Kras inhibitors, methods of making and using the same

Abstract

The present application provides a kind of compound with inhibitory effect on KRAS mutation, its pharmaceutically acceptable salt, stereoisomer, solvate or its prodrug, as shown in formula (I), wherein the definition of each group is detailed in the specification.In addition, the present application also discloses a pharmaceutical composition comprising the compound, and its use in the preparation of a kit for treating cancer, immune diseases or cancer patient prognosis evaluation.

Description

TECHNICAL FIELD

[0001] The present disclosure relates to the field of medicine, in particular to a compound with KRAS inhibitory effect, uses and methods of preparation. BACKGROUND

[0002] Kirsten rat sarcoma 2 viral oncogene homolog (KRas) is a small GTPase and a member of the Ras family. KRas protein is in an inactive state when it binds to GDP; when extracellular growth differentiation factors and the like transmit signals to the KRAS protein, the protein binds to GTP and becomes activated, thereby activating KRAS and downstream signals (Nature Review Cancer 3: 11-22, 2003). The RAS-RAF-MEK-ERK and RAS-PI3K-AKT signaling pathways regulate multiple cellular processes, including cell proliferation, differentiation, and survival. KRAS mutations can continuously activate downstream cell signals, promote cell proliferation, migration, and anti-apoptosis, and induce tumor occurrence.

[0003] KRAS mutations are closely related to tumor formation and development. The role of KRAS in malignancies has been observed more than 30 years ago (see, e.g., Santos et al. (1984) Science 223:661-664). Aberrant expression of KRAS is found in about 20% of all human tumors, and KRAS mutations are detected in 25-30% of lung adenocarcinomas (see, e.g., Samatar and Poulikakos (2014) Nat Rev Drug Disc 13(12):928-942 doi:10.1038 / nrd428). 80% of KRAS mutations occur at codon 12, causing a single amino acid substitution, among which the most predominant are G12C and G12D. KRAS G12C mutation refers to the mutation of glycine at position 12 of the protein to cysteine, and the frequency of tumor occurrence is in turn pancreatic cancer (57%), colorectal cancer (35%), biliary tract cancer (28%), small intestine cancer (17%), lung cancer (16%), endometrial cancer (15%) and ovarian cancer (14%) and the like (Seminars in Cancer Biology. 2019 Jun 27. pii: S1044-579X(18)30060-9). KRAS G12D mutation refers to the mutation of glycine at position 12 of the protein to aspartic acid, and the frequency of tumor occurrence is in turn pancreatic cancer (25.0%), colon cancer (13.3%), rectal cancer (10.1%), non-small cell lung cancer (4.1%) and small cell lung cancer (1.7%) and the like (see, e.g., The AACR Project GENIE Consortium, (2017) Cancer Discovery; 7(8):818-831. Dataset Version 4). In addition to G12C, G12D, KRAS has other mutations, such as G12V, G12A, G12R, G12S, G13D, Y96D, etc. Different KRAS mutations also have different frequencies in different types of cancer cells.

[0004] Due to the frequent mutations of KRAS found in various tumor types, it has become a popular anticancer target in the pharmaceutical industry (see McCormick (2015) Clin Cancer Res. 21(8): 1797-1801). The development of KRAS small molecule inhibitors is generally divided into three methods: (i) competitive ligands to prevent GTP binding; (ii) allosteric modulation to lock KRAS G12C in an inactive state; (iii) disruption of KRAS interaction with its effector proteins and guanine nucleotide exchange factors (GEFs) such as son of sevenless (SOS), RAF, and PI3K, by protein-protein interaction inhibitors.

[0005] Over the past decades, the development of drugs targeting KRAS has mostly failed, so KRAS has been considered undruggable. However, in recent years, with the breakthrough progress in biology and protein structure, including comparative studies of different structures of mutant and wild-type KRAS proteins, small molecule inhibitors targeting KRAS G12C have been successful in clinical trials. Amgen's First-in-Class KRAS G12C inhibitor AMG 510 has been approved by the US FDA for marketing on May 28, 2021, for the treatment of locally advanced or metastatic non-small cell lung cancer with KRAS G12C mutation. Mirati and many biopharmaceutical companies at home and abroad are also developing drugs targeting KRAS, but most of them are targeting KRAS G12C or KRAS G12D mutations. As mentioned above, in addition to KRAS G12C or KRAS G12D mutations, KRAS has other mutations, such as G12V, G12A, G12R, G12S, G13D, Y96D, etc. These KRAS mutations play an important role in the formation and development of various types of cancer. Therefore, it is urgent to develop drugs targeting these KRAS mutations. In addition, with the successful marketing of drugs targeting KRAS G12C, we expect that cancer patients receiving treatment will develop drug resistance. Therefore, in order to meet the unmet clinical needs, it is of great significance to develop innovative new generation broad-spectrum KRAS inhibitors targeting multiple KRAS mutations to combat drug resistance mechanisms. SUMMARY

[0006] In one aspect of the present application, a novel substituted fused ring aromatic compound is provided, which has high inhibitory activity as a selective inhibitor of KRAS mutations.

[0007] In one aspect of the present application, a compound of formula (I), a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof is provided:

[0008]

[0009] in which

[0010] R1is selected from

[0011] R2, R3are each independently selected from hydrogen, halogen, cyano, hydroxyl, -C 1-6 alkyl, -C 1-6 alkyl, -C a alkyl, -C b alkyl, -C 3-9 cycloalkyl, 3- to 9-membered heterocycloalkyl, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-3 alkyl, -C 1-3 alkyl-NR a R b , -C 1-3 alkyl-C 3-9 cycloalkyl, -C 1-3 alkyl-3- to 9-membered heterocycloalkyl, -C 3-9 cycloalkyl-C 1-3 alkoxy, -3- to 9-membered heterocycloalkyl-C 1-3 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C(O)NR a R b , -SO2C 1-3 alkyl, -C 1-3 alkyl-C 2-4 alkenyl, -C 1-3 alkyl-C 2-4 alkynyl, -C 1-3 alkyl-C(O)NR a R b , -C 1-3 alkyl-SO2C 1-3 alkyl, 5- to 6-membered monocyclic heteroaryl, C6- 10 aryl, 8- to 10-membered bicyclic heteroaryl, -C 1-3 alkyl-5- to 6-membered monocyclic heteroaryl, -C 1-3 alkyl-C 6-10 aryl, -C 1-3 alkyl-8- to 10-membered bicyclic heteroaryl, -5- to 6-membered monocyclic heteroaryl-C 1-3 alkyl, -C 6-10 aryl-C 1-3 alkyl, -8- to 10-membered bicyclic heteroaryl-C 1-3 alkyl, -5- to 6-membered monocyclic heteroaryl-C 1-3 alkoxy, -C6-10 aryl-C 1-3 alkoxy, -8- to 10-membered bicyclic heteroaryl-C 1-3 alkoxy, -C 1-3 alkyl-5- to 6-membered monocyclic heteroaryl-C 1-3 alkoxy, -C 1-3 alkyl-C 6-10 aryl-C 1-3 alkoxy, -C 1-3 alkyl-8- to 10-membered bicyclic heteroaryl-C 1-3 alkoxy; and said -C 1-6 alkyl, -C 1-6 alkoxy, -C 1-3 alkyl, -NR a R b , -C 3-9 cycloalkyl, 3- to 9-membered heterocycloalkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, 5- to 6-membered monocyclic heteroaryl, C 6-10 aryl, 8- to 10-membered bicyclic heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, amino, -N(CH3)2, hydroxyl, carboxyl, -C(O)NR a R b ; and said -C

[0012] R2’ is selected from hydrogen or methyl.

[0013] R4 is selected from X or XR7, wherein X is selected from O, N or halogen;

[0014] R7 is selected from hydrogen, -C 1-6 alkyl, -C 1-6 alkoxy, -C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, -C 1-3 alkyl-C 3-10 cycloalkyl, -C 1-3 alkyl-3- to 10-membered heterocycloalkyl, -C 3-10 cycloalkyl-NR a R b , -3- to 10-membered heterocycloalkyl-NR a R b , -C 1-3 alkyl-C 3-10 cycloalkyl-NR a R b , -C 1-3 alkyl-3- to 10-membered heterocycloalkyl-NR a R b ; and said -C 1-6 alkyl, -C 1-6 alkoxy, -C1-3 alkyl-, -C 3-10 cycloalkyl, -3 to 10 membered heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, amino, -N(CH3)2, hydroxyl, carboxyl;

[0015] R5is selected from the group consisting of hydrogen, -C 1-6 alkyl-, -C 1-6 alkoxy-, -C(O)C 1-3 alkyl-, -C(O)C 1-3 alkenyl-, -C(O)C 1-3 alkynyl-, -C(O)C 1-3 alkenyl-C 1-3 alkyl-, -C(O)C 1-3 alkynyl-C 1-3 alkyl;

[0016] R6is selected from the group consisting of hydrogen, halogen, cyano, hydroxyl, -C 1-6 alkyl-, -C 1-6 alkoxy-, -C 1-3 alkyl-hydroxy-, -C 1-3 alkyl-cyano-, -C 1-3 alkyl-C 1-3 alkoxy;

[0017] R a , R b are each independently hydrogen, C 1-3 alkyl, C 1-8 cycloalkyl, or C 1-8 cycloheteroalkyl;

[0018] said heterocycloalkyl, monocyclic heteroaryl, bicyclic heteroaryl has at least one heteroatom selected from the group consisting of N, O, and S as ring atom.

[0019] In one embodiment, in formula (I), R2, R3are each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxyl, -C 1-6 alkyl-, -C 1-6 alkoxy-, 5 to 6 membered monocyclic heteroaryl, C 6-10 aryl, 8 to 10 membered bicyclic heteroaryl, -C 1-3 alkyl-5 to 6 membered monocyclic heteroaryl, -C 1-3 alkyl-C 6-10 aryl, -C 1-3 alkyl-8 to 10 membered bicyclic heteroaryl, -5 to 6 membered monocyclic heteroaryl-C 1-3 alkyl-, -C 6-10 aryl-C 1-3 alkyl, -8 to 10 membered bicyclic heteroaryl-C 1-3 alkyl, -5 to 6 membered monocyclic heteroaryl-C1-3 Alkoxy, -C 6-10 Aryl-C 1-3 Alkoxy, -8 to 10-membered bicyclic heteroaryl-C 1-3 Alkoxy, -C 1-3 Alkyl-5 to 6-membered monocyclic heteroaryl-C 1-3 Alkoxy, -C 1-3 Alkyl-C 6-10 Aryl-C 1-3 Alkoxy, -C 1-3 Alkyl-8 to 10-membered bicyclic heteroaryl-C 1-3 alkoxy groups; and the -C 1-6 Alkyl, alkoxy, -C 1-3 Alkyl-, 5- to 6-membered monocyclic heteroaryl, C 6-10 The aryl group, or 8 to 10 membered bicyclic heteroaryl group, is optionally surrounded by 1, 2, or 3 independently selected from halogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, amino, -N(CH3)2, hydroxyl, carboxyl, -C(O)NR a R b Substituents are substituted.

[0020] In one embodiment, in formula (I), R2' is selected from halogen, cyano, hydroxyl, -C 1-6 Alkyl, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano.

[0021] In one embodiment, in formula (I), R4 is selected from X or XR7, wherein X is selected from O, N or halogen.

[0022] In one embodiment, in formula (I), R7 is selected from hydrogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-10 Cycloalkyl, -3 to 10-membered heterocycloalkyl, -C 1-3 Alkyl-3 to 10-membered heterocyclic alkyl, -3 to 10-membered heterocyclic alkyl-NR a R b -C 1-3 Alkyl-3 to 10-membered heterocyclic alkyl-NR a R b And the -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 1-3 The alkyl- or -3 to 10-membered heterocyclic alkyl group is optionally substituted by 1, 2 or 3 substituents independently selected from halogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, amino, -N(CH3)2, hydroxyl or carboxyl.

[0023] In one embodiment, in formula (I), R5 is selected from hydrogen, -C1-6 Alkyl, -C 1-6 Alkoxy group, -C(O)C 1-3 Alkyl, -C(O)C 1-3 Alkenyl group.

[0024] In one embodiment, in formula (I), R6 is selected from hydrogen, halogen, cyano, hydroxyl, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 1-3 Alkyl-hydroxyl, -C 1-3 Alkyl-cyano, -C 1-3 Alkyl-C 1-3 Alkyl group.

