2,3,4,9,10,13 a,14,15,16, 17-dodecahydro-8H-6, 19- (aminosubunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,12] triazolo-tetradeca-11 (12H) -one (Compound 14)

Step 1:4- (2- (3- ((3-azido-2-hydroxypropyl) (methyl) amino) -3-oxopropyl) -4- ((benzyloxy) carbonyl) piperazin-1-yl) -2-chloro-5, 8-dihydropyrido [3,4-d ] pyrimidine-7 (6H) -carboxylic acid tert-butyl ester

To 3- (4- ((benzyloxy) carbonyl) -1- (7- (tert-butoxycarbonyl) -2-chloro-5, 6,7, 8-tetrahydropyrido [3,4-d ]]To a mixture of pyrimidin-4-yl) piperazin-2-yl propionic acid (1.4 g,2.50 mmol) and DIPEA (1.72 mL,10.0 mmol) in DMF (8 mL) were added EDCI (0.96 g,5.0 mmol) and HOBt (0.68 g,5.0 mmol), followed by 1-azido-3- (methylamino) propan-2-ol hydrochloride (0.42 g,2.50 mmol) and the mixture stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (30 mL), washed with water and brine, and dried over Na ₂ SO ₄ Dried, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (eluting with DCM: meoh=100:1 to 96:4) to give 4- (2- (3- ((3-azido-2-hydroxypropyl) (methyl) amino) -3-oxopropyl) -4- ((benzyloxy) carbonyl) piperazin-1-yl) -2-chloro-5, 8-dihydropyrido [3,4-d ] as a white solid]Pyrimidine-7 (6H) -carboxylic acid tert-butyl ester (1.4 g,83% yield). MS (ESI) M/z 672 (M+H) ⁺ 。

Step 2:13- (azidomethyl) -11-methyl-10-oxo-14-oxa-2,5,11,16,19,23-hexaazatetracyclo [13.7.1.0 {2,7}.0 {17,22} ] ditridecac-1 (23), 15,17 (22) -triene-5, 19-dicarboxylic acid 5-benzyl ester 19-tert-butyl ester

At N ₂ To 4- (2- (3- ((3-azido-2-hydroxypropyl) (methyl) amino) -3-oxopropyl) -4- ((benzyloxy) carbonyl) piperazin-1-yl) -2-chloro-5, 8-dihydropyrido [3,4-d ] under an atmosphere]Pyrimidine-7 (6H) -carboxylic acid tert-butyl ester (1.4 g,2.08 mmol) and Cs ₂ CO ₃ (1.36 g,4.16 mmol) to a mixture of toluene (112 mL) was added Pd (OAc) ₂ (0.09 g,0.42 mmol) and BINAP (0.13 g,0.21 mmol). The mixture is put under N ₂ Degassing three times under atmosphere and under N ₂ Stirring at 100deg.C under atmospheric conditions for 3 hrWhen (1). The mixture was diluted with EtOAc (20 mL), washed with water and brine, and dried over Na ₂ SO ₄ Dried, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (eluting with DCM: meoh=100:1 to 94:6) to give 13- (azidomethyl) -11-methyl-10-oxo-14-oxa-2,5,11,16,19,23-hexaazatetracyclo [13.7.1.0 {2,7}, 0 {17,22}, as a yellow oil]Ditridec-1 (23), 15,17 (22) -triene-5, 19-dicarboxylic acid 5-benzyl ester 19-tert-butyl ester (1 g,76% yield). MS (ESI) M/z 636 (M+H) ⁺ 。

Step 3:13- (azidomethyl) -11-methyl-10-oxo-14-oxa-2,5,11,16,19,23-hexaazatetracyclo [13.7.1.0 {2,7}.0 {17,22} ] ditridecac-1 (23), 15,17 (22) -triene-5-carboxylic acid benzyl ester

Into the solution 13- (azidomethyl) -11-methyl-10-oxo-14-oxa-2,5,11,16,19,23-hexaazatetracyclo [13.7.1.0 {2,7}.0 {17,22} ]To a solution of ditridecarbon-1 (23), 15,17 (22) -triene-5, 19-dicarboxylic acid 5-benzyl ester 19-tert-butyl ester (830 mg,1.31 mmol) in DCM (7 mL) was added TFA (2 mL) and the mixture stirred at room temperature for 3 h. The mixture was treated with saturated NaHCO ₃ The aqueous solution was basified and extracted with DCM (2X 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ Dried, and concentrated to dryness. The residue was purified by silica gel chromatography (eluting with DCM: meoh=100:1 to 4:1) to give 13- (azidomethyl) -11-methyl-10-oxo-14-oxa-2,5,11,16,19,23-hexaazatetracyclo [13.7.1.0 {2,7}, 0 {17,22}, as a yellow solid]Ditridecacarbon-1 (23), 15,17 (22) -triene-5-carboxylic acid benzyl ester (500 mg,72% yield). MS (ESI) M/z 536 (M+H) ⁺ 。

Step 4:13- (azidomethyl) -11-methyl-19- (naphthalen-1-yl) -10-oxo-14-oxa-2,5,11,16,19,23-hexaazatetracyclo [13.7.1.0 {2,7}.0 {17,22} ] ditridec-1 (23), 15,17 (22) -triene-5-carboxylic acid benzyl ester

At N ₂ In the atmosphere to 13- (azidomethyl) -11-methyl-10-oxo-14-oxa-2,5,11,16,19,23-hexaazatetracyclo [13.7.1.0 {2,7}.0 {17,22}]Ditridecacarbon-1 (23), 15,17 (22) -triene-5-carboxylic acid benzyl ester (500 mg,0.93 mmol) and Cs ₂ CO ₃ (913 mg,2.79 mmol) to a mixture of anhydrous 1, 4-dioxane (15 mL) was added 1-bromonaphthalene (0.52 mL,3.72 mmol) and RuPhos Pd G2 (107 mg,0.14 mmol). The mixture is put under N ₂ Degassing three times under atmosphere and under N ₂ Stirring is carried out for 16 hours at 80℃under an atmosphere. The mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by silica gel chromatography (eluting with DCM: meoh=100:1 to 95:5) to give 13- (azidomethyl) -11-methyl-19- (naphthalen-1-yl) -10-oxo-14-oxa-2,5,11,16,19,23-hexaazatetracyclo [13.7.1.0 {2,7}.0 {17,22}, as a yellow solid]Ditridecacarbon-1 (23), 15,17 (22) -triene-5-carboxylic acid benzyl ester (370 mg,60% yield). MS (ESI) M/z 662 (M+H) ⁺ 。

Step 5:13- (aminomethyl) -11-methyl-19- (naphthalen-1-yl) -10-oxo-14-oxa-2,5,11,16,19,23-hexaazatetracyclo [13.7.1.0 {2,7}.0 {17,22} ] ditridec-1 (23), 15,17 (22) -triene-5-carboxylic acid benzyl ester

To 13- (azidomethyl) -11-methyl-19- (naphthalen-1-yl) -10-oxo-14-oxa-2,5,11,16,19,23-hexaazatetracyclo [13.7.1.0 {2,7}.0 {17,22}]To a solution of ditridecarbon-1 (23), 15,17 (22) -trien-5-carboxylic acid benzyl ester (570 mg,0.86 mmol) in THF (8 mL) and water (1 mL) was added triphenylphosphine (452 mg,1.72 mmol). The mixture is put under N ₂ Stirring is carried out for 3 hours at 60℃under an atmosphere. The resulting mixture was concentrated to dryness. The residue was purified by silica gel chromatography (eluting with DCM: meoh=100:1 to 83:17) to give 13- (aminomethyl) -11-methyl-19- (naphthalen-1-yl) -10-oxo-14-oxa-2,5,11,16,19,23-hexaazatetracyclo [13.7.1.0 {2,7}.0 {17,22}, as a yellow solid ]Ditridecacarbon-1 (23), 15,17 (22) -triene-5-carboxylic acid benzyl ester(425 mg,77% yield). MS (ESI) M/z 636 (M+H) ⁺ 。

Step 6:13- [ (dimethylamino) methyl ] -11-methyl-19- (naphthalen-1-yl) -10-oxo-14-oxa-2,5,11,16,19,23-hexaazatetracyclo [13.7.1.0 {2,7}.0 {17,22} ] ditridec-1 (23), 15,17 (22) -triene-5-carboxylic acid benzyl ester

To 13- (aminomethyl) -11-methyl-19- (naphthalen-1-yl) -10-oxo-14-oxa-2,5,11,16,19,23-hexaazatetracyclo [13.7.1.0 {2,7}.0 {17,22}, at 0 ]]To a solution of ditridecarbon-1 (23), 15,17 (22) -triene-5-carboxylic acid benzyl ester (425 mg,0.67 mmol) in MeOH (8 mL) was added para-HCHO (271mg, 3.35 mmol), followed by NaBH ₃ CN (84 mg,1.34 mmol) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was taken up with saturated NaHCO ₃ The aqueous solution was quenched and extracted with EtOAc (3X 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (eluting with DCM: meoh=100:1 to 93:7) to give 13- [ (dimethylamino) methyl as a yellow solid]-11-methyl-19- (naphthalen-1-yl) -10-oxo-14-oxa-2,5,11,16,19,23-hexaazatetracyclo [13.7.1.0 {2,7}.0 {17,22} ]Ditridecacarbon-1 (23), 15,17 (22) -triene-5-carboxylic acid benzyl ester (380 mg,85% yield). MS (ESI) M/z 664 (M+H) ⁺ 。

Step 7:13- [ (dimethylamino) methyl ] -11-methyl-19- (naphthalen-1-yl) -14-oxa-2,5,11,16,19,23-hexaazatetracyclo [13.7.1.0 {2,7}.0 {17,22} ] ditridec-1 (23), 15,17 (22) -trien-10-one

To 13- [ (dimethylamino) methyl]-11-methyl-19- (naphthalen-1-yl) -10-oxo-14-oxa-2,5,11,16,19,23-hexaazatetracyclo [13.7.1.0 {2,7}.0 {17,22}]Ditridecacarbon-1 (23), 15,17 (22) -triene-5-carboxylic acid benzyl ester (330 mg,0.50 mmol)TEA (100 mg,1.0 mmol), triethylsilane (0.54 mL,3.36 mmol) and PdCl were added to a solution in DCM (8 mL) ₂ (57 mg,0.32 mmol). The mixture was stirred at room temperature for 5 hours. The mixture was diluted with DCM (20 mL), washed with water and brine, and dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to dryness. The residue was purified by flash chromatography on silica gel (eluting with DCM: meoh=100:1 to 20:1) to give 13- [ (dimethylamino) methyl as a yellow solid]-11-methyl-19- (naphthalen-1-yl) -14-oxa-2,5,11,16,19,23-hexaazatetracyclo [13.7.1.0 {2,7}.0 {17,22}]Ditridecan-1 (23), 15,17 (22) -trien-10-one (230 mg,87% yield). MS (ESI) M/z 530 (M+H) ⁺ 。

Step 8:13- [ (dimethylamino) methyl ] -11-methyl-19- (naphthalen-1-yl) -5- (prop-2-enoyl) -14-oxa-2,5,11,16,19,23-hexaazatetracyclo [13.7.1.0 {2,7}.0 {17,22} ] ditridec-1 (23), 15,17 (22) -trien-10-one

To 13- [ (dimethylamino) methyl]-11-methyl-19- (naphthalen-1-yl) -14-oxa-2,5,11,16,19,23-hexaazatetracyclo [13.7.1.0 {2,7}.0 {17,22}]To a mixture of ditridecan-1 (23), 15,17 (22) -trien-10-one (230 mg,0.43 mmol) and TEA (0.12 mL,0.86 mmol) in DCM (4 mL) was added EDCI (166 mg,0.86 mmol), HOBt (117 mg,0.86 mmol) and prop-2-enoic acid (0.03 mL,0.43 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with DCM (2×10 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to dryness. The residue was purified by flash column (silica gel, DCM: meoh=10:1) and further purified by preparative HPLC to give 13- [ (dimethylamino) methyl group]-11-methyl-19- (naphthalen-1-yl) -5- (prop-2-enoyl) -14-oxa-2,5,11,16,19,23-hexaazatetracyclo [13.7.1.0 {2,7}.0 {17,22}]Ditridecan-1 (23), 15,17 (22) -trien-10-one (compound 14a:8.7mg,3.4% yield and compound 14b:5.3mg,2.1% yield). MS (ESI) M/z 584 (M+H) ⁺ 。

Compound 14a: ¹ HNMR(400MHz,CDCl ₃ )δ8.24–8.15(m,1H),7.91–7.81(m,1H),7.60(d,J＝8.0Hz,1H),7.54–7.47(m,2H),7.43(t,J＝8.0Hz,1H),7.14(d,J＝7.6Hz,1H),6.60(dd,J＝16.4,10.8Hz,1H),6.37(dd,J＝16.4,1.6Hz,1H),5.77(dd,J＝10.8,2.0Hz,2H),5.02–4.86(m,1H),4.83–4.61(m,1H),4.44(d,J＝13.6Hz,1H),4.30(d,J＝17.6Hz,1H),4.21–3.97(m,3H),3.69(d,J＝12.4Hz,1H),3.47(d,J＝11.6Hz,1H),3.31(t,J＝12.4Hz,2H),2.97(t,J＝10.8Hz,2H),2.81(s,3H),2.77–2.70(m,1H),2.67–2.60(m,1H),2.60–2.56(m,1H),2.56–2.51(m,1H),2.36(s,6H),2.21–2.08(m,4H)。

compound 14b: ¹ HNMR(400MHz,CDCl3)δ8.21(d,J＝8.0Hz,1H),7.94–7.82(m,1H),7.61(d,J＝8.0Hz,1H),7.56–7.47(m,2H),7.43(t,J＝7.6Hz,1H),7.16–7.07(m,1H),6.77–6.52(m,1H),6.42–6.21(m,2H),5.76(d,J＝10.0Hz,1H),4.69(d,J＝12.4Hz,1H),4.41–3.98(m,5H),3.86–3.76(m,1H),3.73–3.61(m,1H),3.33–3.21(m,1H),3.15–2.99(m,4H),2.85–2.69(m,2H),2.69–2.54(m,5H),2.52–2.30(m,7H),2.13(dd,J＝17.6,10.0Hz,1H),1.63(dd,J＝17.6,9.6Hz,1H),1.57–1.47(m,1H)。MS(ESI)m/z:584(M+H) ⁺ 。

the following compounds were prepared according to the above method using different starting materials.

Compound 20a:

¹ H NMR(400MHz,CD ₃ OD)δ8.22(d,J＝9.1Hz,1H),7.88–7.84(m,1H),7.61(d,J＝8.0Hz,1H),7.52–7.46(m,2H),7.45–7.40(m,1H),7.20(d,J＝6.8Hz,1H),6.84(dd,J＝16.4,10.3Hz,1H),6.28(d,J＝16.8Hz,1H),5.82(d,J＝8.9Hz,1H),5.58(s,1H),5.34(t,J＝4.7Hz,1H),4.54–4.37(m,1H),4.16(t,J＝19.6Hz,3H),4.02(s,1H),3.91(d,J＝14.5Hz,1H),3.58(s,2H),3.45(d,J＝23.7Hz,1H),3.13(s,1H),2.94–2.83(m,1H),2.74(s,3H),2.40(s,6H),2.24(s,1H),2.22–2.16(m,1H),2.03(d,J＝5.7Hz,2H),1.60(s,1H),1.35(s,1H)。

compound 20b:

¹ HNMR(400MHz,CDCl3)δ8.20(s,1H),7.88(d,J＝9.4Hz,1H),7.62(d,J＝8.1Hz,1H),7.56–7.49(m,2H),7.44(t,J＝7.8Hz,1H),7.15(d,J＝7.7Hz,1H),6.68(s,1H),6.38(t,J＝12.5Hz,1H),5.78(d,J＝11.1Hz,1H),5.34(dd,J＝14.1,9.6Hz,2H),4.70(s,1H),4.20(d,J＝56.4Hz,3H),3.84(s,2H),3.18(d,J＝83.5Hz,4H),2.82(d,J＝48.9Hz,5H),2.54(d,J＝18.3Hz,6H),2.34(s,1H),2.04–1.97(m,3H),1.50–1.43(m,2H)。

compound 21:

¹ HNMR(400MHz,CDCl ₃ )δ7.80–7.70(m,1H),7.66–7.58(m,1H),7.56–7.44(m,2H),7.33(t,J＝7.6Hz,1H),7.25(s,1H),6.66–6.48(m,1H),6.43–6.29(m,1H),5.94–5.57(m,2H),4.46–4.20(m,4H),4.12–3.93(m,2H),3.89–3.81(m,1H),3.75–3.67(m,1H),3.60–3.53(m,1H),3.43–3.30(m,2H),3.22–3.17(m,1H),3.14–3.06(m,2H),3.04–2.90(m,4H),2.85–2.72(m,2H),2.68–2.50(m,8H),2.48–2.41(m,1H)。

compound 22a:

¹ HNMR(400MHz,CD ₃ OD)δ7.81(d,J＝8.1Hz,1H),7.65(d,J＝8.1Hz,1H),7.48(dd,J＝17.5,7.2Hz,2H),7.39–7.28(m,2H),6.81(d,J＝11.8Hz,1H),6.26(d,J＝16.4Hz,1H),5.83–5.65(m,2H),5.34(t,J＝4.7Hz,1H),5.20(s,1H),4.13(dd,J＝16.4,8.6Hz,2H),3.74–3.49(m,4H),3.17(dd,J＝22.4,11.1Hz,2H),3.01(d,J＝30.2Hz,2H),2.83(s,2H),2.64(d,J＝30.8Hz,2H),2.34(d,J＝8.4Hz,6H),2.15(d,J＝15.7Hz,1H),2.03(d,J＝5.8Hz,2H),1.60(s,2H)。

compound 22b:

¹ HNMR(400MHz,CD ₃ OD)δ7.84(d,J＝8.5Hz,1H),7.71(d,J＝8.1Hz,1H),7.56–7.50(m,2H),7.41–7.35(m,2H),6.84(dd,J＝16.8,10.5Hz,1H),6.28(d,J＝14.7Hz,1H),5.84(s,1H),5.33(d,J＝4.7Hz,3H),4.28(s,2H),3.55(d,J＝17.2Hz,6H),3.13(s,2H),2.88(d,J＝14.3Hz,7H),2.34(s,1H),2.02(s,5H),1.60(s,2H)。

example 5:

15-propenoyl-3- (8-chloronaphthalen-1-yl) -8- ((dimethylamino) methyl) -1,2,3,4,8,9,10,11,13 a,14,15,16, 17-decahydro-12H-6, 19- (aminosubunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazacyclotetradecan-12-one (Compound 16)

Step 1:2- (but-3-en-1-yl) isoindoline-1, 3-dione

1, 3-Dioxoisoindolin-2-yl potassium (9.9 g,53.33 mmol) was added to a stirred mixture of 4-bromobut-1-ene (6.0 g,44.44 mmol) in DMF (25 mL). The resulting mixture was stirred at 80 ℃ overnight. Water (25 mL) was added to the reaction mixture. The resulting mixture was extracted with MTBE (3X 50 mL). The combined organic layers were washed with brine (2×100 ml). The obtained organic layer was subjected to anhydrous Na ₂ SO ₄ Dried, filtered and concentrated in vacuo to give the crude product (9.4 g) as a white solid.

LC-MS rt=1.69 min; MS calculated: 201.1, MS (ESI): 202.1[ M+H ]] ⁺ 。

Step 2:2- (2- (oxaprozin-2-yl) ethyl) isoindoline-1, 3-dione

To a stirred mixture of 2- (but-3-en-1-yl) isoindoline-1, 3-dione (2.01 g,10.0 mmol) in DCM (30 mL) was added mCPBA (3.45 g,20.0 mmol) at 0deg.C. The resulting mixture was stirred at room temperature overnight. Saturated Na at 0 DEG C ₂ SO ₃ The solution was added to the reaction mixture. The resulting mixture was extracted with DCM (2X 30 mL). The combined organic layers were treated with K ₂ CO ₃ The solution (2X 30 mL) and brine (2X 30 mL) were washed. The obtained organic layer was subjected to anhydrous Na ₂ SO ₄ Dried, filtered and concentrated in vacuo to give the crude product as a pale yellow solid(2.1g)。

LC-MS rt=1.22 min; MS calculated: 217.1, MS (ESI): 218.0[ M+H ]] ⁺ 。

Step 3:2- (4-azido-3-hydroxybutyl) isoindoline-1, 3-dione

2- (2- (Oxalopropian-2-yl) ethyl) isoindoline-1, 3-dione (217 mg,1.0 mmol) was added to sodium azide (325 mg,5.0 mmol) in MeOH (6 mL) and H ₂ O (2 mL). Then NH is added ₄ Cl (267 mg,5.0 mmol) was added to the above mixture. The resulting mixture was stirred at 80 ℃ overnight. The reaction mixture was concentrated under vacuum to remove MeOH. Water (10 mL) was then added to the residue. The resulting solution was extracted with DCM (3X 20 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under vacuum. The residue was purified by column chromatography (PE/ea=3/1) to give DP as a white solid ((186 mg, yield: 72%).

LC-MS rt=1.33 min; MS calculated: 260.1, MS (ESI): 261.0[ M+H ]] ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ7.89–7.84(m,2H),7.77–7.71(m,2H),3.93–3.87(m,2H),3.76–3.68(m,1H),3.37–3.24(m,2H),1.87–1.42(m,2H)。

Step 4: N1-benzyl-N2-tritylethane-1, 2-diamine

To a solution of N- (2-aminoethyl) benzylamine (50 g, 0.336 mol) in dichloromethane (20 mL) was added triethylamine (49 mL,0.348 mol) and trityl chloride (93 g, 0.336 mol) at 0deg.C. The reaction mixture was warmed to room temperature and stirred overnight. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. After concentration, the crude title product (160 g, crude) was obtained as a colorless oil, which was used in the next step without further purification.

Step 5:2- (4-Benzylpiperazin-2-yl) acetic acid methyl ester

Will N ¹ -benzyl-N ² Tribenzyl ethane-1, 2-diamine (153 g) was combined with MeCN (770 mL) and K was added as a solid with vigorous stirring ₂ CO ₃ (87.8 g,636 mmol) and KI (1.86 g,11.2 mmol). Finally, (E) -methyl 4-bromobut-2-enoate (66.8 g,373 mmol) was added and the suspension stirred at room temperature overnight. The mixture was filtered and the filter cake was rinsed with MeCN (140 mL) and then DCM (240 mL). The filtrate was concentrated in vacuo. The residue was dissolved in MeOH (240 mL) and a solution of HCl in dioxane (4 m,100 mL) was added. The resulting solution was heated under reflux for 1.5 hours, then cooled to room temperature and concentrated under vacuum. The residue was diluted with water (600 mL) and made acidic (pH about 3) by the addition of 10% HCl. The mixture was washed with EA (2 x 300 ml) and K was added by careful addition of solid ₂ CO ₃ Then, 25% aqueous NaOH (24 mL) was added to make the aqueous phase basic (pH about 9). The mixture was extracted with DCM (3×260 ml) and the combined organic phases were washed with brine, over Na ₂ SO ₄ Dried and concentrated in vacuo to give DP as a pale yellow oil (33 g, yield: 34%, used in both steps).

LC-MS rt=0.35 min; MS calculated: 248.2, MS (ESI): 249.1[ M+H ]] ⁺ 。

Step 5: 4-benzyl-2- (2-methoxy-2-oxoethyl) piperazine-1-carboxylic acid tert-butyl ester

Di-tert-butyl dicarbonate (29 g,133 mmol) was added to a stirred mixture of methyl 2- (4-benzylpiperazin-2-yl) acetate (33 g,133 mol) in DCM (300 mL) at 0deg.C. The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE/ea=10/1) to give the title product as a colorless oil (35.5 g, yield: 90%).

LC-MS rt=1.32 min; MS calculated: 348.2, MS (ESI): 349.2[ M+H ]] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ7.34-7.22(m,5H),4.38-4.31(m,1H),3.79-3.66(m,1H),3.58-3.47(m,4H),3.41-3.34(m,1H),3.08-2.89(m,1H),2.82-2.71(m,2H),2.66-2.54(m,2H),2.05-1.88(m,2H),1.37(s,9H)。

Step 6: 2-allyl piperazine-1, 4-dicarboxylic acid 4-benzyl ester 1- (tert-butyl ester)

At H ₂ Pd/C (100 mg,10%,0.094 mmol) was added to a stirred mixture of tert-butyl 4-benzyl-2- (2-methoxy-2-oxoethyl) piperazine-1-carboxylate (1 g,2.87 mmol) in MeOH (10 mL) under an atmosphere. The resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was filtered, and the filter was concentrated in vacuo to give the title product as a pale yellow solid (670 mg, yield: 90%).

LC-MS rt=0.51 min; MS calculated: 258.2, MS (ESI): 259.1[ M+H ]] ⁺ 。

Step 7:2- (2-methoxy-2-oxoethyl) piperazine-1, 4-dicarboxylic acid 4-benzyl ester 1- (tert-butyl ester)

Cbz-Cl (27.7 g,162.6 mmol) was added to 4-benzyl 2-allylpiperazine-1, 4-dicarboxylic acid 1- (tert-butyl) ester (28.0 g,108.4 mmol) and NaHCO ₃ (27.3 g,325.2 mmol) in EA (200 mL) and H ₂ In a stirred mixture in O (200 mL). The resulting mixture was stirred at room temperature overnight. The mixture was extracted with EA (3 x 200 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE/ea=3/1) to give the title product (42.3 g) as a colorless oil.

LC-MS rt=1.88 min; MS calculated: 392.2, MS (ESI): 293.1[ M-Boc+H ]] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ7.40-7.30(m,5H),5.12-5.04(m,2H),4.45-4.34(m,1H),3.95-3.82(m,2H),3.80-3.66(m,1H),3.53(s,3H),3.14-2.75(m,3H),2.60-2.52(m,1H),2.45-2.32(m,1H),1.39(s,9H)。

Step 8:3- (2-methoxy-2-oxoethyl) piperazine-1-carboxylic acid benzyl ester

TFA (50 mL) was added to a stirred mixture of 4-benzyl 2- (2-methoxy-2-oxoethyl) piperazine-1, 4-dicarboxylic acid 1- (tert-butyl) ester (10.7 g,27.3 mmol) in DCM (100 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo to give the crude product as TFA salt (12.8 g, crude for the next step).

LC-MS rt=0.44 min; MS calculated: 292.1, MS (ESI): 293.0[ M+H ]] ⁺ 。

Step 9:4- (4- ((benzyloxy) carbonyl) -2- (2-methoxy-2-oxoethyl) piperazin-1-yl) -2-chloro-5, 8-dihydropyrido [3,4-d ] pyrimidine-7 (6H) -carboxylic acid tert-butyl ester

DIEA (17.6 g,136.3 mmol) was added to benzyl 3- (2-methoxy-2-oxoethyl) piperazine-1-carboxylate (12.8 g, TFA salt, 27.3 mmol) and 2, 4-dichloro-5, 8-dihydropyrido [3,4-d ]]Pyrimidine-7 (6H) -carboxylic acid tert-butyl ester (8.29 g,27.3 mmol) in DMSO (100 mL). The obtained mixture is treated in the following conditionStirred at 60℃overnight. Will H ₂ O (100 mL) was added to the reaction mixture. The resulting mixture was extracted with DCM (3X 150 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE/ea=3/1) to give the title product as a brown solid (6.1 g, yield: 40%).

LC-MS rt=2.15 min; MS calculated: 559.2, MS (ESI): 560.3[ M+H ]] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ7.42-7.29(m,5H),5.15-5.04(m,2H),4.70-4.55(m,1H),4.50-4.41(m,1H),4.40-4.21(m,1H),4.01-3.91(m,2H),3.79-3.61(m,2H),3.46(s,3H),3.30-3.13(m,3H),3.07-2.90(m,1H),2.72-2.63(m,3H),2.57-2.52(m,1H),1.44(s,9H)。

Step 10:4- (2-chloro-5, 6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3- (2-methoxy-2-oxoethyl) piperazine-1-carboxylic acid benzyl ester

TFA (40 mL) was added to 4- (4- ((benzyloxy) carbonyl) -2- (2-methoxy-2-oxoethyl) piperazin-1-yl) -2-chloro-5, 8-dihydropyrido [3,4-d ] ]Pyrimidine-7 (6H) -carboxylic acid tert-butyl ester (7.8 g,13.9 mmol) in DCM (80 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum. The residue was taken up in saturated NaHCO ₃ The solution was neutralized and the resulting solution was extracted with DCM (3X 100 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated in vacuo to give the crude product (6.4 g, crude) as a pale brown solid.

LC-MS rt=0.99 min; MS calculated: 459.2 MS (ESI): 460.1[ M+H ]] ⁺ 。

Step 11:4- (2-chloro-7- (8-chloronaphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3- (2-methoxy-2-oxoethyl) piperazine-1-carboxylic acid benzyl ester

At N ₂ Pd is put under atmosphere ₂ (dba) ₃ (1.03 g,1.13 mmol) and RuPhos (1.05 g,2.25 mmol) were added to 4- (2-chloro-5, 6,7, 8-tetrahydropyrido [3, 4-d)]Pyrimidine-4-yl) -3- (2-methoxy-2-oxoethyl) piperazine-1-carboxylic acid benzyl ester (3.45 g,7.5 mmol), 1-bromo-8-chloronaphthalene (2.7 g,11.3 mmol), and Cs ₂ CO ₃ (7.34 g,22.5 mmol) in toluene (50 mL). The resulting mixture was stirred at 90 ℃ overnight. Toluene was removed under vacuum. The residue was purified by silica gel column chromatography (PE/ea=3/2) to give the title product as a pale brown solid (2.7 g, yield: 58%).

LC-MS rt=2.58 min; MS calculated: 619.2, MS (ESI): 620.2[ M+H ]] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ7.92(d,J＝8.2Hz,1H),7.75(dd,J＝7.6,5.2Hz,1H),7.59(dd,J＝7.4,1.0Hz,1H),7.57–7.50(m,1H),7.48–7.43(m,1H),7.42–7.28(m,6H),5.19–5.02(m,2H),4.26–4.16(m,1H),4.09–3.92(m,3H),3.89–3.72(m,2H),3.49-3.38(m,5H),3.28–3.17(m,2H),3.15–2.82(m,2H),2.78–2.72(m,1H),2.70–2.65(m,1H),2.49–2.38(m,1H)。

Step 12:4- (2- ((1-azido-4- (1, 3-dioxoisoindolin-2-yl) butan-2-yl) oxy) -7- (8-chloronaphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3- (2-methoxy-2-oxoethyl) piperazine-1-carboxylic acid benzyl ester

At N ₂ BINAP (3411 mg,0.55 mmol) and Pd (OAc) were added under an atmosphere ₂ (62 mg,0.27 mmol) to 4- (2-chloro-7- (8-chloronaphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3, 4-d)]Pyrimidine-4-yl) -3- (2-methoxy-2-oxoethyl) piperazine-1-carboxylic acid benzyl ester (1.7 g,2.74 mmol), 2- (4-azido-3-hydroxybutyl) isoindoline-1, 3-dione (1.07 g,4.11 mmol) and Cs ₂ CO ₃ (2.68 g,8.22 mmol) in toluene (30 mL) with stirringIn the composition. The resulting mixture was stirred at 100℃for 5 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (PE/ea=1/1) to give the title product (1.4 g, yield: 61%) as a yellow solid.

LC-MS rt=2.40 min; MS calculated: 843.3, MS (ESI): 844.1[ M+H ]] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ7.97-7.93(m,1H),7.80-7.75(m,1H),7.70-7.63(m,2H),7.60-7.52(m,3H),7.50-7.43(m,2H),7.40-7.29(m,6H),5.17-5.05(m,3H),4.70-4.35(m,1H),4.02-3.79(m,4H),3.72-3.64(m,3H),3.60-3.52(m,2H),3.45-3.35(m,4H),3.20-2.96(m,4H),2.75-2.66(m,1H),2.61-2.53(m,2H),2.45-2.35(m,1H),2.05-1.93(m,2H)。

Step 13:4- (2- ((4-amino-1-azidobut-2-yl) oxy) -7- (8-chloronaphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -3- (2-methoxy-2-oxoethyl) piperazine-1-carboxylic acid benzyl ester

Hydrazine hydrate (830 mg,16.6 mmol) was added to 4- (2- ((1-azido-4- (1, 3-dioxoisoindolin-2-yl) butan-2-yl) oxy) -7- (8-chloronaphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ]]Pyrimidine-4-yl) -3- (2-methoxy-2-oxoethyl) piperazine-1-carboxylic acid benzyl ester (1.4 g,1.66 mmol) in EtOH (20 mL). The resulting mixture was stirred at 45℃for 3 hours. Et is added to ₂ O (100 mL) was added to the reaction mixture. The resulting mixture was filtered and the filter was concentrated under vacuum to give the crude product (1.2 g) as a pale brown solid.

LC-MS [ mobile phase: from 70% water (0.1% FA) and 30% CH3CN (0.1% FA) to 5% water (0.1% FA) and 90% CH in 2.5 minutes ₃ CN(0.1％ FA)]Purity of: 67%; LC-MS rt=1.43 min; MS calculated: 713.3, MS (ESI): 714.1[ M+H ]] ⁺ 。

Step 14:2- (1- (2- ((4-amino-1-azidobut-2-yl) oxy) -7- (8-chloronaphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -4- ((benzyloxy) carbonyl) piperazin-2-yl) acetic acid

Lithium hydroxide (119 mg,4.98 mmol) was added to 4- (2- ((4-amino-1-azidobut-2-yl) oxy) -7- (8-chloronaphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ]]Pyrimidin-4-yl) -3- (2-methoxy-2-oxoethyl) piperazine-1-carboxylic acid benzyl ester (1.18 g,1.66 mmol) in MeOH/THF/H ₂ O (4 mL/4mL/4 mL). The resulting mixture was stirred at 60℃for 3 hours. MeOH and THF were removed under vacuum. The resulting solution was purified by adding saturated NaH ₂ PO ₄ The solution was neutralized. The resulting solution was extracted with DCM/MeOH (3X 30mL/6 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated in vacuo to give the crude product (930 mg) as a pale yellow solid.

LC-MS rt=1.29 min; MS calculated: 699.3 MS (ESI): 700.3[ M+H ]] ⁺ 。

Step 15:13- (azidomethyl) -19- (8-chloronaphthalen-1-yl) -9-oxo-14-oxa-2,5,10,16,19,23-hexaazatetracyclo [13.7.1.0 ] ² , ⁷ .0 ¹⁷ , ²² ]Ditridecacarbon-1 (23), 15,17 (22) -triene-5-carboxylic acid benzyl ester

HOBt (269 mg,1.99 mmol) and EDCI (382 mg,1.99 mmol) were added to 2- (1- (2- ((4-amino-1-azidobut-2-yl) oxy) -7- (8-chloronaphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ]]Pyrimidin-4-yl) -4- ((benzyloxy) carbonyl) piperazin-2-yl) acetic acid (930 mg,1.33 mmol) in DMF (15 mL). The resulting mixture was stirred at room temperature for 1 hour. DMF was removed under vacuum. The residue was passed through a reverse phase column (MeCN/0.1% FA in H ₂ O from 0 to 1/1) to afford the title product as a brown solid (230 mg, overall yield: 25%).