[0025] In a preferred embodiment, in formula (I), R2 or R2' is selected from hydrogen, methyl, or the following structures:

[0026]

[0027] In a preferred embodiment, in formula (I), R1 is selected from...

[0028] In a preferred embodiment, in formula (I), R4 is selected from halogens or

[0029] In a preferred embodiment, in formula (I), R3 is selected from hydrogen or

[0030] In one embodiment, the compound of formula (I) is as shown in formula (IIIa):

[0031]

[0032] In the formula, R1, R2, and R3 are defined as before.

[0033] In one embodiment, the compound of formula (I) is as shown in formula (IIIb):

[0034]

[0035] In the formula, R1, R2, and R3 are defined as before.

[0036] In one embodiment, the compound of formula (I) is as shown in formula (IIIc):

[0037]

[0038] In the formula, R1, R2, and R3 are defined as before.

[0039] In an embodiment, the compound of Formula (I) includes, but is not limited to, the following listed structures, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof:

[0040]

[0041]

[0042] In another aspect of the present application, there is provided a pharmaceutical composition comprising a compound according to the above, a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug thereof, or a compound prepared by the above method and a pharmaceutically acceptable excipient.

[0043] In an embodiment, the pharmaceutical composition further comprises another drug for treating cancer or immune diseases.

[0044] In another aspect of the present application, there is provided a use of a compound according to the above, a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug thereof, or a compound prepared by the above method in the preparation of a kit for treating cancer, immune diseases, or prognosis evaluation of cancer patients.

[0045] In another aspect of the present application, there is provided a use of a pharmaceutical composition according to the above in the preparation of a kit for treating cancer, immune diseases, or prognosis evaluation of cancer patients.

[0046] In an embodiment, the use is in a disease associated with KRAS mutation.

[0047] In an embodiment, the cancer includes pancreatic cancer, intestinal cancer, lung cancer, biliary tract cancer, endometrial cancer, and ovarian cancer.

[0048] In a preferred embodiment, the cancer includes pancreatic cancer, colorectal cancer, large intestinal cancer, lung adenocarcinoma, non-small cell lung cancer and small cell lung cancer, biliary tract cancer, small intestinal cancer, endometrial cancer, and ovarian cancer.

[0049] In an embodiment, the immune disease is a KRAS-mediated immune disease.

[0050] In another aspect of the present application, there is provided a use of a compound according to the above, a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug thereof, or a compound prepared by the above method in the preparation of a KRAS inhibitor.

[0051] In another aspect of the present application, there is provided a use of a pharmaceutical composition according to the above in the preparation of a KRAS inhibitor.

[0052] Preferably, the KRAS inhibitor is a KRAS G12D inhibitor.

[0053] In another aspect of the present application, there is provided a method for inhibiting KRAS mutation in a biological sample, comprising contacting the biological sample with a compound according to the above, a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate, a prodrug thereof, or a compound prepared by the above method, a pharmaceutical composition according to the above. DETAILED DESCRIPTION

[0054] In accordance with the provisions of the present disclosure, the examples described represent the preferred embodiments of the present application. Of course, it is to be understood that not necessarily all objects or aspects described above will be implemented in any particular application. No limitation on the scope of the application is intended by the inclusion of any particular example, and numerous additions, deletions, or modifications to the described embodiments, or replacement of part or all of the described elements, can be made by those skilled in the art and still be in the scope of this application as defined in the appended claims.

[0055] I. DEFINITIONS

[0056] Unless otherwise defined, all terms used in connection with the present application, including technical and scientific terms, have the same meaning as those commonly understood by one of ordinary skill in the art to which this application pertains. Furthermore, unless otherwise explicitly set forth herein, the use of any form of the terms "comprise", "comprises", "comprising", "include", "includes" or "including" is not intended to exclude any additional features, steps, components, elements, items or steps.

[0057] The compounds of the present disclosure can be asymmetric, e.g., having one or more stereocenters. Unless in particular contexts, otherwise indicated, all stereoisomers are included, e.g., enantiomers and diastereomers. Compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically active form or as racemic mixtures. Optically active forms can be obtained from racemic mixtures by separation of the enantiomers or by synthesis from chiral precursors or chiral reagents. Racemates, diastereomers, enantiomers are all included within the scope of the present disclosure.

[0058] The compounds of the present disclosure also include tautomeric forms. Tautomeric forms arise from the exchange of a single bond and the adjacent double bond together with the migration of a proton.

[0059] The term "optionally" or "optional" means that the subsequently described event or circumstance can or can not occur, and this description includes instances where the event or circumstance occurs and instances where it does not.

[0060] Numerical ranges as used herein are inclusive of the numbers given as endpoints. For example, a range of 1 to 10 includes 1 and 10. 1-6 " C3-6" means that the group can have 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

[0061] The term "substituted" or "substitution" means that any one or more hydrogen atoms on a particular atom or group is / are replaced with a substituent, as long as the valence of the particular atom or group is not normally and the substituted compound is stable. When the substituent is a keto group (i.e., =0), it means that two hydrogen atoms are replaced. Unless otherwise specified, the kind and number of substituents can be any that are chemically possible, on a basis of chemistry.

[0062] In the present disclosure, when any variable (e.g., Rn) occurs more than one time in a compound or substituent, its definition in each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is substituted with 1-5 R groups, then each R group is selected independently of the others. Moreover, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0063] The term "alkyl" refers to saturated aliphatic hydrocarbon groups which are straight-chain or branched-chain groups containing 1 to 20 carbon atoms, preferably alkyl groups containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, most preferably 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 2,2-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof, and the like. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment, and are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate, with the present disclosure preferably methyl, ethyl, isopropyl, t-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl, and hydroxyl-substituted alkyl.

[0064] The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example ethenyl, 1- propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like. The alkenyl group can be substituted or unsubstituted, and when substituted, the substituent groups are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.

[0065] "Alkynyl" refers to (CH≡C-), wherein the alkynyl group can be further substituted with other relevant groups, for example: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, cyano, nitro, phenol, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate.

[0066] The term "cycloalkyl" refers to a saturated monocyclic alkane substituent, the cycloalkyl ring comprising at least 3 carbon atoms, preferably comprising 3 to 12 carbon atoms, more preferably comprising 3 to 6 carbon atoms. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0067] The term "heterocyclyl" or "heterocycloalkyl" refers to a saturated monocyclic cyclic hydrocarbon substituent in which one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen, or S(O)m (where m is an integer from 0 to 2), but excluding ring moieties of -O-O-, -O-S-, or -S-S-, the remaining ring atoms being carbon. Non-limiting examples of heterocyclyl groups include pyrrolyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and the like, preferably pyrrolidinyl, morpholinyl, piperidinyl, cycloheptyl, 1,4-diazepanyl, and piperazinyl.

[0068] The heterocyclyl group can be optionally substituted or unsubstituted, and when substituted, the substituent groups are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, cyano, nitro, chloro, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate.

[0069] The term "aryl" means a 6- to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings which share adjacent pairs of carbon atoms) ring system having a conjugated pi-electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, including benzo 5-10 membered heteroaryl, benzo 3-8 membered cycloalkyl and benzo 3-8 membered heteroalkyl, preferably benzo 5-6 membered heteroaryl, benzo 3-6 membered cycloalkyl and benzo 3-6 membered heteroalkyl, wherein the heterocyclyl is a 1-3 nitrogen, oxygen, sulfur containing heterocyclyl; or also a three membered nitrogen containing fused ring containing a benzene ring.

[0070] The aryl group can be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0071] The term "heteroaryl" means a heteroaromatic system comprising heteroatoms and carbon atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5- or 6-membered, such as imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, thiadiazole, pyrazinyl and the like, preferably triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidyl or thiazolyl; more preferably pyrazolyl, pyrrolyl and oxazolyl.

[0072] The heteroaryl group can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0073] The term "alkoxy" means -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy. The alkoxy group can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0074] "Alkylthio-alkyl" refers to an alkylthio group attached to an alkyl group, where the alkyl and alkylthio groups are as defined above; "alkylaminocarbonyl" refers to (alkyl)-NC(O)-, where the alkyl group is defined as described above; "haloalkyl" refers to an alkyl group substituted with one or more halogens, where the alkyl group is as defined above; "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, where the alkoxy group is as defined above; "haloalkoxy" refers to an alkylthio group substituted with one or more halogens, where the alkylthio group is as defined above; "hydroxyalkyl" refers to an alkyl group substituted with a hydroxyl group, where the alkyl group is as defined above.

[0075] In this disclosure, "hydroxyl" refers to the -OH group; "halogen" refers to fluorine, chlorine, bromine, or iodine; "amino" refers to -NH2; "cyano" refers to -CN; "nitro" refers to -NO2; "carbonyl" refers to -C(O)-; "carboxyl" refers to -C(O)OH; "THF" refers to tetrahydrofuran; "EtOAc" refers to ethyl acetate; "MeOH" refers to methanol; "DMF" refers to N,N-dimethylformamide; "DIPEA" refers to diisopropylethylamine; "TFA" refers to trifluoroacetic acid; "MeCN" refers to acetonitrile; "DMA" refers to N,N-dimethylacetamide; "DCE" refers to 1,2-dichloroethane; "NBS" refers to N... - Bromosuccinimide; "NIS" refers to N-iodosuccinimide; "cbz-cr" refers to benzyl chloroformate; "Pd2(dba)3" refers to tris(dibenzylacetone)dipalladium; "Dppf'" refers to 1,1'-bis(diphenylphosphine)ferrocene; "HATU" refers to 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate; "KHMDS" refers to potassium hexamethyldisilamide; "LiHMDS" refers to lithium bis(trimethylsilylamine); "MeLi" refers to methyllithium; "n-BμLi" refers to n-butyllithium; "NaBH(OAc)3" refers to sodium triacetoxyborohydride.

[0076] All hydrogen atoms described in this disclosure can be replaced by their isotope deuterium.

[0077] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort.

[0078] In this disclosure, It refers to the junction of chemical bonds.

[0079] Medicament or pharmaceutical composition

[0080] The term "pharmaceutically acceptable" means those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0081] The term "pharmaceutically acceptable salt" means those salts of the free acids and bases of the specific compounds which retain the biological effectiveness of the free acids and bases and which have no biological adverse effects. For example, acid (including organic and inorganic acids) addition salts or base addition salts (including organic and inorganic bases).

[0082] The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound that contains an acidic or basic moiety by conventional chemical methods. Generally, the salt preparation methods are either reaction of the free acid or base form of these compounds in a water or an organic solvent or a mixture of both with a stoichiometric amount of the appropriate base or acid.

[0083] The pharmaceutical or pharmaceutical composition of the present disclosure can be administered orally, topically, parenterally, or mucosally (e.g., buccally, by inhalation, or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically-acceptable carriers. It is generally desired to administer using the oral route. The active agent can be administered orally in the form of capsules, tablets, etc. (see Remington: The Science and Practice of Pharmacy, 20th Edition).

[0084] For oral administration in the form of a tablet or capsule, the active drug component can be combined with non-toxic pharmaceutically-acceptable excipients such as binders (e.g., pregelatine dextrose, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, sucrose, dextrose, mannitol, sorbitol and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica, stearic acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate, etc.); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate), coloring agents and flavoring agents, gelatin, sweetening agents, natural and synthetic gums (such as acacia, tragacanth or alginate), buffer salts, carboxymethylcellulose, polyethylene glycol, waxes and the like. For oral administration in liquid form, the drug components can be combined with non-toxic, pharmaceutically-acceptable inert carriers (e.g., ethanol, glycerol, water) and adjuvants, such as preservatives (e.g., sorbic acid, the salts thereof, or methyl or propyl p-hydroxybenzoate) and wetting agents such as sorbitan esters. The liquid formulation can also contain suitable flavoring agents. Stabilizers such as antioxidants (BHA, BHT, propyl gallate, sodium ascorbate, citric acid) can also be added to stabilize the dosage form.

[0085] Tablets comprising the active compound of Formula I of the present disclosure can be coated by methods well known in the art. The compositions of the present disclosure comprising the active compound of Formula I can also be introduced into a bead, microsphere or microcapsule, for example constructed from polyglycolic acid / lactic acid (PGLA). Liquid formulations for oral administration can take the form of, for example, solutions, syrups, suspensions, or emulsions or they can be presented as a dry product for reconstitution with water or other suitable vehicle before use. Formulations for oral administration can be suitably formulated to allow for controlled or delayed release of the active compound.