LC-MS rt=1.73 minThe method comprises the steps of carrying out a first treatment on the surface of the MS calculated: 681.3, MS (ESI): 682.2[ M+H ]] ⁺ 。

Step 16:13- (aminomethyl) -19- (8-chloronaphthalen-1-yl) -9-oxo-14-oxa-2,5,10,16,19,23-hexaazatetracyclo [13.7.1.0 ^2,7 .0 ^17,22 ]Ditridecacarbon-1 (23), 15,17 (22) -triene-5-carboxylic acid benzyl ester

At N ₂ PPh under atmosphere ₃ (177 mg,0.67 mmol) to 13- (azidomethyl) -19- (8-chloronaphthalen-1-yl) -9-oxo-14-oxa-2,5,10,16,19,23-hexaazatetracyclo [ 13.7.1.0) ^2,7 .0 ^17,22 ]Ditridec-1 (23), 15,17 (22) -trien-5-carboxylic acid benzyl ester (230 mg,0.34 mmol) in THF (6 mL) and H ₂ O (1.5 mL). The resulting mixture was stirred at 60 ℃ overnight. The reaction mixture was concentrated in vacuo to give the crude product (324 mg, crude) as a pale brown solid.

LC-MS rt=1.20 min; MS calculated: 655.3, MS (ESI): 656.4[ M+H ]] ⁺ 。

Step 17:19- (8-chloronaphthalen-1-yl) -13- [ (dimethylamino) methyl]-9-oxo-14-oxa-2,5,10,16,19,23-hexaazatetracyclo [13.7.1.0 ] ² , ⁷ .0 ¹⁷ , ²² ]Ditridecacarbon-1 (23), 15,17 (22) -triene-5-carboxylic acid benzyl ester

HOAc (10 mg,0.17 mmol) was added to 13- (aminomethyl) -19- (8-chloronaphthalen-1-yl) -9-oxo-14-oxa-2,5,10,16,19,23-hexaazatetracyclo [13.7.1.0 ] at 0deg.C ² , ⁷ .0 ¹⁷ , ²² ]Ditridecacarbon-1 (23), 15,17 (22) -triene-5-carboxylic acid benzyl ester (324 mg,0.49 mmol), naBH ₃ CN (62 mg,0.99 mmol) and HCHO (74 mg,2.47 mmol) in MeOH (6 mL). The resulting mixture was stirred at room temperature overnight. The reaction mixture was filtered and the filter was placed under vacuumConcentrating. The residue was purified by preparative HPLC to give the title product as a white solid (45 mg, yield: 19%, used in two steps).

LC-MS rt=1.25 min; MS calculated: 683.3, MS (ESI): 684.1[ M+H ]] ⁺ 。

¹ H NMR(400MHz,CD ₃ OD)δ8.45(s,HCOOH,1H),7.82(d,J＝8.0Hz,1H),7.69(d,J＝8.0Hz,1H),7.56-7.47(m,2H),7.43-7.31(m,7H),5.61-5.50(m,1H),5.26-5.08(m,3H),4.41-4.22(m,2H),4.16-4.09(m,1H),4.06-3.96(m,1H),3.65-3.55(m,4H),3.42-3.67(m,3H),3.26-3.20(m,3H),3.13-3.05(m,2H),2.79(s,6H),2.63-2.52(m,1H),2.47-2.25(m,1H),2.12-1.95(m,1H),1.75-1.62(m,1H)。

Step 18:19- (8-chloronaphthalen-1-yl) -13- [ (dimethylamino) methyl]-14-oxa-2,5,10,16,19,23-hexaazatetracyclo [13.7.1.0 ] ² , ⁷ .0 ¹⁷ , ²² ]Ditridecan-1 (23), 15,17 (22) -trien-9-one

50% KOH (0.4 mL) was added to 19- (8-chloronaphthalen-1-yl) -13- [ (dimethylamino) methyl]-9-oxo-14-oxa-2,5,10,16,19,23-hexaazatetracyclo [13.7.1.0 ] ² , ⁷ .0 ¹⁷ , ²² ]Ditridecacarbon-1 (23), 15,17 (22) -triene-5-carboxylic acid benzyl ester (40 mg,0.06 mmol) in EtOH (1.6 mL). The resulting mixture was stirred at 75℃for 1 hour. The reaction mixture was neutralized with 3M HCl. The resulting solution was extracted with DCM (3X 10 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated in vacuo to give the crude product (40 mg, crude) as a pale brown solid.

LC-MS rt=0.52 min; MS calculated: 549.3, MS (ESI): 550.1[ M+H ]] ⁺ 。

Step 19: 15-propenoyl-3- (8-chloronaphthalen-1-yl) -8- ((dimethylamino) methyl) -1,2,3,4,8,9,10,11,13 a,14,15,16, 17-decatetrahydro-12H-6, 19- (aminosubunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazacyclotetradec-n-12-one

Acrylamide-containing (13 mg,0.15 mmol) DCM was added to 19- (8-chloronaphthalen-1-yl) -13- [ (dimethylamino) methyl at 0deg.C]-14-oxa-2,5,10,16,19,23-hexaazatetracyclo [13.7.1.0 ] ² , ⁷ .0 ¹⁷ , ²² ]A stirred mixture of ditridecan-1 (23), 15,17 (22) -trien-9-one (40 mg,0.07 mmol) and TEA (29 mg,0.29 mmol) in DCM (3 mL). The reaction mixture was stirred at 0 ℃ for 10 minutes. The reaction mixture was concentrated under vacuum. The residue was purified by preparative HPLC to give the title product (4.1 mg, MC19-590-127-A1, yield: 10%).

LC-MS rt=0.96 min; MS calculated: 603.3, MS (ESI): 604.3[ M+H ]] ⁺ 。

¹ H NMR(400MHz,CD ₃ OD)δ8.47(s,HCOOH,1H),7.83(d,J＝8.0Hz,1H),7.69(d,J＝8.0Hz,1H),7.55-7.47(m,2H),7.40-7.32(m,2H),6.90-6.72(m,1H),6.32-6.25(m,1H),5.85-5.78(m,1H),5.60-5.50(m,1H),5.05-4.96(m,1H),4.70-4.56(m,1H),4.32-4.24(m,1H),4.15-4.08(m,1H),3.68-3.52(m,5H),3.44-3.38(m,3H),3.18-2.97(m,4H),2.81(s,6H),2.67-2.57(m,1H),2.54-2.47(m,1H),2.45-2.36(m,1H),2.11-1.97(m,1H),1.72-1.62(m,1H)。

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

Compound 17:

¹ H NMR(400MHz,CD ₃ OD)δ8.51(s,1H,HCOOH),7.83(d,J＝7.4Hz,1H),7.69(d,J＝8.3Hz,1H),7.59–7.45(m,2H),7.43–7.27(m,2H),6.97–6.72(m,1H),6.37–6.23(m,1H),5.89–5.74(m,1H),4.79–4.71(m,1H),4.64–4.43(m,1H),4.39–3.84(m,5H),3.81–3.46(m,4H),3.44–3.37(m,1H),3.25–3.03(m,4H),3.00–2.85(m,2H),2.89–2.70(m,3H),2.69–2.62(m,2H),2.58–2.43(m,6H)。

compound 18:

¹ H NMR(400MHz,CD ₃ OD)δ8.45(s,1H,HCO2H),7.86–7.79(m,1H),7.72–7.67(m,1H),7.57–7.47(m,2H),7.43–7.31(m,2H),6.91–6.81(m,1H),6.36–6.21(m,1H),5.87–5.80(m,1H),4.79–4.52(m,2H),4.49–3.92(m,5H),3.68–3.34(m,8H),3.23–3.02(m,3H),2.97–2.78(m,8H),2.74–2.51(m,3H),2.43–2.13(m,1H),1.89–1.77(m,1H)。

compound 19a:

¹ H NMR(400MHz,CD ₃ OD)8.43(s,2H,HCOOH),7.83(d,J＝8.1Hz,1H),7.70(d,J＝8.1Hz,1H),7.59–7.44(m,2H),7.40–7.19(m,2H),6.92–6.76(m,1H),6.35–6.22(m,1H),5.83(d,J＝10.7Hz,1H),5.75–5.61(m,1H),4.59(br s,1H),4.38–4.20(m,2H),4.18–3.70(m,4H),3.69–3.46(m,5H),3.39(s,1H),3.22–3.06(m,3H),2.96–2.77(m,6H),2.65(s,2H),2.42(s,2H),2.06–1.88(m,2H),1.76–1.49(m,3H)。

compound 19b:

¹ H NMR(400MHz,CD ₃ OD)δ8.44(s,2H,HCO2H),7.89–7.79(m,1H),7.70(d,J＝8.2Hz,1H),7.59–7.45(m,2H),7.43–7.28(m,2H),6.93–6.73(m,1H),6.29(d,J＝15.4Hz,1H),5.89–5.76(m,1H),5.22(s,1H),4.76–4.50(m,3H),4.39–4.06(m,3H),3.83–3.41(m,6H),3.13(s,3H),2.97–2.77(m,6H),2.69(br s,2H),2.47(s,3H),1.90–1.75(m,1H),1.71–1.41(m,3H)。

example 6:

2- (14-propenoyl-8- ((dimethylamino) methyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecan-e-15-yl) acetonitrile (Compound 23)

Step 1: 2-amino-3- (benzyloxy) propionic acid methyl ester

SOCl was added at 0deg.C ₂ (279 mL,3.84 mol) was added dropwise to MeOH (2.5L) and the mixture was stirred at 0deg.C for 10 min. 2-amino-3- (benzyloxy) propionic acid (250 g,1.28 mol) was then added in portions, and the resulting mixture was stirred under reflux for 16 hours. The mixture was concentrated to dryness and the residue was diluted with water (1L) and taken up in NaHCO ₃ The aqueous solution was basified to pH about 8 and extracted with DCM (300 ml x 3). The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to dryness to give methyl 2-amino-3- (benzyloxy) propionate (290 g,108% yield) as a yellow oil. MS (ESI) M/z 210 (M+H) ⁺ 。

Step 2: 2-amino-3- (benzyloxy) propan-1-ol

To a solution of methyl 2-amino-3- (benzyloxy) propionate (80 g,0.38 mol) in EtOH (800 mL) was added sodium borohydride (58.1 g,1.53 mol) in portions at 0deg.C. After addition, the mixture was stirred at room temperature for 16 hours. The reaction mixture was treated with saturated NH ₄ The aqueous Cl solution was quenched and neutralized to pH about 8 with 1N aqueous HCl at 0deg.C. Volatiles were removed under vacuum. The aqueous phase was treated with CHCl ₃ IPA (10X 200mL, 3/1) extraction and the combined organic layers were taken up in Na ₂ SO ₄ Dried, filtered and evaporated to dryness to give 2-amino-3- (benzyloxy) propan-1-ol (65.2 g,94% yield) as a white solid. LCMS (ESI) M/z 182 (M+H) ⁺ 。

Step 3: n- (1- (benzyloxy) -3-hydroxy-prop-2-yl) -2-nitrobenzenesulfonamide

To 2-amino-3 at 0 DEG C- (benzyloxy) propan-1-ol (128 g,0.70 mol) and Et ₃ N (196 mL,1.41 mol) to a mixture of DCM (1.3L) was added in portions NsCl (139 g,0.63 mol) and the mixture was stirred at room temperature for 16 h. The mixture was diluted with ice water (1L) and extracted with DCM (2×500 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (PE: etoac=5:1 to 3:1) to give N- (1- (benzyloxy) -3-hydroxypropan-2-yl) -2-nitrobenzenesulfonamide (203 g,84% yield) as a yellow oil. MS (ESI) M/z 367 (M+H) ⁺ 。

Step 4: methanesulfonic acid 3- (benzyloxy) -2- (2-nitrobenzenesulfonamido) propyl ester

N- (1- (benzyloxy) -3-hydroxy-prop-2-yl) -2-nitrobenzenesulfonamide (105 g,0.29 mol) and Et at-78deg.C ₃ N (44 mL,0.32 mol) was added drop wise to a mixture of MsCl (24 mL,0.32 mol) in DCM (1.1L), and the mixture was stirred at-78℃for 1 hour. The reaction was quenched with ice water (700 mL) and extracted with DCM (2×300 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to dryness to give 3- (benzyloxy) -2- (2-nitrobenzenesulfonamido) propyl methanesulfonate (127 g,100% yield) as a yellow oil, which was used directly in the next step. MS (ESI) M/z 445 (M+H) ⁺ ,462(M+18) ⁺ 。

Step 5:2- ((benzyloxy) methyl) -1- ((2-nitrophenyl) sulfonyl) aziridine

Cs was added to a solution of 3- (benzyloxy) -2- (2-nitrobenzenesulfonamido) propyl methanesulfonate (127 g,0.29 mol) in DCM (5.1L) at 0 ℃ ₂ CO ₃ (102 g,0.31 mol) and the mixture was stirred at room temperature for 16 hours. The mixture was treated with ice water(2L) quenched and extracted with DCM (2X 1L). The combined organic phases were washed with brine at below 35 ℃ over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to 200mL. The mixture was diluted with THF (200 mL) and the solution was used directly in the next step. MS (ESI) M/z 349 (M+H) ⁺ ,365(M+18) ⁺ . Note that: not all solvent is removed, as the concentrated aziridine will begin to polymerize upon standing.

Step 6: (3- (benzyloxy) -2- (2-nitrobenzenesulfonamido) propyl) carbamic acid tert-butyl ester

At N ₂ KHMDS (861 mL,0.86mol,1.0M in THF) was added dropwise to a solution of tert-butyl carbamate (101 g,0.86 mol) in THF (1L) under an atmosphere at-78deg.C. After stirring at-78 ℃ for 30 minutes, the solution in step 5 was added dropwise to the mixture, and the resulting mixture was stirred at-78 ℃ to room temperature for 16 hours. The reaction mixture was quenched with ice water (1L) and extracted with EtOAc (2X 500 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (PE: etoac=3:1) to give methyl 3-amino-5-fluoropyridine-4-carboxylate (55 g,41% yield) as a colorless oil. MS (ESI) M/z:366 (M-100+H) ⁺ ,488(M+23) ⁺ 。

Step 7: (E) -methyl 4- (N- (1- (benzyloxy) -3- ((tert-butoxycarbonyl) amino) prop-2-yl) -2-nitrobenzenesulfonamido) but-2-enoate

To 3-amino-5-fluoropyridine-4-carboxylic acid methyl ester (108 g,0.23 mol) and K ₂ CO ₃ (48.0 g,0.35 mol) methyl (E) -4-bromobut-2-enoate (50.0 g,0.28 mol) was added to a mixture in DMF (1.1L), and the mixture was stirred at room temperature for 16 hours. The mixture was poured into ice water (1L),and extracted with EtOAc (3 x 500 ml). The combined organic layers were treated with saturated NH ₄ Aqueous Cl (3X 500 mL) and brine, washed with anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography (PE: etoac=3:1) to give methyl (E) -4- (N- (1- (benzyloxy) -3- ((tert-butoxycarbonyl) amino) prop-2-yl) -2-nitrobenzenesulfonamide) but-2-enoate (132 g,101% yield) as a yellow oil. MS (ESI) M/z 464 (M-100+H) ⁺ ,586(M+23) ⁺ 。

Step 8:2- (5- ((benzyloxy) methyl) -4- ((2-nitrophenyl) sulfonyl) piperazin-2-yl) acetic acid methyl ester

To a solution of methyl (E) -4- (N- (1- (benzyloxy) -3- ((tert-butoxycarbonyl) amino) prop-2-yl) -2-nitrobenzenesulfonamido) but-2-enoate (132 g,0.23 mol) in DCM (1.3L) was added TFA (400 mL) at 0deg.C. After stirring at room temperature for 2 hours, the reaction mixture was concentrated to dryness and the residue was co-evaporated with toluene twice. The residue was dissolved in DCM (500 mL) and saturated NaHCO at 0deg.C ₃ The aqueous solution (500 mL) was neutralized. The layers were separated and the organic layer was washed with brine, over Na ₂ SO ₄ Dried, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (PE: etoac=2:1) to give methyl 2- (5- (benzyloxy) methyl) -4- ((2-nitrophenyl) sulfonyl) piperazin-2-yl) acetate (82 g,75% yield) as a yellow oil. MS (ESI) M/z 464 (M+H) ⁺ 。

Step 9:2- (5- (hydroxymethyl) -4- ((2-nitrophenyl) sulfonyl) piperazin-2-yl) acetic acid methyl ester

To a solution of methyl 2- (5- ((benzyloxy) methyl) -4- ((2-nitrophenyl) sulfonyl) piperazin-2-yl) acetate (80 g,0.17 mol) in DCM (800 mL) was added dropwise BCl at 0deg.C ₃ (518 mL,0.52mol,1M in DCM), and the mixture was stirred at 0deg.C for 1 hr. The reaction was quenched by dropwise addition of MeOH (100 mL). The mixture was concentrated to dryness and the residue was purified by silica gel column chromatography (DCM: meoh=10:1) to give methyl 2- (5- (hydroxymethyl) -4- ((2-nitrophenyl) sulfonyl) piperazin-2-yl) acetate as a yellow oil (55 g,86% yield). MS (ESI) M/z 374 (M+H) ⁺ 。

Step 10:5- (hydroxymethyl) -2- (2-methoxy-2-oxoethyl) -4- ((2-nitrophenyl) sulfonyl) piperazine-1-carboxylic acid tert-butyl ester

To a solution of methyl 2- (5- (hydroxymethyl) -4- ((2-nitrophenyl) sulfonyl) piperazin-2-yl) acetate (55.0 g,0.15 mol) in THF (600 mL) was added water (600 mL), naHCO in sequence at 0deg.C ₃ (24.8 g,0.29 mol) and Boc ₂ O (48.1 g,0.22 mol) and the mixture was stirred at room temperature for 5 hours. The mixture was extracted with EtOAc (2 x 300 ml) and the combined organic layers were washed with water and brine, over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (PE: etoac=5:1) to give tert-butyl 5- (hydroxymethyl) -2- (2-methoxy-2-oxoethyl) -4- ((2-nitrophenyl) sulfonyl) piperazine-1-carboxylate (49.5 g,72% yield) as a yellow oil. MS (ESI) M/z 374 (M-100+H) ⁺ ,496(M+23) ⁺ 。

Step 11:5- (hydroxymethyl) -2- (2-methoxy-2-oxoethyl) piperazine-1-carboxylic acid tert-butyl ester

To 5- (hydroxymethyl) -2- (2-methoxy-2-oxoethyl) -4- ((2-nitrophenyl) sulfonyl) piperazine-1-carboxylic acid tert-butyl ester (50 g,0.10 mol) in CH ₃ Cs was added to a solution in CN (500 mL) ₂ CO ₃ (103 g,0.32 mol) followed by the addition of 4-methoxybenzene-1-thiol (18.5 g,0.13 mol), And the mixture was stirred at room temperature for 16 hours. The mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography (DCM: meoh=10:1) to give (2 r,5 s) -5- (hydroxymethyl) -2- (2-methoxy-2-oxoethyl) piperazine-1-carboxylic acid tert-butyl ester (28.8 g,96% yield) as a yellow solid. MS (ESI) M/z 289 (M+H) ⁺ 。

Step 12:5- (hydroxymethyl) -2- (2-methoxy-2-oxoethyl) -4- (4-methoxybenzyl) piperazine-1-carboxylic acid tert-butyl ester

To a solution of (2 r,5 s) -5- (hydroxymethyl) -2- (2-methoxy-2-oxoethyl) piperazine-1-carboxylic acid tert-butyl ester (28.0 g,97.2 mmol) in DCE (300 mL) was added 4-methoxybenzaldehyde (29.1 g,214 mmol) and AcOH (5.8 g,97.2% mmol), and the mixture was stirred at room temperature for 30 min. NaBH (OAc) was added at 0deg.C ₃ (53.6 g, 255 mmol) was added portionwise to the mixture and the resulting mixture was stirred at room temperature for 16 hours. The mixture was quenched with water and extracted with DCM (3×200 ml). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ Dried, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (eluting with PE: etoac=1:1) to give tert-butyl 5- (hydroxymethyl) -2- (2-methoxy-2-oxoethyl) -4- (4-methoxybenzyl) piperazine-1-carboxylate (35.1 g,86% yield) as a yellow solid. MS (ESI) M/z 409 (M+H) ⁺ 。

Step 13:2- (2-methoxy-2-oxoethyl) -4- (4-methoxybenzyl) -5- (((methylsulfonyl) oxy) methyl) piperazine-1-carboxylic acid tert-butyl ester

To 5- (hydroxymethyl) -2- (2-methoxy-2-oxoethyl) -4- (4-methoxybenzyl) piperazine-1-carboxylic acid tert-butyl ester (8.0 g,19.9 mmol) and Et at 0deg.C ₃ N (4.1 mL,29.4 mmol) to a mixture of DCM (80 mL) was added MsCl (1.8 mL, 2)3.5 mmol) and the mixture was stirred at 0℃for 2 hours. The mixture was quenched with water (100 mL) and extracted with DCM (50 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to dryness to give tert-butyl 2- (2-methoxy-2-oxoethyl) -4- (4-methoxybenzyl) -5- (((methylsulfonyl) oxy) methyl) piperazine-1-carboxylate (9.5 g,100% yield) as a yellow oil, which was used directly in the next step. MS (ESI) M/z 487 (M+H) ⁺ 。

Step 14:5- (cyanomethyl) -2- (2-methoxy-2-oxoethyl) -4- (4-methoxybenzyl) piperazine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 2- (2-methoxy-2-oxoethyl) -4- (4-methoxybenzyl) -5- (((methylsulfonyl) oxy) methyl) piperazine-1-carboxylate (9.5 g,19.5 mmol) in DMSO (100 mL) was added NaCN (1.4 g,29.4 mmol), then NaI (0.6 g,3.9 mmol) was added and the mixture stirred at 50 ℃ for 16 hours. The mixture was quenched with water (200 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with water and brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (PE: etoac=3:1) to give tert-butyl 5- (cyanomethyl) -2- (2-methoxy-2-oxoethyl) -4- (4-methoxybenzyl) piperazine-1-carboxylate (6.9 g,88% yield) as a yellow solid. MS (ESI) M/z 418 (M+H) ⁺ 。

Step 15:2- (5- (cyanomethyl) -4- (4-methoxybenzyl) piperazin-2-yl) acetic acid methyl ester hydrochloride

A solution of 5- (cyanomethyl) -2- (2-methoxy-2-oxoethyl) -4- (4-methoxybenzyl) piperazine-1-carboxylic acid tert-butyl ester (6.4 g,15.3 mmol) in HCl/1, 4-dioxane (60 mL, 4M) was stirred at room temperature for 2 hours. Will be mixedThe product was concentrated to dryness to give methyl 2- (5- (cyanomethyl) -4- (4-methoxybenzyl) piperazin-2-yl) acetate (5.4 g,100% yield) as a yellow solid, which was used in the next step without further purification. MS (ESI) M/z 318 (M+H) ⁺ 。

Step 16: 2-chloro-4- (5- (cyanomethyl) -2- (2-methoxy-2-oxoethyl) -4- (4-methoxybenzyl) piperazin-1-yl) -5, 6-dihydropyrido [3,4-d ] pyrimidine-7 (8H) -carboxylic acid tert-butyl ester

To a solution of methyl 2- (5- (cyanomethyl) -4- (4-methoxybenzyl) piperazin-2-yl) acetate (5.1 g,14.4 mmol) in DMSO (50 mL) was added DIPEA (7.4 g,57.7 mmol) followed by 2, 4-dichloro-5, 6-dihydropyrido [3,4-d ] ]Pyrimidine-7 (8H) -carboxylic acid tert-butyl ester (3.1 g,10.1 mmol). The mixture was stirred at 80℃for 5 hours. Adding another batch of 2, 4-dichloro-5, 6-dihydropyrido [3,4-d ]]Pyrimidine-7 (8H) -carboxylic acid tert-butyl ester (3.1 g,10.1 mmol) and the reaction mixture was stirred at 80℃for a further 16 hours. Adding the last batch of 2, 4-dichloro-5, 6-dihydropyrido [3,4-d ]]Pyrimidine-7 (8H) -carboxylic acid tert-butyl ester (3.1 g,10.1 mmol) and the resulting mixture was stirred at 80℃for a further 3 hours. The reaction mixture was quenched with water (150 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (PE: etoac=2:1) to give 2-chloro-4- (5- (cyanomethyl) -2- (2-methoxy-2-oxoethyl) -4- (4-methoxybenzyl) piperazin-1-yl) -5, 6-dihydropyrido [3,4-d ] as a yellow solid]Pyrimidine-7 (8H) -carboxylic acid tert-butyl ester (4.8 g,57% yield). MS (ESI) M/z 585 (M+H) ⁺ 。

Step 17:2- (1- (2-chloro-5, 6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -5- (cyanomethyl) -4- (4-methoxybenzyl) piperazin-2-yl) acetic acid methyl ester

To 2-chloro-4- (5- (cyanomethyl) -2- (2-methoxy-2-oxoethyl) -4- (4-methoxybenzyl) piperazin-1-yl) -5, 6-dihydropyrido [3,4-d ]To a solution of pyrimidine-7 (8H) -carboxylic acid tert-butyl ester (1.75 g,2.99 mmol) in DCM (8 mL) was added TFA (3 mL) and the mixture was stirred at room temperature for 2H. The mixture was treated with saturated NaHCO ₃ The aqueous solution was basified and extracted with DCM (2X 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ Drying and concentrating to dryness to give 2- (1- (2-chloro-5, 6,7, 8-tetrahydropyrido [3, 4-d) as yellow solid]Pyrimidin-4-yl) -5- (cyanomethyl) -4- (4-methoxybenzyl) piperazin-2-yl) acetic acid methyl ester (1.4 g,96% yield), the product was used directly in the next step. MS (ESI) M/z 485 (M+H) ⁺ 。

Step 18:2- (1- (2-chloro-7- (naphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -5- (cyanomethyl) -4- (4-methoxybenzyl) piperazin-2-yl) acetic acid methyl ester

At N ₂ To 2- (1- (2-chloro-5, 6,7, 8-tetrahydropyrido [3, 4-d) under atmosphere]Pyrimidin-4-yl) -5- (cyanomethyl) -4- (4-methoxybenzyl) piperazin-2-yl) acetic acid methyl ester (1.4 g,2.89 mmol) and Cs ₂ CO ₃ (2.82 g,8.66 mmol) in dry 1, 4-dioxane (20 mL) 1-bromonaphthalene (1.61 mL,11.55 mmol), ruPhos (0.13 g,0.29 mmol) and Pd were added ₂ (dba) ₃ (0.26 g,0.29 mmol). The mixture is put under N ₂ Degassing three times down, and under N ₂ Stirring is carried out for 16 hours at 90℃under an atmosphere. The mixture was diluted with water and extracted with EtOAc (2×20 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ Dried, and concentrated to dryness. The residue was purified by silica gel chromatography (eluting with PE: etoac=10:1 to 55:45) to give 2- (1- (2-chloro-7- (naphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3, 4-d) as a yellow solid]Pyrimidin-4-yl) -5- (cyanomethyl) -4- (4-methoxybenzyl) piperazin-2-yl) acetic acid methyl ester (0.95 g,54% yield).MS(ESI)m/z:611(M+H) ⁺ 。

Step 19:2- (1- (2-chloro-7- (naphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -5- (cyanomethyl) -4- (4-methoxybenzyl) piperazin-2-yl) acetic acid

To 2- (1- (2-chloro-7- (naphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3, 4-d)]To a solution of methyl pyrimidin-4-yl) -5- (cyanomethyl) -4- (4-methoxybenzyl) piperazin-2-yl) acetate (1.3 g,2.13 mmol) in THF (20 mL) and MeOH (20 mL) was added a solution of lithium hydroxide hydrate (0.27 g,6.38 mmol) in water (10 mL). The mixture was stirred at room temperature for 2 hours. The solvent was removed under vacuum. The residue was acidified with 1N aqueous HCl and extracted with EtOAc (2×20 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ Dried, and concentrated to dryness to give 2- (1- (2-chloro-7- (naphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3, 4-d) as a yellow solid]Pyrimidin-4-yl) -5- (cyanomethyl) -4- (4-methoxybenzyl) piperazin-2-yl) acetic acid (1.15 g,91% yield). MS (ESI) M/z 597 (M+H) ⁺ 。

Step 20: n- (3-azido-2-hydroxypropyl) -2- (1- (2-chloro-7- (naphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -5- (cyanomethyl) -4- (4-methoxybenzyl) piperazin-2-yl) -N-methylacetamide

To 2- (1- (2-chloro-7- (naphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3, 4-d)]To a mixture of pyrimidin-4-yl) -5- (cyanomethyl) -4- (4-methoxybenzyl) piperazin-2-yl) acetic acid (1.15 g,1.93 mmol) and DIPEA (1.32 mL,7.70 mmol) in DMF (10 mL) was added EDCI (0.74 g,3.85 mmol) and HOBt (0.52 g,3.85 mmol), followed by 1-azido-3- (methylamino) propan-2-ol hydrochloride (0.32 g,1.93 mmol) and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc (30 mL), washed with water and brine, and dried over Na ₂ SO ₄ Dried, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (eluting with PE: etoac=10:1 to 1:1) to give N- (3-azido-2-hydroxypropyl) -2- (1- (2-chloro-7- (naphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3, 4-d) as a yellow solid]Pyrimidin-4-yl) -5- (cyanomethyl) -4- (4-methoxybenzyl) piperazin-2-yl) -N-methylacetamide (720 mg,59% yield). MS (ESI) M/z 709 (M+H) ⁺ 。

Step 21:2- (8- (azidomethyl) -14- (4-methoxybenzyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1,3,7,11] oxatriazatrideca-15-yl) acetonitrile

At N ₂ To N- (3-azido-2-hydroxypropyl) -2- (1- (2-chloro-7- (naphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3, 4-d) under an atmosphere]Pyrimidin-4-yl) -5- (cyanomethyl) -4- (4-methoxybenzyl) piperazin-2-yl) -N-methylacetamide (600 mg,0.85 mmol) and Cs ₂ CO ₃ (552 mg,1.69 mmol) to a mixture of toluene (48 mL) was added Pd (OAc) ₂ (38 mg,0.17 mmol) and BINAP (53 mg,0.085 mmol). The mixture was degassed three times under an N2 atmosphere and then cooled under N ₂ Stirring is carried out for 16 hours at 100℃under an atmosphere. The mixture was diluted with EtOAc (20 mL), washed with water and brine, and dried over Na ₂ SO ₄ Dried, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (eluting with PE: etoac=40:60 to 15:85) to give 2- (8- (azidomethyl) -14- (4-methoxybenzyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoidene) pyrazino [1, 2-g) as a yellow solid]Pyrido [3,4-d][1,3,7,11]Oxatriazacyclotridec, cat-15-yl) acetonitrile (150 mg,26% yield). MS (ESI) M/z 673 (M+H) ⁺ 。

Step 22:2- (8- (aminomethyl) -14- (4-methoxybenzyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminosubunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1,3,7,11] oxatriazatridec-en-15-yl) acetonitrile

To 2- (8- (azidomethyl) -14- (4-methoxybenzyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (amino subunit) pyrazino [1,2-g]Pyrido [3,4-d][1,3,7,11]To a solution of oxatriazacyclotridecarbon-15-yl) acetonitrile (170 mg,0.25 mmol) in THF (8 mL) and water (1 mL) was added triphenylphosphine (132 mg,0.50 mmol) and the mixture was taken up in N ₂ Stirring is carried out for 2 hours at 50℃under an atmosphere. The resulting mixture was concentrated to dryness to give 2- (8- (aminomethyl) -14- (4-methoxybenzyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminosubunit) pyrazino [1,2-g ] as a yellow solid]Pyrido [3,4-d][1,3,7,11]Oxatriazacyclotridec-15-yl) acetonitrile (290 mg,100% yield), the product was used directly in the next step. MS (ESI) M/z 647 (M+H) ⁺ 。

Step 23:2- (8- ((dimethylamino) methyl) -14- (4-methoxybenzyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1,3,7,11] oxatriazatridec-an-15-yl) acetonitrile

To 2- (8- (aminomethyl) -14- (4-methoxybenzyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminosubunit) pyrazino [1,2-g at 0 ℃C ]Pyrido [3,4-d][1,3,7,11]To a solution of oxatriazacyclotridecarbon (290 mg,0.25 mmol) in MeOH (5 mL) was added para-HCHO (94 mg,1.16 mmol) followed by NaBH ₃ CN (29 mg,0.46 mmol) and the mixture was stirred at room temperature for 16 hours. Mixing the reactionSaturated NaHCO for the compound ₃ The aqueous solution was quenched and extracted with DCM (2X 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ Dried, and concentrated to dryness. The residue was purified by silica gel chromatography (eluting with DCM: meoh=100:1 to 93:7) to give 2- (8- ((dimethylamino) methyl) -14- (4-methoxybenzyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminoidene) pyrazino [1, 2-g) as a yellow solid]Pyrido [3,4-d][1,3,7,11]Oxatriazacyclotridec-15-yl) acetonitrile (120 mg,76% yield). MS (ESI) M/z 675 (M+H) ⁺ 。

Step 24:2- (8- ((dimethylamino) methyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1,3,7,11] oxatriazatridecan-15-yl) acetonitrile

To 2- (8- ((dimethylamino) methyl) -14- (4-methoxybenzyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminoiden) pyrazino [1,2-g at 0 ] ]Pyrido [3,4-d][1,3,7,11]A mixture of oxatriazacyclotridecarbon-15-yl) acetonitrile (120 mg,0.18 mmol) in TFA (1 mL) was added anisole (0.1 mL,0.84 mmol) and the mixture was stirred at 50℃for 16 h. The mixture was concentrated to dryness in vacuo and the residue was taken up in saturated NaHCO ₃ The aqueous solution was basified and extracted with DCM (2X 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to dryness. The residue was dissolved in MeOH (3 mL) and purified under N ₂ Pd/C (25 mg,10% wt) was added under an atmosphere. The mixture is put under N ₂ Degassing three times under atmosphere and under H ₂ Stirred under balloon at room temperature for 2 hours. The mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by flash chromatography on silica gel (eluting with DCM: meoh=10:1) to give 2- (8-) -as a yellow solid((dimethylamino) methyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (amino subunit) pyrazino [1,2-g]Pyrido [3,4-d][1,3,7,11]Oxatriazacyclotridec, cat-15-yl) acetonitrile (60 mg,60% yield). MS (ESI) M/z 555 (M+H) ⁺ 。

Step 25:2- (14-propenoyl-8- ((dimethylamino) methyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1,3,7,11] oxatriazatridec-n-15-yl) acetonitrile

To 2- (8- ((dimethylamino) methyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (amino subunit) pyrazino [1,2-g ] at 0 ℃C]Pyrido [3,4-d][1,3,7,11]Oxatriazacyclotridecarbon (60 mg,0.11 mmol) in DCM (4 mL) was added TEA (0.06 mL,0.43 mmol) followed by prop-2-enoyl chloride (0.017 mL,0.22 mmol) and the reaction mixture stirred at 0deg.C for 2 h. The mixture was diluted with water and extracted with DCM (2×5 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to dryness. The residue was purified by flash column chromatography (silica gel, DCM: meoh=10/1) and further purified by preparative HPLC to give 2- (14-propenoyl-8- ((dimethylamino) methyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (amino subunit) pyrazino [1,2-g]Pyrido [3,4-d][1,3,7,11]Oxatriazacyclotridecarbon, cat-15-yl) acetonitrile (10 mg,15% yield).