[0086] Pharmaceutical or pharmaceutical compositions of the present disclosure can be delivered parenterally, i.e., by intravenous (i.v.), intracerebroventricular (i.c.v.), subcutaneous (s.c.), intraperitoneal (i.p.), intramuscular (i.m.), subdermal (s.d.) or intradermal (i.d.) administration, by direct injection, for example, as a bolus or by continuous infusion. Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers. The compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient can be in powder form for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) before use.

[0087] The pharmaceutical or pharmaceutical composition of the present disclosure can also be formulated for rectal administration, e.g., as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa oil or other glycerides.

[0088] The term "treatment" includes inhibiting, ameliorating, preventing or eliminating one or more symptoms or side effects associated with the disease, disorder or condition being treated.

[0089] The use of the terms "reduce," "inhibit," "mitigate" or "decrease" is relative to a control. The skilled artisan will readily determine the appropriate control for each experiment. For example, a reduced response in a subject or cell treated with a compound is compared to the response in a subject or cell not treated with the compound.

[0090] The term "effective amount" or "therapeutically effective amount" as used herein refers to the dosage sufficient to treat, inhibit or ameliorate one or more symptoms of the disease state being treated or otherwise to otherwise provide the desired pharmacologic and / or physiologic effect. The precise dosage will vary according to factors such as the subject-dependent variables (e.g., age, immune system health, etc.), the disease or condition, and the treatment administered. The effect of the effective amount can be relative to a control. These controls are known in the art and discussed herein, and can be, for example, the subject's condition prior to administration of the drug or pharmaceutical combination or without administration, or in the case of a pharmaceutical combination, the effect of the combination can be compared to the effect of administering only one of the drugs.

[0091] The term "excipient" is used herein to include any other compound that can be included in or on the microparticle that is not a therapeutically or biologically active compound. Thus, the excipient should be pharmaceutically or biologically acceptable or relevant, e.g., the excipient is generally not toxic to the subject. "Excipient" includes a single such compound, and is also intended to include multiple compounds.

[0092] The term "pharmaceutical composition" means a composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable ingredient selected from the group consisting of carriers, diluents, adjuvants, excipients, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweetening agents, flavoring agents, flavoring agents, antibacterial agents, antifungal agents, lubricants, dispersing agents, temperature-sensitive materials, temperature-regulating agents, adhesion agents, stabilizing agents, suspending agents, and the like, as appropriate to the mode and form of administration.

[0093] Use and method of treatment

[0094] The terms "patient," "subject," "individual," and the like are used interchangeably herein and refer to any animal or cell thereof, whether in vitro or in situ, amenable to the methods described herein. In some non-limiting embodiments, the patient, subject, or individual is a human.

[0095] According to the methods of the present disclosure, the compound or composition can be administered using any amount and any route of administration effective for treating or lessening the severity of a KRAS-associated disease.

[0096] The present disclosure relates to a method of inhibiting KRAS in a biological sample comprising the step of contacting the biological sample with a compound of the present disclosure or a composition comprising the compound.

[0097] The term "biological sample" includes, but is not limited to, cell cultures or extracts thereof; biopsy material obtained from a mammal or extracts thereof; and blood, saliva, urine, fecal, semen, tears, or other body fluids or extracts thereof. Inhibition of enzymes in a biological sample can be used for a variety of purposes known to those of skill in the art. Examples of such purposes include, but are not limited to, biological analysis, gene expression studies, and biological target identification.

[0098] The present disclosure provides a method of inhibiting KRAS in a patient comprising the step of administering to the patient a compound of the present disclosure or a composition comprising the compound.

[0099] The provided compounds are KRAS inhibitors and are therefore useful for treating one or more disorders associated with KRAS activity. Accordingly, in certain embodiments, the present disclosure provides a method for treating a KRAS-mediated disorder comprising the step of administering to a patient in need thereof a compound of the present disclosure or a pharmaceutically acceptable composition thereof.

[0100] As used herein, the term "KRAS-mediated" disorder, disease, and / or condition means any disease or other deleterious condition in which KRAS or a mutant thereof is known to play a role. Accordingly, another embodiment of the present disclosure relates to treating or lessening the severity of one or more diseases in which KRAS or a mutant thereof is known to play a role.

[0101] The present disclosure provides a method for treating one or more disorders, diseases, and / or conditions, wherein the disorder, disease, or condition is a proliferative disease, such as a cancer, an inflammatory disorder, or a viral infection.

[0102] In certain embodiments, the present disclosure provides a method of treating a cancer or another proliferative disorder comprising administering to a patient having a cancer or another proliferative disorder a compound or composition of the present disclosure. In certain embodiments, the method of treating a cancer or another proliferative disorder comprises administering to a mammal a compound and composition of the present disclosure. In certain embodiments, the mammal is a human.

[0103] As used herein, the terms "inhibiting cancer" and "inhibiting cancer cell proliferation" mean inhibiting the growth, division, maturation, or survival of a cancer cell, and / or causing the death of a cancer cell by cytotoxicity, nutrient depletion, or induction of apoptosis, individually or together with other cancer cells.

[0104] Examples of tissues containing cancer cells that are inhibited from proliferating by the compounds and compositions described herein and methods described herein include, but are not limited to, breast, prostate, brain, blood, bone marrow, liver, pancreas, epidermis, kidney, colon, ovary, lung, testis, penis, thyroid, parathyroid, pituitary, thymus, retina, uvea, conjunctiva, spleen, head, neck, trachea, gall bladder, rectum, salivary gland, adrenal gland, throat, esophagus, lymph node, sweat gland, sebaceous gland, muscle, heart, and stomach.

[0105] The cancer treated by the compounds or compositions of the present disclosure is melanoma, liposarcoma, lung cancer, breast cancer, prostate cancer, leukemia, kidney cancer, esophageal cancer, brain cancer, lymphoma, or colon cancer. In certain embodiments, the cancer is primary effusion lymphoma (PEL).

[0106] The compounds of the present disclosure can be used to treat a proliferative disease selected from a benign or malignant tumor, carcinoma, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, or gastrointestinal cancer, especially colon cancer or colorectal adenoma, or a tumor of the neck and head, hyperplasia of the epidermis, psoriasis, hyperplasia of the prostate, neoplasia, neoplasia of epithelial character, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma, Hodgkin's and non-Hodgkin's lymphoma, breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, MYD88 driven disorder, DLBCL, ABC DLBCL, IL-1 driven disorder, and indolent or smoldering multiple myeloma or leukemia of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, ovary, colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone, or thyroid.

[0107] The cancers described herein include, without limitation, leukemia (e.g., acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin's disease or non-Hodgkin's disease), Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, and solid tumors, e.g., sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, lung cancer, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma).

[0108] In some embodiments, the cancer is a glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.

[0109] In some embodiments, the cancer is an acoustic neuroma, astrocytoma (e.g., Grade I-pilocytic astrocytoma, Grade II-low grade astrocytoma, Grade III-anaplastic astrocytoma, or Grade IV-glioblastoma (GBM)), chordoma, CNS lymphoma, craniopharyngioma, brain stem glioma, ependymoma, mixed glioma, optic nerve glioma, subependymal ependymoma, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma, pituitary tumor, primitive neuroectodermal (PNET) tumor, or schwannoma. In some embodiments, the cancer is a type that is more common in children than in adults, e.g., brain stem glioma, craniopharyngioma, ependymoma, juvenile pilocytic astrocytoma (JPA), medulloblastoma, optic nerve glioma, pineal tumor, primitive neuroectodermal tumor (PNET), or rhabdoid tumor. In some embodiments, the patient is an adult patient. In some embodiments, the patient is a child or pediatric patient.

[0110] In another embodiment, the cancer includes, without limitation, mesothelioma, hepatobiliary (liver and bile duct), bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, anal region cancer, stomach cancer, gastrointestinal (stomach, colorectal and duodenum), uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small bowel cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell cancer, renal pelvis cancer, non-Hodgkin's lymphoma, spinal axis tumor, brain stem glioma, pituitary adenoma, adrenal cortex cancer, gall bladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the cancers.

[0111] In some embodiments, the cancer is selected from hepatocellular carcinoma, ovarian cancer, ovarian epithelial cancer, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; cholangiocellular carcinoma; soft tissue and synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing's sarcoma; anaplastic thyroid carcinoma; adrenal cortex adenoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic carcinoma; gastrointestinal / stomach (GIST) cancer; lymphoma; head and neck squamous cell carcinoma (SCCHN); salivary gland cancer; glioma or brain cancer; neurofibromatosis-1 associated malignant peripheral nerve sheath tumor (MPNST); Waldenstrom's macroglobulinemia; or medulloblastoma.

[0112] The term "primary tumor" is used in contrast to secondary tumors. A primary tumor is a tumor that first appears in a location such as the lung, liver, intestine, head, or skin, and can be referred to as primary lung cancer, primary liver cancer, primary intestinal cancer, etc.

[0113] The term "inflammatory disease" includes the autoimmune, allergic and inflammatory disorders described, such as those selected from the group consisting of arthritis, ankylosing spondylitis, inflammatory bowel disease, ulcerative colitis, gastritis, pancreatitis, Crohn's disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, rheumatic fever, gout, organ or graft rejection, acute or chronic graft-versus-host disease, chronic allograft rejection, Behcet's disease, uveitis, psoriasis, dermatitis, atopic dermatitis, dermatomyositis, myasthenia gravis, Grave's disease, Hashimoto's thyroiditis, Sjogren's syndrome, and blistering disorders (e.g., pemphigus vulgaris), antibody-mediated vasculitis syndromes, including ANCA-associated vasculitis, purpura, and immune complex vasculitis (cancer or infection stage one or two). The allergic disorders can be selected from the group consisting of contact dermatitis, celiac disease, asthma, hypersensitivity to house dust mites, pollen and related allergens, berylliosis. The respiratory disorders can be selected from the group consisting of asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pulmonary edema, pulmonary embolism, pneumonia, pulmonary sarcoidosis, pulmonary fibrosis, respiratory failure, acute respiratory distress syndrome, primary pulmonary hypertension, and emphysema, among others.

[0114] The term "viral infection" includes, but is not limited to, retroviral infection, hepatitis viral infection, Zika virus infection, dengue virus infection, and the like.

[0115] Method of combination therapy

[0116] The present disclosure provides combination therapy using the compounds as described herein with other therapeutic agents. The term "combination therapy" as used herein encompasses the administration of these agents in a sequential manner, i.e., where each therapeutic agent is administered at a different time, as well as the administration of these therapeutic agents, or at least two agents, substantially contemporaneously. The sequential, or substantially contemporaneous, administration of each agent can be effected by any appropriate route, including, but not limited to, oral routes, intravenous routes, intramuscular, subcutaneous routes, and direct absorption through mucous membrane tissues. The agents can be administered by the same route or by different routes. For example, a first agent can be administered orally, while a second agent is administered intravenously. Further, a selected combination agent can be administered by intravenous injection, while the other agents of the combination can be administered orally. Alternatively, for example, two or more agents can be administered by intravenous or subcutaneous injection.

[0117] Examples

[0118] The present disclosure is further illustrated by reference to the following examples. The description of the specific exemplary embodiments of the present disclosure is intended for purposes of illustration and example only. These descriptions are not intended to limit the present disclosure to the precise forms set forth and, as such, many modifications and variations are possible in light of the above teachings without departing from the spirit and scope of the present disclosure. The exemplary embodiments are chosen and described in order to explain the principles of the present disclosure and its practical application and to enable others skilled in the art to best utilize the present disclosure in various embodiments and various modifications, as are suited to the particular use contemplated.

[0119] The experimental methods used in the following examples are conventional methods unless otherwise specified.

[0120] The materials, reagents, etc. used in the following examples can be obtained commercially unless otherwise specified.

[0121] Instruments and reagents:

[0122] NMR: Agilent 400MR DD2 nuclear magnetic instrument, the determination solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD) and deuterated chloroform (CDCl3), and the internal standard is tetramethylsilane (TMS). Liquid chromatography-mass spectrometry (LC-MS): Agilent 1260 Infinity II-Infinity Lab LC / MSD mass spectrometer. HPLC: Agilent 1260 Infinity II high pressure liquid chromatograph (Sunfire C18 5um 150x4.6mm chromatographic column).

[0123] Thin layer chromatography silica gel plate: HSGF254 silica gel plate (Yantai Jiangyou Silica Gel Development Co., Ltd.), specification 0.9mm-1mm. TLC silica gel plate: GF254 silica gel plate (Yu Cheng Chemical Industry (Shanghai) Co., Ltd.), specification 0.2mm=0.25mm. Column chromatography: carrier 300-400 mesh silica gel (Qingdao Hai Lang Silica Gel Drier Co., Ltd.), Flash column (Ajell Fenuo Claricep Flash amorphous silica gel purification column).

[0124] Reagents: 4-nitro-1H-indole, ethyl isothiocyanate, (1-methylpyrrolidin-2-yl)methanol, 4-bromobenzonitrile, N-ethyl-N-methylazetidinium hydrochloride, 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, 1-iodo-4-(trifluoromethyl)benzene, 1-iodo-4-methoxybenzene, 1-fluoro-4-iodobenzene, 2-(bromomethyl)naphthalene, 1-(chloromethyl)-4-methoxybenzene, 1-fluoro-3-iodobenzene, 1-fluoro-2-iodobenzene, 4-chloroiodobenzene, 1-iodo-3-(trifluoromethyl)benzene, 1-(bromomethyl)-4-(trifluoromethyl)benzene, 3-iodophenol, 3-iodobenzonitrile, iodobenzene, 1-iodonaphthalene, 2-iodobenzonitrile, tert-butyl (4-iodophenyl)carbamate, 1-iodo-4-(trifluoromethoxy)benzene, 5-iodo-1-methyl-1H-imidazole, 3-iodopyridine, ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol, 4-iodobenzonitrile, p-fluoroiodobenzene, 2-fluoro-5-iodobenzonitrile, 2-fluoro-4-iodobenzonitrile, 1-chloro-3-iodobenzene, m-iodotoluene, o-iodotoluene, 4-iodobenzoic acid tert-butyl ester, 4-iodobenzamide, 1,2-difluoro-4-iodobenzene, (2-fluorophenyl)boronic acid, 1-chloro-3-iodobenzene, 2,2-dimethyloxirane, acryloyl chloride, piperazine-1-carboxylic acid tert-butyl ester, 1-iodo-7-(methyloxy)naphthalene, (S)-3-methylpiperazine-1-carboxylic acid tert-butyl ester, and other reagents and starting materials were purchased from Shanghai Biotech, Leyan Reagent Co., Ltd., Jiangsu Aikang Biomedicine R&D Co., Ltd., Anjieji Chemical Reagent Co., Ltd., Shanghai Macklin Reagent Co., Ltd., Saun Chemical Reagent Co., Ltd., or synthesized by methods known in the art.

[0125] Unless otherwise specified, all reactions of the present disclosure were carried out under continuous magnetic stirring under dry nitrogen or argon, with dry solvents, and the reaction temperature was in degrees Celsius.

[0126] The following are the numbers of intermediates:

[0127]

[0128] Preparation of Intermediate I-1: tert-butyl (1R, 5S)-3-(2-chloro-7H-pyrrolo[2,3-h]quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0129]

[0130] First Step: Preparation of tert-butyl 4-nitro-1H-indole-1-carboxylate (I-1a)

[0131] To a solution of 4-nitro-lH-indole (10 g, 62 mmol) and 4-dimethylaminopyridine (733 mg, 6 mmol) in acetonitrile (150 ml) was added di-tert-butyl dicarbonate (14.84 g, 68 mmol) slowly. The reaction was stirred at room temperature for 0.5 h. The reaction was quenched by adding a small amount of water and the solvent was removed by distillation under reduced pressure. The crude product was added to 500 ml of water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the target product tert-butyl 4-nitro-lH-indole-l-carboxylate (I-la, 16.24 g, 99.89% yield). The product was used directly in the next step.

[0132] Second Step: Preparation of tert-butyl 4-amino-lH-indole-l-carboxylate (I-lb)

[0133] To a solution of tert-butyl 4-nitro-lH-indole-l-carboxylate (I-la, 10 g, 38.13 mmol) in methanol (200 ml) was added 10% palladium on carbon (4.06 g, 38.13 mmol) and the reaction was stirred at room temperature for 16 h. The filtrate was collected by filtration and the solvent was removed by distillation under reduced pressure. The product was purified by flash column chromatography (ethyl acetate: petroleum ether = 1:4) to give the target product tert-butyl 4-amino-lH-indole-l-carboxylate (I-lb, 8.48 g, 95.82% yield). MS (ESI) [M+H] + 233.1.

[0134] Third Step: Preparation of tert-butyl 4-(3-(ethoxycarbonyl)thio ureido)-lH-indole-l- carboxylate (I-lc)

[0135] To a solution of tert-butyl 4-amino-lH-indole-l-carboxylate (8.48 g, 36.5 mmol) in dichloromethane (150 ml) was added ethyl isothiocyanate (I-lb, 4.79 g, 36.51 mmol) and the reaction was stirred at room temperature for 1 h under nitrogen. The reaction was concentrated under reduced pressure to give the target product tert-butyl 4-(3-(ethoxycarbonyl)thio ureido)-lH-indole-l-carboxylate (I-lc, 12.06 g, 90.88% yield). MS (ESI) [M+H] + 364.2.

[0136] Fourth Step: Preparation of tert-butyl (Z)-4-(((ethoxycarbonyl)amino)(ethylthio)methylidene)amino)-lH-indole-l-carboxylate (I-lc)

[0137] Dissolve 4-(3-(ethoxycarbonyl)thioureido)-lH-indole-1-carboxylic acid tert-butyl ester (I-1c, 13.86 g, 38.14 mmol) and potassium carbonate (10.54 g, 76.28 mmol) in acetone (200 mL) and slowly add iodoe thane (6.84, 43.86 mmol) dropwise. Stir the reaction at room temperature for 16 hours. Concentrate the reaction under reduced pressure to give the target product tert-butyl (z)-4-(((ethoxycarbonyl)amino)(ethylthio)methylidene)amino)-lH-indole-1-carboxylate (I-1d, 16.1 g, 108% yield). MS (ESI) [M+H] + 392.3.

[0138] Fifth Step: Preparation of 2-(ethylthio)-3,7-dihydro-4H-pyrrolo[2,3- h]quinazolin-4-one (I-1e)

[0139] Dissolve tert-butyl (z)-4-(((ethoxycarbonyl)amino)(ethylthio)methylidene)amino)-lH-indole-1-carboxylate (I-1d, 16.1 g, 41.13 mmol) in diphenyl ether (140 mL) and heat the reaction to 200 °C under a nitrogen atmosphere for 2 hours. Cool the reaction to room temperature and dilute with petroleum ether. Filter the reaction and wash the solid with petroleum ether. Dry the solid to give the target product 2-(ethylthio)-3,7-dihydro-4H-pyrrolo[2,3- h]quinazolin-4-one (I-1e, 8.3 g, 82.26% yield). MS (ESI) [M+H] + 246.1.

[0140] Sixth Step: Preparation of 1.7-dihydro-2H-pyrrolo[2.3-h]quinazoline-2.4(3H)- dione (I-1f)

[0141] Dissolve 2-(ethylthio)-3,7-dihydro-4H-pyrrolo[2,3-h]quinazolin-4-one (I-1e, 8.3 g, 33.84 mmol) in 6 M hydrochloric acid (80.3 mL) and ethanol (80.3 mL) and heat the reaction to 80 °C for 16 hours. Filter the reaction while hot to collect the solid and wash the solid with ethanol. Dry the solid to give the target product 1.7-dihydro-2H-pyrrolo[2.3-h]quinazoline-2.4(3H)-dione (I-1f, 7 g, 103% yield). MS (ESI) [M+H] + 202.1.

[0142] Seventh Step: Preparation of 2,4-dichloro-7H-pyrrolo[2,3-h]quinazoline (I-1g)

[0143] Dissolve 1.7-dihydro-2H-pyrrolo[2.3-h]quinazolin-2,4(3H)-dione (7 g, 34.79 mmol) in phosphorus oxychloride (80 ml), add N,N-diisopropylethylamine (1-1f, 13.49 g, 13.49 mmol), and react at 80°C for 5 hours under nitrogen protection. Remove the large amount of phosphorus oxychloride by distillation under reduced pressure, quench the remaining product with water, extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the target product 2,4-dichloro-7H-pyrrolo[2,3-h]quinazoline (1-1g, 6.98 g, yield 84.30%). MS (ESI) [M+H] + 237.9, MS (ESI) [M+H] + 239.9.

[0144] Eighth Step: Preparation of tert-butyl (1R, 5S)-3-(2-chloro-7H-pyrrolo[2,3-h]quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1-1)

[0145] Dissolve 2,4-dichloro-7H-pyrrolo[2,3-h]quinazoline (1-1g, 6.4 g, 26.88 mmol) in N-methylpyrrolidone (100 ml), add tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5.71, 26.88 mmol) and N,N-diisopropylethylamine (10.42 g, 80.64 mmol) successively at 0°C, and react at 0°C for 1 hour. Add 100 ml of water to the reaction solution, extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the target product tert-butyl (1R, 5S)-3-(2-chloro-7H-pyrrolo[2,3-h]quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1-1, 6.07 g, yield 54.54%). MS (ESI) [M+H] + 414.3, MS (ESI) [M+H+2] + 416.3.

[0146] Preparation of Intermediate 1-2: tert-butyl (1R, 5S)-3-(2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0147]

[0148] First step: Preparation of tert-butyl (1R, 5S)-3-(2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (I-2)

[0149] Tert-butyl (1R, 5S)-3-(2-chloro-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (I-1, 700 mg, 1.69 mmol) was dissolved in anhydrous 1,4-dioxane (5 ml), and (S)-(1-methylpyrrolidin-2-yl)methanol (524 mg, 3.38 mmol) and N,N-diisopropylethylamine (874 mg, 6.76 mmol) were added. The reaction was carried out at 85°C for 16 hours. After removing the solvent under reduced pressure, the target product tert-butyl (1R, 5S)-3-(2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (I-2, 165 mg, yield 21.57%) was obtained by purification using a flash column (dichloromethane:methanol = 10:1). MS (ESI) [M+H] + 493.4.

[0150] Preparation of intermediate I-3: tert-butyl 4-((1R, 5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline-7-carboxylate

[0151]

[0152] First step: Preparation of tert-butyl 4-((1R, 5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-chloro-7H-pyrrolo[2,3-h]quinoline-7-carboxylate (I-3a)

[0153] To a solution of tert-butyl (1R,5S)-3-(2-chloro-7H-pyrrolo[2,3-h]quinazolin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1-1, 3.63 g, 8.77 mmol) and 4- dimethylaminopyridine (108 mg, 0.88 mmol) in acetonitrile (80 ml) was added di-tert- butyl dicarbonate (2.11 g, 9.65 mmol) slowly. The reaction was stirred at room temperature for 0.5 h. The reaction was quenched by adding a small amount of water and the solvent was removed by distillation under reduced pressure. The crude product was dissolved in 100 ml of water and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The target product, tert-butyl 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)-2-chloro-7H-pyrrolo[2,3-h]quinoline-7-carboxylate (1-3a, 3.72 g, 82.48% yield) was obtained after purification by flash column (methanol: dichloromethane = 0% ~ 10%). + 514.4, MS (ESI) [M+H] + 516.3.