¹ H NMR(400MHz,CDCl ₃ )δ8.27-8.13(m,1H),7.89-7.80(m,1H),7.64-7.56(m,1H),7.56-7.46(m,2H),7.46-7.37(m,1H),7.17-7.07(m,1H),6.80-6.61(m,1H),6.47-6.35(m,1H),5.97-5.76(m,2H),5.11-4.72(m,1H),4.49-4.08(m,5H),3.76-3.32(m,4H),3.15-2.94(m,3H),2.81-2.51(m,8H),2.47-2.32(m,6H),1.91-1.75(m,2H)。MS(ESI)m/z:609(M+H) ⁺ 。

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

Compound 25:

¹ H NMR(400MHz,CDCl ₃ )δ8.25–8.10(m,1H),7.93–7.81(m,1H),7.61(d,J＝8.0Hz,1H),7.55–7.46(m,2H),7.43(t,J＝7.6Hz,1H),7.16–7.05(m,1H),6.78–6.57(m,1H),6.48–6.31(m,1H),5.90–5.74(m,1H),5.60–4.81(m,2H),4.73–3.90(m,6H),3.84–3.51(m,3H),3.48–3.08(m,4H),3.04–2.65(m,7H),2.59–2.31(m,8H),1.97–1.58(m,4H)。

compound 27:

¹ H NMR(400MHz,CD ₃ OD)δ8.24–8.21(m,1H),7.90–7.81(m,1H),7.61(d,J＝8.0Hz,1H),7.51–7.38(m,3H),7.21(d,J＝7.0Hz,1H),6.90(s,1H),6.35–6.25(m,1H),5.88–5.83(m,1H),5.69(s,1H),4.22–4.10(m,5H),3.71(m,3H),3.48(s,2H),3.24–2.86(m,6H),2.82–2.43(m,10H),2.10-2.00(m,1H),1.95–1.65(m,6H)。

compound 28:

¹ H NMR(400MHz,CD ₃ OD)δ8.22(d,J＝4.6Hz,1H),7.85(dd,J＝6.9,2.5Hz,1H),7.60(d,J＝8.2Hz,1H),7.53–7.45(m,2H),7.42(m,1H),7.19(d,J＝7.3Hz,1H),6.98–6.74(m,1H),6.34-6.31(m,1H),5.85-5.82(m,1H),5.61–5.17(m,1H),4.53(m,1H),4.27(m,1H),4.22–4.02(m,3H),3.96–3.73(m,2H),3.61–3.39(m,2H),3.26(s,3H),3.12(m,1H),3.05–2.90(m,3H),2.86(m,1H),2.79(m,1H),2.76–2.66(m,2H),2.65–2.55(m,1H),2.50(m,1H),2.40–2.23(m,7H),2.07–1.80(m,2H)。

compound 29:

¹ HNMR(400MHz,CDCl ₃ )δ8.22–8.20(m,1H),7.88–7.83(m,1H),7.61(d,J＝8.3Hz,1H),7.51–7.40(m,3H),7.21(d,J＝7.9Hz,1H),6.95-6.92(m,1H),6.33(d,J＝15.3Hz,1H),5.87(d,J＝9.4Hz,1H),5.35-5.33(m,1H),4.58(s,2H),4.23-4.18(m,3H),3.70-3.63(m,2H),3.22–3.07(m,4H),2.99-2.94(m,1H),2.79-2.76(m,5H),2.59-2.53(m,1H),2.33(s,6H),2.19(m,1H),2.12–1.92(m,4H),1.87-1.85(m,1H),1.63-1.60(m,1H)。

Compound 30:

¹ HNMR(400MHz,CD ₃ OD)δ8.24-8.22(m,1H),7.88-7.85(m,1H),7.62(d,J＝8.2Hz,1H),7.53–7.39(m,3H),7.21(d,J＝7.4Hz,1H),6.93-6.90(m,1H),6.37-6.35(m,1H),5.97-5.87(m,2H),4.48-4.08(m,7H),3.86-3.31(m,4H),3.17-2.89(m,7H),2.79-2.72(m,9H),2.21-1.93(m,2H)。

compound 31:

¹ HNMR(400MHz,CD ₃ OD)δ8.24-8.16(m,1H),7.91-7.79(m,1H),7.61(d,J＝8.2Hz,1H),7.51-7.39(m,3H),7.21-7.19(m,1H),7.03-6.80(m,1H),6.35-6.31(m,1H),5.91-5.81(m,1H),5.60-5.57(m,1H),4.71-4.63(m,2H),4.42-4.34(m,1H),4.19-4.10(m,4H),3.94-3.91(m,1H),3.69-3.37(m,4H),3.31-2.92(m,6H),2.73-2.63(m,3H),2.02-1.98(m,1H)。

compound 32:

¹ HNMR(400MHz,CD ₃ OH)δ8.53-8.51(m,1H),8.23-8.21(m,1H),7.85-7.83(m,1H),7.63–7.59(m,1H),7.52–7.47(m,3H),7.22-7.20(m,1H),6.35-6.31(m,1H),5.97-5.77(m,2H),5.17-5.15(m,1H),4.57(s,2H),4.27-4.20(4H),3.47(s,2H),3.15-3.13(m,4H),2.85-2.74(m,9H),2.04-2.01(m,1H),1.73-1.69(m,5H),1.57-1.55(m,3H),1.32-1.28(m,2H)。

compound 33:

¹ H NMR(400MHz,CDCl ₃ ) ¹ H NMR(400MHz,MeOD)δ8.46(s,1H),8.16(s,1H),7.85(s,1H),7.59(d,J＝8.1Hz,1H),7.51–7.37(m,3H),7.19(d,J＝7.0Hz,1H),6.90(dd,J＝17.0,10.5Hz,1H),6.31(d,J＝16.8Hz,1H),5.84(d,J＝10.2Hz,1H),5.49(s,1H),4.18(ddd,J＝85.5,78.7,69.2Hz,7H),3.52(d,J＝92.3Hz,4H),3.22–2.84(m,7H),2.69(t,J＝23.1Hz,9H),2.02(d,J＝71.1Hz,2H)。

compound 34:

¹ HNMR(400MHz,DMSO-d ₆ )δ8.15-8.14(m,1H),7.95-7.93(m,1H),7.66(d,J＝8.2Hz,1H),7.60–7.51(m,2H),7.47-7.45(m,1H),7.24(d,J＝7.4Hz,1H),6.97(m,1H),6.28-6.26(m,1H),5.88-5.86(m,1H),5.03(s,1H),4.89–4.55(m,1H),4.46–4.20(m,2H),4.20–4.10(m,3H),3.96–3.84(m,1H),3.67(d,J＝13.9Hz,1H),3.60–3.44(m,2H),3.24-3.16(m,3H),3.03(m,2H),2.87(s,3H),2.65-2.60(m,2H),2.09-2.07(m,2H)。

compound 35:

¹ HNMR(400MHz,CD ₃ OD)δ7.30–7.22(m,2H),7.09–6.78(m,4H),6.43–6.24(m,1H),5.91–5.81(m,1H),5.12–4.92(m,1H),4.80–4.63(m,1H),4.61–4.47(m,1H),4.46–3.85(m,7H),3.82–3.69(m,1H),3.67–3.52(m,1H),3.44–3.33(m,1H),3.25–3.04(m,4H),2.98(s,3H),2.83–2.62(m,2H),2.27-2.24(m,1H)。

compound 36:

¹ H NMR(400MHz,CD ₃ OD)δ8.22-8.20(m,1H),7.92–7.82(m,1H),7.61(d,J＝8.3Hz,1H),7.52–7.39(m,3H),7.23-7.21(m,1H),7.10-6.81(m,1H),6.36-6.34(m,1H),5.89-5.87(m,1H),5.12(m,1H),4.60-4.53(m,1H),4.43–3.91(m,5H),3.79(m,4H),3.16(m,6H),2.97–2.55(m,6H),2.50–2.32(m,6H),2.05-2.00(m,1H)。

compound 37:

¹ H NMR(400MHz,DMSO-d ₆ )δ8.24–8.08(m,1H),7.93(m,1H),7.65(d,J＝8.2Hz,1H),7.59–7.51(m,2H),7.47(t,J＝7.8Hz,1H),7.23(d,J＝7.4Hz,1H),6.96(m,1H),6.26(m,1H),5.89–5.77(m,1H),5.02(s,1H),4.61(m,1H),4.36(m,1H),4.30–4.20(m,1H),4.19–4.10(m,3H),3.95–3.68(m,2H),3.55(m,3H),3.25–3.11(m,3H),3.03(m,2H),2.86(s,3H),2.64(m,2H),2.05(m,1H)。

compound 38:

¹ H NMR(400MHz,DMSO-d ₆ )δ8.21–8.12(m,1H),7.94(dd,J＝6.0,2.4Hz,1H),7.66(d,J＝8.4Hz,1H),7.61–7.51(m,2H),7.51–7.42(m,1H),7.26–7.14(m,1H),7.05–6.59(m,1H),6.31–6.03(m,1H),5.87–5.64(m,1H),4.99–4.56(m,2H),4.54–4.42(m,1H),4.41–4.17(m,2H),4.17–3.66(m,5H),3.64–3.50(m,2H),3.19–2.92(m,4H),2.89–2.63(m,4H),2.46–2.37(m,1H),2.33–2.11(m,7H),1.88–1.65(m,1H),1.50–1.19(m,1H)。

compound 39a:

¹ H NMR(400MHz,DMSO-d ₆ )δ8.21–8.11(m,1H),7.97–7.89(m,1H),7.65(d,J＝8.4Hz,1H),7.58–7.50(m,2H),7.46(t,J＝7.6Hz,1H),7.26–7.16(m,1H),6.97–6.61(m,1H),6.23–6.02(m,1H),5.83–5.63(m,1H),5.04–4.67(m,1H),4.63–4.36(m,2H),4.32–3.91(m,6H),3.88–3.72(m,1H),3.64–3.43(m,1H),3.23–3.00(m,4H),2.69(s,3H),2.35–1.64(m,4H),1.63–1.27(m,1H)。

compound 39b:

¹ H NMR(400MHz,DMSO-d ₆ )δ8.23–8.11(m,1H),7.97–7.88(m,1H),7.64(d,J＝7.6Hz,1H),7.58–7.50(m,2H),7.49–7.42(m,1H),7.19(t,J＝8.4Hz,1H),6.99–6.85(m,1H),6.30–6.14(m,1H),5.87–5.70(m,1H),4.85–3.78(m,10H),3.65–3.46(m,1H),3.14–2.88(m,4H),2.76(s,3H),2.25–1.93(m,3H),1.92–1.69(m,1H),1.59–1.32(m,1H)。MS(ESI)m/z:552(M+H) ⁺ 。

compound 40:

¹ H NMR(400MHz,CD ₃ OD)δ8.27–8.16(m,1H),7.89–7.81(m,1H),7.61(d,J＝8.0Hz,1H),7.52–7.46(m,2H),7.43(t,J＝7.6Hz,1H),7.20(d,J＝7.2Hz,1H),7.10–6.86(m,1H),6.40–6.30(m,1H),5.88(d,J＝10.4Hz,1H),5.18–4.96(m,1H),4.81–4.62(m,2H),4.59–4.46(m,1H),4.46–4.31(m,2H),4.26–4.06(m,5H),4.01–3.90(m,1H),3.85–3.72(m,2H),3.71–3.60(m,2H),3.46–3.37(m,1H),3.22–3.06(m,6H),2.83–2.74(m,1H),2.51–2.34(m,6H),1.64–1.55(m,3H),1.48–1.42(m,1H)。

compound 41:

¹ H NMR(400MHz,CD ₃ OD)δ8.22(d,J＝6.9Hz,1H),7.89–7.83(m,1H),7.61(d,J＝8.3Hz,1H),7.49(dd,J＝5.9,3.6Hz,2H),7.43(t,J＝7.8Hz,1H),7.20(d,J＝7.3Hz,1H),6.95(d,J＝39.2Hz,1H),6.40–6.30(m,1H),5.88(d,J＝10.5Hz,1H),5.12(s,2H),4.55(d,J＝11.0Hz,2H),4.33–3.89(m,6H),3.72(dd,J＝23.9,18.6Hz,2H),3.37(s,2H),3.14(ddd,J＝38.4,21.1,11.1Hz,5H),2.91–2.65(m,7H),2.40(dd,J＝24.0,15.5Hz,1H),2.05(d,J＝27.4Hz,2H),1.90(d,J＝28.5Hz,3H)。

compound 42:

¹ H NMR(400MHz,CD ₃ OD)δ8.22(d,J＝3.3Hz,1H),7.89–7.82(m,1H),7.61(d,J＝8.3Hz,1H),7.53–7.40(m,3H),7.24–7.15(m,1H),7.08–6.85(m,1H),6.36(dd,J＝16.0,7.3Hz,1H),5.84(t,J＝34.0Hz,1H),5.06(d,J＝48.1Hz,1H),4.53(d,J＝11.7Hz,1H),4.40–3.90(m,6H),3.84–3.59(m,3H),3.52–3.36(m,1H),3.27–3.07(m,6H),2.88(d,J＝21.3Hz,4H),2.80–2.59(m,4H),2.49–2.32(m,1H),1.84(s,1H),1.63(s,3H),1.48(s,1H),1.29(s,1H)。

compound 43:

¹ H NMR(400MHz,CD ₃ OD)δ8.21(d,J＝6.2Hz,1H),7.89–7.82(m,1H),7.61(d,J＝8.3Hz,1H),7.51–7.46(m,2H),7.43(t,J＝7.8Hz,1H),7.20(m,1H),6.90(m,1H),6.41–6.30(m,1H),5.93–5.83(m,1H),5.62-5.55(m,1H),5.11(m,1H),4.68–4.44(m,2H),4.33–3.96(m,5H),3.70-3.64(m,2H),3.50-3.47(m,1H),3.27–2.94(m,6H),2.89(s,2H),2.80–2.40(m,11H),2.28(m,3H),2.10(m,1H)。

compound 44:

¹ H NMR(400MHz,CD ₃ OD)δ8.28–8.15(m,1H),7.86(m,1H),7.61(d,J＝8.3Hz,1H),7.51–7.41(m,3H),7.20(d,J＝7.1Hz,1H),7.03(m,1H),6.43–6.26(m,1H),5.88(m,1H),5.11(m,1H),4.80–4.44(m,3H),4.41–3.95(m,6H),3.79–3.37(m,6H),3.21–2.94(m,8H),2.88(s,2H),2.84–2.72(m,2H),2.64(s,1H),2.52–2.25(m,1H),2.20(m,2H),2.13(s,3H)。

compound 45:

¹ H NMR(400MHz,CD ₃ OD)δ8.21(d,J＝5.1Hz,1H),7.90–7.82(m,1H),7.61(d,J＝8.2Hz,1H),7.51–7.47(m,2H),7.43(t,J＝7.8Hz,1H),7.20(d,J＝7.3Hz,1H),7.08–6.85(m,1H),6.41–6.30(m,1H),5.93–5.82(m,1H),5.46(t,J＝39.4Hz,1H),5.04(d,J＝51.6Hz,1H),4.69–4.48(m,2H),4.28–4.07(m,4H),3.98(d,J＝11.9Hz,2H),3.85–3.40(m,3H),3.25–3.15(m,1H),3.12(d,J＝10.4Hz,2H),3.06–2.92(m,3H),2.89(s,1H),2.69(d,J＝9.5Hz,3H),2.61–2.52(m,6H),2.48(s,1H),2.22–2.02(m,3H),2.01–1.89(m,2H),1.65–1.49(m,3H),1.38–1.27(m,1H)。

compound 48a:

¹ H NMR(400MHz,MeOD)δ8.21(dd,J＝6.5,3.3Hz,1H),7.86(dd,J＝6.5,2.9Hz,1H),7.61(d,J＝8.1Hz,1H),7.52–7.39(m,3H),7.20(d,J＝7.0Hz,1H),7.03(dd,J＝17.0,10.6Hz,1H),6.35(dd,J＝17.3,8.9Hz,1H),5.89(dd,J＝10.5,1.6Hz,1H),5.10(s,1H),4.94(d,J＝7.5Hz,1H),4.61(d,J＝11.1Hz,1H),4.51(d,J＝14.4Hz,1H),4.44–4.07(m,5H),3.86–3.34(m,9H),3.24–3.05(m,4H),2.94–2.74(m,4H),2.52–2.31(m,6H),2.04(dd,J＝14.1,6.7Hz,2H)。

compound 48b:

¹ H NMR(400MHz,MeOD)δ8.25–8.18(m,1H),7.86(dd,J＝6.3,2.9Hz,1H),7.61(d,J＝8.1Hz,1H),7.53–7.46(m,2H),7.43(t,J＝7.8Hz,1H),7.23–7.17(m,1H),6.90(dd,J＝16.9,10.7Hz,1H),6.34(dd,J＝16.8,1.6Hz,1H),5.88(dd,J＝10.7,1.6Hz,1H),5.53(d,J＝11.5Hz,1H),5.10(d,J＝82.9Hz,1H),4.65–4.45(m,2H),4.08(dd,J＝59.0,41.3,14.8Hz,6H),3.77–3.69(m,4H),3.48(d,J＝1.2Hz,3H),3.12(d,J＝9.8Hz,5H),2.64(t,J＝24.8Hz,9H),2.41(s,1H),2.05(dd,J＝14.7,8.2Hz,2H)。

compound 49a:

¹ H NMR(400MHz,MeOD)δ8.38(s,1H),8.21(dd,J＝6.3,3.0Hz,1H),7.86(dd,J＝6.2,3.2Hz,1H),7.62(d,J＝8.2Hz,1H),7.53–7.39(m,3H),7.20(d,J＝7.0Hz,1H),6.90(dd,J＝16.6,10.6Hz,1H),6.35(dd,J＝16.7,1.7Hz,1H),5.88(dd,J＝10.6,1.7Hz,1H),5.52(d,J＝9.1Hz,1H),5.05(d,J＝57.6Hz,2H),4.55(d,J＝6.8Hz,2H),4.03(dt,J＝64.7,34.3Hz,8H),3.14(d,J＝5.9Hz,9H),2.95–2.57(m,5H),2.38–2.02(m,3H),1.87(s,4H),1.68(s,2H)。

compound 49b:

¹ H NMR(400MHz,MeOD)δ8.24–8.16(m,1H),7.86(dd,J＝6.4,2.9Hz,1H),7.61(d,J＝8.2Hz,1H),7.55–7.37(m,3H),7.19(d,J＝7.5Hz,1H),7.00(d,J＝10.6Hz,1H),6.35(dd,J＝15.9,8.0Hz,1H),5.93–5.83(m,1H),5.11(s,2H),4.77(d,J＝5.5Hz,1H),4.56(dd,J＝36.6,12.3Hz,2H),4.35–3.89(m,5H),3.82–3.35(m,5H),3.15(dd,J＝31.4,20.9,9.9Hz,8H),2.91(s,3H),2.83–2.54(m,2H),2.37–2.23(m,2H),1.84(s,4H),1.66(s,2H)。

compound 50:

¹ H NMR(400MHz,CD ₃ OD)δ8.21(d,J＝4.9Hz,1H),7.90–7.80(m,1H),7.61(d,J＝8.2Hz,1H),7.46(ddd,J＝26.1,9.9,5.1Hz,3H),7.20(d,J＝7.4Hz,1H),6.97(ddd,J＝53.6,16.7,10.6Hz,1H),6.41–6.27(m,1H),5.88(dd,J＝10.6,1.8Hz,1H),5.30(d,J＝156.3Hz,1H),4.62–4.49(m,2H),4.37–3.86(m,6H),3.80–3.42(m,3H),3.27–2.98(m,6H),2.90(s,2H),2.66(s,2H),2.49(d,J＝13.1Hz,2H),2.30(s,3H),2.24(s,3H)。

compound 51:

¹ H NMR(400MHz,CD ₃ OD)δ8.25–8.17(m,1H),7.86(d,J＝6.6Hz,1H),7.61(d,J＝8.1Hz,1H),7.52–7.40(m,3H),7.20(d,J＝7.2Hz,1H),6.42–6.28(m,1H),5.91–5.84(m,1H),5.40(d,J＝45.9Hz,1H),5.05(d,J＝48.3Hz,1H),4.68(s,1H),4.62–4.40(m,2H),4.40–4.26(m,1H),4.25–4.11(m,3H),4.10(d,J＝8.2Hz,1H),3.98(d,J＝12.3Hz,2H),3.81–3.46(m,3H),3.41–3.33(m,3H),3.24–3.16(m,2H),3.16–3.07(m,2H),3.05–2.93(m,2H),2.91–2.74(m,3H),2.66(d,J＝25.0Hz,2H),2.48–2.24(m,1H),2.23–2.05(m,3H)。

compound 52:

¹ H NMR(400MHz,CD ₃ OD)δ8.23–8.12(m,1H),7.87–7.79(m,1H),7.59(d,J＝8.2Hz,1H),7.50–7.38(m,3H),7.17(d,J＝7.3Hz,1H),6.96(ddd,J＝50.2,16.6,10.6Hz,1H),6.36(d,J＝16.8Hz,1H),5.88(d,J＝10.6Hz,1H),5.53(t,J＝11.8Hz,1H),5.02(s,1H),4.69–4.56(m,1H),4.39(dd,J＝43.2,11.1Hz,1H),4.23–4.08(m,3H),4.06–3.79(m,3H),3.75–3.46(m,3H),3.28–3.00(m,6H),2.93(dd,J＝23.9,9.5Hz,2H),2.52(ddd,J＝33.4,27.6,20.5Hz,10H),2.32(d,J＝28.6Hz,3H),2.23–2.13(m,1H)。

compound 53:

¹ H NMR(400MHz,CD ₃ OD)δ8.47(s,1H),7.89–7.84(m,1H),7.62(d,J＝8.4Hz,1H),7.51–7.47(m,2H),7.43(t,J＝7.6Hz,1H),7.37–7.27(m,1H),7.20(d,J＝7.2Hz,1H),7.09–6.86(m,1H),6.41–6.31(m,1H),5.93–5.83(m,1H),5.15–5.02(m,1H),4.71–4.65(m,1H),4.46–4.30(m,2H),4.29–4.04(m,5H),3.87–3.75(m,2H),3.70–3.60(m,2H),3.49–3.41(m,3H),3.24–3.16(m,3H),3.14–3.11(m,1H),3.10–3.07(m,1H),3.03–2.99(m,1H),2.97–2.89(m,2H),2.82(s,3H),2.36–2.23(m,1H),2.12–1.98(m,2H),1.63–1.41(m,5H)。

compound 54:

¹ H NMR(400MHz,CD ₃ OD)δ8.26–8.15(m,1H),7.90–7.82(m,1H),7.61(d,J＝8.4Hz,1H),7.52–7.47(m,2H),7.45–7.40(m,1H),7.23–7.17(m,1H),7.09–6.87(m,1H),6.36(d,J＝17.1Hz,1H),5.97–5.77(m,1H),5.59(t,J＝11.9Hz,1H),5.22–4.94(m,1H),4.75–4.32(m,4H),4.28–4.04(m,5H),4.00–3.90(m,1H),3.84–3.55(m,5H),3.45–3.37(m,1H),3.23–3.06(m,6H),2.83–2.71(m,3H),2.51–2.44(m,3H),2.42–2.24(m,4H),1.95–1.45(m,3H)。

compound 55:

¹ H NMR(400MHz,CD ₃ OD)δ8.21(dd,J＝6.7,2.8Hz,1H),7.88–7.84(m,1H),7.61(d,J＝8.2Hz,1H),7.51–7.41(m,3H),7.21(t,J＝6.2Hz,1H),7.08–6.87(m,1H),6.39–6.33(m,1H),5.90–5.86(m,1H),5.08(s,1H),4.72–4.65(m,1H),4.53–4.34(m,2H),4.27–3.93(m,5H),3.81–3.59(m,4H),3.48–3.36(m,3H),3.26–3.06(m,5H),3.03–2.91(m,3H),2.83–2.76(m,3H),2.69(s,1H),2.31–2.25(m,1H),2.02–1.84(m,2H),1.71–1.56(m,2H),1.50–1.30(m,4H),1.25–1.17(m,1H)。

compound 56:

¹ H NMR(400MHz,MeOD)δ8.21-8.19(m,1H),δ7.87-7.85(m,1H),7.63-7.60(m,1H),7.50-7.33(m,3H),7.24-7.20(m,1H),7.11-6.80(m,1H),6.36-6.32(m,1H),5.87(m,1H),5.35-5.32(m,2H),4.58-4.56(m,2H),4.23-4.16(m,2H),3.79–3.71(m,2H),3.58–3.46(m,2H),3.17-3.03(m,7H),2.97-2.82(m,5H),2.05-2.01(m,1H),1.65-1.76(m,4H),1.61-1.50(m,2H),1.33-1.28(m,6H)。

compound 57:

¹ H NMR(400MHz,CD ₃ OD)δ7.81(t,J＝8.3Hz,1H),7.71–7.64(m,1H),7.54–7.48(m,2H),7.46–7.29(m,2H),7.09–6.83(m,1H),6.35–6.29(m,1H),5.93–5.85(m,1H),5.15(s,1H),4.74–4.46(m,2H),4.44–4.16(m,4H),4.12–3.90(m,2H),3.82–3.45(m,4H),3.25–3.04(m,5H),3.01–2.79(m,3H),2.67(d,J＝12.8Hz,1H),2.34–1.97(m,1H)。

compound 58:

¹ H NMR(400MHz,MeOD)δ8.34(s,1H),8.21(s,1H),7.89–7.83(m,1H),7.62(d,J＝8.0Hz,1H),7.49(dd,J＝6.1,3.3Hz,2H),7.43(t,J＝7.9Hz,1H),7.20(d,J＝5.3Hz,1H),6.99(dd,J＝38.2,28.0Hz,1H),6.36(dd,J＝16.5,7.9Hz,1H),5.89(d,J＝10.5Hz,1H),5.34(d,J＝4.6Hz,1H),5.11(s,1H),4.63(d,J＝11.3Hz,1H),4.54(s,1H),4.34(s,1H),4.17(dd,J＝35.2,20.7Hz,4H),3.79(s,1H),3.24–3.17(m,3H),3.14–3.00(m,4H),2.91(d,J＝4.8Hz,3H),2.88(s,2H),2.83(s,3H),2.79(s,1H),2.76–2.71(m,1H),2.65(s,1H),2.21–2.16(m,1H),2.03(d,J＝5.5Hz,1H),1.60(s,1H),1.37(d,J＝6.6Hz,1H),0.90(s,1H)。

compound 59:

¹ H NMR(400MHz,MeOD)δ8.12(m,1H),δ7.76(m,1H),7.53(m,1H),7.38–7.32(m,3H),7.13–7.11(m,1H),6.86-6.84(m,1H),6.23(d,J＝16.8Hz,1H),5.78(d,J＝8.0Hz,1H),4.49-4.41(m,1H),4.23-3.99(m,3H),3.84–3.81(m,1H),3.80-3.54(m,3H),3.53-3.27(m,4H),3.20–2.55(m,11H),2.12–1.85(m,3H)，1.85-1.55(m,6H)，1.54–1.39(m,1H)，1.23-1.20(m,3H)。

compound 60:

¹ H NMR(400MHz,CD ₃ OD)δ8.22(m,1H),7.86(m,1H),7.61(d,J＝8.3Hz,1H),7.52–7.40(m,3H),7.20(m,1H),7.02–6.75(m,1H),6.42–6.25(m,1H),5.89-5.87(m,1H),5.08(m,1H),4.53-4.49(m,1H),4.29–3.96(m,4H),3.88–3.57(m,4H),3.26–2.98(m,8H),2.92–2.63(m,5H),2.52–2.26(m,6H),2.07–1.75(m,2H),1.43–1.25(m,1H)。MS(ESI)m/z:623(M+H) ⁺ 。

compound 61:

¹ H NMR(400MHz,CD ₃ OD)δ8.22(s,1H),7.86(dd,J＝6.7,2.6Hz,1H),7.61(d,J＝8.2Hz,1H),7.46(ddd,J＝15.6,7.5,3.1Hz,3H),7.21(dd,J＝7.0,3.3Hz,1H),7.01–6.68(m,1H),6.34(d,J＝16.6Hz,1H),5.87(d,J＝10.5Hz,1H),5.06(s,1H),4.59(s,1H),4.43–3.89(m,5H),3.70(dd,J＝82.0,55.6Hz,4H),3.12(dt,J＝41.6,20.9Hz,7H),2.83(dd,J＝26.1,16.2Hz,4H),2.57–2.07(m,6H),1.90–1.29(m,10H)。

compound 62:

¹ H NMR(400MHz,CD ₃ OD)δ8.28–8.18(m,1H),7.91–7.81(m,1H),7.61(d,J＝8.0Hz,1H),7.53–7.39(m,3H),7.25–7.16(m,1H),7.08–6.75(m,1H),6.42–6.27(m,1H),5.92–5.83(m,1H),5.29–4.95(m,1H),4.63–4.47(m,1H),4.40–3.92(m,5H),3.86–3.40(m,4H),3.27–3.01(m,9H),2.95–2.88(m,1H),2.85–2.74(m,2H),2.71–2.48(m,8H),2.36–2.08(m,3H),1.99–1.90(m,2H),1.69–1.55(m,2H),1.35–1.26(m,1H)。

compound 64:

¹ H NMR(400MHz,MeOD)δ8.21(d,J＝6.5Hz,1H),7.86(d,J＝6.1Hz,1H),7.62(dd,J＝8.1,2.9Hz,1H),7.49(dd,J＝5.8,3.7Hz,2H),7.43(t,J＝7.7Hz,1H),7.23–7.17(m,1H),7.08–6.79(m,1H),6.35(dd,J＝15.9,10.5Hz,1H),5.89(d,J＝10.6Hz,1H),5.03(d,J＝63.9Hz,1H),4.65–4.46(m,2H),4.43–3.99(m,5H),3.99–3.55(m,3H),3.40(s,1H),3.27–3.02(m,5H),2.94–2.19(m,18H),2.01(d,J＝6.6Hz,2H)。

compound 65:

¹ H NMR(400MHz,MeOD)δ8.21(d,J＝6.0Hz,1H),7.85(s,1H),7.61(d,J＝8.1Hz,1H),7.51–7.38(m,3H),7.20(d,J＝7.2Hz,1H),6.98(dd,J＝39.2,28.6Hz,1H),6.36(dd,J＝16.0,9.5Hz,1H),5.89(d,J＝10.1Hz,1H),5.11(s,1H),4.79–4.71(m,1H),4.56(dd,J＝30.0,13.1Hz,2H),4.36–4.04(m,5H),3.95–3.58(m,5H),3.43(d,J＝39.3Hz,2H),3.23(dd,J＝16.6,8.8Hz,4H),3.15–3.04(m,3H),2.88(s,2H),2.71(dd,J＝41.7,26.3Hz,3H),2.37–2.10(m,7H),1.95(s,2H)。

compound 66:

¹ H NMR(400MHz,CD ₃ OD)δ8.27–8.17(m,1H),7.90–7.83(m,1H),7.64–7.59(m,1H),7.52–7.46(m,2H),7.46–7.41(m,1H),7.25–7.18(m,1H),7.02–6.76(m,1H),6.38–6.30(m,1H),5.88(d,J＝10.3Hz,1H),5.66–5.00(m,1H),4.27–4.09(m,4H),3.81–3.64(m,3H),3.53–3.45(m,2H),3.14–3.08(m,3H),2.83–2.76(m,3H),2.21–2.14(m,2H),2.05–2.00(m,2H),1.98–1.90(m,2H),1.66–1.55(m,2H),1.38–1.26(m,10H)。

compound 67:

¹ H NMR(400MHz,CD ₃ OD)δ8.53-8.51(m,1H),7.85(d,J＝3.4Hz,1H),7.61(d,J＝8.3Hz,1H),7.50–7.47(m,2H),7.44(d,J＝7.8Hz,1H),7.20(d,J＝7.3Hz,1H),7.03(m,1H),6.36(m,1H),5.88(m,1H),5.11(m,1H),4.65–4.44(m,3H),4.38–4.03(m,6H),3.16(m,8H),2.89(s,3H),2.41(m,8H),2.06(m,3H)。

compound 68:

¹ H NMR(400MHz,CD ₃ OD)δ7.87–7.77(m,1H),7.72–7.61(m,1H),7.55–7.43(m,2H),7.39–7.19(m,2H),7.08–6.82(m,1H),6.41–6.28(m,1H),5.92–5.82(m,1H),5.26–4.89(m,1H),4.69–4.44(m,2H),4.35–4.17(m,2H),4.09–3.91(m,2H),3.75–3.47(m,3H),3.27–3.05(m,4H),2.98–2.78(m,3H)。

compound 69:

¹ H NMR(400MHz,DMSO-d ₆ )δ7.97–7.87(m,1H),7.81–7.69(m,1H),7.62–7.51(m,2H),7.49–7.35(m,2H),7.05–6.79(m,1H),6.32–6.13(m,1H),5.91–5.72(m,1H),5.15–4.88(m,1H),4.41–4.06(m,5H),3.84–3.69(m,4H),3.09–2.91(m,6H),2.83–2.63(m,8H),2.04–1.96(m,2H),1.81–1.67(m,6H),1.54–1.43(m,2H)。

compound 70:

¹ H NMR(400MHz,CD ₃ OD)δ7.81(t,J＝7.7Hz,1H),7.68(t,J＝9.7Hz,1H),7.50(dd,J＝19.2,6.9Hz,2H),7.37(dd,J＝10.0,5.5Hz,2H),6.97(ddd,J＝36.7,21.6,10.2Hz,1H),6.35(dd,J＝15.8,7.9Hz,1H),5.85(dd,J＝26.8,18.1Hz,1H),5.29(dd,J＝42.9,38.4Hz,1H),4.70–4.53(m,2H),4.33(dt,J＝37.9,19.7Hz,3H),3.82(ddd,J＝55.1,45.4,17.6Hz,6H),3.19–3.02(m,4H),2.99–2.76(m,3H),2.70–2.56(m,3H),2.37(dd,J＝21.8,13.0Hz,6H),2.21–2.00(m,2H)。

compound 71a:

¹ H NMR(400MHz,MeOD)δ8.30–8.20(m,1H),7.93–7.84(m,1H),7.64(d,J＝8.2Hz,1H),7.55–7.48(m,2H),7.45(t,J＝7.8Hz,1H),7.23(d,J＝7.5Hz,1H),7.09–6.87(m,1H),6.42–6.33(m,1H),5.90(d,J＝10.7Hz,1H),5.15–4.92(m,1H),4.86–4.75(m,2H),4.65–4.50(m,1H),4.45–4.26(m,2H),4.26–4.14(m,2H),4.15–3.99(m,2H),3.93–3.74(m,1H),3.60(m,1H),3.58–3.40(m,2H),3.36(m,1H),3.28–3.19(m,2H),3.18–3.12(m,2H),3.09(s,3H),3.04(m,2H),3.01–2.94(m,2H),2.91–2.83(m,2H),2.80(m,2H),2.79–2.73(m,2H),2.72–2.65(m,3H)。

compound 71b:

¹ H NMR(400MHz,MeOD)δ8.23(m,1H),7.88(m,1H),7.63(d,J＝8.0Hz,1H),7.57–7.48(m,2H),7.45(t,J＝7.6Hz,1H),7.27–7.18(m,1H),7.04–6.69(m,1H),6.36(d,J＝16.5Hz,1H),5.89(d,J＝10.5Hz,1H),5.36–4.98(m,2H),4.69–4.48(m,1H),4.43–4.28(m,1H),4.27–4.12(m,2H),4.05(m,2H),3.83(m,1H),3.73(m,2H),3.60–3.40(m,2H),3.29(m,1H),3.19(m,4H),3.18(s,3H),3.11–3.05(m,2H),3.04(m,2H),2.95(m,2H),2.89–2.84(m,2H),2.81(m,2H),2.75(s,3H),2.73–2.65(m,1H)。

compound 72:

¹ H NMR(400MHz,MeOD)δ8.49(s,1H),8.21(d,J＝3.4Hz,1H),7.86(d,J＝5.9Hz,1H),7.62(d,J＝8.1Hz,1H),7.56–7.33(m,3H),7.20(d,J＝7.4Hz,1H),6.96(ddd,J＝50.4,16.6,10.7Hz,1H),6.36(dd,J＝16.6,8.3Hz,1H),5.89(d,J＝10.1Hz,1H),5.62(d,J＝108.7Hz,1H),5.11(s,2H),4.77–4.50(m,2H),4.39–3.96(m,8H),3.94–3.58(m,3H),3.48(s,2H),3.29–2.98(m,6H),2.92–2.77(m,2H),2.76–2.54(m,2H),2.51–2.32(m,2H),1.92(d,J＝83.6Hz,2H)。

compound 74:

¹ H NMR(400MHz,MeOD)δ8.30–8.19(m,1H),7.93–7.84(m,1H),7.64(d,J＝8.2Hz,1H),7.58–7.48(m,2H),7.45(m,1H),7.24(m,1H),7.11–6.82(m,1H),6.37(d,J＝16.7Hz,1H),5.91(d,J＝10.5Hz,1H),5.28–4.91(m,2H),4.82–4.44(m,2H),4.37–4.04(m,4H),4.00–3.68(m,2H),3.69–3.49(m,2H),3.38(m,2H),3.36(m,2H),3.25(s,3H),3.22–3.15(m,2H),3.12(m,2H),3.08–2.97(m,2H),2.95–2.85(m,1H),2.82(m,2H),2.17(m,1H),2.10–1.98(m,4H)。

compound 75:

¹ H NMR(400MHz,MeOD)δ8.30–8.19(m,1H),7.95–7.85(m,1H),7.71–7.61(m,1H),7.56–7.48(m,2H),7.46(t,J＝6.5Hz,1H),7.23(t,J＝7.7Hz,1H),7.09–6.82(m,1H),6.47–6.28(m,1H),5.90(d,J＝9.8Hz,1H),5.28–4.99(m,2H),4.82–4.48(m,2H),4.43–4.03(m,4H),4.02–3.77(m,2H),3.78–3.68(m,1H),3.59(m,2H),3.43(m,2H),3.38(s,3H),3.30–3.20(m,2H),3.20–3.12(m,2H),3.12–3.01(m,2H),2.97–2.81(m,2H),2.81–2.40(m,2H),2.35–2.14(m,2H),2.15–2.04(m,4H)。

compound 76:

¹ H NMR(400MHz,CD ₃ OD)δ7.82(t,J＝8.4Hz,1H),7.69(d,J＝8.2Hz,1H),7.51(t,J＝8.3Hz,2H),7.37(t,J＝7.7Hz,2H),7.02(dt,J＝55.2,27.8Hz,1H),6.36(d,J＝17.1Hz,1H),5.88(t,J＝9.0Hz,1H),5.50(d,J＝11.3Hz,1H),5.15(s,1H),4.72–4.50(m,5H),4.40–4.22(m,3H),4.14–3.89(m,3H),3.73–3.59(m,3H),3.27–3.03(m,6H),2.64(dd,J＝27.9,9.8Hz,8H),2.45–2.25(m,5H)。

compound 77:

¹ H NMR(400MHz,CD ₃ OD)δ7.84(d,J＝7.6Hz,1H),7.72(d,J＝8.3Hz,1H),7.52(d,J＝4.5Hz,2H),7.43–7.31(m,2H),6.90(s,1H),6.34(d,J＝16.5Hz,1H),5.88(d,J＝8.9Hz,1H),5.49–5.26(m,1H),5.13(s,1H),4.67–4.45(m,1H),4.42–4.09(m,3H),4.00(dd,J＝34.5,19.8Hz,2H),3.81–3.46(m,7H),3.25–3.02(m,6H),2.97–2.83(m,3H),2.69(s,1H),2.26(d,J＝55.6Hz,4H),1.63(d,J＝13.2Hz,1H),1.46–1.22(m,2H)。MS(ESI)m/z:669(M+H) ⁺ 。

compound 78:

¹ H NMR(400MHz,CDCl ₃ )δ7.71–7.61(m,2H),7.40(dd,J＝14.9,7.1Hz,1H),7.33(t,J＝7.6Hz,1H),7.20(ddd,J＝32.6,16.3,6.3Hz,2H),6.97(dt,J＝27.6,12.6Hz,1H),6.51–6.41(m,1H),5.92–5.82(m,1H),5.15(s,1H),4.82(s,1H),4.66(d,J＝13.3Hz,1H),4.51–4.19(m,3H),4.11–3.72(m,4H),3.65–3.34(m,3H),3.21(ddd,J＝26.4,14.9,6.7Hz,3H),3.10(d,J＝4.4Hz,2H),3.06–2.95(m,2H),2.91(t,J＝8.2Hz,3H),2.87–2.61(m,5H),2.43(d,J＝5.0Hz,6H)。

compound 81:

¹ H NMR(400MHz,MeOD)δ7.99–7.83(m,1H),7.74–7.63(m,1H),7.54–7.35(m,3H),7.10–6.80(m,1H),6.44–6.26(m,1H),5.91–5.75(m,1H),5.22–4.99(m,1H),4.72–4.51(m,3H),4.35–3.97(m,5H),3.80–3.54(m,4H),3.38–3.34(m,1H),3.26–3.03(m,7H),2.96–2.80(m,3H),2.72–2.57(m,3H),2.56–2.48(m,3H)。

compound 82:

¹ H NMR(400MHz,MeOD)δ9.12–8.99(m,1H),8.36–8.18(m,1H),8.08(t,J＝7.8Hz,1H),7.85(d,J＝7.6Hz,1H),7.62(td,J＝7.9,4.0Hz,1H),7.11–6.81(m,1H),6.35(dd,J＝17.1,7.7Hz,1H),5.86(dt,J＝29.8,14.9Hz,2H),5.16(d,J＝7.9Hz,1H),4.74–4.65(m,1H),4.57(d,J＝6.2Hz,2H),4.46–4.24(m,3H),4.05(dd,J＝28.5,14.7Hz,2H),3.76(dd,J＝37.3,13.0Hz,2H),3.24(d,J＝7.3Hz,1H),3.16(d,J＝12.5Hz,1H),3.07(s,3H),2.98–2.79(m,3H),2.70(dd,J＝34.9,11.3Hz,4H),2.52–2.29(m,7H)。

compound 83:

¹ H NMR(400MHz,MeOD)δ8.49(s,1H),7.74(dd,J＝14.8,6.5Hz,1H),7.65(dd,J＝15.8,8.0Hz,1H),7.38(dd,J＝15.6,9.2Hz,1H),7.25(t,J＝9.2Hz,1H),7.12–6.81(m,1H),6.35(dd,J＝16.7,6.8Hz,1H),5.90(dd,J＝34.1,23.8Hz,2H),5.36–5.32(m,1H),4.58(s,2H),4.38–4.21(m,2H),4.16–4.05(m,2H),3.75–3.46(m,4H),3.24(d,J＝7.6Hz,1H),3.14(d,J＝10.4Hz,1H),3.07(s,1H),2.84(s,2H),2.81(s,1H),2.69(s,1H),2.60(s,2H),2.53(d,J＝6.7Hz,3H),2.20(d,J＝7.4Hz,1H),2.03(d,J＝5.2Hz,1H),1.66–1.54(m,1H),1.31(d,J＝17.2Hz,7H)。

compound 124:

¹ H NMR(400MHz,MeOD)δ7.83(dd,J＝7.4,5.4Hz,1H),7.73–7.62(m,1H),7.59–7.43(m,2H),7.40–7.30(m,2H),7.00–6.72(m,1H),6.41–6.26(m,1H),5.86(t,J＝10.7Hz,1H),5.13(d,J＝33.2Hz,1H),4.58(s,2H),4.48–3.56(m,9H),3.24–2.70(m,12H),2.50(d,J＝8.6Hz,4H),2.38(d,J＝28.3Hz,2H)。

compound 126:

¹ H NMR(400MHz,MeOD)δ8.51(s,1H),8.01–7.83(m,1H),7.73(d,J＝8.1Hz,1H),7.56–7.27(m,3H),7.15–6.78(m,1H),6.34(d,J＝17.2Hz,1H),5.88(d,J＝10.3Hz,1H),5.34(s,1H),4.58(s,5H),4.35–4.22(m,2H),4.17–3.56(m,7H),3.20–3.03(m,6H),2.85(s,1H),2.69(s,1H),2.19(t,J＝7.5Hz,1H),2.13–1.90(m,6H),1.60(s,1H)。

compound 128:

¹ H NMR(400MHz,MeOD)δ7.88(dd,J＝14.2,8.3Hz,1H),7.71(t,J＝9.5Hz,1H),7.56–7.29(m,3H),6.99–6.78(m,1H),6.34(d,J＝16.7Hz,1H),5.87(t,J＝9.3Hz,1H),5.12(s,1H),4.58(s,3H),4.33–3.95(m,4H),3.83–3.46(m,6H),3.22–2.86(m,5H),2.58(d,J＝32.6Hz,7H),2.35–2.12(m,2H)。

example 7:

14-propenoyl-8- ((dimethylamino) methyl) -10, 15-dimethyl-3- (naphthalen-1-yl) -1,2,3,4,9,10,12 a,13,14,15, 16-dodecahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecanyl-11 (8H) -ketoformate salt (Compound 24)

Step 1: (2-aminopropyl) carbamic acid tert-butyl ester:

a solution of propane-1, 2-diamine (5.98 g,80.8 mmol) and tert-butyl phenyl carbonate (15.8 g,80.8 mmol) in ethanol (90 mL) was stirred at 80℃for 18 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography on silica gel (eluting with PE: ea=1:1; dcm/MeOH: 10/1) to give the desired product as a pale yellow oil (10.7 g, yield: 56%).

LC-MS rt=1.2 min; MS calculated: 174.1, MS (ESI) m/z 175.1[ M+H ]] ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ4.94(s,1H),3.21–3.10(m,1H),3.06–2.97(m,1H),2.89(m,1H),1.45(s,9H),1.07(d,J＝6.4Hz,2H)。

Step 2: (E) -4- ((1- ((tert-butoxycarbonyl) amino) prop-2-yl) amino) but-2-enoic acid methyl ester

To a mixture of tert-butyl (2-aminopropyl) carbamate (20 g,115 mmol), DIEA (30 g,230 mmol) in DCM (300 mL) was added methyl (E) -4-bromobut-2-enoate (20.5 g,230 mmol). The mixture was stirred at room temperature for 5 hours. Adding H ₂ O (200 mL), the aqueous phase was extracted with DCM (200 mL x 2). The organic phase was washed with brine (200 mL), and dried over Na ₂ SO ₄ Dried, filtered and concentrated. The residue was purified by column chromatography (PE: ea=3:1 to DCM: meoh=30:1) to give the desired product as a yellow oil (20.1 g, yield: 63.9%).

LC-MS rt=1.377 minutes; MS calculated: 272.17 MS (ESI): 273.0[ M+H ] ] ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ7.02-6.95(m,1H),6.00(dd,J＝15.7,1.8Hz,1H),4.96–4.83(m,1H),3.74(s,3H),3.51–3.33(m,2H),3.18(m,1H),3.02–2.96(m,1H),2.80(m,1H),1.45(s,9H),1.06(d,J＝6.4Hz,3H)。

Step 3: (E) -methyl 4- (((benzyloxy) carbonyl) (1- ((tert-butoxycarbonyl) amino) prop-2-yl) amino) but-2-enoate

To (E) -4- ((1- ((tert-butoxycarbonyl) amino) prop-2-yl) amino) but-2-enoic acid methyl ester (20 g,73.5 mmol), naHCO ₃ (24.7 g, 254 mmol) in EtOAc (150 mL) and H ₂ CbzCl (13.8 g,80.9 mmol) was slowly added to the mixture in O (150 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was extracted with EA (200 ml x 2). The combined organic phases were washed with brine (200 mL), and dried over Na ₂ SO ₄ Dried, filtered and concentrated to give the desired product (28 g crude, yield: 63.9%) as a yellow oil, which was used in the next step without further purification.

LC-MS rt=1.737 min; MS calculated: 406.21, MS (ESI): 307.1[ M-Boc+H ]] ⁺ 。

Step 4:5- (2-methoxy-2-oxoethyl) -2-methylpiperazine-1-carboxylic acid benzyl ester

A mixture of methyl (E) -4- (((benzyloxy) carbonyl) (1- ((tert-butoxycarbonyl) amino) prop-2-yl) amino) but-2-enoate (28 g,69.0 mmol) in HCl/1, 4-dioxane (150 mL, 4M) and MeOH (150 mL) was stirred at 80℃for 2 hours. After concentration, the residue was taken up in saturated NaHCO ₃ The aqueous solution was adjusted to ph=7-8. The aqueous phase was extracted with EA (200 mL x 3), washed with brine (200 mL), and dried over Na ₂ SO ₄ Dried, filtered and concentrated. The residue was purified by column chromatography (PE: ea=1:1) to give the desired product (10.8 g, yield: 50.7%) as a yellow oil.

LC-MS rt=1.431 min; MS calculated: 306.16, MS (ESI): 307.0[ M+H ]] ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ7.41–7.28(m,5H),5.14(s,2H),4.28(m,1H),3.87(m,1H),3.69(s,3H),2.98(m,2H),2.78(m,2H),2.47–2.30(m,2H),1.24(d,J＝6.8Hz,3H)。

Step 5:4- (4- ((benzyloxy) carbonyl) -2- (2-methoxy-2-oxoethyl) -5-methylpiperazin-1-yl) -2-chloro-5, 8-dihydropyrido [3,4-d ] pyrimidine-7 (6H) -carboxylic acid tert-butyl ester

To 5- (2-methoxy-2-oxoethyl) -2-methylpiperazine-1-carboxylic acid benzyl ester (2 g,6.5 mmol), 2, 4-dichloro-5, 8-dihydropyrido [3,4-d ]]A mixture of pyrimidine-7 (6H) -carboxylic acid tert-butyl ester (2 g,6.5 mmol) in DMSO (150 mL) was added DIEA (3.3 g,26 mmol). The mixture was stirred at 80℃for 24 hours. After cooling to room temperature and dilution with water, the mixture was extracted with EA (100 ml x 3). The organic phase was washed with brine (50 ml x 3), dried over Na ₂ SO ₄ Dried, filtered and concentrated. The residue was purified by column chromatography (PE: ea=2:1) to give the desired product as a yellow solid (1.4 g, yield: 38%).

LC-MS rt=2.0 min; MS calculated: 573.2, MS (ESI): 574.2[ M+H ]] ⁺

¹ H NMR(400MHz,CDCl ₃ )δ7.38–7.29(m,5H),5.21–5.11(m,2H),4.71–4.54(m,2H),4.41(m,1H),4.32–4.15(m,2H),3.92–3.69(m,2H),3.63(s,3H),3.36(m,1H),3.26–3.08(m,2H),2.72–2.48(m,4H),1.51–1.46(s,9H),1.19(d,J＝6.2Hz,3H)。

Step 6:4- (2-chloro-5, 6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -5- (2-methoxy-2-oxoethyl) -2-methylpiperazine-1-carboxylic acid benzyl ester

To 4- (4- ((benzyloxy) carbonyl) -2- (2-methoxy-2-oxoethyl) -5-methylpiperazin-1-yl) -2-chloro-5, 8-dihydropyrido [3,4-d]To a mixture of pyrimidine-7 (6H) -carboxylic acid tert-butyl ester (5.0 g,8.7 mmol) in DCM (100 mL) was added TFA (15 mL). The mixture was stirred at room temperatureMix for 3 hours. The mixture was concentrated under reduced pressure. The residue was poured into water and saturated NaHCO ₃ Adjust to ph=8. The mixture was extracted with DCM (50 mL. Times.3). The organic phase was washed with brine, dried over Na ₂ SO ₄ Dried, and concentrated to give the desired product as a yellow solid (4.0 g, MC20-474-049, yield: 97%).

LC-MS [ mobile phase: from 95% water (0.1% FA) and 5% CH in 2.5 minutes ₃ CN (0.1% FA) to 5% water (0.1% FA) and 90% CH ₃ CN(0.1％ FA)]Purity of: 67%; LC-MS rt=1.0 min; MS calculated: 473.1, MS (ESI): 474.1[ M+H ]] ⁺

Step 7:4- (2-chloro-7- (naphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -5- (2-methoxy-2-oxoethyl) -2-methylpiperazine-1-carboxylic acid benzyl ester

4- (2-chloro-5, 6,7, 8-tetrahydropyrido [3, 4-d)]Pyrimidine-4-yl) -5- (2-methoxy-2-oxoethyl) -2-methylpiperazine-1-carboxylic acid benzyl ester (500 mg,1.05 mmol), 1-bromonaphthalene (328 mg,1.58 mmol), pd ₂ (dba) ₃ (97 mg,0.11 mmol), ruPhos (98 mg,0.21 mmol) and Cs ₂ CO ₃ A mixture of (685 mg,2.1 mmol) in toluene (20 mL) was stirred under argon at 90deg.C for 16 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE: ea=5:1) to give the compound (200 mg, yield: 32%) as a yellow solid.

LC-MS rt=2.3 min; MS calculated: 599.3 MS (ESI): 600.1[ M+H ]] ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ8.20–8.13(m,1H),7.89–7.82(m,1H),7.61(d,J＝8.2Hz,1H),7.53–7.47(m,2H),7.43(t,J＝7.8Hz,1H),7.38–7.29(m,5H),7.11(d,J＝7.4Hz,1H),5.16(s,2H),4.77–4.65(m,1H),4.37–4.23(m,4H),4.02(dd,J＝14.1,5.9Hz,1H),3.68(s,3H),3.46-3.82(m,1H),3.33–3.09(m,3H),2.98–2.78(m,2H),2.66(d,J＝5.6Hz,2H),1.23(d,J＝6.3Hz,3H)。

Step 8:2- (4- ((benzyloxy) carbonyl) -1- (2-chloro-7- (naphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -5-methylpiperazin-2-yl) acetic acid

To 4- (2-chloro-7- (naphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ]]Pyrimidine-4-yl) -5- (2-methoxy-2-oxoethyl) -2-methylpiperazine-1-carboxylic acid benzyl ester (500 mg,0.83 mmol) in a mixture of water (4 mL) and THF (4 mL) LiOH (133 mg,3.33 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. After concentration, the residue was taken up in saturated NaH ₂ PO ₄ The aqueous solution was adjusted to ph=5-6. The aqueous phase was extracted with EA (40 ml x 3). The organic phase was washed with brine (50 mL), and dried over Na ₂ SO ₄ Dried, filtered and concentrated to give the desired product as a yellow solid (481 mg, yield: 98.7%).

LC-MS rt=2.135 min; MS calculated: 585.21, MS (ESI): 586.1[ M+H ] ] ⁺ 。

Step 9:5- (2- ((3-azido-2-hydroxypropyl) (methyl) amino) -2-oxoethyl) -4- (2-chloro-7- (naphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) -2-methylpiperazine-1-carboxylic acid benzyl ester

To 2- (4- ((benzyloxy) carbonyl) -1- (2-chloro-7- (naphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ]]To a mixture of pyrimidin-4-yl) -5-methylpiperazin-2-yl acetic acid (481mg, 0.82 mmol), DIEA (424 mg,3.3 mmol) in DMF (10 mL) was added HATU (405 mg,1.07 mmol) and after 10 min 1-azido-3- (methylamino) propan-2-ol (139 mg,1.07 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was diluted with water and extracted with EA (40 ml x 3). The organic phase was washed with brine (50 ml x 2), dried over Na ₂ SO ₄ Dried, filtered and concentrated. The residue was purified by column chromatography (PEEa=1:1) to afford the desired product as a yellow solid (440 mg, yield: 76%).

LC-MS rt=2.163 min; MS calculated: 697.29 MS (ESI): 698.2[ M+H ]] ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ8.19–8.12(m,1H),7.86(d,J＝6.3,3.1Hz,1H),7.61(d,J＝8.2Hz,1H),7.54–7.47(m,2H),7.42(m,1H),7.39–7.30(m,5H),7.11(d,J＝7.4Hz,1H),5.22–5.10(m,2H),4.73(br s,1H),4.35–4.19(m,4H),4.13–4.05(m,1H),3.93(br s,1H),3.43–3.29(m,4H),3.25(m,4H),2.90–2.88(m,1H),2.80(s,3H),2.56(m,1H),1.21(d,J＝8.2Hz,3H)。

Step 10: benzyl 8- (azidomethyl) -10, 15-dimethyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,9,10,11,12 a,13,15, 16-dodecahydro-6, 18- (aminosubunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecanyl-14 (8H) -carboxylate

5- (2- ((3-azido-2-hydroxypropyl) (methyl) amino) -2-oxoethyl) -4- (2-chloro-7- (naphthalen-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ]]Pyrimidine-4-yl) -2-methylpiperazine-1-carboxylic acid benzyl ester (300 mg,0.43 mmol), pd ₂ (dba) ₃ (19 mg,0.086 mmol), BINAP (27 mg,0.043 mmol) and Cs ₂ CO ₃ A mixture of (280 mg,0.86 mmol) in toluene (20 mL) was stirred under argon at 120℃for 16 h. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give a crude product (300 mg). The crude product was used in the next step without further purification.

LC-MS rt=2.0 min; MS calculated: 661.3, MS (ESI): 622.2[ M+H ]] ⁺ 。

Step 11: benzyl 8- (aminomethyl) -10, 15-dimethyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,9,10,11,12 a,13,15, 16-dodecahydro-6, 18- (aminosubunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecanate-14 (8H) -carboxylate

8- (azidomethyl) -10, 15-dimethyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,9,10,11,12 a,13,15, 16-dodecahydro-6, 18- (aminosubunit) pyrazino [1,2-g]Pyrido [3,4-d][1]Oxa [3,7,11]]Triazacyclotridecarboxylic acid benzyl ester (1.5 g, crude) and PtO ₂ A mixture of (150 mg,0.66 mmol) in MeOH (20 mL) was stirred under hydrogen (balloon) at room temperature for 1 hour. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by preparative TLC (eluted with DCM/MeOH: 15/1) to give the desired product as an off-white solid (305 mg, two-step yield: 37%).

¹ H NMR(400MHz,CD ₃ OD)δ8.25–8.15(m,1H),7.89–7.80(m,1H),7.64–7.55(m,1H),7.53–7.45(m,2H),7.45–7.40(m,1H),7.40–7.26(m,5H),7.22–7.15(m,1H),5.17(s,2H),4.42–4.33(m,1H),4.31–3.95(m,5H),3.91–3.38(m,4H),3.26–3.12(m,2H),3.09–2.66(m,8H),2.68–2.42(m,2H),1.36–1.30(m,3H)。

Step 12:8- ((dimethylamino) methyl) -10, 15-dimethyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,9,10,11,12 a,13,15, 16-dodecahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridec-c-14 (8H) -carboxylic acid benzyl ester

To 8- (aminomethyl) -10, 15-dimethyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,9,10,11,12 a,13,15, 16-dodecahydro-6, 18- (aminosubunit) pyrazino [1,2-g]Pyrido [3,4-d][1]Oxa [3,7,11]]A solution of triazacyclotridecarboxylic acid benzyl ester (190 mg,0.28 mmol), (CHO) n (129 mg,1.43 mmol) and AcOH (2 drops) in MeOH (4 mL) was stirred at room temperature for 10 min, then NaBH was added ₃ CN (91 mg,1.43 mmol), and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure, and the residue was taken upThe material was purified by preparative TLC (eluted with DCM/MeOH: 15/1) to give the title product as a grey solid (120 mg, yield: 60%).

¹ H NMR(400MHz,CD ₃ OD)δ8.22(d,J＝8.3Hz,1H),7.87–7.81(m,1H),7.64–7.56(m,1H),7.53–7.45(m,2H),7.44–7.27(m,6H),7.23–7.15(m,1H),5.17(s,2H),4.48–3.98(m,7H),3.74–3.40(m,3H),3.20–2.83(m,6H),2.78–2.62(m,4H),2.62–2.47(m,2H),2.44–1.88(m,6H),1.40–1.27(m,3H)。

Step 13:8- ((dimethylamino) methyl) -10, 15-dimethyl-3- (naphthalen-1-yl) -1,2,3,4,9,10,12 a,13,14,15, 16-dodecahydro-6, 18- (aminosubunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecan-11 (8H) -one

8- ((dimethylamino) methyl) -10, 15-dimethyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,9,10,11,12 a,13,15, 16-dodecahydro-6, 18- (aminosubunit) pyrazino [1,2-g ]Pyrido [3,4-d][1]Oxa [3,7,11]]Triazacyclotridecarboxylic acid benzyl ester (190 mg,0.29 mmol), NH ₃ H ₂ A mixture of O (0.5 drops) and Pd/C (95 mg, wt.:10%) in MeOH (5 mL) was stirred under hydrogen (balloon) at room temperature for 16 hours. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title product as an off-white solid (120 mg, yield: 74%).

Step 14: 14-propenoyl-8- ((dimethylamino) methyl) -10, 15-dimethyl-3- (naphthalen-1-yl) -1,2,3,4,9,10,12 a,13,14,15, 16-dodecahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecan-11 (8H) -one

To a solution of 8- ((dimethylamino) methyl) -10, 15-dimethyl-3- (naphthalen-1-yl) -1,2,3,4,9,10,12 a,13,14,15, 16-dodecahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazacyclotridecac-one (40 mg,0.075 mmol) and TEA (30 mg,0.30 mmol) in DCM (5 mL) was added dropwise a solution of acryloyl chloride (8.5 mg,0.098 mmol) in DCM (4 mL) under Ar. The mixture was stirred at room temperature for 20 minutes. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (ACN/water containing 0.05% FA) to give the title product (9 mg, yield: 19%, purity 90%).

LC-MS rt=0.94 min; MS calculated: 583.3, MS (ESI) m/z 584.5[ M+H ]] ⁺ 。

¹ H NMR(400MHz,DMSO-d6)δ8.23–8.13(m,1H),7.95–7.87(m,1H),7.64(d,J＝8.1Hz,1H),7.58–7.50(m,2H),7.49–7.41(m,1H),7.26–7.16(m,1H),6.83(s,1H),6.25–6.06(m,1H),5.79–5.42(m,2H),4.78–4.30(m,2H),4.29–3.90(m,5H),3.87–3.35(m,4H),3.21–2.69(m,5H),2.67–2.53(m,3H),2.46–2.36(m,2H),2.27–2.15(m,6H),1.40–1.24(m,3H)。

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

Compound 26:

¹ H NMR(400MHz,CDCl ₃ )δ8.18(d,J＝7.4Hz,1H),7.87(d,J＝8.2Hz,1H),7.62(d,J＝7.0Hz,1H),7.52–7.50(m,2H),7.43–7.41(m,2H),7.12(s,1H),6.53–6.49(m,1H),5.96–5.68(m,1H),5.35(br s,3H),4.22(br s,1H),3.71–3.64(m,2H),3.42–3.25(m,3H),2.88(br s,5H),2.26–2.16(m,4H),2.01(br s,6H),1.63(br s,4H)。

example 8:

2- ((12 aR, 15S) -14-propenoyl-10-methyl-3- (naphthalen-1-yl) -1,2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1,3,7,11] oxatriazatrideca-15-yl) acetonitrile (Compound 46)

Step 1: 2-chloro-4- ((2R, 5S) -5- (cyanomethyl) -2- (2-hydroxyethyl) -4- (4-methoxybenzyl) piperazin-1-yl) -5, 6-dihydropyrido [3,4-d ] pyrimidine-7 (8H) -carboxylic acid tert-butyl ester

To 2-chloro-4- ((2 r,5 s) -5- (cyanomethyl) -2- (2-methoxy-2-oxoethyl) -4- (4-methoxybenzyl) piperazin-1-yl) -5, 6-dihydropyrido [3,4-d ] at 0 ℃]To a solution of pyrimidine-7 (8H) -carboxylic acid tert-butyl ester (1.0 g,1.71 mmol) in THF (20 mL) was added LiBH ₄ (1.3 mL,5.14mmol, 4M). After the addition, the mixture was stirred at 0 ℃ for 4 hours. The reaction mixture was treated with saturated NH ₄ The aqueous Cl solution was quenched and extracted with EtOAc (2X 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (eluting with PE: etoac=3:1 to 1:1) to give 2-chloro-4- ((2 r,5 s) -5- (cyanomethyl) -2- (2-hydroxyethyl) -4- (4-methoxybenzyl) piperazin-1-yl) -5, 6-dihydropyrido [3,4-d ] as a colorless oil ]Pyrimidine-7 (8H) -carboxylic acid tert-butyl ester (650 mg,68% yield). MS (ESI) M/z 557 (M+H) ⁺ 。

Step 2: 2-chloro-4- ((2R, 5S) -5- (cyanomethyl) -4- (4-methoxybenzyl) -2- (2-oxoethyl) piperazin-1-yl) -5, 6-dihydropyrido [3,4-d ] pyrimidine-7 (8H) -carboxylic acid tert-butyl ester

To a solution of oxalyl chloride (502 mg,3.96 mmol) in DCM (10 mL) was added DMSO (463 mg,5.94 mmol) dropwise at-78deg.C. After the addition, the mixture was stirred at-78 ℃ for 1 hour. Then 2-chloro-4- ((2R, 5S) -5- (cyanomethyl) -2- (2-hydroxyethyl) -4- (4-methoxybenzyl) piperazin-1-yl) -5, 6-dihydropyrido [3,4-d]a solution of pyrimidine-7 (8H) -carboxylic acid tert-butyl ester (550 mg,0.99 mmol) in DCM (5 mL) and the mixture stirred at this temperature for an additional 3 hours. TEA (599 mg,0.83 mmol) was added and the mixture was stirred at-78℃to room temperature for 30 min. The reaction mixture was quenched with water and extracted with DCM (2×20 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to dryness to give 2-chloro-4- ((2 r,5 s) -5- (cyanomethyl) -4- (4-methoxybenzyl) -2- (2-oxoethyl) piperazin-1-yl) -5, 6-dihydropyrido [3,4-d ] as a yellow oil]Pyrimidine-7 (8H) -carboxylic acid tert-butyl ester (550 mg crude, 100% yield). MS (ESI) M/z 555 (M+H) ⁺ 。

Step 3: 2-chloro-4- ((2 r,5 s) -5- (cyanomethyl) -2- (2- ((2-hydroxyethyl) (methyl) amino) ethyl) -4- (4-methoxybenzyl) piperazin-1-yl) -5, 6-dihydropyrido [3,4-d ] pyrimidine-7 (8H) -carboxylic acid tert-butyl ester

To 2-chloro-4- ((2R, 5S) -5- (cyanomethyl) -4- (4-methoxybenzyl) -2- (2-oxoethyl) piperazin-1-yl) -5, 6-dihydropyrido [3,4-d]To a solution of pyrimidine-7 (8H) -carboxylic acid tert-butyl ester (550 mg,0.99 mmol) in DCE (10 mL) was added 2- (methylamino) ethanol (163 mg,2.18 mmol) and AcOH (6.0 mg,0.1 mmol), and the mixture was stirred at room temperature for 30 min. NaBH (OAc) was added at 0deg.C ₃ (545 mg,2.57 mmol) was added portionwise to the mixture and the resulting mixture was stirred at room temperature for 16 hours. The mixture was quenched with water and extracted with DCM (3×20 ml). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ Dried, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (eluting with DCM: meoh=50:1 to 10:1) to give 2-chloro-4- ((2 r,5 s) -5- (cyanomethyl) -2- (2- ((2-hydroxyethyl) (methyl) amino) ethyl) -4- (4-methoxybenzyl) piperazin-1-yl) -5, 6-dihydropyrido [3,4-d ] as a yellow solid]Pyrimidine-7 (8H) -carboxylic acid tert-butyl ester (330 mg,54% yield). MS (ESI) M/z 614 (M+H) ⁺ 。

Step 4: (12 aR, 15S) -15- (cyanomethyl) -14- (4-methoxybenzyl) -10-methyl-1, 2,8,9,10,11,12 a,13,14,15, 16-dodecahydro-6, 18- (aminosubunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1,3,7,11] oxatriazatridec-3 (4H) -carboxylic acid tert-butyl ester

At N ₂ To 2-chloro-4- ((2 r,5 s) -5- (cyanomethyl) -2- (2- ((2-hydroxyethyl) (methyl) amino) ethyl) -4- (4-methoxybenzyl) piperazin-1-yl) -5, 6-dihydropyrido [3,4-d ] under an atmosphere]Pyrimidine-7 (8H) -carboxylic acid tert-butyl ester (380 mg,0.62 mmol) and Cs ₂ CO ₃ (404 mg,1.24 mmol) to a mixture of toluene (30 mL) was added Pd (OAc) ₂ (34 mg,0.12 mmol) and BINAP (39 mg,0.06 mmol). The mixture is put under N ₂ Degassing three times under atmosphere and under N ₂ Stirring is carried out for 16 hours at 100℃under an atmosphere. The mixture was diluted with EtOAc (20 mL), washed with water and brine, and dried over Na ₂ SO ₄ Dried, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (eluting with DCM: meoh=30:1 to 10:1) to give (12 ar,15 s) -15- (cyanomethyl) -14- (4-methoxybenzyl) -10-methyl-1, 2,8,9,10,11,12 a,13,14,15, 16-dodecahydro-6, 18- (aminoiden) pyrazino [1, 2-g) as a yellow solid]Pyrido [3,4-d][1,3,7,11]Oxatriazacyclotridecarboxylic acid tert-butyl ester (250 mg,70% yield). MS (ESI) M/z 578 (M+H) ⁺ 。

Step 5:2- ((12 aR, 15S) -14- (4-methoxybenzyl) -10-methyl-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminosubunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1,3,7,11] oxatriazatridecan-15-yl) acetonitrile

To (12 aR, 15S) -15- (cyanomethyl) -14- (4-methoxybenzyl) -10-methyl-1, 2,8,9,10,11,12 a,13,14,15, 16-dodecahydro-6, 18- (aminosubunit) pyrazino [1,2-g]Pyrido [3,4-d][1,3,7,11]oxa-IIITo a solution of tert-butyl azatridec-3 (4H) -carboxylate (250 mg,0.43 mmol) in DCM (3 mL) was added TFA (1 mL) and the mixture was stirred at room temperature for 2H. The mixture was treated with saturated NaHCO ₃ The aqueous solution was basified and extracted with DCM (2×10 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to dryness to give 2- ((12 ar,15 s) -14- (4-methoxybenzyl) -10-methyl-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminosubunit) pyrazino [1, 2-g) as a yellow solid]Pyrido [3,4-d][1,3,7,11]Oxatriazacyclotridec, ridec-15-yl) acetonitrile (200 mg,98% yield), the product was used directly in the next reaction. MS (ESI) M/z 478 (M+H) ⁺ 。

Step 6:2- ((12 aR, 15S) -14- (4-methoxybenzyl) -10-methyl-3- (naphthalen-1-yl) -1,2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1,3,7,11] oxatriazatridec-n-15-yl) acetonitrile

At N ₂ Under atmosphere to 2- ((12 aR, 15S) -14- (4-methoxybenzyl) -10-methyl-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminosubunit) pyrazino [1,2-g]Pyrido [3,4-d][1,3,7,11]Oxatriazacyclotridecarbon, tri-15-yl) acetonitrile (200 mg,0.42 mmol) and Cs ₂ CO ₃ (240 mg,0.84 mmol) to a mixture of anhydrous 1, 4-dioxane (5 mL) was added 1-bromonaphthalene (348 mg,1.68 mmol), ruphos Pd G2 (33 mg,0.04 mmol). Mix N ₂ Degassing three times under atmosphere and under N ₂ Stirring is carried out for 16 hours at 90℃under an atmosphere. The mixture was diluted with EtOAc (20 mL), washed with water and brine, and dried over Na ₂ SO ₄ Dried, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (eluting with DCM: meoh=50:1 to 20:1) to give 2- ((12 ar,15 s) -14- (4-methoxybenzyl) -10-methyl-3- (naphthalen-1-yl) -1,2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1, 2-g) as a yellow solid]Pyrido [3,4-d][1,3,7,11]Oxatriazacyclotridecarbon, cat-15-yl) acetonitrile (80 mg,31% yield). MS (ESI) M/z 604 (M+H) ⁺ 。