[0154] Second Step: Preparation of tert-butyl 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3- h]quinoline-7-carboxylate (1-3)

[0155] To a reaction flask were added tert-butyl 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)-2-chloro-7H-pyrrolo[2,3-h]quinoline-7-carboxylate (1-3a, 5 g, 9.7 mmol), S-(1-methylpyrrolidin-2-yl)methanol (2.24 g, 19.4 mmol), cesium carbonate (4.75 g, 14.6 mmol), BINAP (1.21 g, 1.94 mmol) and palladium acetate (0.43 g, 1.94 mmol) and dissolved in toluene (100 ml). The system was purged with nitrogen for 3 times and heated to 110 °C for 16 h. After the reaction was completed, the system was cooled to room temperature, quenched with water and extracted with ethyl acetate. The organic phase was collected and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The target product, tert-butyl 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((S)-1- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline-7-carboxylate (2-b) (5 g, 86.7% yield, brown solid) was obtained after purification by flash column (methanol: dichloromethane = 0% ~ 10%). +593.75

[0156] Preparation of Intermediate I-4: tert-butyl 4-((lR,5S)-8-(tert-butoxycarbonyl)- 3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizidin- 7a(5H)-yloxy)-7H-pyrrolo[2,3-h]quinoline-7-carboxylate

[0157]

[0158] First Step: Preparation of tert-butyl 4-((lR,5S)-8-(tert-butoxycarbonyl)- 3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizidin- 7a(5H)-yloxy)-7H-pyrrolo[2,3-h]quinoline-7-carboxylate (I-4)

[0159] Tert-butyl 4-((lR,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3- yl)-2-chloro-7H-pyrrolo[2,3-h]quinoline-7-carboxylate (I-3a, 500 mg, 0.97 mmol), cesium carbonate (476 mg, 1.46 mmol) and ((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizidin-7a(5H)-yl)methanol (170 mg, 1.07 mmol) were dissolved in toluene (10 ml), palladium acetate (43 mg, 0.19 mmol) and l,l'-binaphthalene-2,2'-bis- diphenylphosphine (118 mg, 0.19 mmol) were added under nitrogen protection, and the reaction was carried out at 130 °C for 16 hours. The solvent was removed by distillation under reduced pressure, and the crude product was purified by flash (dichloromethane:methanol = 10:1) to obtain the target product tert-butyl 4-((lR,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizidin-7a(5H)-yloxy)-7H-pyrrolo[2,3-h]quinoline-7-carboxylate (I-4, 407 mg, yield 65.86 %). MS (ESI) [M+H] + 637.3.

[0160] Example 1: Preparation of tert-butyl 4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 2-chloro-7H-pyrrolo[2,3-h]quinoline-7-carboxylate

[0161]

[0162] tert-Butyl (1R,5S)-3-(2-chloro-7H-pyrrolo[2,3-h]quinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (1-1, 100 mg, 0.24 mmol) was dissolved in dichloromethane (3 ml), trifluoroacetic acid (0.5 ml) was added slowly, and the reaction was allowed to proceed at room temperature for 1 hour. The solvent was removed under reduced pressure, and the crude product was purified by TLC (MeOH:DCM = 10:1) to obtain compound 1: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octanyl-3-yl)-2-chloro-7H-pyrrolo[2,3- h]quinazoline (52 mg, yield 50.49%). MS (ESI) [M+H] + 314.2. 1 H NMR (600 MHz, DMSO-d6) δ 11.91 (s, 1H), 9.16 (s, 2H), 7.68-7.60 (m, 2H), 7.51 (t, J = 2.5 Hz, 1H), 7.01 (s, 1H), 4.32 (d, J = 13.3 Hz, 2H), 4.15 (s, 2H), 3.67 (d, J = 13.6 Hz, 2H), 2.04-1.90 (m, 4H).

[0163] Example 2: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((S)-1- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinazoline trifluoroacetate salt

[0164]

[0165] First step: tert-Butyl (1R,5S)-3-(2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H- pyrrolo[2,3-h]quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2-a)

[0166] Intermediate 1-1 (700 mg, 1.69 mmol) was dissolved in anhydrous 1,4-dioxane (5 ml), (S)-(1-methylpyrrolidin-2-yl)methanol (524 mg, 3.38 mmol) and N,N- diisopropylethylamine (874 mg, 6.76 mmol) were added. The reaction was allowed to proceed at 85 °C for 16 hours. After removing the solvent under reduced pressure, the target product tert-butyl (1R,5S)-3-(2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3- h]quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2-a, 165 mg, yield 21.57%) was purified by a flash column (dichloromethane:methanol = 10:1). MS (ESI) [M+H] +493.4.

[0167] Second Step: 4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((S)-l- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinazoline trifluoroacetate (2)

[0168] Tert-butyl (lR,5S)-3-(2-((S)-l-methylpyrrolidin-2-yl)methoxy)-7H- pyrrolo[2,3-h]quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2-a, 100 mg, 0.2 mmol) was dissolved in dichloromethane (1 ml) and trifluoroacetic acid (1 ml) and reacted at room temperature for 0.5 hours. The solvent was removed under reduced pressure and the crude product was purified by TLC plate (dichloromethane:methanol = 8:1) to give compound 2: 4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((S)-l- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinazoline trifluoroacetate (18 mg, yield 17.82%). MS (ESI)

[0169] [M+H]+393.4.1H NMR (600 MHz, DMSO-d6) δ 11.83 (s, 1H), 9.94 (s, 1H), 7.56 (d, J = 9.0 Hz, 1H), 7.47 (d, J = 9.0 Hz, 1H), 7.41 (t, J = 2.4 Hz, 1H), 6.96 (s, 1H), 5.76 (s, 1H), 4.73 (dd, J = 16.6, 10.2 Hz, 2H), 4.22 (d, J = 13.1 Hz, 2H), 4.12 (s, 2H), 3.76 (d, J = 13.5 Hz, 2H), 3.47 (d, J = 15.2 Hz, 2H), 3.02 (s, 1H), 2.83 (d, J = 34.3 Hz, 3H), 2.25 (s, 1H), 2.11 - 1.80 (m, 7H).

[0170] Example 3: 7-Benzyl-4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((S)-l- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinazoline trifluoroacetate

[0171]

[0172] First Step: Tert-butyl (lR,5S)-3-(7-benzyl-2-chloro-7H-pyrrolo[2,3-h]quinazolin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3-a)

[0173] Intermediate I-1 (2 g, 4.8 mmol) and cesium carbonate (3.13 g, 9.6 mmol) were dissolved in N,N-dimethylformamide (50 ml), and benzyl bromide (903 mg, 5.28 mmol) was added, and the reaction was allowed to proceed at room temperature for 1 hour. The reaction solution was added to 200 ml of water, and extraction was performed with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target product tert-butyl (1R, 5S)-3-(7-benzyl-2-chloro-7H-pyrrolo[2,3-h]quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3-a, 1.87 g, yield 77.24%). MS (ESI) [M+H] + 504.3.

[0174] Second step: tert-butyl (1R, 5S)-3-(7-benzyl-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3-b)

[0175] Tert-butyl (1R, 5S)-3-(7-benzyl-2-chloro-7H-pyrrolo[2,3-h]quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3-a, 1.86 g, 3.69 mmol) and cesium carbonate (6.01 g, 18.45 mmol) were dissolved in anhydrous 1,4-dioxane (30 ml), and (S)-(1-methylpyrrolidin-2-yl)methanol (2.12 g, 18.45 mmol) and N,N-diisopropylethylamine (2.38 g, 18.45 mmol) were added. The reaction was allowed to proceed at 165°C for 16 hours. The crude product was added to 100 ml of water, extraction was performed with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and purification was performed by a flash column (dichloromethane:methanol=10:1) to obtain compound 3: tert-butyl (1R, 5S)-3-(7-benzyl-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3-b, 879 mg, yield 40.88%). MS (ESI) [M+H] + 583.5.

[0176] Third step: 7-benzyl-4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinazoline trifluoroacetate (1)

[0177] Tert-butyl (1R,5S)-3-(7-benzyl-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H- pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3-b, 50 mg, 0.09 mmol) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (1 ml) and reacted at room temperature for 0.5 hours. The solvent was removed under reduced pressure and the crude product was purified by flash (dichloromethane:methanol = 8:1) to give the target product 7-benzyl-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((S)-1- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline trifluoroacetate (3, 7.1 mg, yield 13.22%). MS (ESI) [M+H]+483.4.1H NMR (400 MHz, DMSO-d6) δ 7.53-7.48 (m, 2H), 7.38 (d, J = 9.1 Hz, 1H), 7.29 (t, J = 7.2 Hz, 2H), 7.23 (d, J = 7.0 Hz, 1H), 7.19 (d, J = 7.2 Hz, 2H), 6.93 (d, J = 2.9 Hz, 1H), 5.48 (s, 2H), 4.41 (dd, J = 10.7, 4.6 Hz, 1H), 4.15-4.05 (m, 3H), 3.43 (s, 3H), 2.93 (dd, J = 10.0, 3.9 Hz, 1H), 2.61-2.50 (m, 2H), 2.37 (s, 3H), 2.18-2.11 (m, 1H), 1.99-1.86 (m, 2H), 1.72-1.57 (m, 7H).

[0178] Example 4: Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((S)-1- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline-7-yl)benzonitrile trifluoroacetate

[0179]

[0180] First step: Tert-butyl (1R,5S)-3-(7-(4-cyanophenyl)-2-((S)-1-methylpyrrolidin-2- yl)methoxy)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4-a)

[0181] Intermediate I-2 (79 mg, 0.16 mmol), cuprous iodide (6 mg, 0.032 mmol), metformin (8 mg, 0.064 mmol) and cesium carbonate (104 mg, 0.32 mmol) were dissolved in N,N-dimethylformamide (5 ml), then 4-bromobenzonitrile (58 mg, 0.32 mmol) was added and reacted at 130 °C for 16 hours. The crude product was added to 50 ml of water and extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by flash column chromatography (dichloromethane:methanol = 10:1) to obtain the target product tert-butyl (1R,5S)-3-(7-(4-cyanophenyl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4-a, 25.5 mg, yield 26.84 %). MS (ESI) [M+H] + 594.5.

[0182] Second step: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-7-yl)benzonitrile trifluoroacetate salt (4)

[0183] Tert-butyl (1R,5S)-3-(7-(4-cyanophenyl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4-a, 25.5 mg, 0.04 mmol) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (1 ml) and reacted at room temperature for 1 hour. The solvent was removed by distillation under reduced pressure, and the crude product was purified by flash column chromatography (dichloromethane:methanol = 8:1) to obtain compound 4 (HSN004004): 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-7-yl)benzonitrile trifluoroacetate salt (19.3 mg, yield 80.42 %). MS (ESI) [M+H] + 494.4. 1H NMR (400 MHz, CD3OD) δ 8.00 (d, J = 8.5 Hz, 2H), 7.82 (d, J = 8.6 Hz, 3H), 7.76 (d, J = 3.4 Hz, IH), 7.71 (d, J = 9.3 Hz, IH), 7.45 (d, J = 3.3 Hz, IH), 4.99-4.95 (m, IH), 4.84-4.74 (m, 3H), 4.24 (s, 2H), 4.03-3.90 (m, 3H), 3.78 (s, IH), 3.25-3.16 (m, 2H), 3.13 (s, 3H), 2.50-2.40 (m, IH), 2.27-2.08 (m, 7H).

[0184] Example 5: Preparation of l-(4-((lR,5S)-3,8-diazabicyclo[3.2.1]octanyl-3-yl)-7-(4- (trifluoromethyl)phenyl)-7H-pyrrolo[2,3-h]quinazolin-2-yl)-N,N-diethylazetidin-3-amine trifluoroacetate salt

[0185]

[0186] First step: tert-butyl (lR,5S)-3-(2-(3-(diethylamino)azetidin-l-yl)-7H-pyrrolo[2,3- h]quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5-a)

[0187] Intermediate 1-1 (200 mg, 0.48 mmol) and N-ethyl-N-methylazetidinium hydrochloride (193 mg, 0.96 mmol) were dissolved in 1,4-dioxane (12 ml), N,N- diisopropylethylamine (310 mg, 2.4 mmol) was added, and the reaction was carried out at 120 °C for 4 hours. The solvent was removed by distillation under reduced pressure, and the crude product was purified by flash (dichloromethane:methanol = 10:1) to obtain the target product tert-butyl (lR,5S)-3-(2-(3-(diethylamino)azetidin-l-yl)-7H-pyrrolo[2,3- h]quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5-a, 280 mg, yield 115%). MS (ESI) [M+H] + 506.5.

[0188] Second step: tert-butyl (lR,5S)-3-(2-(3-(diethylamino)azetidin-l-yl)-7-(4- (trifluoromethyl)phenyl)-7H-pyrrolo[2,3-h]quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (5-b)

[0189] tert-Butyl (1R,5S)-3-(2-(3-(diethylamino)azetidin-1-yl)-7-(4- (trifluoromethyl)phenyl)-7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8-diazabicyclo[3.2.1] octane-8-carboxylate (5-b, 17.4 mg, 0.03 mmol) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (1 ml) at room temperature for 1 hour. The solvent was removed by distillation under reduced pressure, and the crude product was purified by Pre-HPLC to obtain compound 5: 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octanyl-3-yl)-7-(4- (trifluoromethyl)phenyl)-7H-pyrrolo[2,3-h]quinolin-2-yl)-N,N-diethylazetidin-3-amine trifluoroacetate salt (15.1 mg, yield 84.97%). MS (ESI) [M+H] + 650.4.

[0190] Third Step: 1-(4-((1R,5s)-3,8-diazabicyclo[3.2.1]octanyl-3-yl)-7-(4- (trifluoromethyl)phenyl)-7H-pyrrolo[2,3-h]quinolin-2-yl)-N,N-diethylazetidin-3-amine trifluoroacetate salt (5)

[0191] tert-Butyl (1R,5S)-3-(2-(3-(diethylamino)azetidin-1-yl)-7-(4- (trifluoromethyl)phenyl)-7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8-diazabicyclo[3.2.1] octane-8-carboxylate (5-b, 17.4 mg, 0.03 mmol) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid

[0192] (1 ml) at room temperature for 1 hour. The solvent was removed by distillation under reduced pressure, and the crude product was purified by Pre-HPLC to obtain compound 5: 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octanyl-3-yl)-7-(4- (trifluoromethyl)phenyl)-7H-pyrrolo[2,3-h]quinolin-2-yl)-N,N-diethylazetidin-3-amine trifluoroacetate salt (15.1 mg, yield 84.97%). MS (ESI) [M+H] + 550.5. 1H NMR (400 MHz, CD3OD) δ 7.95 (d, J = 8.4 Hz, 2H), 7.82 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 3.4 Hz, 1H), 7.73 (d, J = 9.3 Hz, 1H), 7.62 (d, J = 9.2 Hz, 1H), 7.50 (d, J = 3.2 Hz, 1H), 4.81 (d, J = 14.5 Hz, 2H), 4.71 (dd, J = 15.2, 9.4 Hz, 3H), 4.50 (dd, J = 12.6, 6.1 Hz, 1H), 4.22 (s, 2H), 3.91 (d, J = 14.1 Hz, 2H), 3.36 - 3.31 (m, 3H), 2.10 (s, 4H), 1.37 (t, J = 7.3 Hz, 6H), 1.28 (s, 2H).

[0193] Example 6: Preparation of 4-((lR,5S)-3,8-diazabicyclo[3.2. l]octan-3-yl)-2-((S)-l- methylpyrrolidin-2-yl)methoxy)-7-(4-(trifluoromethyl)phenyl)-7H-pyrrolo[2,3- h]quinazoline trifluoroacetate

[0194]

[0195] First Step: tert-Butyl (lR,5S)-3-(2-((S)-l-methylpyrrolidin-2-yl)methoxy)-7-(4- (trifluoromethyl)phenyl)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2. l]octane-8- carboxylate (6-a)

[0196] Intermediate I-2 (100 mg, 0.2 mmol), cuprous iodide (19 mg, 0.1 mmol), metformin (13 mg, 0.1 mmol) and cesium carbonate (130 mg, 0.4 mmol) were dissolved in N,N- dimethylformamide (5 ml), then 1-iodo-4-(trifluoromethyl)benzene (163 mg, 0.6 mmol) was added and reacted at 130 °C for 16 hours. The crude product was added to 50 ml of water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, then purified on a TLC plate (dichloromethane:methanol = 10:1) to obtain the target product tert-butyl (lR,5S)-3-(2-((S)-l-methylpyrrolidin-2-yl)methoxy)-7-(4- (trifluoromethyl)phenyl)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2. l]octane-8- carboxylate (6-a, 54.7 mg, yield 42.97 %). MS (ESI) [M+H] + 637.5.

[0197] Step 2: 4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((S)-l-methylpyrrolidin-2- yl)methoxy)-7-(4-(trifluoromethyl)phenyl)-7H-pyrrolo[2,3-h]quinazoline trifluoroacetate (6)

[0198] Tert-butyl (lR,5S)-3-(2-((S)-l-methylpyrrolidin-2-yl)methoxy)-7-(4- (trifluoromethyl)phenyl)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (6-a, 54.7 mg, 0.09 mmol) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (0.5 ml) and reacted at room temperature for 1 hour. The solvent was removed under reduced pressure and the crude product was purified by Pre-HPLC to give compound 6: 4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((S)-l-methylpyrrolidin-2- yl)methoxy)-7-(4-(trifluoromethyl)phenyl)-7H-pyrrolo[2,3-h]quinazoline trifluoroacetate (13.5 mg, yield 24.15 %). MS (ESI) [M+H] + 537.4. 1 H NMR (400 MHz, CD3OD) δ 7.96 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 7.3 Hz, 3H), 7.79 (d, J = 3.4 Hz, IH), 7.71 (d, J = 9.3 Hz, IH), 7.46 (d, J = 3.3 Hz, IH), 5.00 (dd, J = 12.4, 3.0 Hz, IH), 4.87 - 4.75 (m, 4H), 4.25 (s, 2H), 3.99 (dd, J = 13.8, 8.0 Hz, 3H), 3.80 (s, IH), 3.14 (s, 3H), 2.51 - 2.41 (m, IH), 2.29 - 2.07 (m, 7H).

[0199] Example 7: Preparation of 4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(4- methoxyphenyl)-2-((S)-l-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinazoline trifluoroacetate

[0200]

[0201] First step: tert-butyl (1R, 5S)-3-(7-(4-methoxyphenyl)-2-((S)-1- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (7-a)

[0202] Intermediate I-2 (100 mg, 0.2 mmol), cuprous iodide (19 mg, 0.1 mmol), metformin (13 mg, 0.1 mmol) and cesium carbonate (130 mg, 0.4 mmol) were dissolved in N,N-dimethylformamide (5 ml), then 1-iodo-4-methoxybenzene (140 mg, 0.6 mmol) was added and reacted at 130 °C for 16 hours. The crude product was added to 50 ml of water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, then purified on a TLC plate (dichloromethane:methanol = 10:1) to obtain the target product tert-butyl (1R, 5S)-3-(7-(4-methoxyphenyl)-2-((S)-1- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (7-a, 44.8 mg, yield 37.33 %). MS (ESI) [M+H] + 599.5.

[0203] Second step: 4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(4-methoxyphenyl)- 2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline trifluoroacetate salt (7)

[0204] Tert-butyl (1R, 5S)-3-(7-(4-methoxyphenyl)-2-((S)-1- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (7-a, 44.8 mg, 0.07 mmol) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (0.5 ml) and reacted at room temperature for 1 hour. The solvent was removed by distillation under reduced pressure, and the crude product was purified by Pre-HPLC to obtain compound 7: 4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(4-methoxyphenyl)- 2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline trifluoroacetate salt: 6.1 mg, yield 13.32 %). MS (ESI) [M+H] + 499.6. 1H NMR (400 MHz, CD3OD) δ 7.76 (d, J = 9.2 Hz, 1 H), 7.62 (d, J = 3.3 Hz, 1 H), 7.54 (d, J = 9.2 Hz, 1 H), 7.47 (d, J = 8.8 Hz, 2 H), 7.37 (d, J = 3.2 Hz, 1 H), 7.15 (d, J = 8.9 Hz, 2 H), 4.99 (dd, J = 12.4, 2.8 Hz, 1 H), 4.86 - 4.71 (m, 4 H), 4.24 (s, 2 H), 3.96 (dd, J = 14.0, 9.1 Hz, 3 H), 3.87 (d, J = 16.9 Hz, 3 H), 3.80 (s, 1 H), 3.14 (s, 3 H), 2.46 (dd, J = 16.8, 9.4 Hz, 1 H), 2.29 - 2.06 (m, 7 H).

[0205] Example 8: Preparation of 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(4- fluorophenyl)-7H-pyrrolo[2,3-h]quinazolin-2-yl)-N,N-diethylazetidin-3-amine trifluoroacetate salt

[0206]

[0207] First Step: tert-Butyl (1R,5S)-3-(2-(3-(diethylamino)azetidin-1-yl)-7-(4- fluorophenyl)-7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (8-a)

[0208] tert-Butyl (1R,5S)-3-(2-(3-(diethylamino)azetidin-1-yl)-7-(4-fluorophenyl)-7H-pyrrolo[2,3- h]quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (8-a, 18 mg, 15% yield) was obtained by dissolving tert-butyl (1R,5S)-3-(2-(3-(diethylamino)azetidin-1-yl)-7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (5-a, 100 mg, 0.2 mmol), cuprous iodide (19 mg, 0.1 mmol), metformin (13 mg, 0.1 mmol), and cesium carbonate (130 mg, 0.4 mmol) in N,N-dimethylformamide (5 ml), then adding 1-fluoro-4-iodobenzene (133 mg, 0.6 mmol), and reacting at 130 °C for 16 hours. The crude product was added to 50 ml of water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and then purified on a TLC plate (dichloromethane:methanol = 10:1) to obtain the target product tert-butyl (1R,5S)-3-(2-(3-(diethylamino)azetidin-1-yl)-7-(4-fluorophenyl)-7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (8-a, 18 mg, 15% yield). MS (ESI) [M+H] + 600.5.

[0209] Second Step: 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(4-fluorophenyl)-7H-pyrrolo[2,3-h]quinolin-2-yl)-N,N-diethylazetidin-3-amine trifluoroacetate (8)

[0210] Tert-butyl (1R,5S)-3-(2-(3-(diethylamino)azetidin-1-yl)-7-(4-fluorophenyl)-7H-pyrrolo[2,3- h]quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (8-a, 18 mg, 0.03 mmol) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (0.5 ml) and reacted at room temperature for 1 hour. The solvent was removed under reduced pressure and the crude product was purified by Pre-HPLC to give compound 8: 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(4-fluorophenyl)-7H-pyrrolo[2,3- h]quinolin-2-yl)-N,N-diethylazetidin-3-amine trifluoroacetate salt (9.18 mg, yield 49.84%). MS (ESI) [M+H]+500.4.1H NMR (400 MHz, DMSO-d6) δ 10.73-10.54 (m, 1H), 9.37 (s, 1H), 9.21 (s, 1H), 7.73 (s, 1H), 7.65-7.59 (m, 2H), 7.46 (t, J=8.7 Hz, 2H), 7.40-7.25 (m, 2H), 4.44 (d, J=23.0 Hz, 6H), 4.15 (s, 2H), 3.69-3.67 (m, 2H), 3.20 (s, 4H), 1.95 (d, J=25.3 Hz, 4H), 1.21 (t, J=7.2 Hz, 7H).

[0211] Example 9: Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(4- fluorophenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline trifluoroacetate salt

[0212]

[0213] First step: Preparation of tert-butyl (1R,5S)-3-(7-(4-fluorophenyl)-2-((S)-1- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (9-a)

[0214] Intermediate I-2 (100 mg, 0.171 mmol), 1-fluoro-4-iodobenzene (189 mg, 0.855 mmol), copper iodide (16.25 mg, 0.086 mmol), cesium carbonate (111 mg, 0.342 mmol), metformin (11 mg, 0.086 mmol) were dissolved in N,N-dimethylformamide (3 ml), replaced with nitrogen three times, and reacted at 130 °C overnight. Water (30 ml) was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target product tert-butyl (1R,5S)-3-(7-(4-fluorophenyl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3) (9-a, 40 mg, crude, yield 29.5 %). MS (ESI) [M+H] + 569.7.

[0215] Second Step: Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(4- fluorophenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline trifluoroacetate salt (9)

[0216] Tert-butyl (1R,5S)-3-(7-(4-fluorophenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (9-a, 40 mg, 0.068 mmol) was dissolved in dichloromethane (3 ml), and trifluoroacetic acid (1 ml) was added, and the mixture was reacted at room temperature for 2 hours. Concentration under reduced pressure, and purification by preparative HPLC (FA, 0.1 %) gave compound 9: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(4-fluorophenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline trifluoroacetate salt (1.53 mg, yield 4.6 %). MS (ESI) [M+H] + 487.6. 1HNMR (600 MHz, CDC13) δ 7.56 (d, J = 9.2 Hz, IH), 7.48-7.46 (m, IH), 7.43 (s, IH), 7.41 (d, J = 6.4 Hz, IH), 7.30-7.27 (m, 3H), 7.09 (s, IH), 5.19-5.12 (m, 2H), 4.85 (s, 2H), 4.62-4.56 (m, 2H), 4.16 (s, 3H), 3.84-3.81 (m, IH), 2.06-1.99 (m, 5H), 0.92-0.79 (m, 8H).