Step 7:2- ((12 aR, 15S) -10-methyl-3- (naphthalen-1-yl) -1,2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1,3,7,11] oxatriazatridec-15-yl) acetonitrile

To 2- ((12 aR, 15S) -14- (4-methoxybenzyl) -10-methyl-3- (naphthalen-1-yl) -1,2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminosubunit) pyrazino [1, 2-g) at 0 ℃]Pyrido [3,4-d][1,3,7,11]To a mixture of oxatriazacyclotridec, ridec-15-yl) acetonitrile (80 mg,0.13 mmol) in TFA (2 mL) was added anisole (0.05 mL). The mixture is put under N ₂ Deaeration was carried out three times and stirred at 50℃for 16 hours. The mixture was concentrated to dryness in vacuo and the residue was taken up in saturated NaHCO ₃ The aqueous solution was basified and extracted with DCM (2X 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to dryness to give 2- ((12 aR, 15S) -10-methyl-3- (naphthalen-1-yl) -1,2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1, 2-g) as a yellow solid]Pyrido [3,4-d][1,3,7,11]Oxatriazacyclotridecarbon, cat-15-yl) acetonitrile (60 mg,100% yield). MS (ESI) M/z 484 (M+H) ⁺ 。

Step 8:2- ((12 aR, 15S) -14-propenoyl-10-methyl-3- (naphthalen-1-yl) -1,2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1,3,7,11] oxatriazatridecan-15-yl) acetonitrile

To 2- ((12 aR, 15S) -10-methyl-3- (naphthalen-1-yl) -1,2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiminos)Base) pyrazino [1,2-g]Pyrido [3,4-d][1,3,7,11]Oxatriazacyclotridecarbon (60 mg,0.12 mmol) in DCM (3 mL) was added TEA (0.09 mL,0.64 mmol), followed by the addition of prop-2-enoyl chloride (22 mg,0.24 mmol) at 0deg.C and the reaction mixture stirred at 0deg.C for 0.5 h. The mixture was diluted with water and extracted with DCM (2×10 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to dryness. The residue was purified by preparative HPLC to give 2- ((12 ar,15 s) -14-propenoyl-10-methyl-3- (naphthalen-1-yl) -1,2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g]Pyrido [3,4-d][1,3,7,11]Oxatriazacyclotridecarbon, cat-15-yl) acetonitrile (11.4 mg, 18% yield). ¹ H NMR(400MHz,CD ₃ OD)δ8.22(d,J＝6.5Hz,1H),7.90–7.81(m,1H),7.60(d,J＝8.2Hz,1H),7.51–7.39(m,3H),7.19(d,J＝7.4Hz,1H),6.97–6.76(m,1H),6.32(m,1H),5.86(m,1H),5.04(s,1H),4.61–4.37(m,3H),4.11(m,4H),3.50(m,3H),3.14(m,5H),2.70(m,4H),2.36(s,3H),1.74(m,1H),1.61(m,1H)。MS(ESI)m/z:538(M+H) ⁺ 。

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

Compound 47:

¹ H NMR(400MHz,DMSO-d ₆ )δ8.15(s,1H),7.98–7.90(m,1H),7.65(d,J＝8.4Hz,1H),7.57–7.51(m,2H),7.47(t,J＝7.6Hz,1H),7.23(d,J＝7.2Hz,1H),6.91(dd,J＝16.4,10.4Hz,1H),6.24(d,J＝16.8Hz,1H),5.83(d,J＝10.4Hz,1H),5.07–4.62(m,2H),4.26–4.04(m,5H),3.91–3.69(m,2H),3.56–3.49(m,2H),3.19–3.04(m,4H),2.89–2.72(m,2H),2.42–2.30(m,4H),2.26–2.13(m,2H),1.58–1.41(m,2H)。

example 9:

3-propenoyl-15-chloro-13-fluoro-14- (2-fluoro-6-methoxyphenyl) -2, 6-dimethyl-2, 3, 4a,6,7,8, 9-octahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,10] triazatridecan-5 (1H) -one (Compound 91)

Step 1: 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid

To a solution of 2-amino-4-bromo-3-fluorobenzoic acid (10 g,42.73 mmol) in DMF (80 mL) was added 1-chloropyrrolidine-2, 5-dione (5.99 g,44.86 mmol) at room temperature. The resulting mixture was stirred at 70 ℃ overnight. The mixture was cooled to room temperature and poured into cold brine (150 mL). The precipitate was collected by filtration, washed with water and dried to give the desired product 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid (7.8 g, 67.99%) as a grey solid. LC/MS ESI (m/z): 268[ M+H ]] ⁺ 。

Step 2: 7-bromo-6-chloro-8-fluoro-1, 2,3, 4-tetrahydroquinazoline-2, 4-dione

A mixture of 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid (7 g,26.07 mmol) and urea (31.32 g,521.47 mmol) was stirred at 180℃for 8 hours. The mixture was cooled to 100 ℃ and hot water (70 mL) was added. The resulting mixture was stirred at 100℃for 10 minutes. The solid was then collected by filtration and washed 3 times with cold water and dried to give the desired product 7-bromo-6-chloro-8-fluoro-1, 2,3, 4-tetrahydroquinazoline-2, 4-dione (5.2 g, 67.96%) as a grey solid. LC/MS ESI (m/z): 293[ M+H ]] ⁺ 。

Step 3: 7-bromo-2, 4, 6-trichloro-8-fluoroquinazoline

To 7-bromo-6-chloro-8-fluoro-1, 2,3, 4-tetrahydroquinazoline-2, 4-dione (5.2 g,17.72 mmol) at 0deg.C in POCl ₃ DIPEA (5 mL) was added to the mixture in (50 mL), and the resulting mixture was stirred under reflux overnight. The mixture was left at room temperature and then concentrated in vacuo to remove POCl ₃ . Dilute with ethyl acetate (30 mL) and slowly pour the reaction mixture into ice-cold water with stirring. After 15 minutes, the mixture was extracted twice with ethyl acetate. The combined extracts were washed with brine, over Na ₂ SO ₄ Dried and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0-2% ethyl acetate/petroleum ether) to give the desired product 7-bromo-2, 4, 6-trichloro-8-fluoroquinazoline (3.8 g, 64.92%) as a yellow solid. ¹ H NMR(400MHz,DMSO-d6)δ8.00(t,J＝2.0Hz,1H)。

Step 4:5- ((3-hydroxypropyl) (methyl) carbamoyl) -2-methylpiperazine-1, 4-dicarboxylic acid 1-benzyl ester 4- (tert-butyl ester)

To a solution of 4- ((benzyloxy) carbonyl) -1- (tert-butoxycarbonyl) -5-methylpiperazine-2-carboxylic acid (3 g,7.93 mmol) and DIEA (3.93 mL,23.78 mmol) in DMF (50 mL) was added HATU (4.52 g,11.89 mmol) and 3- (methylamino) propan-1-ol (0.71 g,7.93 mmol). The mixture was stirred at room temperature for 3 hours. The mixture was then poured into water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ Dried, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-70% ethyl acetate/petroleum ether) to give 1-benzyl 4- (tert-butyl) 5- ((3-hydroxypropyl) (methyl) carbamoyl) -2-methylpiperazine-1, 4-dicarboxylic acid as a yellow oil (3 g, 84.18%). LC/MS ESI (m/z): 450[ M+H ]] ⁺ 。

Step 5:5- ((3-hydroxypropyl) (methyl) carbamoyl) -2-methylpiperazine-1-carboxylic acid benzyl ester

To a solution of 1-benzyl 4- (tert-butyl) 5- ((3-hydroxypropyl) (methyl) carbamoyl) -2-methylpiperazine-1, 4-dicarboxylic acid (2 g,4.45 mmol) in dioxane (2 mL) was added HCl/dioxane (10 mL,4 n). The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated to give benzyl 5- ((3-hydroxypropyl) (methyl) carbamoyl) -2-methylpiperazine-1-carboxylate (1.7 g, 109.35%) as a yellow oil (HCl salt). LC/MS (ESI) m/z 350[ M+H ]] ⁺ 。

Step 6:4- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) -5- ((3-hydroxypropyl) (methyl) carbamoyl) -2-methylpiperazine-1-carboxylic acid benzyl ester

To a solution of benzyl 5- ((3-hydroxypropyl) (methyl) carbamoyl) -2-methylpiperazine-1-carboxylate (1.59 g,4.54 mmol) in dioxane (30 mL) was added DIEA (1.5 mL,9.08 mmol) and 7-bromo-2, 4, 6-trichloro-8-fluoroquinazoline (1.5 g,4.54 mmol). The reaction mixture was stirred at 50 ℃ overnight. The mixture was then concentrated and the residue was purified by flash column chromatography (silica gel, 0-60% ethyl acetate/petroleum ether) to give benzyl 4- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) -5- ((3-hydroxypropyl) (methyl) carbamoyl) -2-methylpiperazine-1-carboxylate (1.3 g, 44.51%) as a yellow solid. LC/MS (ESI) m/z 642/644[ M+H ] ] ⁺ 。

Step 7: 14-bromo-15-chloro-13-fluoro-2, 6-dimethyl-5-oxo-1, 2,4a,5,6,7,8, 9-octahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,10] triazatridec-e-3 (4H) -carboxylic acid benzyl ester

To 4- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) -5- ((3-hydroxypropyl) (methyl) carbamoyl) -2-methylpiperazine-1-carboxylic acid benzyl ester (1).To a solution of 3g,2.02 mmol) in DMSO (20 mL) was added KF (0.12 g,2.02 mmol). The reaction mixture was stirred at 120 ℃ overnight. The mixture was then poured into water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ Dried, and concentrated. The residue was purified by flash column chromatography (silica gel, 50% ethyl acetate/petroleum ether) to give 14-bromo-15-chloro-13-fluoro-2, 6-dimethyl-5-oxo-1, 2,4a,5,6,7,8, 9-octahydro-11, 17- (aminosubunit) benzo [ d ] as a yellow solid]Pyrazino [1,2-g][1]Oxa [3,7,10]Triazacyclotridecarboxylic acid benzyl ester (600 mg, 48.93%). LC/MS (ESI) m/z 606/608[ M+H ]] ⁺ 。

Step 8: 15-chloro-13-fluoro-14- (2-fluoro-6-methoxyphenyl) -2, 6-dimethyl-5-oxo-1, 2,4a,5,6,7,8, 9-octahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,10] triazatrideca-3 (4H) -carboxylic acid benzyl ester

To 14-bromo-15-chloro-13-fluoro-2, 6-dimethyl-5-oxo-1, 2,4a,5,6,7,8, 9-octahydro-11, 17- (aminosubunit) benzo [ d ]]Pyrazino [1,2-g][1]Oxa [3,7,10]Triazacyclotridecarboxylic acid benzyl ester (350 mg,0.58 mmol), K ₂ CO ₃ (239 mg,1.73 mmol) and (2-fluoro-6-methoxyphenyl) boronic acid (196 mg,1.15 mmol) in dioxane (20 mL) and H ₂ Pd (PPh) was added to a solution in O (4 mL) ₃ ) ₄ (67 mg,0.06 mmol). The reaction mixture was taken up in N ₂ Degassing three times, and in N ₂ Stirred overnight at 115 ℃. The mixture was then concentrated and the residue was purified by flash column chromatography (silica gel, 0-50% ethyl acetate/petroleum ether) to give 15-chloro-13-fluoro-14- (2-fluoro-6-methoxyphenyl) -2, 6-dimethyl-5-oxo-1, 2,4a,5,6,7,8, 9-octahydro-11, 17- (aminosubunit) benzo [ d ] as a pink solid]Pyrazino [1,2-g][1]Oxa [3,7,10]Triazacyclotridecarboxylic acid benzyl ester (200 mg, 53.18%). LC/MS ESI (m/z): 652[ M+H ]] ⁺ 。

Step 9: 15-chloro-13-fluoro-14- (2-fluoro-6-methoxyphenyl) -2, 6-dimethyl-5-oxo-1, 2,4a,5,6,7,8, 9-octahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,10] triazatrideca-3 (4H) -carboxylic acid tert-butyl ester

To 15-chloro-13-fluoro-14- (2-fluoro-6-methoxyphenyl) -2, 6-dimethyl-5-oxo-1, 2,4a,5,6,7,8, 9-octahydro-11, 17- (aminosubunit) benzo [ d ] ]Pyrazino [1,2-g][1]Oxa [3,7,10]Triazacyclotridecarboxylic acid benzyl ester (130 mg,0.20 mmol) and Boc ₂ To a solution of O (130 mg,0.60 mmol) in MeOH (15 mL) was added PtO ₂ (100 mg,0.20 mmol). The reaction mixture was treated with H ₂ Deaeration was carried out three times and stirred at room temperature overnight under normal pressure. The mixture was then filtered through celite and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, 0-60% ethyl acetate/petroleum ether) to give 15-chloro-13-fluoro-14- (2-fluoro-6-methoxyphenyl) -2, 6-dimethyl-5-oxo-1, 2,4a,5,6,7,8, 9-octahydro-11, 17- (aminosubunit) benzo [ d ] as a white solid]Pyrazino [1,2-g][1]Oxa [3,7,10]Triazacyclotridecarboxylic acid tert-butyl ester (50 mg, 40.58%). LC/MS (ESI) m/z 618[ M+H ]] ⁺ 。

Step 10: 15-chloro-13-fluoro-14- (2-fluoro-6-methoxyphenyl) -2, 6-dimethyl-2, 3, 4a,6,7,8, 9-octahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,10] triazatridecan-5 (1H) -one

To 15-chloro-13-fluoro-14- (2-fluoro-6-methoxyphenyl) -2, 6-dimethyl-5-oxo-1, 2,4a,5,6,7,8, 9-octahydro-11, 17- (aminosubunit) benzo [ d ]]Pyrazino [1,2-g][1]Oxa [3,7,10]To a solution of tert-butyl triazacyclotridecacarbonate (3 (4H) -carboxylate (50 mg,0.08 mmol) in dioxane (2 mL) was added HCl/dioxane (2 mL, 4N). The reaction mixture was stirred at room temperature for 1 hour. Concentrating the mixture To give 15-chloro-13-fluoro-14- (2-fluoro-6-methoxyphenyl) -2, 6-dimethyl-2, 3, 4a,6,7,8, 9-octahydro-11, 17- (aminosubunit) benzo [ d ] as a white solid]Pyrazino [1,2-g][1]Oxa [3,7,10]Triazacyclotridecarboxylic acid-5 (1H) -one (41 mg, 97.85%) (HCl salt). LC/MS (ESI) m/z 518[ M+H ]] ⁺ 。

Step 11: 3-propenoyl-15-chloro-13-fluoro-14- (2-fluoro-6-methoxyphenyl) -2, 6-dimethyl-2, 3, 4a,6,7,8, 9-octahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,10] triazatridecan-5 (1H) -one

To 15-chloro-13-fluoro-14- (2-fluoro-6-methoxyphenyl) -2, 6-dimethyl-2, 3, 4a,6,7,8, 9-octahydro-11, 17- (aminosubunit) benzo [ d ] at 0 DEG C]Pyrazino [1,2-g][1]Oxa [3,7,10]To a solution of triazacyclotridecarboxylic acid-5 (1H) -one (40 mg,0.07 mmol) and DIEA (0.04 mL,0.23 mmol) in DCM (10 mL) was added acryloyl chloride (10 mg,0.09 mmol). The reaction mixture was stirred at 0 ℃ for 10 minutes. The mixture was then poured onto NaHCO ₃ In aqueous solution and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO ₄ ) And concentrated. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18X 21mm, MECN/H with 0.1% FA ₂ O) purification to give 3-propenoyl-15-chloro-13-fluoro-14- (2-fluoro-6-methoxyphenyl) -2, 6-dimethyl-2, 3, 4a,6,7,8, 9-octahydro-11, 17- (aminosubunit) benzo [ d ]]Pyrazino [1,2-g][1]Oxa [3,7,10]Triazacyclotridecarboxylic acid-5 (1H) -one (17 mg, 38.48%). LC/MS (ESI) m/z 572[ M+H ]] ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ7.68(d,J＝37.9Hz,1H),7.47–7.33(m,1H),6.89–6.78(m,2H),6.72–6.30(m,2H),5.95–5.68(m,1H),5.06–3.96(m,9H),3.81–3.69(m,3H),3.59(d,J＝11.5Hz,1H),3.36(s,1H),2.88(s,3H),2.37–2.01(m,2H),1.52–1.34(m,3H)。

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

Compound 92:

¹ H NMR(400MHz,CDCl ₃ )δ7.81–7.72(m,3H),7.31(dd,J＝15.0,8.2Hz,1H),6.92–6.73(m,2H),6.70–6.56(m,1H),6.48–6.32(m,1H),5.79(d,J＝10.4Hz,1H),5.70–5.55(m,1H),4.94–4.26(m,6H),4.06–3.52(m,3H),3.19–2.86(m,3H),2.76–2.56(m,3H),1.53–1.40(m,3H)。

compound 93:

¹ H NMR(400MHz,CDCl ₃ )δ7.65–7.39(m,1H),7.32–7.26(m,1H),6.95–6.80(m,1H),6.75–6.27(m,3H),5.78(dd,J＝30.3,10.5Hz,1H),4.90–3.99(m,8H),3.65–3.50(m,1H),3.39–3.22(m,2H),2.88(d,J＝9.4Hz,2H),2.27–1.99(m,2H),1.55–1.37(m,3H)。

compound 94a:

¹ H NMR(400MHz,DMSO-d ₆ )δ10.26(s,1H),7.80(d,J＝20.3Hz,2H),7.36(dd,J＝15.4,8.2Hz,1H),6.94–6.78(m,3H),6.20(d,J＝15.8Hz,1H),5.81–5.71(m,1H),5.32–4.30(m,4H),4.11–3.88(m,5H),3.14–3.05(m,1H),2.34–2.28(m,1H),2.14–2.04(m,1H),1.40(br,3H)。

compound 94b:

¹ H NMR(400MHz,DMSO-d ₆ )δ10.27(s,1H),7.96–7.67(m,2H),7.35(dd,J＝15.5,8.2Hz,1H),6.95–6.66(m,3H),6.20(d,J＝18.4Hz,1H),5.77(d,J＝12.3Hz,1H),5.43–4.44(m,4H),4.02–3.68(m,5H),3.22–2.95(m,1H),2.39–2.19(m,1H),2.16–2.01(m,1H),1.41(br,3H)。

compound 95:

¹ H NMR(400MHz,DMSO-d ₆ )δ10.21(s,1H),8.64–8.51(m,1H),7.93–7.73(m,1H),7.35(dd,J＝15.4,8.3Hz,1H),6.95–6.78(m,3H),6.22(t,J＝18.3Hz,1H),5.83–5.73(m,1H),4.94–4.44(m,3H),4.43–4.11(m,3H),4.10–3.88(m,2H),2.84–2.56(m,2H),1.98(dt,J＝12.9,7.1Hz,2H),1.41(ddd,J＝6.8,5.1,3.3Hz,3H)。

compound 96:

¹ H NMR(400MHz,CDCl ₃ )δ7.84–7.76(m,1H),7.43(q,J＝8.3Hz,1H),6.88–6.81(m,2H),6.39(d,J＝16.5Hz,1H),6.04–5.93(m,1H),5.83–5.77(m,1H),4.46(d,J＝13.0Hz,2H),3.83–3.75(m,4H),3.73–3.65(m,2H),2.86–2.74(m,2H),2.67(s,3H),2.64–2.57(m,2H),2.42–2.35(m,7H),2.01(s,2H),1.58–1.56(m,3H),1.44–1.41(m,1H),1.33–1.30(m,1H)。

compound 98:

¹ HNMR(400MHz,MeOD-d ₄ )δ7.80(s,1H),7.51(dd,J＝15.2,8.4Hz,1H),7.00(t,J＝11.6Hz,2H),6.88(t,J＝8.7Hz,1H),6.41–6.32(m,1H),5.91(dd,J＝17.1,15.5Hz,2H),4.58(s,2H),4.29(d,J＝14.2Hz,1H),3.94(d,J＝12.0Hz,1H),3.79(d,J＝6.9Hz,3H),3.48(d,J＝1.6Hz,1H),3.19–3.09(m,3H),3.03–2.95(m,2H),2.79(d,J＝44.6Hz,5H),2.51–2.34(m,7H),2.09(d,J＝14.8Hz,1H)。

compound 99:

¹ H NMR(400MHz,DMSO-d ₆ )δ7.94(dd,J＝130.8,58.1Hz,1H),7.39–7.31(m,1H),7.02–6.93(m,1H),6.82(dd,J＝21.7,8.7Hz,2H),6.25(d,J＝17.0Hz,1H),5.83(d,J＝10.6Hz,1H),5.49(t,J＝11.7Hz,1H),4.96(dd,J＝14.9,7.9Hz,1H),4.63(d,J＝9.0Hz,1H),4.48–4.30(m,2H),4.21(s,1H),3.98(dd,J＝58.5,14.1Hz,3H),3.22–3.00(m,4H),2.86(s,1H),2.67(s,2H),2.13–1.88(m,1H)。

compound 101:

¹ H NMR(400MHz,DMSO)δ7.84(d,J＝29.9Hz,1H),7.61–7.51(m,1H),7.08(d,J＝8.5Hz,1H),7.04–6.88(m,2H),6.26(dd,J＝16.7,2.0Hz,1H),5.85(t,J＝12.1Hz,1H),5.49(s,1H),4.95(s,1H),4.67(d,J＝10.5Hz,1H),4.48–4.33(m,2H),4.31–3.98(m,3H),3.84(d,J＝12.6Hz,1H),3.77(dd,J＝6.1,3.2Hz,3H),3.72–3.44(m,2H),3.18(ddd,J＝46.5,35.9,11.3Hz,3H),2.88(d,J＝7.0Hz,2H),2.69(t,J＝5.6Hz,1H),1.94(dd,J＝58.6,51.2Hz,1H)。

compound 108:

¹ H NMR(400MHz,CD ₃ OD)δ8.11–7.78(m,1H),7.55–7.48(m,1H),7.01–6.97(m,1H),6.94–6.82(m,2H),6.36(d,J＝17.6Hz,1H),5.94–5.84(m,1H),4.62–4.54(m,1H),4.50–4.30(m,2H),4.27–4.11(m,2H),3.90–3.66(m,5H),3.57–3.38(m,2H),3.22–2.98(m,9H),2.85–2.76(m,2H),2.16–2.03(m,2H),1.93–1.59(m,8H)。

compound 110A:

¹ H NMR(400MHz,MeOD)δ8.06–7.70(m,1H),7.31(t,J＝8.0Hz,1H),7.02–6.73(m,4H),6.37(d,J＝16.3Hz,1H),5.89(d,J＝10.5Hz,1H),5.06(s,1H),4.67–4.38(m,4H),4.22(d,J＝14.7Hz,2H),4.00(d,J＝12.3Hz,2H),3.77–3.55(m,1H),3.24–3.04(m,3H),3.00(s,1H),2.81(s,2H),2.07(d,J＝14.5Hz,1H)。

compound 110B:

¹ H NMR(400MHz,MeOD)δ7.95(s,1H),7.32(t,J＝7.9Hz,1H),7.08–6.74(m,4H),6.36(d,J＝16.6Hz,1H),5.90(d,J＝10.6Hz,1H),5.04(s,1H),4.60–4.37(m,4H),4.23(d,J＝15.0Hz,2H),4.07–3.79(m,2H),3.72–3.59(m,1H),3.26–3.12(m,3H),3.01(s,2H),2.77(s,1H),2.37–2.08(m,1H)。

compound 111:

¹ H NMR(400MHz,DMSO)δ9.73(s,1H),7.80(t,J＝15.4Hz,1H),7.30(t,J＝7.8Hz,1H),7.19–7.09(m,1H),7.01–6.88(m,3H),6.26(d,J＝17.6Hz,1H),5.85(t,J＝12.3Hz,1H),5.00–4.62(m,2H),4.42(dd,J＝20.9,11.4Hz,2H),4.25(d,J＝14.1Hz,1H),4.19–4.01(m,2H),3.95–3.80(m,1H),3.69–3.49(m,2H),3.27–3.00(m,3H),2.88(d,J＝7.1Hz,2H),2.67(d,J＝5.6Hz,1H),1.98(dd,J＝32.3,23.0Hz,1H)。

compound 112:

¹ H NMR(400MHz,MeOD)δ8.25(d,J＝220.2Hz,1H),7.51(dd,J＝15.2,8.1Hz,1H),7.08–6.83(m,3H),6.38(d,J＝15.7Hz,1H),5.90(d,J＝9.9Hz,1H),4.77(d,J＝11.3Hz,2H),4.65–4.33(m,4H),3.99(s,1H),3.78(d,J＝1.6Hz,3H),3.24–3.06(m,3H),2.91(s,3H),2.80–2.51(m,7H),2.17(s,2H),1.83–1.44(m,8H)。

compound 113A:

¹ H NMR(400MHz,MeOD)δ7.93(s,1H),7.23(dd,J＝8.3,3.8Hz,2H),7.04–6.79(m,3H),6.36(d,J＝16.7Hz,1H),5.89(d,J＝10.6Hz,1H),5.67(t,J＝11.4Hz,1H),4.61–4.38(m,4H),4.23(d,J＝14.9Hz,2H),3.98(dd,J＝26.1,12.1Hz,1H),3.80(d,J＝10.8Hz,1H),3.71–3.59(m,1H),3.28–3.09(m,3H),3.00(s,2H),2.83(d,J＝51.5Hz,2H),2.29–2.10(m,1H)。

compound 113B:

¹ H NMR(400MHz,MeOD)δ7.87(d,J＝85.9Hz,1H),7.22(d,J＝8.3Hz,2H),7.03–6.86(m,3H),6.37(d,J＝16.6Hz,1H),5.88(t,J＝10.1Hz,1H),5.64(t,J＝11.4Hz,1H),4.58(s,3H),4.22(d,J＝15.2Hz,2H),4.04–3.89(m,2H),3.66(s,1H),3.48(s,1H),3.13(t,J＝24.1Hz,3H),3.03–2.93(m,2H),2.83(s,2H),2.10–2.03(m,1H)。

compound 114:

¹ H NMR(400MHz,MeOD)δ7.99(s,1H),7.58–7.51(m,1H),7.43–7.24(m,3H),6.95(ddd,J＝48.6,16.7,10.7Hz,1H),6.36(d,J＝16.7Hz,1H),5.90(d,J＝10.6Hz,1H),5.69(d,J＝11.5Hz,1H),4.76(dd,J＝19.2,8.5Hz,2H),4.63–4.38(m,3H),4.24(dd,J＝14.8,5.9Hz,2H),4.07–3.93(m,1H),3.87–3.32(m,3H),3.27–3.14(m,2H),3.02–2.77(m,3H),2.20(dd,J＝60.9,11.3Hz,1H)。

compound 115:

¹ H NMR(400MHz,MeOD)δ7.98(s,1H),7.10–6.86(m,3H),6.78–6.70(m,1H),6.36(d,J＝16.7Hz,1H),5.90(d,J＝10.4Hz,1H),5.68(t,J＝11.6Hz,1H),4.79–4.71(m,1H),4.58–4.39(m,3H),4.23(d,J＝15.6Hz,2H),4.02(d,J＝12.9Hz,1H),3.89–3.47(m,2H),3.29–3.08(m,3H),3.01(s,2H),2.82(d,J＝31.4Hz,2H),2.30–2.08(m,1H)。

compound 116:

¹ HNMR(400MHz,MeOD-d ₄ )δ7.78(d,J＝8.3Hz,1H),7.49(t,J＝7.1Hz,1H),7.26–7.14(m,3H),7.06–6.86(m,2H),6.38(d,J＝16.7Hz,1H),5.91(d,J＝10.5Hz,1H),5.04(s,2H),4.81–4.69(m,1H),4.58–4.47(m,2H),4.33–4.15(m,2H),4.09–3.79(m,2H),3.66(d,J＝7.1Hz,1H),3.35(s,1H),3.26–3.09(m,2H),2.80(d,J＝9.3Hz,1H),2.32–2.12(m,2H),2.03(d,J＝5.4Hz,1H),1.60(s,1H)。

compound 117:

¹ H NMR(400MHz,MeOD)δ8.15(s,1H),8.08–7.85(m,2H),7.35(dt,J＝15.0,7.0Hz,2H),7.10–6.79(m,1H),6.37(d,J＝16.7Hz,1H),5.90(d,J＝10.6Hz,1H),5.70(s,1H),4.79–4.72(m,1H),4.53(dd,J＝26.4,15.1Hz,3H),4.24(d,J＝15.4Hz,2H),4.06–3.85(m,2H),3.67(s,1H),3.18(dd,J＝36.0,19.9Hz,3H),3.02(s,2H),2.93–2.74(m,2H),2.36–2.14(m,1H)。

compound 118:

¹ HNMR(400MHz,DMSO-d ₆ )δ12.67(s,1H),8.21(s,1H),7.92–7.63(m,2H),7.35(t,J＝7.5Hz,1H),7.21(d,J＝7.2Hz,1H),6.94(dd,J＝16.8,10.7Hz,1H),6.27(d,J＝16.7Hz,1H),5.85(t,J＝12.3Hz,1H),4.98(s,1H),4.68(d,J＝8.0Hz,1H),4.48–4.26(m,3H),4.20–4.04(m,2H),3.95–3.82(m,1H),3.76–3.50(m,3H),3.24–3.02(m,2H),2.89(s,3H),2.06–1.98(m,1H)。

compound 122:

¹ H NMR(400MHz,DMSO)δ8.10(d,J＝7.7Hz,1H),7.93(t,J＝10.4Hz,2H),7.63(d,J＝6.5Hz,1H),7.46(d,J＝7.3Hz,1H),7.33(s,2H),7.03–6.83(m,1H),6.27(d,J＝17.0Hz,1H),5.88(d,J＝10.9Hz,1H),4.88(d,J＝77.4Hz,1H),4.67(s,1H),4.38(dd,J＝36.9,24.7Hz,3H),4.06(d,J＝90.2Hz,2H),3.74(dd,J＝85.1,42.9Hz,3H),3.28–3.03(m,3H),2.90(s,2H),2.70(d,J＝16.0Hz,1H),2.16–1.93(m,4H)。

compound 123:

¹ H NMR(400MHz,MeOD)δ8.13(d,J＝8.1Hz,1H),8.09–8.03(m,1H),7.98(s,1H),7.66(t,J＝7.6Hz,1H),7.50(dd,J＝19.9,8.0Hz,2H),7.06–6.82(m,1H),6.37(d,J＝16.9Hz,1H),5.90(d,J＝10.6Hz,1H),5.04(s,1H),4.65–4.39(m,4H),4.25(d,J＝15.3Hz,2H),4.15–3.78(m,2H),3.67(s,1H),3.29–3.14(m,3H),3.02(s,2H),2.81(d,J＝15.0Hz,1H),2.23(d,J＝50.0Hz,1H)。

compound 125:

¹ H NMR(400MHz,MeOD)δ8.13(d,J＝8.2Hz,1H),8.09–8.03(m,1H),7.86(d,J＝53.1Hz,1H),7.66(t,J＝7.7Hz,1H),7.55–7.43(m,2H),6.96–6.82(m,1H),6.36(d,J＝16.7Hz,1H),5.89(dd,J＝10.6,1.6Hz,1H),5.38(s,1H),4.53(d,J＝39.9Hz,4H),4.19(dd,J＝62.2,19.5Hz,4H),3.70(s,2H),3.15(d,J＝64.5Hz,2H),2.41(dd,J＝66.4,14.2Hz,2H)。

compound 127:

¹ H NMR(400MHz,MeOD)δ8.14(d,J＝8.3Hz,1H),8.10–8.04(m,1H),8.01(d,J＝4.3Hz,1H),7.67(t,J＝7.7Hz,1H),7.55–7.43(m,2H),7.08–6.82(m,1H),6.37(d,J＝16.8Hz,1H),6.03(s,1H),5.90(d,J＝10.6Hz,1H),4.58(s,5H),4.33–4.17(m,2H),4.00(dd,J＝35.6,17.3Hz,1H),3.72(dt,J＝13.3,6.6Hz,1H),3.26–3.17(m,2H),3.12(d,J＝13.1Hz,2H),3.05–2.94(m,2H),2.82(d,J＝11.0Hz,2H),2.54(d,J＝6.4Hz,6H),2.22(dd,J＝40.4,14.1Hz,1H)。

compound 132:

¹ H NMR(400MHz,CDCl ₃ )δ8.02(d,J＝7.3Hz,1H),7.94–7.69(m,2H),7.65–7.49(m,2H),7.48–7.32(m,2H),7.02–6.87(m,1H),6.51(d,J＝16.9Hz,1H),5.93(d,J＝9.3Hz,1H),5.21–5.07(m,1H),4.95–4.57(m,1H),4.54–4.27(m,3H),4.19–3.97(m,2H),3.87–3.58(m,2H),3.30–3.18(m,1H),3.15–2.90(m,5H),2.81–2.66(m,1H),2.44–2.31(m,1H)。

example 10:

2- (3-propenoyl-15-chloro-13-fluoro-14- (2-fluoro-6-methoxyphenyl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatrideca-2-yl) acetonitrile (compound 97)

Step 1: 3-amino-2, 2' -difluoro-6 ' -methoxy- [1,1' -biphenyl ] -4-carboxylic acid

To 2-amino-4-bromo-3-fluorobenzoic acid (10.00 g,43.00 mmol), 2-fluoro-6-methoxyphenylboronic acid (36.00 g,213.00 mmol) and Na ₂ CO ₃ (27.00 g,258.00 mmol) Pd (PPh) was added to a mixture of DMSO (200 mL) ₃ ) ₄ (2.5 g,2.15 mmol). The mixture was degassed and backfilled with nitrogen multiple times. The mixture was stirred at 110 ℃ overnight. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added. The organic layer was discarded and 1M HCl solution was added to the aqueous phase to adjust to pH<3. The aqueous phase was extracted with ethyl acetate (200 ml x 2), the combined organic layers were washed with brine, and dried over Na ₂ SO ₄ Dried and concentrated in vacuo to give 3-amino-2, 2' -difluoro-6 ' -methoxy- [1,1' -biphenyl as a yellow solid]-4-formic acid (10 g,84% yield). LC/MS (ESI) m/z 280.1[ M+H ]] ⁺ 。

Step 2: 3-amino-6-chloro-2, 2' -difluoro-6 ' -methoxy- [1,1' -biphenyl ] -4-carboxylic acid

To 3-amino-2, 2' -difluoro-6 ' -methoxy- [1,1' -biphenyl]To a solution of 4-formic acid (11.00 g,39.39 mmol) in DMF (200 mL) was added NCS (10.52 g,78.79 mmol). The reaction mixture was stirred at 100℃for 3 hours. The reaction mixture was cooled to room temperature and addedWater, the desired product residue was filtered and the filter cake was dried to give 3-amino-6-chloro-2, 2' -difluoro-6 ' -methoxy- [1,1' -biphenyl as a yellow solid ]-4-formic acid (10 g, 80.91%). LC/MS (ESI) m/z 314[ M+H ]] ⁺ 。

Step 3: 6-chloro-8-fluoro-7- (2-fluoro-6-methoxyphenyl) quinazoline-2, 4 (1H, 3H) -dione

3-amino-6-chloro-2, 2' -difluoro-6 ' -methoxy- [1,1' -biphenyl]A mixture of 4-formic acid (10.00 g,35.81 mmol) and urea (43.02 g,716.23 mmol) in N ₂ Stirring was carried out at 190℃for 3 hours. The reaction mixture was then cooled to 80 ℃ and water (50 mL) was added, the mixture was filtered and the filter cake dried to give 6-chloro-8-fluoro-7- (2-fluoro-6-methoxyphenyl) quinazoline-2, 4 (1 h,3 h) -dione (10 g, 82.44%) as a yellow solid. LC/MS (ESI) m/z 339[ M+H ]] ⁺ 。

Step 4:2,4, 6-trichloro-8-fluoro-7- (2-fluoro-6-methoxyphenyl) quinazoline

To 6-chloro-8-fluoro-7- (2-fluoro-6-methoxyphenyl) quinazoline-2, 4 (1H, 3H) -dione (10.00 g,29.52 mmol) in POCl at 0deg.C ₃ DIPEA (20 mL) was added dropwise to the solution in (200 mL). The reaction mixture was heated at 110 ℃ overnight. The reaction was concentrated and the residue was dissolved in DCM, added to ice water and extracted with DCM. The organic layer was purified by Na ₂ SO ₄ Dried, and concentrated. The residue was purified by column chromatography to give 2,4, 6-trichloro-8-fluoro-7- (2-fluoro-6-methoxyphenyl) quinazoline (5.8 g, 52.3%) as a yellow solid. LC/MS (ESI) m/z 375[ M+H ] ] ⁺ 。

Step 5:2- (cyanomethyl) -4- (2, 6-dichloro-8-fluoro-7- (2-fluoro-6-methoxyphenyl) quinazolin-4-yl) -5- (2- ((2-hydroxyethyl) (methyl) amino) -2-oxoethyl) piperazine-1-carboxylic acid tert-butyl ester

A mixture of 2,4, 6-trichloro-8-fluoro-7- (2-fluoro-6-methoxyphenyl) quinazoline (794 mg,2.12 mmol), tert-butyl 2- (cyanomethyl) -5- (2- ((2-hydroxyethyl) (methyl) amino) -2-oxoethyl) piperazine-1-carboxylate (480 mg,1.41 mmol) and DIPEA (406 mg,4.23 mmol) was dissolved in anhydrous dioxane (10 mL). The mixture is put under N ₂ Stirring is carried out at 50℃for 16 hours. The reaction mixture was cooled to room temperature, diluted with ice water, extracted with EA, the organic layer was washed with brine and concentrated in vacuo. The residue was purified by column chromatography to give tert-butyl 2- (cyanomethyl) -4- (2, 6-dichloro-8-fluoro-7- (2-fluoro-6-methoxyphenyl) quinazolin-4-yl) -5- (2- ((2-hydroxyethyl) (methyl) amino) -2-oxoethyl) piperazine-1-carboxylate (680 mg, 70.98%) as a yellow solid. LC/MS (ESI) m/z 679[ M+H ]] ⁺ 。

Step 6: 15-chloro-2- (cyanomethyl) -13-fluoro-14- (2-fluoro-6-methoxyphenyl) -7-methyl-6-oxo-1, 2,4a,5,6,7,8, 9-octahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatridecano-3 (4H) -carboxylic acid tert-butyl ester

A mixture of tert-butyl 2- (cyanomethyl) -4- (2, 6-dichloro-8-fluoro-7- (2-fluoro-6-methoxyphenyl) quinazolin-4-yl) -5- (2- ((2-hydroxyethyl) (methyl) amino) -2-oxoethyl) piperazine-1-carboxylate (680 mg,1.00 mmol) and KF (29 mg,5.00 mmol) in anhydrous DMSO (30 mL) was reacted in N ₂ Stirred overnight at 120 ℃. The reaction was cooled to room temperature, diluted with water and extracted with EA. The organic layer was washed with brine and concentrated in vacuo. The residue was purified by column chromatography to give 15-chloro-2- (cyanomethyl) -13-fluoro-14- (2-fluoro-6-methoxyphenyl) -7-methyl-6-oxo-1, 2,4a,5,6,7,8, 9-octahydro-11, 17- (aminosubunit) benzo [ d ] as a yellow solid]Pyrazino [1,2-g][1]Oxa-type[3,7,11]Triazacyclotridecarboxylic acid tert-butyl ester (350 mg, 54.39%). LC/MS (ESI) m/z 643[ M+H ]] ⁺ 。

Step 7:2- (15-chloro-13-fluoro-14- (2-fluoro-6-methoxyphenyl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatridecan-2-yl) acetonitrile

To 15-chloro-2- (cyanomethyl) -13-fluoro-14- (2-fluoro-6-methoxyphenyl) -7-methyl-6-oxo-1, 2,4a,5,6,7,8, 9-octahydro-11, 17- (aminosubunit) benzo [ d ]]Pyrazino [1,2-g ][1]Oxa [3,7,11]]To a solution of t-butyl triazatridec-3 (4H) -carboxylate (350 mg,0.54 mmol) in DCM (10 mL) was added TFA (1 mL) and the mixture stirred at room temperature for 2H. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography to give 2- (15-chloro-13-fluoro-14- (2-fluoro-6-methoxyphenyl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminosubunit) benzo [ d ] as a yellow solid]Pyrazino [1,2-g][1]Oxa [3,7,11]]Triazacyclotridecan-2-yl) acetonitrile (180 mg, 60.91%). LC/MS (ESI) m/z 543[ M+H ]] ⁺ 。

Step 8:2- (3-propenoyl-15-chloro-13-fluoro-14- (2-fluoro-6-methoxyphenyl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatrideca-2-yl) acetonitrile

To 2- (15-chloro-13-fluoro-14- (2-fluoro-6-methoxyphenyl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminosubunit) benzo [ d ] at 0 ℃]Pyrazino [1,2-g][1]Oxa [3,7,11]]To a solution of triazacyclotridecarbon-2-yl) acetonitrile (180 mg,0.33 mmol) and DIPEA (128 mg,0.99 mmol) in DCM (5 mL) was added acryloyl chloride (60 mg,0.66 mmol). The reaction was carried out at room temperature Stirring for 1.5 hours. Ice water was added to the mixture, extracted with DCM and the organic layer was extracted over Na ₂ SO ₄ Drying and concentrating. The residue was purified by column chromatography to give the title compound by preparative HPLC (column: YMC-actual three C18 x 21mm, mecn/H with 0.1% fa ₂ O) further purification to give 2- (3-propenoyl-15-chloro-13-fluoro-14- (2-fluoro-6-methoxyphenyl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminosubunit) benzo [ d)]Pyrazino [1,2-g][1]Oxa [3,7,11 ]]Triazacyclotridec-2-yl) acetonitrile (8.6 mg, 4.35%). LC/MS (ESI) m/z 597[ M+H ]] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ8.05–7.71(m,1H),7.56(dd,J＝15.5,8.3Hz,1H),7.07(d,J＝8.5Hz,1H),7.02(d,J＝8.7Hz,1H),6.99–6.91(m,1H),6.32–6.16(m,1H),5.83(d,J＝10.8Hz,1H),5.03–4.89(m,1H),4.39(ddd,J＝72.7,52.1,9.4Hz,4H),4.05(d,J＝14.3Hz,1H),3.90(d,J＝12.8Hz,1H),3.79–3.75(m,3H),3.63–3.47(m,1H),3.24–2.94(m,4H),2.86(s,2H),2.69(d,J＝5.9Hz,2H),2.01(dd,J＝52.0,9.0Hz,1H)。

Example 11:

2- (3-propenoyl-15-chloro-13-fluoro-14- (2-fluoro-6-methoxyphenyl) -6-methyl-5-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,10] triazatrideca-2-yl) acetonitrile (Compound 100)

Step 1:5- (2- (tert-butoxy) -1-cyano-2-oxoethyl) pyrazine-2-carboxylic acid methyl ester

To a solution of tert-butyl 2-cyanoacetate (25.00 g,177.09 mmol) in THF (800 mL) was added t-BuOK (19.87 g,177.09 mmol) at 0deg.C. The mixture was stirred at room temperature for 0.5 hours, then 5-chloropyrazine was added Methyl oxazine-2-carboxylate (20.37 g,118.06 mmol) the reaction mixture was stirred at 80℃for 16 h. The reaction was cooled to room temperature. The yellow solid was filtered and the solid was dried in vacuo to give methyl 5- (2- (tert-butoxy) -1-cyano-2-oxoethyl) pyrazine-2-carboxylate (25 g, 76.36%) as a yellow solid. LC/MS (ESI) M/z 278 (M+H) ⁺ 。

Step 2:5- (cyanomethyl) pyrazine-2-carboxylic acid methyl ester

A mixture of methyl 5- (2- (tert-butoxy) -1-cyano-2-oxoethyl) pyrazine-2-carboxylate (24.00 g,86.55 mmol) and p-toluenesulfonic acid (14.90 g,86.55 mmol) in toluene (800 mL) was heated at 110℃for 3 h. TLC showed no starting material left. The reaction mixture was concentrated by H ₂ O (200 mL) was quenched, extracted with EA and the organic layer was extracted with saturated NaHCO ₃ Washing with Na ₂ SO ₄ Dried, filtered and concentrated to give the crude product, which was further purified by column chromatography to give methyl 5- (cyanomethyl) pyrazine-2-carboxylate (9.5 g, 61.95%) as a yellow solid. LC/MS (ESI) M/z 178 (M+H) ⁺ 。

Step 3:5- (cyanomethyl) -5, 6-dihydropyrazine-1, 2 (4H) -dicarboxylic acid 1- (tert-butyl) 2-methyl ester

To a mixture of methyl 5- (cyanomethyl) pyrazine-2-carboxylate (9.50 g,53.62 mmol) in ethyl acetate (500 mL) was added Boc ₂ O (17.2 mL,80.44 mmol), pd/C (4 g,10% Pd carbon), and the reaction was stirred with a hydrogen balloon at 50℃for 16 hours. The reaction was incomplete, replaced with a fresh hydrogen balloon, and the reaction mixture was stirred at 50 ℃ for an additional 24 hours. The reaction was completed, the mixture was filtered, water was added to the filtrate and extracted twice with EA. The organic layer was washed with brine and concentrated. The residue was purified by column chromatography to give a yellow solid1- (cyanomethyl) -5, 6-dihydropyrazine-1, 2 (4H) -dicarboxylic acid 1- (tert-butyl) 2-methyl ester (12 g, 79.55%). LC/MS (ESI) M/z 282 (M+H) ⁺ 。

Step 4:5- (cyanomethyl) piperazine-1, 2-dicarboxylic acid 1- (tert-butyl) 2-methyl ester

To a solution of 1- (tert-butyl) 2-methyl 5- (cyanomethyl) -5, 6-dihydropyrazine-1, 2 (4H) -dicarboxylic acid (10.00 g,35.55 mmol) in MeOH (100 mL) was added AcOH (20 mL) and sodium cyanoborohydride (4.47 g,71.09 mmol). The reaction mixture was taken up in N ₂ Stirring was carried out at 30℃for 16 hours. The reaction mixture was concentrated and saturated NaHCO was added ₃ The solution was extracted twice with EA. The organic layer was washed with brine and concentrated in vacuo. The residue was purified by column chromatography to give 1- (tert-butyl) 2-methyl 5- (cyanomethyl) piperazine-1, 2-dicarboxylic acid as a yellow solid (8 g, 79.43%). LC/MS (ESI) M/z 284 (M+H) ⁺ 。

Step 5: 4-benzyl 5- (cyanomethyl) piperazine-1, 2, 4-tricarboxylic acid 1- (tert-butyl) 2-methyl ester

For 1- (tert-butyl) 2-methyl 5- (cyanomethyl) piperazine-1, 2-dicarboxylate (8.00 g,28.24 mmol) and K ₂ CO ₃ (11.71 g,84.71 mmol) in MeCN (80 mL) and H ₂ To the mixture in O (50 mL) was added benzyl chloroformate (9.63 g,56.47 mmol) dropwise at 0deg.C. The reaction mixture was stirred at 0 ℃ for 2 hours. The reaction mixture was extracted twice with EA, and the organic layer was washed with brine, dried and concentrated. The residue was purified by column chromatography to give 4-benzyl 5- (cyanomethyl) piperazine-1, 2, 4-tricarboxylic acid 1- (tert-butyl) 2-methyl ester (8 g, 67.87%) as a white solid. LC/MS (ESI) M/z 418 (M+H) ⁺ 。

Step 6:4- ((benzyloxy) carbonyl) -1- (tert-butoxycarbonyl) -5- (cyanomethyl) piperazine-2-carboxylic acid

A solution of 4-benzyl 1- (tert-butyl) 2-methyl 5- (cyanomethyl) piperazine-1, 2, 4-carboxylate (8.00 g,19.16 mmol) in MeOH (45 mL) and THF (30 mL), and a solution of NaOH (0.77 g,19.16 mmol) in water (14 mL) was added to the mixture. The mixture was stirred at room temperature for 16 hours. The mixture was concentrated, the residue was dissolved in water (10 mL), adjusted to ph=4 with HCl (2.0N), the desired product was precipitated, filtered to give a solid, which was dissolved in DCM, over Na ₂ SO ₄ Dried, filtered and the filtrate concentrated to give 4- ((benzyloxy) carbonyl) -1- (tert-butoxycarbonyl) -5- (cyanomethyl) piperazine-2-carboxylic acid (7 g, 90.54%) as a colorless oil. LC/MS (ESI) M/z 404 (M+H) ⁺ 。

Step 7:2- (cyanomethyl) -5- ((3-hydroxypropyl) (methyl) carbamoyl) piperazine-1, 4-dicarboxylic acid 1-benzyl ester 4- (tert-butyl ester)

To a mixture of 4- ((benzyloxy) carbonyl) -1- (tert-butoxycarbonyl) -5- (cyanomethyl) piperazine-2-carboxylic acid (2.00 g,4.96 mmol), HATU (3.77 g,9.92 mmol) and DIPEA (1.92 g,14.87 mmol) in DMF (30 mL) was added 3- (methylamino) propan-1-ol (0.66 g,7.44 mmol) at 0 ℃. The reaction mixture was stirred at room temperature for 16 hours. Ice water was added to the reaction mixture and extracted twice with EA. The organic layer was washed with brine and concentrated. The residue was purified by column chromatography to give 1-benzyl 2- (cyanomethyl) -5- ((3-hydroxypropyl) (methyl) carbamoyl) piperazine-1, 4-dicarboxylic acid 4- (tert-butyl) ester (1.5 g, 63.76%) as a yellow solid. LC/MS (ESI) M/z 475 (M+H) ⁺ 。

Step 8:2- (cyanomethyl) -5- ((3-hydroxypropyl) (methyl) carbamoyl) piperazine-1-carboxylic acid benzyl ester

A mixture of 1-benzyl 4- (tert-butyl) 2- (cyanomethyl) -5- ((3-hydroxypropyl) (methyl) carbamoyl) piperazine-1, 4-dicarboxylic acid (1.50 g,3.16 mmol) in HCl/dioxane (4N, 30 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated to give benzyl 2- (cyanomethyl) -5- ((3-hydroxypropyl) (methyl) carbamoyl) piperazine-1-carboxylate (1.18 g, 100%), which was used directly in the next step without further purification. LC/MS (ESI) m/z 375[ M+H ] ] ⁺ 。

Step 9:2- (cyanomethyl) -4- (2, 6-dichloro-8-fluoro-7- (2-fluoro-6-methoxyphenyl) quinazolin-4-yl) -5- ((3-hydroxypropyl) (methyl) carbamoyl) piperazine-1-carboxylic acid benzyl ester

A mixture of 2,4, 6-trichloro-8-fluoro-7- (2-fluoro-6-methoxyphenyl) quinazoline (1.50 g,4.01 mmol), benzyl 2- (cyanomethyl) -5- ((3-hydroxypropyl) (methyl) carbamoyl) piperazine-1-carboxylate (1.00 g,2.67 mmol) and DIEA (1.33 mL,8.01 mmol) in anhydrous dioxane (30 mL). The mixture is put under N ₂ Stirring was carried out at 50℃for 18 hours. The mixture was cooled to room temperature, poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were concentrated in vacuo. The residue was purified by flash column chromatography to give the title compound (700 mg, 36.73%) as a yellow solid. LC/MS (ESI) m/z 713[ M+H ]] ⁺ 。

Step 10: 15-chloro-2- (cyanomethyl) -13-fluoro-14- (2-fluoro-6-methoxyphenyl) -6-methyl-5-oxo-1, 2,4a,5,6,7,8, 9-octahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,10] triazatridecane-3 (4H) -carboxylic acid benzyl ester

Go to 2-Benzyl (cyanomethyl) -4- (2, 6-dichloro-8-fluoro-7- (2-fluoro-6-methoxyphenyl) quinazolin-4-yl) -5- ((3-hydroxypropyl) (methyl) carbamoyl) piperazine-1-carboxylate (700 mg,0.98 mmol) in anhydrous DMSO (10 mL) was added KF (1500 mg,9.81 mmol). The mixture was stirred at 120℃for 18 hours. The reaction mixture was cooled to room temperature, poured into brine (40 mL) and extracted with ethyl acetate (30 mL x 3). The organic layers were combined and concentrated in vacuo. The residue was purified by flash column chromatography to give 15-chloro-2- (cyanomethyl) -13-fluoro-14- (2-fluoro-6-methoxyphenyl) -6-methyl-5-oxo-1, 2,4a,5,6,7,8, 9-octahydro-11, 17- (aminosubunit) benzo [ d ] ]Pyrazino [1,2-g][1]Oxa [3,7,10]Triazacyclotridecarboxylic acid benzyl ester (340 mg, 51.19%). LC/MS (ESI) m/z 677[ M+H ]] ⁺ 。

Step 11:2- (15-chloro-13-fluoro-14- (2-fluoro-6-methoxyphenyl) -6-methyl-5-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,10] triazatridecan-2-yl) acetonitrile

To 15-chloro-2- (cyanomethyl) -13-fluoro-14- (2-fluoro-6-methoxyphenyl) -6-methyl-5-oxo-1, 2,4a,5,6,7,8, 9-octahydro-11, 17- (aminosubunit) benzo [ d ]]Pyrazino [1,2-g][1]Oxa [3,7,10]To a mixture of benzyl triazacyclotridecarbonate-3 (4H) -carboxylate (340 mg,0.5 mmol) in MeOH (25 mL) was added Pd/C (300 mg,10% Pd carbon). H to be reacted at 1atm ₂ Stirred overnight at room temperature. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give 2- (15-chloro-13-fluoro-14- (2-fluoro-6-methoxyphenyl) -6-methyl-5-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminosubunit) benzo [ d)]Pyrazino [1,2-g][1]Oxa [3,7,10]Triazacyclotridecan-2-yl) acetonitrile (272 mg, 100%). The residue was used directly in the next step. LC/MS (ESI) m/z 543[ M+H ]] ⁺ 。

Step 12:2- (3-propenoyl-15-chloro-13-fluoro-14- (2-fluoro-6-methoxyphenyl) -6-methyl-5-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,10] triazatrideca-2-yl) acetonitrile

At N ₂ To 2- (15-chloro-13-fluoro-14- (2-fluoro-6-methoxyphenyl) -6-methyl-5-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminosubunit) benzo [ d ] at 0 ℃]Pyrazino [1,2-g][1]Oxa [3,7,10]To a solution of triazacyclotridecarbon-2-yl) acetonitrile (250 mg,0.46 mmol) and DIEA (0.23 mL,1.38 mmol) in DCM (5 mL) was added acryloyl chloride (0.07 mL,0.92 mmol). The reaction mixture was stirred at room temperature for 1.5 hours. The mixture was poured onto NaHCO ₃ In an aqueous solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO ₄ ) And concentrated in vacuo. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18X 21mm, MECN/H with 0.1% FA ₂ O) to give 2- (3-propenoyl-15-chloro-13-fluoro-14- (2-fluoro-6-methoxyphenyl) -6-methyl-5-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminosubunit) benzo [ d ]]Pyrazino [1,2-g][1]Oxa [3,7,10]Triazacyclotridecarbon-2-yl) acetonitrile (3.5 mg compound 100a and 2.3mg compound 100b, 2.11%). LC/MS (ESI) m/z 597[ M+H ]] ⁺ 。

Compound 100a:

¹ H NMR(400MHz,DMSO-d ₆ )δ7.86(dd,J＝39.0,10.7Hz,1H),7.56(dd,J＝15.5,8.4Hz,1H),7.07(dd,J＝8.3,3.6Hz,1H),6.99(ddd,J＝28.3,16.2,12.1Hz,2H),6.36–6.15(m,1H),5.80(dd,J＝24.2,11.4Hz,1H),4.95(d,J＝66.9Hz,1H),4.67(d,J＝56.1Hz,2H),4.35(d,J＝61.3Hz,4H),3.94(t,J＝11.6Hz,1H),3.76(d,J＝10.1Hz,3H),3.22–2.99(m,4H),2.78(s,2H),2.27–1.76(m,3H)。

compound 100b:

¹ H NMR(400MHz,DMSO-d ₆ )δ8.09(t,J＝37.6Hz,1H),7.56(dd,J＝15.6,8.4Hz,1H),7.08(d,J＝8.3Hz,1H),7.01(t,J＝8.6Hz,1H),6.93–6.68(m,1H),6.16(t,J＝23.7Hz,1H),5.84–5.66(m,1H),4.89–4.53(m,3H),4.41(dd,J＝29.9,18.6Hz,2H),4.27–3.82(m,3H),3.77(s,3H),3.30(s,4H),2.70(s,2H),2.23–1.74(m,3H)。

the following compounds were prepared according to the above method using different starting materials.

Compound 102:

¹ H NMR(400MHz,DMSO-d ₆ )δ8.20(s,1H),7.99(dt,J＝49.8,27.8Hz,1H),7.56(dd,J＝15.7,8.3Hz,1H),7.01(tdd,J＝27.8,19.0,9.0Hz,3H),6.35–6.08(m,1H),5.92–5.73(m,1H),5.25–4.11(m,7H),3.95(dd,J＝14.9,10.9Hz,1H),3.76(dd,J＝7.1,5.1Hz,3H),3.21–3.08(m,4H),2.83(d,J＝4.1Hz,2H),2.78–2.59(m,2H),2.23(dd,J＝20.6,8.2Hz,8H)。

example 12:

2- (14-propenoyl-4-fluoro-10-methyl-3- (naphthalen-1-yl) -11-oxo-8, 9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [4,3-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile (Compound 104)

Step 1: (2-chloro-3-fluoropyridin-4-yl) carbamic acid tert-butyl ester

To a solution of 2-chloro-3-fluoroisonicotinic acid (34 g,0.19 mol), TEA (35.63 mL,0.58 mol) and 4A (60 g) in toluene (300 mL) and t-BuOH (300 mL) was added DPPA (61.50 mL,0.29 mol). The reaction mixture was stirred at 110℃for 3 hours. The reaction was diluted with ice water and then extracted twice with EA. The combined extracts were concentrated in vacuo and the residue was purified by Biotage (0 to 20% EA/PE) to giveTo the title compound (2-chloro-3-fluoropyridin-4-yl) carbamic acid tert-butyl ester (40 g, 83.69%) as a white solid. LC/MS ESI (m/z): 319[ M+H ]] ⁺ 。

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

To a solution of tert-butyl (2-chloro-3-fluoropyridin-4-yl) carbamate (40 g,0.16 mol) in DCM (300 mL) was added HCl/dioxane (300 mL) and the reaction mixture was stirred at room temperature for 2 hours. The mixture was filtered and the filter cake was washed with saturated NaHCO ₃ The solution (500 mL) was diluted and then extracted twice with EA. The combined extracts were washed with brine and concentrated to give 2-chloro-3-fluoropyridin-4-amine. (24 g, 99%) as a yellow solid LC/MS ESI (m/z): 147[ M+H ]] ⁺ 。

Step 3: 2-chloro-3-fluoro-5-iodopyridin-4-amine

To a solution of 2-chloro-3-fluoropyridin-4-amine (24 g,0.16 mol) in acetonitrile (300 mL) was added NIS (48 g,0.19 mol) and 4-methylbenzenesulfonic acid (1.80 g,0.008 mol). The reaction mixture was stirred at 70 ℃ overnight. The mixture was diluted with ice water and then extracted twice with EA. The combined extracts were washed with brine and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0% to 20% ethyl acetate/petroleum ether to give the title compound 2-chloro-3-fluoro-5-iodopyridin-4-amine (30 g, 67.55%) as a white solid. LC/MS ESI (m/z): 273[ M+H ]] ⁺ 。

Step 4: 4-amino-6-chloro-5-fluoro-nicotinic acid ethyl ester

To 2-chloro-3-fluoro-5-iodopyridin-4-amine (30 g,0.11 mol) and TEA45.7mL,0.33 mol) in EtOH (500 mL) was added Pd (PPh) ₃ ) ₂ Cl ₂ (7.73 g,0.01 mol) and then the reaction mixture was stirred under CO at 80℃overnight. The mixture was concentrated in vacuo. The residue was triturated with MeOH (20 mL) to give 4-amino-6-chloro-5-fluoronicotinic acid ethyl ester (17 g, 70.89%) as a yellow solid. LC/MS (ESI) M/z 219 (M+H) ⁺ 。

Step 5: 4-amino-5-fluoro-6- (naphthalen-1-yl) nicotinic acid ethyl ester

To 4-amino-6-chloro-5-fluoronicotinic acid ethyl ester (17 g,77.98 mmol) and K ₂ CO ₃ (32.52 g,233.94 mmol) in dioxane (200 mL) and H ₂ To a solution of O (40 mL) was added naphthalene-1-ylboronic acid (26.8 g,155.96 mmol) and Pd (PPh) ₃ ) ₄ (9.22 g,7.80 mmol). The reaction is carried out in N ₂ Stirred overnight at 100 ℃. The reaction was diluted with ice water and then extracted twice with EA. The organic layer was separated, washed with saturated NaCl, and concentrated in vacuo. The residue was triturated with MeOH (20 mL) to give the title compound 4-amino-5-fluoro-6- (naphthalen-1-yl) nicotinic acid ethyl ester (19.8 g, 81.90%) as a white solid. LC/MS ESI (m/z): 311[ M+H ]] ⁺ 。

Step 6: 5-fluoro-6- (naphthalen-1-yl) -4- (3- (2, 2-trichloroacetyl) ureido) nicotinic acid ethyl ester

To a solution of ethyl 4-amino-5-fluoro-6- (naphthalen-1-yl) nicotinate (19.8 g,63.87 mmol) in THF (200 mL) was added 2, 2-trichloroacetyl isocyanate (31.74 g,63.87 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated to give ethyl 5-fluoro-6- (naphthalen-1-yl) -4- (3- (2, 2-trichloroacetyl) ureido) nicotinate (40 g, crude) as a yellow oil. LC/MS ESI (m/z): 498[ M+H ]] ⁺ 。

Step 7: 8-fluoro-7- (naphthalen-1-yl) pyrido [4,3-d ] pyrimidine-2, 4-diol

To a solution of 5-fluoro-6- (naphthalen-1-yl) -4- (3- (2, 2-trichloroacetyl) ureido) nicotinic acid ethyl ester (crude) (40 g,63.87 mmol) in MeOH (300 mL) was added NH ₃ MeOH (50 m, 7M). The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo. The residue was triturated with MeOH (20 mL) to give 8-fluoro-7- (naphthalen-1-yl) pyrido [4,3-d ] as a white solid]Pyrimidine-2, 4-diol (19.5 g,99.45%, two steps). LC/MS ESI (m/z): 308[ M+H ]] ⁺ 。

Step 8:2, 4-dichloro-8-fluoro-7- (naphthalen-1-yl) pyrido [4,3-d ] pyrimidine

To 8-fluoro-7- (naphthalen-1-yl) pyrido [4,3-d ] at 0deg.C]Pyrimidine-2, 4-diol (5 g,16.29 mmol) in POCl ₃ DIEA (8.7 mL,48.87 mmol) was added to the solution in (100 mL). The reaction mixture was stirred at 110℃for 3 hours. The mixture was concentrated in vacuo and the residue was slowly poured onto ice-cold saturated NaHCO ₃ In (2) stirring for 10 minutes. The mixture was extracted twice with DCM. The organic layer was separated, washed with saturated NaCl, and concentrated in vacuo. The residue was triturated with MTBE (20 mL) to give the title compound 2, 4-dichloro-8-fluoro-7- (naphthalen-1-yl) pyrido [4,3-d ] as a yellow solid]Pyrimidine (4.1 g, 73.38%). LC/MS ESI (m/z): 340[ M+MeO-Cl ] ] ⁺ 。

Step 9:2- (1- (tert-butoxycarbonyl) -5- (cyanomethyl) -4- (4-methoxybenzyl) piperazin-2-yl) acetic acid

To 5- (cyanomethyl) -2- (2-methoxy-2-oxoethyl) -4- (4-methoxybenzyl) piperaquineT-butyl oxazine-1-carboxylate (1.6 g,3.83 mmol) in MeOH (30 mL) and H ₂ To a solution of O (10 mL) was added NaOH (0.46 g,11.50 mmol). The mixture was then stirred at room temperature overnight. The mixture was concentrated and the residue was diluted with water. The resulting aqueous solution was acidified with HCl (2.0M) to ph=4-5. The resulting precipitate was isolated, dissolved in DCM, and purified by Na ₂ SO ₄ Dried, filtered and concentrated in vacuo to give 2- (1- (tert-butoxycarbonyl) -5- (cyanomethyl) -4- (4-methoxybenzyl) piperazin-2-yl) acetic acid (1.45 g, 93.78%) as a white solid.

LC/MS ESI(m/z):404[M+H] ⁺ 。

Step 10:5- (cyanomethyl) -2- (2- ((2-hydroxyethyl) (methyl) amino) -2-oxoethyl) -4- (4-methoxybenzyl) piperazine-1-carboxylic acid tert-butyl ester

To a solution of 2- (1- (tert-butoxycarbonyl) -5- (cyanomethyl) -4- (4-methoxybenzyl) piperazin-2-yl) acetic acid (1.45 g,3.59 mmol), 2- (methylamino) ethan-1-ol (0.40 g,5.39 mmol) and DIPEA (1.39 g,10.78 mmol) in DMF (30 mL) was added HATU (2.73 g,7.19 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was diluted with ice water and extracted twice with EA. The combined extracts were washed with brine and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0% to 100% ethyl acetate/petroleum ether to give tert-butyl 5- (cyanomethyl) -2- (2- ((2-hydroxyethyl) (methyl) amino) -2-oxoethyl) -4- (4-methoxybenzyl) piperazine-1-carboxylate (1.6 g, 96.67%) as a yellow solid. LC/MS ESI (m/z): 461[ M+H ] ] ⁺ 。

Step 11:2- (5- (cyanomethyl) -4- (4-methoxybenzyl) piperazin-2-yl) -N- (2-hydroxyethyl) -N-methylacetamide

To 5- (cyanomethyl) -2- (2- ((2-hydroxyethyl)To a solution of tert-butyl (methyl) (amino) -2-oxoethyl) -4- (4-methoxybenzyl) piperazine-1-carboxylate (1.6 g,3.47 mmol) in DCM (20 mL) was added HCl/dioxane (4 m,20 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo and the residue was slowly poured onto ice-cold NaHCO with stirring ₃ Is a kind of medium. The mixture was extracted twice with DCM. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified with silica gel column (0% to 15% methanol/dichloromethane) to give 2- (5- (cyanomethyl) -4- (4-methoxybenzyl) piperazin-2-yl) -N- (2-hydroxyethyl) -N-methylacetamide (350 mg, 27.95%) as a yellow oil. LC/MS ESI (m/z): 361[ M+H ]] ⁺ 。

Step 12:2- (1- (2-chloro-8-fluoro-7- (naphthalen-1-yl) pyrido [4,3-d ] pyrimidin-4-yl) -5- (cyanomethyl) -4- (4-methoxybenzyl) piperazin-2-yl) -N- (2-hydroxyethyl) -N-methylacetamide

To 2, 4-dichloro-8-fluoro-7- (naphthalen-1-yl) pyrido [4,3-d ] at 0deg.C]To a solution of pyrimidine (334 mg,0.97 mmol) and DIPEA (0.48 mL,2.91 mmol) in DCM (10 mL) was added 2- (5- (cyanomethyl) -4- (4-methoxybenzyl) piperazin-2-yl) -N- (2-hydroxyethyl) -N-methylacetamide (350 mg,0.97 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted twice with EA. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified with silica gel column (100% EA) to give 2- (1- (2-chloro-8-fluoro-7- (naphthalen-1-yl) pyrido [4, 3-d) as a yellow solid ]Pyrimidin-4-yl) -5- (cyanomethyl) -4- (4-methoxybenzyl) piperazin-2-yl) -N- (2-hydroxyethyl) -N-methylacetamide (185 mg, 28.52%). LC/MS ESI (m/z): 668[ M+H ]] ⁺ 。

Step 13:2- (4-fluoro-14- (4-methoxybenzyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-8, 9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [4,3-d ] [1] oxa [3,7,11] triazatridec-en-15-yl) acetonitrile

To 2- (1- (2-chloro-8-fluoro-7- (naphthalen-1-yl) pyrido [4, 3-d)]To a solution of pyrimidin-4-yl) -5- (cyanomethyl) -4- (4-methoxybenzyl) piperazin-2-yl) -N- (2-hydroxyethyl) -N-methylacetamide (133 mg,0.20 mmol) in toluene (10 mL) was added BINAP (25 mg,0.04 mmol), CS ₂ CO ₃ (194 mg,0.60 mmol) and Pd (OAc) ₂ (5 mg,0.02 mmol). The reaction mixture was then taken up in N ₂ Stirring was carried out at 100℃for 18 hours. The reaction mixture was concentrated and diluted with water and extracted twice with EA. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by silica gel column (100% EA) to give 2- (4-fluoro-14- (4-methoxybenzyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-8, 9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminosubunit) pyrazino [1,2-g as a yellow solid ]Pyrido [4,3-d ]][1]Oxa [3,7,11]]Triazacyclotridec-15-yl) acetonitrile (110 mg, 87.48%). LC/MS ESI (m/z): 632[ M+H ]] ⁺ 。

Step 14:2- (4-fluoro-10-methyl-3- (naphthalen-1-yl) -11-oxo-8, 9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminosubunit) pyrazino [1,2-g ] pyrido [4,3-d ] [1] oxa [3,7,11] triazatridecan-15-yl) acetonitrile

To 2- (4-fluoro-14- (4-methoxybenzyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-8, 9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminoiden) pyrazino [1,2-g]Pyrido [4,3-d ]][1]Oxa [3,7,11]]To a solution of triazacyclotridecarbon-15-yl) acetonitrile (110 mg,0.17 mmol) in TFA (5 mL) was added anisole (0.01 mL,0.04 mmol). The reaction mixture was taken up in N ₂ Stirred overnight at 40 ℃. The mixture was slowly poured into ice-cold saturated NaHCO ₃ In (3) stirring for 30 minutes. The mixture was extracted twice with DCM. 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 20% methanol in dichloromethane to give 2- (4-fluoro-10-methyl-3- (naphthalen-1-yl) -11-oxo-8, 9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminosubunit) pyrazino [1,2-g as a yellow oil ]Pyrido [4,3-d ]][1]Oxa [3,7,11]]Triazacyclotridec-15-yl) acetonitrile (45 mg, 50.52%). LC/MS ESI (m/z): 512[ M+H ]] ⁺ 。

Step 15:2- (14-propenoyl-4-fluoro-10-methyl-3- (naphthalen-1-yl) -11-oxo-8, 9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminosubunit) pyrazino [1,2-g ] pyrido [4,3-d ] [1] oxa [3,7,11] triazatridecan-15-yl) acetonitrile