[0217] Example 10: Preparation of 4-((lR,5S)-3,8-diazabicyclo[3.2. l]octan-3-yl)-2-((S)-l- methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-2-ylmethyl)-7H-pyrrolo[2,3-h]quinoline

[0218]

[0219] First Step: Preparation of tert-butyl (lR,5S)-3-(2-((S)-l-methylpyrrolidin-2-yl)methoxy)-7- (naphthalen-2-ylmethyl)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2. l]octane-8- carboxylate (10-a)

[0220] Intermediate O-2 (50 mg, 0.10 mmol) was dissolved in chloroform (3 ml), 2- (bromomethyl)naphthalene (26 mg, 0.12 mmol) and N,N-diisopropylethylamine (26 mg, 0.20 mmol) were added and the reaction was allowed to proceed at room temperature overnight. Water (5 ml) was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (dichloromethane:methanol) to give the target product tert-butyl (lR,5S)-3-(2-((S)-l-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-2- ylmethyl)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2. l]octane-8-carboxylate (10-a, 41 mg, 64.1% yield). MS (ESI) [M+H] + 633.4

[0221] Second Step: Preparation of 4-((lR,5S)-3,8-diazabicyclo[3.2. l]octan-3-yl)-2-((S)-l- methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-2-ylmethyl)-7H-pyrrolo[2,3-h]quinoline (10)

[0222] Tert-butyl (1R, 5S)-3-(2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-2- ylmethyl)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10-a, 20 mg, 0.03 mmol) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (500 μL) was added. The reaction was stirred at room temperature for 4 hours. After concentration under reduced pressure, the product was purified by preparative HPLC to give compound 10: 4-((1R, 5S)-3, 8-diazabicyclo[3.2.1]octan-3-yl)-2-((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-2-ylmethyl)-7H-pyrrolo[2,3-h]quinoline (8 mg, 48.5% yield). MS (ESI) [M+H] + 533.3Example 11: Preparation of 4-((1R, 5S)-3, 8-diazabicyclo[3.2.1]octan-3-yl)-7-(4- methoxybenzyl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline

[0223]

[0224] First Step: Preparation of tert-butyl (1R, 5S)-3-(7-(4-methoxybenzyl)-2-((S)-1- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3, 8-diazabicyclo[3.2.1]octane-8- carboxylate (11-a)

[0225] Intermediate I-2 (44 mg, 0.09 mmol) was dissolved in N,N-dimethylformamide (3 ml) and 1-(chloromethyl)-4-methoxybenzene (16 mg, 0.10 mmol) and cesium carbonate (65 mg, 0.20 mmol) were added. The reaction was stirred at room temperature overnight. Water (5 ml) was added and the organic phase was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The product, tert-butyl (1R, 5S)-3-(7-(4-methoxybenzyl)-2-((S)-1- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3, 8-diazabicyclo[3.2.1]octane-8- carboxylate (11-a, 51 mg, 93.2% yield) was purified by flash column chromatography (dichloromethane:methanol). MS (ESI) [M+H] + 613.3

[0226] Step 2: Preparation of 4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(4- methoxybenzyl)-2-((S)-l-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3- h]quinazoline (11)

[0227] tert-Butyl (lR,5S)-3-(7-(4-methoxybenzyl)-2-((S)-l-methylpyrrolidin-2- yl)methoxy)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (11-a, 20 mg, 0.03 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (500 μL) was added, and the reaction was stirred at room temperature for 4 hours. After concentration under reduced pressure, the compound 11, 4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(4-methoxybenzyl)-2-((S)-l- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinazoline (8 mg, 47.9% yield) was purified by preparative HPLC. MS (ESI) [M+H] + 513.3

[0228] Example 12: Preparation of 4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(3- fluorophenyl)-2-((S)-l-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinazoline trifluoroacetate salt

[0229]

[0230] Step 1: Preparation of tert-butyl (lR,5S)-3-(7-(3-fluorophenyl)-2-((S)-l- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (12-a)

[0231] Intermediate I-2 (100 mg, 0.169 mmol), 1-fluoro-3-iodobenzene (0.118 ml, 1.01 mmol), metformin (13 mg, 0.101 mmol, ), copper iodide (19 mg, 0.10 mmol) and cesium carbonate (132 mg, 0.41 mmol) were dissolved in N,N-dimethylformamide (2 ml), the reaction system was replaced by nitrogen and heated to 130 °C under nitrogen for 16 hours. The reaction system was cooled to room temperature, quenched with water, extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column (dichloromethane / methanol = 10 / 1) to obtain tert-butyl (1R,5S)-3-(7-(3-fluorophenyl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (12-a, 25 mg, yield 25 %). MS (ESI) [M+H] + 587.3

[0232] Second step: Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(3- fluorophenyl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline trifluoroacetate salt (12)

[0233] Tert-butyl (1R,5S)-3-(7-(3-fluorophenyl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (12-a, 25 mg, 0.04 mmol) was dissolved in dichloromethane / trifluoroacetic acid (2 ml / 0.7 ml), the reaction solution was reacted at 20 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated and purified by preparative liquid chromatography to obtain compound 12: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(3-fluorophenyl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline trifluoroacetate salt (11.7 mg, yield 56 %). MS (ESI) [M+H] + 487.3. 1HNMR (400 MHz, DMSO-d6) δ 10.73 - 10.54 (m, 1H), 9.37 (s, 1H), 9.21 (s, 1H), δ 7.70 (d, J = 3.2 Hz, 1H), 7.63 (dd, J = 15.8, 7.0 Hz, 2H), 7.58 - 7.52 (m, 1H), 7.51 - 7.41 (m, 2H), 7.33 - 7.27 (m, 1H), 7.14 (d, J = 3.1 Hz, 1H), 4.80 (dd, J = 12.3, 3.4 Hz, 1H), 4.66 (dd, J = 12.4, 7.0 Hz, 1H), 4.34 (d, J = 13.8 Hz, 2H), 4.16 (s, 2H), 3.86 (s, 1H), 3.66 (d, J = 14.5 Hz, 3H), 3.19 - 3.11 (m, 1H), 2.98 (s, 2H), 2.33 - 2.28 (m, 1H), 2.11 - 2.04 (m, 1H), 2.00 - 1.87 (m, 6H).

[0234] Example 13: Preparation of 4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(2- fluorophenyl)-2-((S)-l-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinazoline trifluoroacetate

[0235]

[0236] First Step: Preparation of tert-butyl (lR,5S)-3-(7-(2-fluorophenyl)-2-((S)-l- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (13-a)

[0237] Intermediate I-2 (100 mg, 0.169 mmol), 1-fluoro-2-iodobenzene (0.118 ml, 1.01 mmol), metformin (13 mg, 0.101 mmol), copper iodide (19 mg, 0.10 mmol) and cesium carbonate (132 mg, 0.41 mmol) were dissolved in N,N-dimethylformamide (2 ml), the reaction system was replaced with nitrogen and heated to 130 °C under nitrogen for 16 hours. The reaction system was cooled to room temperature, quenched with water, extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column (dichloromethane / methanol = 10 / 1) to obtain tert-butyl (1R,5S)-3-(7-(3-fluorophenyl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (13-a, 22 mg, yield 22%). MS (ESI) [M+H] + 587.3

[0238] Second step: Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(2- fluorophenyl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline trifluoroacetate salt (13)

[0239] Tert-butyl (1R,5S)-3-(7-(2-fluorophenyl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (13-a, 22 mg, 0.04 mmol) was dissolved in dichloromethane / trifluoroacetic acid (2 ml / 0.7 ml), the reaction solution was reacted at 20 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated and purified by preparative liquid chromatography to obtain compound 13: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(2-fluorophenyl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline trifluoroacetate salt (11 mg, yield 55%). MS (ESI) [M+H] + 487.3. 1H NMR (400 MHz, DMSO-d6) δ 10.73 - 10.54 (m, 1H), 9.37 (s, 1H), 9.21 (s, 1H), δ 7.69 - 7.63 (m, 2H), 7.61 - 7.53 (m, 2H), 7.47 - 7.43 (m, 1H), 7.23 - 7.14 (m, 3H), 4.80 (dd, J = 12.3, 3.4 Hz, 1H), 4.66 (dd, J = 12.4, 7.0 Hz, 1H), 4.34 (d, J = 13.8 Hz, 2H), 4.16 (s, 2H), 3.86 (s, 1H), 3.66 (d, J = 14.5 Hz, 3H), 3.19 - 3.11 (m, 1H), 2.98 (s, 2H), 2.33 - 2.28 (m, 1H), 2.11 - 2.04 (m, 1H), 2.00 - 1.87 (m, 6H).

[0240] Example 14: Preparation of 4-((lR,5S)-3,8-diazabicyclo[3.2. l]octan-3-yl)-7-(4- chlorophenyl)-2-((S)-l-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinazoline trifluoroacetate salt

[0241]

[0242] First Step: Preparation of tert-butyl (lR,5S)-3-(7-(4-chlorophenyl)-2-((S)-l- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8-diazabicyclo[3.2. l]octane-8-carboxylate (14-a)

[0243] Intermediate 1-2 (60 mg, 0.12 mmol), 4-chloroiodobenzene (142 mg, 0.6 mmol), cesium carbonate (80 mg, 0.24 mmol), copper iodide (12 mg, 0.06 mmol), metformin (8 mg, 0.06 mmol) were dissolved in DMF (5 mL), the reaction system was replaced by nitrogen and heated to 130 °C under nitrogen for 16 hours. The reaction system was cooled to room temperature, quenched with water, extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by flash column (methanol: dichloromethane = 0% ~ 10%) to give the target product tert-butyl (lR,5S)-3-(7-(4-chlorophenyl)-2-((S)-l-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8-diazabicyclo[3.2. l]octane-8-carboxylate (14-a, 28 mg, yield 38.10%, light yellow solid). MS (ESI) [M+H]+ 603.28.

[0244] Step 2: Preparation of 4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(4- fluorophenyl)-2-((S)-l-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3- h]quinazoline trifluoroacetate salt (14)

[0245] Step 2: Preparation of 4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(4- fluorophenyl)-2-((S)-l-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3- h]quinazoline trifluoroacetate salt (14) + 503.28. 1 H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 9.23 (d, J = 9.6 Hz, 1H), 9.08 (s, 1H), 7.75 (d, J = 3.1 Hz, 1H), 7.67 (q, J = 8.7 Hz, 2H), 7.49 (d, J = 9.2 Hz, 1H), 7.21 (d, J = 3.0 Hz, 1H), 4.79 (dd, J = 12.4, 3.3 Hz, 1H), 4.65 (dd, J = 12.4, 7.0 Hz, 1H), 4.32 (d, J = 13.7 Hz, 2H), 4.16 (s, 2H), 3.85 (s, 1H), 3.64 (d, J = 14.0 Hz, 2H), 3.16 (s, 1H), 2.97 (s, 3H), 2.30 (d, J = 7.8 Hz, 1H), 2.14 - 2.03 (m, 3H), 2.01 - 1.87 (m, 6H).

[0246] Example 15: Preparation of 4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((S)- 1 -methylpyrrolidin-2-yl)methoxy)-7-(3-(trifluoromethyl)phenyl)-7H- pyrrolo[2,3-h]quinazoline trifluoroacetate salt

[0247]

[0248] First step: preparation of tert-butyl (1R, 5S)-3-(2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(3- (trifluoromethyl)phenyl)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (15-a)

[0249] Intermediate I-2 (50 mg, 0.10 mmol), 1-iodo-3-(trifluoromethyl)benzene (138 mg, 0.51 mmol), metformin (7 mg, 0.05 mmol), cuprous iodide (10 mg, 0.05 mmol) and cesium carbonate (66 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (2 ml), the reaction system was replaced by nitrogen and heated to 130 °C under nitrogen for 16 hours. The reaction system was cooled to room temperature, quenched with water, extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain tert-butyl (1R, 5S)-3-(2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(3-(trifluoromethyl)phenyl)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (15-a, 80 mg, crude). MS (ESI) [M+H] + 637.3.