To 2- (4-fluoro-10-methyl-3- (naphthalen-1-yl) -11-oxo-8, 9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminoiden) pyrazino [1,2-g at 0 ℃C]Pyrido [4,3-d ]][1]Oxa [3,7,11]]To a solution of triazacyclotridecarboxylic acid-15-yl) acetonitrile (45 mg,0.09 mmol) and DIPEA (0.05 mL,0.26 mmol) in DCM (5 mL) was added acryloyl chloride (0.02 mL,0.17 mmol). After the addition, the reaction mixture was stirred at room temperature for 2 hours. The mixture was quenched with ice water and then extracted twice with DCM. The combined extracts were washed with water and brine, dried and concentrated. The residue was purified by silica gel column (0% to 20% methanol/dichloromethane) to give a crude product which was further purified by preparative HPLC to give 2- (14-acryl-4-fluoro-10-methyl-3- (naphthalen-1-yl) -11-oxo-8, 9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminosubunit) pyrazino [1, 2-g) ]Pyrido [4,3-d ]][1]Oxa [3,7,11]]Triazacyclotridec-15-yl) acetonitrile (6.7 mg, 12.47%). LC/MS ESI (m/z): 566[ M+H ]] ⁺ 。

¹ H NMR(400MHz,MeOD)δ9.27(d,J＝20.0Hz,1H),8.10–7.94(m,2H),7.65(s,3H),7.53(dd,J＝23.4,15.6Hz,2H),7.08–6.80(m,1H),6.37(d,J＝17.1Hz,1H),5.91(d,J＝10.8Hz,1H),4.89(s,1H),4.58(s,5H),4.34–4.05(m,3H),3.68(s,1H),3.40(s,1H),3.13(s,2H),3.01–2.85(m,3H),2.12(dd,J＝37.3,24.0Hz,1H)。

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

Compound 105:

¹ H NMR(400MHz,MeOD)δ9.35(d,J＝40.3Hz,1H),8.09–7.95(m,2H),7.71–7.61(m,3H),7.55(t,J＝7.7Hz,1H),7.48(dd,J＝13.2,6.1Hz,1H),6.88–6.64(m,1H),6.42–6.14(m,1H),5.80(d,J＝10.9Hz,1H),5.12(d,J＝22.4Hz,1H),4.58(dd,J＝21.6,13.7Hz,3H),4.42–4.17(m,3H),4.04(d,J＝12.6Hz,1H),3.40(s,2H),3.14(d,J＝9.1Hz,1H),2.99(d,J＝17.1Hz,1H),2.84(d,J＝21.3Hz,3H),2.36(s,1H),2.08(d,J＝54.7Hz,1H)。

compound 106:

¹ H NMR(400MHz,MeOD)δ9.39(d,J＝52.3Hz,1H),8.10–8.04(m,1H),8.00(d,J＝7.9Hz,1H),7.72–7.61(m,3H),7.55(t,J＝7.5Hz,1H),7.47(t,J＝7.7Hz,1H),6.99–6.67(m,1H),6.41–6.21(m,1H),5.98–5.75(m,1H),5.23–5.10(m,1H),4.68–4.48(m,3H),4.30–4.22(m,1H),3.50–3.41(m,2H),3.27–3.23(m,2H),3.13–2.83(m,6H),2.68–2.50(m,7H),2.35–2.10(m,2H)。

compound 107:

¹ H NMR(400MHz,MeOD)δ9.51–8.38(m,1H),8.11–8.04(m,1H),8.00(d,J＝7.6Hz,1H),7.71–7.59(m,3H),7.59–7.52(m,1H),7.47(t,J＝7.2Hz,1H),6.99–6.79(m,1H),6.46–6.31(m,1H),6.00–5.79(m,1H),5.35–4.95(m,2H),4.71–4.48(m,3H),4.34–4.18(m,1H),3.52–3.38(m,2H),3.26–2.90(m,7H),2.90–2.79(m,3H),2.73–2.66(m,1H),2.61(s,3H),2.51(s,1H),2.22–1.98(m,1H)。

compound 129:

¹ H NMR(400MHz,MeOD)δ9.21(dd,J＝18.7,3.7Hz,1H),8.16(dd,J＝7.9,1.5Hz,1H),8.11–8.06(m,1H),7.71–7.63(m,2H),7.53(td,J＝9.0,3.3Hz,1H),6.89(dd,J＝15.9,10.0Hz,1H),6.37(d,J＝16.7Hz,1H),6.05(s,1H),5.91(d,J＝10.7Hz,1H),5.34(s,1H),4.29(s,1H),3.09(s,2H),2.87(d,J＝22.6Hz,4H),2.40(dd,J＝23.3,8.3Hz,7H),2.22–2.16(m,3H),2.03(dd,J＝11.0,6.9Hz,3H),1.69(d,J＝8.8Hz,1H),1.64–1.57(m,3H)。

compound 130:

¹ H NMR(400MHz,MeOD)δ9.21(s,1H),8.17(d,J＝6.5Hz,1H),8.12–8.06(m,1H),7.68(dt,J＝11.4,7.7Hz,2H),7.54(td,J＝8.9,5.4Hz,1H),6.97–6.79(m,1H),6.37(d,J＝16.6Hz,1H),5.96–5.87(m,1H),4.23(d,J＝18.2Hz,2H),3.74(s,1H),3.54–3.41(m,2H),3.21(dd,J＝14.4,8.0Hz,2H),2.91(d,J＝8.7Hz,6H),2.82–2.69(m,1H),2.42(d,J＝17.1Hz,2H),2.24–2.03(m,1H),1.60(s,1H),1.31(d,J＝18.1Hz,5H)。

compound 131:

¹ H NMR(400MHz,CDCl ₃ )δ9.10(d,J＝42.1Hz,1H),7.95(s,1H),7.83(d,J＝7.6Hz,1H),7.53(d,J＝8.8Hz,1H),7.46(d,J＝7.9Hz,1H),7.38(d,J＝7.9Hz,1H),7.06–6.99(m,1H),6.89–6.80(m,1H),6.61–6.50(m,1H),6.47–6.38(m,1H),5.87(d,J＝8.7Hz,1H),5.35–5.24(m,2H),4.96–4.82(m,1H),4.61–4.43(m,2H),4.33–4.21(m,1H),4.13–3.94(m,2H),3.65–3.54(m,1H),3.00–2.71(m,5H),2.30–2.20(m,1H),2.18–2.11(m,1H)。

example 13:

2- (3-propenoyl-15-chloro-13-fluoro-14- (2-fluoro-6-methoxyphenyl) -7-methyl-6-oxo-9- (2- (piperidin-1-yl) ethyl) -1,2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminoiden) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatrideca-2-yl) acetonitrile (compound 109)

Step 1: 7-bromo-8-fluoroquinazoline-2, 4 (1H, 3H) -dione

A mixture of 2-amino-4-bromo-3-fluorobenzoic acid (5 g,21.4 mmol) and urea (25.7 g,0.43 mol) was stirred at 190℃for 3 hours. The mixture was cooled to 100 ℃ and water (100 mL) was added. The mixture was stirred for 10 minutes and filtered. The filter cake was washed with water and dried under vacuum to give 7-bromo-8-fluoro-1, 2,3, 4-tetrahydroquinazoline-2, 4-dione (7.0 g,100% yield) as a grey solid, which was used directly in the next reaction without purification. MS (ESI) M/z 259/261 (M+H) ⁺ 。

Step 2: 7-bromo-2, 4-dichloro-8-fluoroquinazoline

DIPEA (10 mL,27.0 mol) at 0deg.C in POCl ₃ To a solution in (100 mL) was added 7-bromo-8-fluoro-1, 2,3, 4-tetrahydroquinazoline-2, 4-dione (7.0 g,27.0 mmol) in portions, and the mixture was stirred at 110℃for 16 h. The mixture was concentrated to dryness under reduced pressure. The residue was dissolved in DCM (100 mL) and the solution was added dropwise to ice water. The layers were separated and the organic layer was washed with brine, over Na ₂ SO ₄ Dried, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (eluting with PE: etoac=100:1 to 10:1) to give 7-bromo-2, 4-dichloro-8-fluoroquinazoline (4.4 g,55% yield) as a yellow solid. MS (ESI) M/z 295/297 (M+H) ⁺ 。

Step 3: (2R, 5S) -5- (cyanomethyl) -2- (2- ((2-hydroxyethyl) (methyl) amino) -2-oxoethyl) -4- (4-methoxybenzyl) piperazine-1-carboxylic acid tert-butyl ester

To 2- ((2R, 5S) -1- (tert-butoxycarbonyl) -5- (cyanomethyl) -4- (4-methoxybenzyl) piperazin-2-yl) acetic acid (400 mg,0.99 mmol) and TEA (0.51 mL,3.72 mmol) in DCM (10 mL)EDCI (470 mg,2.48 mmol) and HOBt (335 mg,2.48 mmol) were added to the mixture, then 2- (methylamino) ethanol (186 mg,2.48 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM (20 mL), washed with water and brine, and dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (eluting with DCM: meoh=30:1) to give (2 r,5 s) -5- (cyanomethyl) -2- (2- ((2-hydroxyethyl) (methyl) amino) -2-oxoethyl) -4- (4-methoxybenzyl) piperazine-1-carboxylic acid tert-butyl ester (400 mg,88% yield) as a yellow solid. MS (ESI) M/z 461 (M+H) ⁺ 。

Step 4:2- ((2 r,5 s) -5- (cyanomethyl) -4- (4-methoxybenzyl) piperazin-2-yl) -N- (2-hydroxyethyl) -N-methylacetamide

A solution of (2R, 5S) -5- (cyanomethyl) -2- (2- ((2-hydroxyethyl) (methyl) amino) -2-oxoethyl) -4- (4-methoxybenzyl) piperazine-1-carboxylic acid tert-butyl ester (400 mg,0.87 mmol) in HCl/1, 4-dioxane (10 mL) was stirred at room temperature for 2 hours. The mixture was concentrated to dryness under reduced pressure. The residue was dissolved in water (10 mL) with saturated NaHCO ₃ The aqueous solution and brine were basified and extracted with DCM (3×10 ml). The combined organic phases were washed with brine, dried over Na ₂ SO ₄ Dried, filtered and evaporated to dryness to give 2- ((2 r,5 s) -5- (cyanomethyl) -4- (4-methoxybenzyl) piperazin-2-yl) -N- (2-hydroxyethyl) -N-methylacetamide (320 mg,100% yield) as a yellow solid. MS (ESI) M/z 361 (M+H) ⁺ 。

Step 5:2- ((2 r,5 s) -1- (7-bromo-2-chloro-8-fluoroquinazolin-4-yl) -5- (cyanomethyl) -4- (4-methoxybenzyl) piperazin-2-yl) -N- (2-hydroxyethyl) -N-methylacetamide

To 7-bromo-2, 4-dichloro-8-fluoroquinazoline (526 mg, 1.7)To a solution of 8 mmol) in 1, 4-dioxane (10 mL) was added DIPEA (0.9 mL,5.56 mmol), followed by 2- ((2 r,5 s) -5- (cyanomethyl) -4- (4-methoxybenzyl) piperazin-2-yl) -N- (2-hydroxyethyl) -N-methylacetamide (320 mg,0.89 mmol) and the mixture stirred at 50 ℃ for 4 hours. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with PE: etoac=3:1) to give 2- ((2 r,5 s) -1- (7-bromo-2-chloro-8-fluoroquinazolin-4-yl) -5- (cyanomethyl) -4- (4-methoxybenzyl) piperazin-2-yl) -N- (2-hydroxyethyl) -N-methylacetamide (170 mg,27% yield) as a yellow solid. MS (ESI) M/z 619/621 (M+H) ⁺ 。

Step 6:2- ((2 s,4 ar) -14-bromo-13-fluoro-3- (4-methoxybenzyl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminoiden) benzo [ d ] pyrazino [1,2-g ] [1,3,7,11] oxatriazatrideca-2-yl) acetonitrile

To a solution of 2- ((2 r,5 s) -1- (7-bromo-2-chloro-8-fluoroquinazolin-4-yl) -5- (cyanomethyl) -4- (4-methoxybenzyl) piperazin-2-yl) -N- (2-hydroxyethyl) -N-methylacetamide (150 mg,0.24 mmol) in THF (10 mL) was added NaH (19.4 mg,0.48mmol,60% dispersed in mineral oil) in portions at 0 ℃ and the mixture was stirred at room temperature for 1 hour. The reaction was quenched with ice water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with brine, dried over Na ₂ SO ₄ Dried, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with DCM: meoh=100:1 to 20:1) to give 2- ((2 s,4 ar) -14-bromo-13-fluoro-3- (4-methoxybenzyl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminoidenebenzo [ d) as a yellow solid]Pyrazino [1,2-g][1,3,7,11]Oxatriazacyclotridecarbon, 2-yl) acetonitrile (90 mg,64% yield). MS (ESI) M/z 583/585 (M+H) ⁺ 。

Step 7:2- ((2 s,4 ar) -13-fluoro-14- (2-fluoro-6-hydroxyphenyl) -3- (4-methoxybenzyl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1,3,7,11] oxatriazatrideca-2-yl) acetonitrile

To 2- ((2 s,4 ar) -14-bromo-13-fluoro-3- (4-methoxybenzyl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminosubunit) benzo [ d)]Pyrazino [1,2-g][1,3,7,11]Oxatriazacyclotridecarbon (90 mg,0.15 mmol) acetonitrile and (2-fluoro-6-hydroxyphenyl) boronic acid (48 mg,0.31 mmol) in 1, 4-dioxane (2.5 mL) and H ₂ Na was added to the mixture in O (0.5 mL) ₂ CO ₃ (49 mg,0.46 mmol) and Pd (PPh) ₃ ) ₄ (18 mg,0.015 mmol). The mixture is put under N ₂ Deaeration was performed three times and stirred at 100℃for 16 hours. The mixture was diluted with EtOAc (10 mL) and washed with water and brine, over Na ₂ SO ₄ Dried, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with DCM: meoh=100:1 to 30:1) to give 2- ((2 s,4 ar) -13-fluoro-14- (2-fluoro-6-hydroxyphenyl) -3- (4-methoxybenzyl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminosubunit) benzo [ d) as a yellow solid]Pyrazino [1,2-g][1,3,7,11]Oxatriazacyclotridecarbon, 2-yl) acetonitrile (80 mg,85% yield). MS (ESI) M/z 615 (M+H) ⁺ 。

Step 8:2- ((2 s,4 ar) -13-fluoro-14- (2-fluoro-6-hydroxyphenyl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminoiden) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatridecan-2-yl) acetonitrile

To a mixture containing 2- ((2S, 4 aR) -13-fluoro-14- (2-fluoro-6-hydroxyphenyl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminosubunit) benzo [ d ] at 0 DEG C]Pyrazino [1,2-g][1]Oxa [3,7,11]]Triazacyclotridecarbon-2-yl) acetonitrile (80 mg,0.13 mmol) was added TFA (2 mL) and anisole (0.1 mL,0.84 mmol) to a round bottom flask and the mixture was taken up in N ₂ Stirred overnight at 50 ℃ under an atmosphere. The mixture was concentrated to dryness and the residue was taken up with saturated NaHCO ₃ The aqueous solution was basified and extracted with EtOAc (2×10 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to dryness to give 2- ((2 s,4 ar) -13-fluoro-14- (2-fluoro-6-hydroxyphenyl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminosubunit) benzo [ d) as a yellow solid]Pyrazino [1,2-g][1]Oxa [3,7,11]]Triazacyclotridec-2-yl) acetonitrile (60 mg,93% yield). MS (ESI) M/z 495 (M+H) ⁺ 。

Step 9:2- ((2 s,4 ar) -3-propenoyl-13-fluoro-14- (2-fluoro-6-hydroxyphenyl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminoiden) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatridecan-2-yl) acetonitrile

To 2- ((2S, 4 aR) -13-fluoro-14- (2-fluoro-6-hydroxyphenyl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminosubunit) benzo [ d ]]Pyrazino [1,2-g][1]Oxa [3,7,11]]To a mixture of triazacyclotridecarbon-2-yl) acetonitrile (60 mg,0.12 mmol) and TEA (0.06 mL,0.48 mmol) in DCM (3 mL) was added prop-2-enoyl chloride (0.02 mL,0.24 mmol). The mixture was stirred at 0 ℃ for 1 hour. The mixture was diluted with water and extracted with DCM (2×5 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to dryness. The residue was dissolved in MeOH (2 mL) and K was added ₂ CO ₃ (33 mg,0.24 mmol). The mixture was stirred at room temperature for 1 hour. The resulting mixture was filtered, and the filtrate was concentrated to dryness. The residue was purified by preparative HPLC to give 2- ((2 s,4 ar) -3-propenoyl-13-fluoro-14- (2-fluoro-6-hydroxyphenyl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17-(amino subunit) benzo [ d]Pyrazino [1,2-g][1]Oxa [3,7,11 ]]Triazacyclotridec-2-yl) acetonitrile (3 mg,5% yield).

¹ H NMR(400MHz,CD ₃ OD)δ7.84(d,J＝8.6Hz,1H),7.44–7.22(m,2H),6.95(dd,J＝51.9,10.8Hz,1H),6.79–6.65(m,2H),6.36(d,J＝15.2Hz,1H),5.90(d,J＝10.5Hz,1H),5.20-5.13(m,1H),4.58–4.54(m,3H),4.25(d,J＝15.3Hz,3H),3.98(dd,J＝30.8,12.7Hz,2H),3.68(d,J＝22.5Hz,2H),3.48(s,1H),3.02(s,3H),2.79(s,2H)。MS(ESI)m/z:549(M+H) ⁺

Example 14:

bioassays

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

Phosphate ERK 1/2 assay in H358:

h358 cells were cultured in RPMI-1640 and 10%1 foetal calf serum (FCS;) Is grown in T75 flasks until a confluence of about 80% is reached. On day 1, 6000 cells/well were seeded in 384 well plates and incubated at 37℃with 5% CO 2. Diluted compound was added by Echo 550, final DMSO 0.5%, cells were incubated at 37 ℃,5% CO ₂ Incubate for 3 hours. The medium was then removed and the cells were fixed by Apricot with 3.7% formaldehyde in PBS (PFA). Washed once with PBS. Cells were permeabilized with cold 100% methanol and washed repeatedly with PBS once. Li-Cor blocking buffer was added to each well and incubated for 1.5 hours at RT. The blocking buffer was removed and a primary antibody mixture (rabbit anti-pERK, mouse anti-GAPDH) was added. Incubate overnight at 4 ℃. On day 2, a total of 3 washes with PBST (Tween-20-containing PBS) and then secondary antibody mixtures (goat anti-rabbit 800CW (in combination solution at 1:800 dilution) and goat anti-mouse 680RD (in combination solution at 1:800 dilution) were added and incubated at RT for 60 minutes in the absence of light. Cleaning the floor surface with moist non-pile tissue and +.>Imagers scan the bed (if applicable) to avoid any obstructions during the scan. The plate was scanned with detection in 700nm and 800nm channels.

Table 2 provides the results for exemplary compounds of formula (I).

TABLE 2

KRAS (G12C): SOS1 nucleotide exchange assay

GDP-loaded KRAS (G12C) was thawed and GDP-loaded KRAS (G12C) was diluted to 500nM in RBD-RAS binding buffer. Preparation of master mix (6 μl): 96 well x (1. Mu.l of diluted GDP-loaded KRAS (G12C), 500 nM+5. Mu.l RBD-RAS binding buffer). Mu.l of the master mix was added to each well. Serial dilutions of test compounds in DMSO were prepared at 200X test concentrations. The compound was then diluted 20-fold in deionized water to prepare a 10X intermediate solution. For positive and negative controls, water with 5% DMSO was used as 10X intermediate, so that all wells included the same amount of DMSO. Mu.l of 10 Xintermediate solution of test compound was added to the test wells. Mu.l of 5% DMSO was added to the positive control wells and the negative control wells. Plates were briefly centrifuged and incubated for 30 min at room temperature. GTP (10 mM) was thawed on ice and SOS1 was thawed. SOS1 was diluted at 5. Mu.M in RBD-RAS binding buffer. GTP (10 mM) and diluted SOS1 (5. Mu.M) were mixed at a ratio of 1:1. The exchange reaction was initiated by adding 2. Mu.l of GTP/SOS1 mixture to the test wells and the positive control wells. RBD-cRAF was thawed and diluted at 25nM in RBD-RAS binding buffer. After 30 min incubation with SOS1/GTP (RBD-RAS buffer of negative control), 1. Mu.l of diluted RBD-cRAF (25 nM) was added to all wells. Plates were briefly centrifuged and incubated for 30 min at room temperature. The 3X immune buffer was diluted in deionized water to prepare a 1X immune buffer. One volume of 3X immune buffer was added to two volumes of deionized water. Glutathione acceptor beads (perkinelmer#al109C) and nickel chelating donor beads (perkinelmer#as101d) were diluted 1:500 and 1:250, respectively, in 1x immunization buffer. It was necessary to add 20 μl of acceptor bead/donor bead mixture to each well. Thus, 16 μl of glutathione acceptor beads and 32 μl of nickel donor beads were added to 8ml of 1x immunization buffer). Incubate for 30 minutes at room temperature. The alpha count is read using a compatible reader.

3D cell viability assay

H358 (ATCC CRL-5807) cells were purchased from ATCC company, and each cell was cultured in a medium supplemented with 10% Fetal Bovine Serum (FBS) according to the manufacturer's recommended protocol. Cells were seeded at 1000 cells/well in each growth medium in 96-well tissue culture plates and allowed to adhere overnight on day 0. The following day after plating, cells were treated with a 9-point 3-fold dilution series of test compound (100 μl final volume per well) and after 5 days cell viability was monitored according to manufacturer's recommendations, with 50ml CellTiter-Glo reagent added, vigorously mixed, covered, and placed on a plate shaker for 20 minutes before assessing luminescence signals to ensure complete cell lysis.

KRAS-G12C/cRAF binding assay

Frozen reagents were thawed on ice. A working solution was prepared by diluting 500XTag2-KRAS-G12C protein stock (Cisbio, 63ADK000CB20 PEG) and 10mM GTP (Sigma, V900868) stock with dilution buffer (Cisbio, 62 DLBDDF). A working solution was prepared by diluting 100X anti-Tag 1-Eu3+ stock (Cisbio, 63ADK000CB20 PEG) and 50X anti-Tag 2-XL665 (Cisbio, 63ADK000CB20 PEG) with detection buffer (Cisbio, 62DB1 FDG). Compounds were diluted manually 10-fold in DMSO, 3-fold. Then 0.2 μl of compound was transferred to 384 assay plates by ECHO. mu.L of KRAS G12C & GTP at the indicated concentration was added to 384 assay plates and centrifuged at 1000RPM for 1 minute. mu.L of cRAF (Cisbio, 63ADK000CB20 PEG) at the indicated concentration was added to the assay plate and centrifuged at 1000RPM for 1 minute. Incubate at 25℃for 15 minutes. mu.L of the anti-Tag 1-Eu and anti-Tag 2-XL665 mixture was added to the assay plate. Centrifuge at 1000RPM for 1 minute and incubate at 4℃for 2 hours. The 665/615nm ratio on Envision was read. Data analysis: the ratio of each well was calculated (ratio 665nm/615 nm). The% inhibition is calculated as follows:

Inhibition% = 100- (signal) _cmpd -signal _{Ave_PC} ) (Signal) _{Ave_VC} -signal _{Ave_PC} )×100

Signal signal _{ave_pc} : average ratio of positive controls on the plate.

Signal signal _{ave_vc} : average ratio of negative controls on the plate.

IC50 was calculated and the effect dose curve for compound (cmpd) was plotted: IC50 was calculated by fitting the log of% inhibition and compound concentration to a nonlinear regression (dose response-variable slope) with Graphpad 8.0.

Y=bottom+ (top-bottom)/(1+10 ++logic 50-X schl slope)

X: logarithm of inhibitor concentration; y: inhibition%.

The compounds of the present disclosure exhibit an IC of 0.5nM to 10000nM ₅₀ Values. Some compounds of the present disclosure exhibit an IC of 1-5000nM ₅₀ Values. Some compounds of the present disclosure exhibit an IC of 1-4000nM ₅₀ Values. Some compounds of the present disclosure exhibit an IC of 1-3000nM ₅₀ Values. Some compounds of the present disclosure exhibit an IC of 1-2000nM ₅₀ Values. Some compounds of the present disclosure exhibit an IC of 1-1000nM ₅₀ Values. Some compounds of the present disclosure exhibit an IC of 1-500nM ₅₀ Values.

DMPK study

Measurement a): MDCK-MDR1 Pgp assessment

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

The Efflux Ratio (ER) of glycoprotein (P-gp) reflects the likelihood that the compound will be pumped from the brain by BBB efflux transporters. The substrate of P-gp generally has brain penetrating lesions.

According to table 3, reference compound 1AMG-510 (sotoracicb) and reference compound 2MRTX849 (adaglacicb) are strong Pgp substrates, which prevent these compounds from entering the interstitial space of the brain. In contrast, the exemplary compounds provided herein in table 3 show a great improvement in Pgp efflux tendencies.

TABLE 3 Table 3

Measurement b): MDCK-BCRP BCRP evaluation

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

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

Claims (71)

1. A compound having the formula (I):

Or a pharmaceutically acceptable salt thereof,

wherein the method comprises the steps of

Ring a is heterocyclyl or heteroaryl;

u is C (R) ^a ) Or N;

g isOr->

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

Each R ^b Independently is hydrogen, deuterium, halogen, cyano, alkyl, alkoxy, heteroalkyl, or heteroaryl, wherein the alkyl, the heteroalkyl, and the heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of: hydroxy, halogen, -NR ^c R ^d And heterocyclyl optionally substituted with one or more groups independently selected from hydroxy, halogen, cyano, and amino;

each R ^c Independently hydrogen, deuterium, alkyl, alkenyl, alkynyl or haloalkyl;

R ^d selected from the group consisting of: optionally heteroaryl or N (R) ^c ) ₂ Substituted alkyl haloalkyl group,

-C(O)N(R ^c ) ₂ 、-(CH ₂ ) _n NHC (O) -alkyl, heterocyclyl, and heteroaryl, wherein the heterocyclyl and heteroaryl are optionally substituted with one or more groups independently selected from: halo, hydroxy, amino, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, heteroalkyl, hydroxyalkyl, -O-haloalkyl, and-S-haloalkyl;

W is C (R) ^e ) Or N;

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

Each R is independently selected from the group consisting of: oxo, hydroxy, halogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, -C (O) OR ^c 、-C(O)N(R ^c ) ₂ 、-N(R ^c ) ₂ And heteroaryl, wherein said alkyl, said alkenyl, said alkynyl, and said heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of: cyano, hydroxy, halogen, -OR ^c or-N (R) ^c ) ₂ ；

Ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted with one or more R ^f Substitution;

each R ^f Independently selected from the group consisting of: oxo, hydroxy, halo, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of: hydroxy, halogen, cyano, -OR ^c 、-N(R ^c ) ₂ And heteroaryl;

t is O or S;

y is aryl or heteroaryl, each of which is optionally substituted with one or more R ^f Substitution;

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

q is- (CH) ₂ ) _m V-, wherein- (CH) ₂ ) _m -optionally substituted with hydroxy, halogen, cyano or amino;

v is selected from bond, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally substituted with one or more groups independently selected from: hydroxy, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl;

z is selected from the group consisting of: hydrogen, hydroxy, halogen, -N (R) ^c ) ₂ Alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -COOH, -NHC (=nh) NH ₂ 、-C(O)N(R ^c ) ₂ 、-OR ^c 、-(CH ₂ OR ^c )(CH ₂ ) _p OR ^c 、-N(R ^c ) C (O) -aryl, -N (R) ^c ) C (O) -heterocyclyl, -C (O) N (R) ^c ) -heterocyclyl and- (CH) ₂ ) _p -heterocyclyl, wherein said cycloalkyl, said heterocyclyl, said aryl and said heteroaryl are optionally substituted with one or more R ^g Substituted, and-N (R) ^c ) Aryl moieties in C (O) -aryl and- (CH) ₂ ) _p -heterocyclyl, -N (R) ^c ) C (O) -heterocyclyl and-C (O) N (R) ^c ) The heterocyclyl moiety in the heterocyclyl is optionally substituted with one or more R ^h Substitution;

each R ^g Independently selected from hydroxy, halogen, -C (O) H, alkyl, alkoxy, haloalkyl, hydroxyalkyl, or-N (R) ^c ) ₂ ；

Each R ^h Independently selected from oxo, hydroxy, halogen, alkyl, heteroalkyl, hydroxyalkyl, haloalkyl, alkoxy, -M-phenyl, -M-phenylSO ₂ F、-N(R ^c ) ₂ 、-SO ₂ F. -C (O) (alkyl) or-C (O) (haloalkyl), wherein said alkyl, said heteroalkyl, said hydroxyalkyl, said haloalkyl and said alkoxy are optionally substituted with one or more groups independently selected from aryl, heteroaryl or t-butyldimethylsilyloxy;

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

l is-L ¹ -L ² -L ³ -；

L ¹ And L ³ Independently selected from the group consisting of: bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, -N (R) ⁱ ) -alkyl-, -alkyl-N (R) ⁱ )-、-S(O) _n -alkyl-, -alkyl-S (O) _n -, -alkyl-C (=o) -, -C (=o) -alkyl-, -N (R) ⁱ ) C (=o) -alkyl-, -C (=o) N (R ⁱ ) -alkyl-and-alkyl-C (=o) N (R ⁱ ) -, wherein the alkyl, the alkenyl, the alkynyl, the heteroalkyl, the heteroalkenyl, the heteroalkynyl, and-N (R ⁱ ) -alkyl-, -alkyl-N (R) ⁱ )-、-S(O) _n -alkyl-, -alkyl-S (O) _n -, -alkyl-C (=o) -, -C (=o) -alkyl-, -N (R) ⁱ ) C (=o) -alkyl-, -C (=o) N (R ⁱ ) -alkyl-and-alkyl-C (=o) N (R ⁱ ) The alkyl moiety in (E) is optionally substituted with one or more R ^j Substitution;

R ⁱ selected from the group consisting of: hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, the heteroalkyl, the cycloalkyl, the heterocyclyl, the aryl, and the heteroaryl are optionally substituted with one or more groups independently selected from hydroxy, halogen, cyano, amino, or alkyl;

R ^j selected from hydroxy, halogen, cyano, amino, or alkyl optionally substituted with one or more groups independently selected from: halogen, hydroxy, cyano, cycloalkyl, heterocyclyl or-N (R) ^c ) ₂ Wherein the heterocyclyl is optionally substituted with one or more groups selected from: hydroxy, halogen, cyano, amino, alkyl or-N (R) ^c ) ₂ ；

L ² Selected from the group consisting of: bond, -O-, -S-, -N (R) ⁱ )-、-S(O) _n -、-S-S-、-S(O) _n -N(R ⁱ )-、-N(R ⁱ )-S(O) _n -、-C(＝O)-、-C(＝S)-、-C(＝O)N(R ⁱ )-、-C(＝S)N(R ⁱ )-、-N(R ⁱ )C(＝O)-、-N(R ⁱ )C(＝S)-、-OC(＝O)O-、-C(＝O)N(R ⁱ )-S(O) _n -、-S(O) _n -N(R ⁱ )C(＝O)-、-N(R ⁱ )C(＝O)-N(R ⁱ )-、-N(R ⁱ )-S(O) _n -N(R ⁱ ) -, cycloalkyl, heterocyclyl, aryl and heteroaryl;

m is an integer from 0 to 3;

p is an integer from 0 to 4;

n is an integer from 0 to 2;

r is 1 or 2;

provided that it is

When (when)When it is a triple bond, then R ^a Absent, R ^b Exists and r is 1;

or whenWhen it is a double bond, then R ^a In presence of R ^b Exists and R is 2, or R ^a And R is ^b And the carbon atoms to which they are attached form a chain optionally substituted with one or more R ^e Substituted cycloalkyl groups.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein G is N-C (O) -C (R ^a )＝C(R ^b ) _r 。

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein G is N-SO ₂ C(R ^a )＝C(R ^b ) _r 。

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ^a Is hydrogen, deuterium, cyano, halogen or alkyl.

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein G is N-C (O) -c≡c (R ^b ) _r 。

6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein G is N-SO ₂ C≡C(R ^b ) _r 。

7. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein each R ^b Independently is hydrogen, deuterium, alkyl, heteroalkyl, or heteroaryl, wherein said alkyl, said heteroalkyl, and said heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of: halogen, -NR ^c R ^d And heterocyclyl optionally substituted with one or more groups selected from hydroxy, halogen, cyano and amino.

8. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein U is N.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein U is C (R ^a )。

10. The compound according to claim 9, or a pharmaceutically acceptable salt thereof, wherein R ^a Is hydrogen.

11. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein ring a is heterocyclyl.

12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein ring a is a bridged heterocyclyl.

13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein ring a is selected from the group consisting of:

wherein the method comprises the steps ofRepresents a single bond or a double bond.

14. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein ring a is a spiroheterocyclyl or a fused heterocyclyl.

15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein ring a is selected from the group consisting of:

wherein s is an integer of 0 to 3, and q is an integer of 1 to 4.

16. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ring a is

17. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring a is heteroaryl.

18. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein W is N.

19. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein W is C (R ^e )。

20. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein ring B is optionally substituted with one or more R ^f Substituted cycloalkyl groups.

21. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein ring B is optionally substituted with one or more R ^f Substituted heterocyclyl groups.

22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein ring B is piperidinyl or 1,2,3, 6-tetrahydropyridinyl, each of which is optionally substituted with one or more R independently selected from oxo, alkyl, alkynyl, heteroalkyl, or cyano ^f Wherein said alkyl, said alkynyl, said heteroalkyl are optionally substituted with one OR more substituents selected from cyano, halogen, -OR ^c 、-N(R ^c ) ₂ Or a heteroaryl group.

23. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein ring B is optionally substituted with one or more R ^f Substituted aryl.

24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein ring B is optionally substituted with one or more R independently selected from amino, hydroxy, halo, or haloalkyl ^f A substituted phenyl group.

25. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein ring B is optionally substituted with one or more R ^f Substituted heteroaryl groups.

26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein ring B is optionally substituted with one or more R independently selected from amino, hydroxy, halo, or haloalkyl ^f Substituted pyridinyl or pyrimidinyl.

27. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein T is O.

28. The compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein T is S.

29. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Y is optionally substituted with one or more R ^f Substituted aryl.

30. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein Y is phenyl or naphthyl, each of which is optionally substituted with one or more R ^f And (3) substitution.

31. Root of Chinese characterThe compound according to claim 29 or 30, or a pharmaceutically acceptable salt thereof, wherein R ^f Is hydroxy, halogen, amino, alkyl, alkenyl, alkynyl, haloalkyl, haloalkynyl or cycloalkyl.

32. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein Y is optionally substituted with one or more R ^f Substituted heteroaryl groups.

33. The compound of claim 32, or a pharmaceutically acceptable salt thereof, wherein Y is selected from benzothienyl, benzimidazolyl, quinazolinyl, benzotriazolyl, thienyl, thienopyridinyl, isoquinolinyl, indolyl, or indazolyl, each of which is optionally substituted with one or more R ^f And (3) substitution.

34. The compound according to claim 32 or 33, or a pharmaceutically acceptable salt thereof, wherein R ^f Is hydroxy, halogen, amino, alkyl, alkenyl, alkynyl, haloalkyl, haloalkynyl or heteroaryl.

35. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein E is-O-.

36. A compound according to any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein E is-S-.

37. The compound according to any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein E is-N (R ^c )-。

38. The compound according to any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein E is alkynyl.

39. The compound of claim 38, or a pharmaceutically acceptable salt thereof, wherein E is ethynyl.

40. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein V is a bond.

41. The compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein V is heterocyclyl optionally substituted with one or more groups independently selected from: oxo, hydroxy, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl.

42. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein V is heterocyclyl selected from the group consisting of:

each of which is optionally substituted with one or more groups independently selected from the group consisting of: oxo, hydroxy, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl.

43. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Z is hydrogen, hydroxy, halo, alkyl, haloalkyl, -N (R ^c ) ₂ 、-N(R ^c ) C (O) -heterocyclyl or-C (O) N (R) ^c ) -heterocyclyl, wherein-N (R ^c ) C (O) -heterocyclyl and-C (O) N (R) ^c ) The heterocyclyl moiety in the heterocyclyl is optionally substituted with one or more R ^h And (3) substitution.

44. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein L ¹ And L ³ Independently selected from the group consisting of bond, alkyl, -N (R) ⁱ ) -alkyl-, -alkyl-N (R) ⁱ )-、-S(O) _n -alkyl-, -alkyl-S (O) _n -, -alkyl-C (=o) -, -C (=o) -alkyl-, -N (R) ⁱ ) C (=o) -alkyl-, -C (=o) N (R ⁱ ) -alkyl-or-alkyl-C (=o) N (R ⁱ ) -, wherein the alkyl group and-N (R ⁱ ) -alkyl-, -alkyl-N (R) ⁱ )-、-S(O) _n -alkyl-, -alkyl-S (O) _n -, -alkyl-C (=o) -, -C (=o) -alkyl-, -N (R) ⁱ ) C (=o) -alkyl-, -C (=o) N (R ⁱ ) -alkyl-and-alkyl-C (=o) N (R ⁱ ) The alkyl moiety in (E) is optionally substituted with one or more R ^j And (3) substitution.

45. The compound of claim 44, or a pharmaceutically acceptable salt thereof, wherein said alkyl or said alkyl moiety is optionally substituted with one or more R ^j Substituted- (CH) ₂ ) _t -, and t is an integer from 0 to 10.

46. The compound according to claim 44 or 45, or a pharmaceutically acceptable salt thereof, wherein R ^j Selected from hydrogen or alkyl optionally substituted with one or more groups independently selected from: halogen, -N (R) ^c ) ₂ Or optionally one or more groups selected from alkyl or-N (R ^c ) ₂ A heterocyclic group substituted with a group of (a).

47. A compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, wherein L ¹ And L ³ Independently selected from alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl, each of which is optionally substituted with one or more R ^j And (3) substitution.

48. The compound of claim 47, or a pharmaceutically acceptable salt thereof, wherein L ¹ And L ³ Independently selected from- (CH) ₂ ) _u CH＝CH(CH ₂ ) _v -、-(CH ₂ ) _u CH≡CH(CH ₂ ) _v -、-O(CH ₂ ) _t -、-(CH ₂ ) _t O-、-S(CH ₂ ) _t -、-(CH ₂ ) _t S-、-O(CH ₂ ) _u CH＝CH(CH ₂ ) _v -、-(CH ₂ ) _u CH＝CH(CH ₂ ) _v O-、-O(CH ₂ ) _u CH≡CH(CH ₂ ) _v -、-(CH ₂ ) _u CH≡CH(CH ₂ ) _v O-,-S(CH ₂ ) _u CH＝CH(CH ₂ ) _v -、-(CH ₂ ) _u CH＝CH(CH ₂ ) _v S-、-S(CH ₂ ) _u CH≡CH(CH ₂ ) _v -、-(CH ₂ ) _u CH≡CH(CH ₂ ) _v S-、-O(CH ₂ ) _u CH＝CH(CH ₂ ) _v S-、-S(CH ₂ ) _u CH＝CH(CH ₂ ) _v O-、-O(CH ₂ ) _u CH≡CH(CH ₂ ) _v S-or-S (CH) ₂ ) _u CH≡CH(CH ₂ ) _v O-, each of which is optionally substituted with one or more R ^j Substitution, wherein u and v are independently integers from 0 to 10.

49. The compound according to claim 47 or 48, or a pharmaceutically acceptable salt thereof, wherein R ^j Selected from hydrogen or alkyl optionally substituted with one or more groups independently selected from: halogen, -N (R) ^c ) ₂ Or optionally one or more groups selected from alkyl or-N (R ^c ) ₂ A heterocyclic group substituted with a group of (a).

50. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein L ² Selected from-O-, -N (R) ⁱ )-、-S(O) _n -、-C(＝O)N(R ⁱ ) -or-N (R) ⁱ )C(＝O)-。

51. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein L ¹ Is alkyl, heteroalkyl or-S (O) _n -alkyl-, L ² is-C (=O) -, and L ³ Is a key.

52. A compound according to any one of claims 1 to 50An agent or a pharmaceutically acceptable salt thereof, wherein L ¹ Is a bond, alkyl, heteroalkyl, or-N (R) ⁱ ) -alkyl-, L ² is-O-, -S-or-N (R) ⁱ ) -, and L ³ Is a bond, alkyl, alkenyl or heteroalkyl.

53. A compound according to any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof, wherein L ¹ Is a bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl or-S (O) _n -alkyl-, L ² is-S (O) _n -or-S-S-, and L ³ Is a bond, alkyl, alkenyl, alkynyl or heteroalkyl.

54. A compound according to any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof, wherein L ¹ Is a bond, alkyl, alkenyl, heteroalkyl, -N (R) ⁱ ) -alkyl-, -N (R) ⁱ ) C (=o) -alkyl-or-C (=o) N (R ⁱ ) -alkyl-, L ² is-S (O) _n -N(R ⁱ )-、-N(R ⁱ )-S(O) _n -、-C(＝O)N(R ⁱ )-、-C(＝S)N(R ⁱ )-、-N(R ⁱ )C(＝O)-、-N(R ⁱ )C(＝S)-、-OC(＝O)O-、-C(＝O)N(R ⁱ )-S(O) _n -、-S(O) _n -N(R ⁱ )C(＝O)-、-N(R ⁱ )C(＝O)-N(R ⁱ ) -or-N (R) ⁱ )-S(O) _n -N(R ⁱ ) -, and L ³ Is a bond, alkyl, alkenyl or-alkyl-S (O) _n -。

55. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L is selected from-CH ₂ C(＝O)N(R ⁱ )CH ₂ -、-C(＝O)N(R ⁱ )(CH ₂ ) ₂ -、-CH ₂ N(R ⁱ )C(O)CH ₂ -、-CH ₂ CH ₂ N(R ⁱ )C(O)-、-CH ₂ CH ₂ N(R ⁱ )CH ₂ -、-CH ₂ N(R ⁱ )CH ₂ CH ₂ -、-CH ₂ OCH ₂ CH ₂ -or-CH ₂ CH ₂ OCH ₂ -, each of which is optionally substituted with one or more R ^j And (3) substitution.

56. The compound of claim 1, having formula (Ia) or formula (Ib):

Or a pharmaceutically acceptable salt thereof,

wherein R is ¹ Is hydrogen, hydroxy, halogen, cyano, alkyl or alkynyl, wherein said alkyl and said alkynyl are optionally substituted with one or more groups independently selected from hydroxy, halogen and cyano.

57. The compound of claim 56, or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of-CH ₂ C(＝O)N(R ⁱ )CH ₂ -、-C(＝O)N(R ⁱ )(CH ₂ ) ₂ -、-CH ₂ N(R ⁱ )C(O)CH ₂ -、-CH ₂ CH ₂ N(R ⁱ )C(O)-、-CH ₂ CH ₂ N(R ⁱ )CH ₂ -、-CH ₂ N(R ⁱ )CH ₂ CH ₂ -、-CH ₂ OCH ₂ CH ₂ -or-CH ₂ CH ₂ OCH ₂ -, each of which is optionally substituted with one or more R ^j And (3) substitution.

58. The compound of claim 56 or 57, or a pharmaceutically acceptable salt thereof, wherein E is O or S.

59. The compound of claim 1, selected from the group consisting of:

1- (8- ((dimethylamino) methyl) -3- (naphthalen-1-yl) -1,2,3,4,8,9,10,11,12,13 a,14,16, 17-decatetrahydro-15H-6, 19- (aminosubunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7] diazacyclotetradec-15-yl) prop-2-en-1-one

1- (8- ((dimethylamino) methyl) -3- (naphthalen-1-yl) -1,2,3,4,8,9,10,11,12,13,14,15 a,16,18, 19-hexadeca-17H-6, 21- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7] diazepan-17-yl) prop-2-en-1-one

1- (8- ((dimethylamino) methyl) -3- (naphthalen-1-yl) -1,2,3,4,8,9,10,13 a,14,16, 17-dodecahydro-15H-6, 19- (aminosubunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7] diaza-tetradec-1-yl) prop-2-en-1-one

1- (8- ((dimethylamino) methyl) -3- (naphthalen-1-yl) -1,2,3,4,8,9,10,11,12,15 a,16,18, 19-decatetrahydro-17H-6, 21- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7] diazacyclohexadec-17-yl) prop-2-en-1-one

9-propenoyl-4- ((dimethylamino) methyl) -16- (naphthalen-1-yl) -5,6,8,9,10,11,14,15,16,17-decahydro-2, 13- (aminosubunit) -8, 12-methylenepyrido [3,4-d ] [1] oxa [3,7,10,13] tetraazacyclopentadec-7 (4H) -one

1- (4- ((dimethylamino) methyl) -17- (naphthalen-1-yl) -4,5,8,9,11,12,15,16,17,18-decahydro-10H-2, 14- (aminosubunit) -9, 13-methylenepyrido [3,4-d ] [1] oxa [3,7,10] triazacyclo hexadec-10-yl) prop-2-en-1-one

1- (4- ((dimethylamino) methyl) -17- (naphthalen-1-yl) -4,5,6,7,8,9,11,12,15,16,17,18-dodecahydro-10H-2, 14- (aminosubunit) -9, 13-methylenepyrido [3,4-d ] [1] oxa [3,7,10] triazacyclo hexadecan-10-yl) prop-2-en-1-one

1- (4- ((dimethylamino) methyl) -18- (naphthalen-1-yl) -5,6,9,10,12,13,16,17,18,19-decahydro-2, 15- (aminosubunit) -10, 14-methylenepyrido [3,4-d ] [1] oxa [3,7,10] triazacyclo heptadec-in-11 (4H) -yl) prop-2-en-1-one

1- (4- ((dimethylamino) methyl) -18- (naphthalen-1-yl) -5,6,7,8,9,10,12,13,16,17,18,19-dodecahydro-2, 15- (aminosubunit) -10, 14-methylenepyrido [3,4-d ] [1] oxa [3,7,10] triazacyclo heptadec-in-11 (4H) -yl) prop-2-en-1-one

14-propenoyl-8- ((dimethylamino) methyl) -3- (naphthalen-1-yl) -1,2,3,4,9,10,12 a,13,14,15, 16-dodecahydro-6, 18- (aminosubunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecan-11 (8H) -one (isomer 1)

1- (8- ((dimethylamino) methyl) -3- (naphthalen-1-yl) -1,2,3,4,8,9,10,11,13a,14,16, 17-dodecahydro-6, 19- (aminosubunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1,10] oxa [3,7] diaza-tetradeca-n-15 (13H) -yl) prop-2-en-1-one

1- (4- ((dimethylamino) methyl) -18- (naphthalen-1-yl) -4,5,6,7,9,10,12,13,16,17,18,19-dodecahydro-11H-2, 15- (aminosubunit) -10, 14-methylenepyrido [3,4-d ] [1,13] dioxa [3,7,10] triazacyclo heptadec-11-yl) prop-2-en-1-one

15-propenoyl-8- ((dimethylamino) methyl) -10-methyl-3- (naphthalen-1-yl) -1,2,3,4,9,10,13 a,14,15,16, 17-dodecahydro-8H-6, 19- (aminosubunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,12] triazacyclotetradec-11 (12H) -one

1- (3- (8-chloronaphthalen-1-yl) -8- ((dimethylamino) methyl) -1,2,3,4,8,9,10,11,12,13,14,15 a,16,18, 19-hexadeca hydro-17H-6, 21- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7] diazacyclohexadec-17-yl) prop-2-en-1-one

15-propenoyl-3- (8-chloronaphthalen-1-yl) -8- ((dimethylamino) methyl) -1,2,3,4,8,9,10,11,13 a,14,15,16, 17-decatetrahydro-12H-6, 19- (aminosubunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazacyclotetradec-n-12-one

14-propenoyl-3- (8-chloronaphthalen-1-yl) -8- ((dimethylamino) methyl) -10-methyl-1, 2,3,4,9,10,12 a,13,14,15, 16-dodecahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecano-11 (8H) -one

14-propenoyl-3- (8-chloronaphthalen-1-yl) -8- ((dimethylamino) methyl) -10-methyl-1, 2,3,4,9,10,12 a,13,14,15, 16-dodecahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecano-11 (8H) -one

16-propenoyl-3- (8-chloronaphthalen-1-yl) -8- ((dimethylamino) methyl) -1,2,3,4,9,10,11,12,14 a,15,16,17, 18-decatetrahydro-6, 20- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazacyclopentadec-3 (8H) -one

15-propenoyl-8- ((dimethylamino) methyl) -3- (naphthalen-1-yl) -1,2,3,4,9,10,13 a,14,15,16, 17-dodecahydro-8H-6, 19- (aminosubunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,12] triazacyclotetradecan-11 (12H) -one

11-propenoyl-18- (8-chloronaphthalen-1-yl) -4- ((dimethylamino) methyl) -8-methyl-5,6,8,9,10,11,12,13,16,17,18,19-dodecahydro-2, 15- (aminosubunit) -10, 14-methylenepyrido [3,4-d ] [1] oxa [3,7,10,13] tetraazacyclo heptadecan-7 (4H) -one

15-propenoyl-3- (8-chloronaphthalen-1-yl) -8- ((dimethylamino) methyl) -1,2,3,4,9,10,13 a,14,15,16, 17-dodecahydro-8H-6, 19- (aminosubunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,10] triazacyclotetradec-11 (12H) -one

2- (14-propenoyl-8- ((dimethylamino) methyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecan-e-15-yl) acetonitrile

14-propenoyl-8- ((dimethylamino) methyl) -10, 15-dimethyl-3- (naphthalen-1-yl) -1,2,3,4,9,10,12 a,13,14,15, 16-dodecahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-11 (8H) -ketoformate salt

2- (16-propenoyl-8- ((dimethylamino) methyl) -12-methyl-3- (naphthalen-1-yl) -13-oxo-1, 2,3,4,8,9,10,11,12,13,14 a,15,16,17, 18-hexadeca hydro-6, 20- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazacyclopentadec-17-yl) acetonitrile

14-propenoyl-8- ((dimethylamino) methyl) -15-methyl-3- (naphthalen-1-yl) -1,2,3,4,9,10,12 a,13,14,15, 16-dodecahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecan-11 (8H) -one

2- (14-propenoyl-10-methyl-3- (naphthalen-1-yl) -11-oxo-8- (2- (pyrrolidin-1-yl) ethyl) -1,2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridec-15-yl) acetonitrile

2- (15-propenoyl-8- ((dimethylamino) methyl) -11-methyl-3- (naphthalen-1-yl) -12-oxo-1, 2,3,4,9,10,11,12,13 a,14,15,16, 17-decahydro-8H-6, 19- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazacyclotetradec-n-16-yl) acetonitrile

2- (14-propenoyl-8- (2- (dimethylamino) ethyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecan-15-yl) acetonitrile

2- ((8R, 12aR, 15S) -14-propenoyl-8- ((dimethylamino) methyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecan-15-yl) acetonitrile

2- (14-propenoyl-10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecan-15-yl) acetonitrile

2- (14-propenoyl-10-methyl-3- (naphthalen-1-yl) -11-oxo-8- (piperidin-1-ylmethyl) -1,2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridec-e-yl-2-15-yl) acetonitrile

2- ((8S, 12aR, 15S) -14-propenoyl-8- ((dimethylamino) methyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecan-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecan-en-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-10-methyl-11-oxo-3-phenyl-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((8R, 12aS, 15R) -14-propenoyl-8- ((dimethylamino) methyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecan-15-yl) acetonitrile

2- ((12 aS, 15R) -14-propenoyl-10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecan-en-15-yl) acetonitrile

2- (14-propenoyl-8- ((dimethylamino) methyl) -11-methyl-3- (naphthalen-1-yl) -12-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,10] triazatridec-n-15-yl) acetonitrile

2- (14-propenoyl-11-methyl-3- (naphthalen-1-yl) -12-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,10] triazatridecan-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-10- (4- (dimethylamino) butyl) -3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecan-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-10-methyl-3- (naphthalen-1-yl) -11-oxo-9- (pyrrolidin-1-ylmethyl) -1,2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridec- -c-n-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-10-methyl-3- (naphthalen-1-yl) -11-oxo-9- (piperidin-1-ylmethyl) -1,2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridec- -c-n-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-10-methyl-9- ((4-methylpiperazin-1-yl) methyl) -3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-9- ((3- (dimethylamino) azetidin-1-yl) methyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-9- ((4- (dimethylamino) piperidin-1-yl) methyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-10-methyl-3- (naphthalen-1-yl) -1,2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridec-en-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-11-methyl-3- (naphthalen-1-yl) -1,2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminosubunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,10] triazatridec- -2-yl) acetonitrile

2- (14-propenoyl-10-methyl-9- (2-morpholinoethyl) -3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridec- -c-n-15-yl) acetonitrile

2- (14-propenoyl-10-methyl-3- (naphthalen-1-yl) -11-oxo-9- (2- (piperidin-1-yl) ethyl) -1,2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridec-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-9- ((dimethylamino) methyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridec-en-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-9- (azetidin-1-ylmethyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-n-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-10- (2- (4-methylpiperazin-1-yl) ethyl) -3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-n-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-10- (2- (1-methylpiperidin-4-yl) ethyl) -3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridec-n-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-10- (3- (4-methylpiperazin-1-yl) propyl) -3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-n-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-10- (3- (1-methylpiperidin-4-yl) propyl) -3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridec-n-15-yl) acetonitrile

2- ((12 aS, 15R) -14-propenoyl-10-methyl-3- (naphthalen-1-yl) -11-oxo-8- (piperidin-1-ylmethyl) -1,2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridec- -c-in-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-3- (8-chloronaphthalen-1-yl) -10-methyl-11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminosubunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-n-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-9- (2- (dimethylamino) ethyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-n-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-10-methyl-3- (naphthalen-1-yl) -11-oxo-8- (2- (piperidin-1-yl) ethyl) -1,2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridec-en-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-8- (2- (dimethylamino) ethyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridec- -c-n-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-10-methyl-8- (2- (1-methylpiperidin-4-yl) ethyl) -3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-8- ((4- (dimethylamino) piperidin-1-yl) methyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecan-in-15-yl) acetonitrile

2- (14-propenoyl-9- (2- (4- (dimethylamino) piperidin-1-yl) ethyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridec- -c-n-15-yl) acetonitrile

2- (14-propenoyl-10-methyl-9- (2- (4-methylpiperazin-1-yl) ethyl) -3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridec-15-yl) acetonitrile

2- (14-propenoyl-9- (2- (3- (dimethylamino) azetidin-1-yl) ethyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecan-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-10-methyl-8- ((1-methylpyrrolidin-2-yl) methyl) -3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecen-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-9- (2- (dimethylamino) ethyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-n-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-3- (8-chloronaphthalen-1-yl) -10-methyl-11-oxo-9- (piperidin-1-ylmethyl) -1,2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecan-in-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-3- (8-chloronaphthalen-1-yl) -10-methyl-11-oxo-8- (2- (pyrrolidin-1-yl) ethyl) -1,2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecan-15-yl) acetonitrile

2- ((8R, 12aR, 15S) -14-propenoyl-3- (8-chloronaphthalen-1-yl) -8- ((dimethylamino) methyl) -10-methyl-11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-10-methyl-8- ((4-methylpiperazin-1-yl) methyl) -3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecan-in-15-yl) acetonitrile

2- (14-propenoyl-9- (2- (azetidin-1-yl) ethyl) -10-methyl-3- (naphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridec-n-15-yl) acetonitrile

2- (14-propenoyl-10-methyl-3- (naphthalen-1-yl) -11-oxo-9- (2- (pyrrolidin-1-yl) ethyl) -1,2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridec-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-10-methyl-3- (naphthalen-1-yl) -11-oxo-8- (pyrrolidin-1-ylmethyl) -1,2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridec- -in-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-10-methyl-3- (naphthalen-1-yl) -11-oxo-8- (2- (pyrrolidin-1-yl) ethyl) -1,2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (amino subunit) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatridecan-in-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-3- (8-chloronaphthalen-1-yl) -10- (2- (4-methylpiperazin-1-yl) ethyl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-3- (8-chloronaphthalen-1-yl) -10-methyl-8- (1-methylpyrrolidin-2-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoylidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((8R, 12aR, 15S) -14-propenoyl-8- ((dimethylamino) methyl) -10-methyl-3- (8-methylnaphthalen-1-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((8 r,12ar,15 s) -14-propenoyl-3- (8-chloro-3-hydroxynaphthalen-1-yl) -8- ((dimethylamino) methyl) -10-methyl-11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((8R, 12aR, 15S) -14-propenoyl-8- ((dimethylamino) methyl) -3- (8-ethynylnaphthalen-1-yl) -10-methyl-11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((8 r,12ar,15 s) -14-propenoyl-3- (8-chloro-7-fluoronaphthalen-1-yl) -8- ((dimethylamino) methyl) -10-methyl-11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((8R, 12aR, 15S) -14-propenoyl-3- (5-chloroisoquinolin-4-yl) -8- ((dimethylamino) methyl) -10-methyl-11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-n-15-yl) acetonitrile

2- ((8 r,12ar,15 s) -14-propenoyl-8- ((dimethylamino) methyl) -3- (7-fluoro-8-methylnaphthalen-1-yl) -10-methyl-11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((8 r,12ar,15 s) -14-propenoyl-8- ((dimethylamino) methyl) -3- (8-ethynyl-7-fluoronaphthalen-1-yl) -10-methyl-11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((8R, 12aR, 15S) -14-propenoyl-8- ((dimethylamino) methyl) -10-methyl-3- (5-methylisoquinolin-4-yl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-n-15-yl) acetonitrile

2- ((8R, 12aR, 15S) -14-propenoyl-3- (5-chloro-6-fluoroisoquinolin-4-yl) -8- ((dimethylamino) methyl) -10-methyl-11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((8R, 12aR, 15S) -14-propenoyl-3- (5-chloroquinolin-4-yl) -8- ((dimethylamino) methyl) -10-methyl-11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoylidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-3- (8-chloronaphthalen-1-yl) -10-methyl-11-oxo-8- (tetrahydro-1H-pyrrolizin-7 a (5H) -yl) -1,2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((12 aR, 15S) -3- (8-chloronaphthalen-1-yl) -14- (2-fluoroacryloyl) -10-methyl-11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((8R, 12aR, 15S) -3- (8-chloronaphthalen-1-yl) -8- ((dimethylamino) methyl) -14- (2-fluoroacryloyl) -10-methyl-11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-n-15-yl) acetonitrile

3-propenoyl-15-chloro-13-fluoro-14- (2-fluoro-6-methoxyphenyl) -2, 6-dimethyl-2, 3, 4a,6,7,8, 9-octahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,10] triazatridecano [ 5 (1H) -one 3-propenoyl-15-chloro-13-fluoro-14- (2-fluoro-6-hydroxyphenyl) -2, 7-dimethyl-1, 2,3, 4a,5,8, 9-octahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatridecano [ 6 (7H) -one 3 ] acryl-15-chloro-13-fluoro-14- (2-fluoro-6-hydroxyphenyl) -2, 6-dimethyl-2, 3, 4a,6,7,8, 9-octahydro-11, 17- (amino subunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,10] triazatrideca-5 (1H) -one 3-acryl-15-chloro-13-fluoro-14- (2-fluoro-6-hydroxyphenyl) -2-methyl-1, 2,3, 4a,5,8, 9-octahydro-11, 17- (amino subunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatrideca-6 (7H) -one 3-acryl -15-chloro-13-fluoro-14- (2-fluoro-6-hydroxyphenyl) -2-methyl-2, 3, 4a,6,7,8, 9-octahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,10] triazacyclotrideca-2, 7,11] oxa [3,7,11] triazacyclotrideca-2 (1H) -one 3-propenoyl-15-chloro-9- ((dimethylamino) methyl) -13-fluoro-14- (2-fluoro-6-methoxyphenyl) -2, 7-dimethyl-1, 2,3, 4a,5,8, 9-octahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazacyclotrideca-6 (7H) -one

2- (3-propenoyl-15-chloro-13-fluoro-14- (2-fluoro-6-methoxyphenyl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatrideca-2-yl) acetonitrile

2- (3-propenoyl-15-chloro-9- ((dimethylamino) methyl) -13-fluoro-14- (2-fluoro-6-methoxyphenyl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (amino subunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatrideca-2-yl) acetonitrile

2- (3-propenoyl-15-chloro-13-fluoro-14- (2-fluoro-6-hydroxyphenyl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatrideca-2-yl) acetonitrile

2- (3-propenoyl-15-chloro-13-fluoro-14- (2-fluoro-6-methoxyphenyl) -6-methyl-5-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,10] triazatrideca-2-yl) acetonitrile

2- ((2 s,4 ar) -3-propenoyl-15-chloro-13-fluoro-14- (2-fluoro-6-hydroxyphenyl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatrideca-2-yl) acetonitrile

2- (3-propenoyl-15-chloro-9- ((dimethylamino) methyl) -13-fluoro-14- (2-fluoro-6-methoxyphenyl) -6-methyl-5-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (amino subunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,10] triazatrideca-2-yl) acetonitrile

3-propenoyl-15-chloro-9- ((dimethylamino) methyl) -13-fluoro-14- (2-fluoro-6-methoxyphenyl) -2, 6-dimethyl-2, 3, 4a,6,7,8, 9-octahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,10] triazatrideca-5 (1H) -one

2- (14-propenoyl-4-fluoro-10-methyl-3- (naphthalen-1-yl) -11-oxo-8, 9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminosubunit) pyrazino [1,2-g ] pyrido [4,3-d ] [1] oxa [3,7,11] triazatridecan-15-yl) acetonitrile

2- (14-propenoyl-4-fluoro-11-methyl-3- (naphthalen-1-yl) -12-oxo-8, 9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [4,3-d ] [1] oxa [3,7,10] triazatrideca-15-yl) acetonitrile

2- (14-propenoyl-8- ((dimethylamino) methyl) -4-fluoro-11-methyl-3- (naphthalen-1-yl) -12-oxo-8, 9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [4,3-d ] [1] oxa [3,7,10] triazatridecan-15-yl) acetonitrile

2- (14-propenoyl-8- ((dimethylamino) methyl) -4-fluoro-10-methyl-3- (naphthalen-1-yl) -11-oxo-8, 9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [4,3-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((2 s,4 ar) -3-propenoyl-15-chloro-13-fluoro-14- (2-fluoro-6-methoxyphenyl) -7-methyl-6-oxo-9- (2- (piperidin-1-yl) ethyl) -1,2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminoiden) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatrideca-n-2-yl) acetonitrile

2- ((2 s,4 ar) -3-propenoyl-13-fluoro-14- (2-fluoro-6-hydroxyphenyl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminoiden) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatridecan-2-yl) acetonitrile

2- (3-propenoyl-15-chloro-13-fluoro-14- (3-hydroxyphenyl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatridec-2-yl) acetonitrile 2- ((2 s,4 ar) -3-propenoyl-15-chloro-13-fluoro-14- (2-hydroxyphenyl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatridec-2-yl) acetonitrile

2- ((2 s,4 ar) -3-propenoyl-15-chloro-13-fluoro-14- (2-fluoro-6-methoxyphenyl) -7-methyl-6-oxo-8- (2- (piperidin-1-yl) ethyl) -1,2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminoiden) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatrideca-n-2-yl) acetonitrile

2- ((2 s,4 ar) -3-propenoyl-15-chloro-13-fluoro-14- (2-fluoro-6-methoxyphenyl) -7-methyl-6-oxo-8- (2- (piperidin-1-yl) ethyl) -1,2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminoiden) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatrideca-n-2-yl) acetonitrile

2- ((2 s,4 ar) -3-propenoyl-15-chloro-13-fluoro-14- (2-fluorophenyl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminoiden) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatridecan-2-yl) acetonitrile

2- ((2 s,4 ar) -3-propenoyl-15-chloro-13-fluoro-14- (2-fluoro-5-hydroxyphenyl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatrideca-2-yl) acetonitrile

2- (3-propenoyl-15-chloro-13-fluoro-14- (6-hydroxynaphthalen-1-yl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatrideca-2-yl) acetonitrile

2- ((2 s,4 ar) -3-propenoyl-15-chloro-13-fluoro-14- (1H-indazol-7-yl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (amino subunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatrideca-2-yl) acetonitrile

2- ((2 s,4 ar) -3-propenoyl-14- (1H-benzo [ d ] imidazol-7-yl) -15-chloro-13-fluoro-7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminoiden) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatrideca-2-yl) acetonitrile

2- ((2 s,4 ar) -3-propenoyl-15-chloro-13-fluoro-14- (7-hydroxynaphthalen-1-yl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminoiden) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatridec-2-yl) acetonitrile

2- ((2 s,4 ar) -3-propenoyl-15-chloro-13-fluoro-14- (3-hydroxynaphthalen-1-yl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminoiden) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatridec-2-yl) acetonitrile

2- ((2 s,4 ar) -3-propenoyl-15-chloro-13-fluoro-14- (2-fluoro-6-hydroxyphenyl) -7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminosubunit) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatrideca-2-yl) acetonitrile

2- ((2 s,4 ar) -3-propenoyl-15-chloro-13-fluoro-7-methyl-14- (8-methylnaphthalen-1-yl) -6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminoiden) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatridec-2-yl) acetonitrile

2- ((2 s,4 ar) -3-propenoyl-15-chloro-14- (8-chloro-7-fluoronaphthalen-1-yl) -13-fluoro-7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminoiden) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatrideca-2-yl) acetonitrile

2- ((8S, 12aR, 15S) -14-propenoyl-3- (8-chloronaphthalen-1-yl) -8- ((dimethylamino) methyl) -10-methyl-11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((2 s,4 ar) -3-propenoyl-15-chloro-14- (8-chloro-7-fluoronaphthalen-1-yl) -13-fluoro-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminoiden) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatrideca-2-yl) acetonitrile

2- ((8 r,12ar,15 s) -14-propenoyl-3- (8-chloro-7-fluoronaphthalen-1-yl) -10-methyl-11-oxo-8- (pyrrolidin-1-ylmethyl) -1,2,3,4,8,9,10,11,12 a,13,14,15, 16-decatetrahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((2 s,4ar,9 r) -3-propenoyl-15-chloro-14- (8-chloro-7-fluoronaphthalen-1-yl) -9- ((dimethylamino) methyl) -13-fluoro-7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminoiden) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatridec-2-yl) acetonitrile

2- ((8S, 12aR, 15S) -14-propenoyl-3- (8-chloro-7-fluoronaphthalen-1-yl) -8- ((dimethylamino) methyl) -11-oxo-1, 2,3,4,8,9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [3,4-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((8 r,12ar,15 s) -14-propenoyl-3- (8-chloro-7-fluoronaphthalen-1-yl) -8- ((dimethylamino) methyl) -4-fluoro-10-methyl-11-oxo-8, 9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminoiden) pyrazino [1,2-g ] pyrido [4,3-d ] [1] oxa [3,7,11] triazatrideca-15-yl) acetonitrile

2- ((8S, 12aR, 15S) -14-propenoyl-3- (8-chloro-7-fluoronaphthalen-1-yl) -8- ((dimethylamino) methyl) -4-fluoro-11-oxo-8, 9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [4,3-d ] [1] oxa [3,7,11] triazatridec- -in-15-yl) acetonitrile

2- ((12 aR, 15S) -14-propenoyl-3- (8-chloronaphthalen-1-yl) -4-fluoro-10-methyl-11-oxo-8, 9,10,11,12 a,13,14,15, 16-decahydro-6, 18- (aminoidene) pyrazino [1,2-g ] pyrido [4,3-d ] [1] oxa [3,7,11] triazatridecan-in-15-yl) acetonitrile and

2- ((2 s,4 ar) -3-propenoyl-15-chloro-14- (8-chloronaphthalen-1-yl) -13-fluoro-7-methyl-6-oxo-1, 2,3, 4a,5,6,7,8, 9-decahydro-11, 17- (aminoiden) benzo [ d ] pyrazino [1,2-g ] [1] oxa [3,7,11] triazatrideca-2-yl) acetonitrile

Or a pharmaceutically acceptable salt thereof.

60. A pharmaceutical composition comprising a compound according to any one of claims 1 to 59, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

61. A method of inhibiting KRas G12C activity in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1-59, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 60.

62. A method of treating KRas G12C-associated cancer, the method comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-59, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 60.

63. The method of claim 62, wherein the KRas G12C-related cancer is selected from the group consisting of:

(i) Heart cancer: sarcomas (hemangiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma;

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

(iii) Gastrointestinal cancer: esophageal carcinoma (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric carcinoma (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagon tumor, gastrinoma, carcinoid tumor, schuz intestinal peptide tumor), small intestine cancer (adenocarcinoma, lymphoma, carcinoid tumor, kaposi's sarcoma, smooth myoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, smooth myoma);

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

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

(vi) Biliary tract cancer: gall bladder cancer, ampulla cancer, bile duct cancer; bone cancer: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, ewing's sarcoma, malignant lymphoma (reticulosarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondral tumor (bone exochondral osteowart), benign chondrioma, chondroblastoma, cartilage myxoid fibroma, osteoid osteoma and giant cell tumor;

(vii) Nervous system cancer: head bone cancer (osteoma, hemangioma, granuloma, xanthoma, malformed osteomyelitis), meningioma (meningioma, glioblastoma), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma);

(viii) Gynecological cancer: uterine cancer (endometrial cancer (serous cyst adenocarcinoma, mucinous cyst adenocarcinoma, unclassified cancer), granulosa cell tumors, sertoli-Leydig cell tumor, asexual cell tumors, malignant teratomas), vulval cancer (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube cancer (carcinoma);

(ix) Blood cancer: hematological cancers (myelogenous leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphoblastic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma);

(x) Skin cancer: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, cutaneous fibroma, keloids, psoriasis; and

(xi) Adrenal cancer: neuroblastoma.

64. The method of claim 63, wherein the cancer is non-small cell lung cancer, colorectal cancer, rectal cancer, or pancreatic cancer.

65. The method of claim 64, wherein the cancer is associated with brain metastasis.

66. A method of treating cancer in a subject in need thereof, the method comprising: (a) knowing that the cancer is associated with a KRas G12C mutation; and (b) administering to the subject an effective amount of a compound according to any one of claims 1 to 59, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 60.

67. The method of any one of claims 61-66, wherein the administering is by a route selected from the group consisting of: parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, cerebrospinal, intrasynovial, intrathecal, intramuscular, intravitreal, intravenous, intraarterial, oral, buccal, sublingual, transdermal, topical, intratracheal, intrarectal, subcutaneous and topical administration.

68. The method of any one of claims 61-67, wherein the compound is administered simultaneously, separately or sequentially with one or more additional therapeutic agents.

69. The method of claim 68, wherein the one or more additional therapeutic agents are selected from an anti-PD-1 or PD-L1 antagonist, a MEK inhibitor, a CDK4/CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, a SHP2 inhibitor, a SOS1 inhibitor, an mTOR inhibitor, a VEGFR inhibitor, an EGFR antibody, a platinum agent, or pemetrexed (pemetrexed).

70. Use of a compound according to any one of claims 1 to 59, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 60, in the manufacture of a medicament for the treatment of cancer.

71. A compound according to any one of claims 1 to 59, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 60, for use in the treatment of cancer.