[0250] Second step: preparation of 4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((S)-1- methylpyrrolidin-2-yl)methoxy)-7-(3-(trifluoromethyl)phenyl)-7H-pyrrolo[2,3-h]quinoline trifluoroacetate salt (15)

[0251] Tert-butyl (1R, 5S)-3-(2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(3-(trifluoromethyl)phenyl)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (15-a, 80 mg, 0.13 mmol) was dissolved in dichloromethane / trifluoroacetic acid (2 ml / 0.7 ml), the reaction solution was reacted at 20 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated and purified by preparative liquid chromatography to obtain compound 15: 4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(3-(trifluoromethyl)phenyl)-7H-pyrrolo[2,3-h]quinoline trifluoroacetate salt (4.6 mg, yield 7%). MS (ESI) [M+H] + 537.3. 1H NMR (400MHz, DMSO-d6) δ9.87-9.79 (m, 1H), 9.18 (d, J=9.7Hz, 1H), 9.03-8.97 (m, 1H), 8.01-7.93 (m, 2 H), 7.92-7.79 (m, 3H), 7.72 (d, J=9.2Hz, 1H), 7.51 (d, J=9.2Hz, 1H), 7.23 (d, J=3.1Hz, 1H), 4.79 (dd, J=12.4, 3.5Hz, 1H), 4.65 (dd, J=12.5, 7.0Hz, 1H), 4.33 (d, J=13.4Hz, 2H), 4.16 (s, 2H), 3.92-3.79 (m , 2H), 3.63 (d, J=14.0Hz, 2H), 3.20-3.09 (m, 2H), 2.98 (s, 3H), 2.11-2.04 (m, 1H), 2.01-1.85 (m, 6H).

[0252] Example 16: Preparation of 4-((1R,5S)-3,8-diazacyclic[3.2.1]octane-3-yl)-2-((S)-1-methylpyrrolidine-2-yl)methoxy)-7-(4-(trifluoromethyl)benzyl)-7H-pyrrole[2,3-h]quinazolin trifluoroacetate

[0253]

[0254] Step 1: Preparation of tert-butyl(1R,5S)-3-(2-((S)-1-methylpyrrolidine-2-yl)methoxy)-7-(4-(trifluoromethyl)benzyl)-7H-pyrrolo[2,3-h]quinazolin-4-yl)-3,8-diazacyclic[3.2.1]octane-8-carboxylic acid ester (16-a)

[0255] Intermediate I-2 (50.0 mg, 0.102 mmol), 1-(bromomethyl)-4-(trifluoromethyl)benzene (36.4 mg, 0.153 mmol), and cesium carbonate (99.7 mg, 0.306 mmol) were dissolved in N,N-dimethylformamide (1.5 mL) and reacted overnight at 25 °C. Water (20 mL) was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the target product tert-butyl(1R,5S)-3-(2-((S)-1-methylpyrrolidine-2-yl)methoxy)-7-(4-(trifluoromethyl)benzyl)-7H-pyrrolo[2,3-h]quinazolin-4-yl)-3,8-diazacyclic[3.2.1]octane-8-carboxylic acid ester (3) (16-a, 85 mg, crude product, yield 128.8%). MS(ESI)[M+H]+651.63.

[0256] Step 2: Preparation of 4-((lR,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((S)-l- methylpyrrolidin-2-yl)methoxy)-7-(4-(trifluoromethyl)benzyl)-7H-pyrrolo[2,3- h]quinazoline trifluoroacetate (16)

[0257] Tert-butyl (lR,5S)-3-(7-(4-fluorophenyl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)- 7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (16-a, 85 mg, 0.131 mmol) was dissolved in dichloromethane (3 ml), trifluoroacetic acid (1 ml) was added and the reaction was stirred at room temperature for 3 hours. Concentration under reduced pressure and purification by preparative HPLC (FA, 0.1%) gave compound 16: 4-((lR,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((S)-l- methylpyrrolidin-2-yl)methoxy)-7-(4-(trifluoromethyl)benzyl)-7H-pyrrolo[2,3- h]quinazoline trifluoroacetate (12.76 mg, 17.69% yield). MS (ESI) [M+H] + 551.6. 1 HNMR (600 MHz, CD3OD) δ 7.74 (d, J = 9.3 Hz, IH), 7.67 (d, J = 9.2 Hz, IH), 7.60 (d, J = 8.0 Hz, IH), 7.53 (d, J = 3.1 Hz, IH), 7.49 (d, J = 9.2 Hz, IH), 7.33 (dd, J = 14.5, 8.2 Hz, 2H), 7.24 (d, J = 3.1 Hz, IH), 5.66 (d, J = 14.9 Hz, 2H), 4.93 (dd, J = 12.5, 3.0 Hz, IH), 4.77-4.75 (m, IH), 4.61 (d, J = 11.9 Hz, 2H), 4.22 (d, J = 23.5 Hz, 3H), 3.97 (s, 2H), 3.82-3.73 (m, 4H), 2.47-2.42 (m, 2H), 2.26-2.09 (m, 8H).

[0258] Example 17: Preparation of 3-(4-((lR,5S)-3,8-diazabicyclo[3.2.1]octanyl-3-yl)-2- ((S)-l-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-7-yl)phenol trifluoroacetate

[0259]

[0260] First Step: Preparation of (1R, 5S)-3-(7-(3-hydroxyphenyl)-2-((S)-1- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (17-a)

[0261] Intermediate I-3 (100 mg, 0.17 mmol), 3-iodophenol (186 mg, 0.84 mmol), metformin (11 mg, 0.084 mmol), cuprous iodide (16 mg, 0.084 mmol), and cesium carbonate (274 mg, 0.84 mmol) were dissolved in N,N-dimethylformamide (1.5 ml), the reaction system was replaced with nitrogen and heated to 130 °C for 16 hours under nitrogen. The reaction system was cooled to room temperature, quenched with water, extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (1R, 5S)-3-(7-(3-hydroxyphenyl)-2-((S)-1- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (17-a, 30 mg, yield 30.1%) without further purification for the next step. MS (ESI) [M+H] + 585.2

[0262] Second Step: Preparation of 3-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-7-yl)phenol trifluoroacetate salt (17)

[0263] (1R, 5S)-3-(7-(3-hydroxyphenyl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H- pyrrolo[2,3-h]quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (17-a, 30 mg, 0.05 mmol) was dissolved in acetonitrile / trifluoroacetic acid (1 ml / 0.5 ml), and the reaction solution was reacted at 20 °C for 1 hour. The reaction solution was separated and purified by preparative liquid chromatography to obtain compound 17: 3-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((S)-1- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-7-yl)phenol trifluoroacetate salt (11.16 mg, yield 37%). MS (ESI) [M+H] + 485.3. 1HNMR (400 MHz, CD3OD) δ 7.96-7.90 (m, 2H), 7.88-7.80 (m, 3H), 7.79 (d, J = 3.4 Hz, IH), 7.71 (d, J = 9.3 Hz, IH), 7.50-7.41 (m, IH), 5.05-4.95 (m, IH), 4.87-4.76 (m, 4H), 4.25 (s, 2H), 4.05-3.92 (m, 3H), 3.80 (s, IH), 3.14 (s, 3H), 2.51-2.41 (m, IH), 2.29-2.07 (m, 7H).

[0264] Example 18: Preparation of 3-(4-((lR,5S)-3,8-diazabicyclo[3.2. l]octanyl-3-yl)-2-((S)-l- methylpyrrolidin-2-yl)methyloxy)-7H-pyrrolo[2,3-h]quinazolin-7-yl)benzonitrile trifluoroacetic acid salt

[0265]

[0266] First Step: tert-Butyl (lR,5S)-3-(7-(3-cyanophenyl)-2-((S)-l-methylpyrrolidin-2- yl)methyloxy)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2. l]octane-8- carboxylate (18-a)

[0267] Intermediate I-3 (100 mg, 0.17 mmol), cuprous iodide (17 mg, 0.09 mmol), metformin (12 mg, 0.09 mmol) and cesium carbonate (111 mg, 0.34 mmol) were dissolved in N,N-dimethylformamide (5 ml), then 3-iodobenzonitrile (195 mg, 0.85 mmol) was added and reacted at 130 °C for 16 hours. The crude product was added to 50 ml of water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified on a TLC plate (dichloromethane:methanol = 10:1) to obtain the target product tert-butyl (lR,5S)-3-(7-(3-cyanophenyl)-2-((S)-l-methylpyrrolidin-2-yl)methyloxy)-7H- pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2. l]octane-8-carboxylate (18-a, 58 mg, yield 57.43 %). MS (ESI) [M+H] + 594.4.

[0268] Step 2: 3-(4-((lR,5S)-3,8-diazabicyclo[3.2.1]octanyl-3-yl)-2-((S)-l- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinazolin-7-yl)benzonitrile trifluoroacetate (18)

[0269] Tert-butyl (lR,5S)-3-(7-(3-cyanophenyl)-2-((S)-l-methylpyrrolidin-2-yl)methoxy)- 7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (18-a, 58 mg, 0.1 mmol) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (1 ml) and reacted at room temperature for 1 hour. The solvent was removed under reduced pressure and the crude product was purified by Pre-HPLC to give compound 18: 3-(4-((lR,5S)-3,8-diazabicyclo[3.2.1]octanyl-3-yl)-2-((S)-l- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinazolin-7-yl)benzonitrile trifluoroacetate (10.08 mg, 17.04% yield). MS (ESI) [M+H] + 494.3. 1 HNMR (400 MHz, DMSO-d6) δ 9.96 (s, IH), 9.30 (d, J = 9.9 Hz, IH), 9.16 (s, IH), 8.17 (s, IH), 8.00 (d, J = 8.1 Hz, IH), 7.94 (d, J = 7.7 Hz, IH), 7.82 (dd, J = 11.1, 5.4 Hz, 2H), 7.71 (d, J = 9.2 Hz, IH), 7.57 (d, J = 9.2 Hz, IH), 7.25 (d, J = 3.1 Hz, IH), 4.80 (dd, J = 12.3, 3.4 Hz, IH), 4.66 (dd, J = 12.4, 7.0 Hz, IH), 4.34 (d, J = 13.8 Hz, 2H), 4.16 (s, 2H), 3.86 (s, IH), 3.66 (d, J = 14.5 Hz, 4H), 3.14 (s, IH), 2.98 (s, 2H), 2.30 (d, J = 8.0 Hz, IH), 2.07 (d, J = 12.0 Hz, IH), 2.00 - 1.87 (m, 6H).

[0270] Example 19: Preparation of 4-((lR,5S)-3,8-diazabicyclo[3.2.1]octanyl-3-yl)-2-((S)-l- methylpyrrolidin-2-yl)methoxy)-7-phenyl-7H-pyrrolo[2,3-h]quinoline trifluoroacetate

[0271]

[0272] First step: tert-Butyl (1R, 5S)-3-(2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7- phenyl-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (19-a)

[0273] Intermediate I-3 (100 mg, 0.17 mmol), cuprous iodide (17 mg, 0.09 mmol), metformin (12 mg, 0.09 mmol) and cesium carbonate (111 mg, 0.34 mmol) were dissolved in N,N-dimethylformamide (5 ml), then iodobenzene (173 mg, 0.85 mmol) was added and reacted at 130 °C for 16 hours. The crude product was added to 50 ml of water and extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and then purified on a TLC plate (dichloromethane:methanol = 10:1) to obtain the target product tert-butyl (1R, 5S)-3-(2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7-phenyl-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (19-a, 33 mg, yield 34.02%). MS (ESI) [M+H] + 569.4.

[0274] Second step: 4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((S)-1-methylpyrrolidin-2- yl)methoxy)-7-phenyl-7H-pyrrolo[2,3-h]quinoline trifluoroacetate (HSN004025)

[0275] Tert-butyl (1R, 5S)-3-(2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7-phenyl-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (19-a, 33 mg, 0.06 mmol) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (1 ml) and reacted at room temperature for 1 hour. The solvent was removed by distillation under reduced pressure, and the crude product was purified by Prep-HPLC to obtain compound 19: 4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7-phenyl-7H-pyrrolo[2,3-h]quinoline trifluoroacetate (4.93 mg, yield 14.59%). MS (ESI) [M+H] + 469.3. 1HNMR (400 MHz, DMSO-d6) δ 10.02 (s, IH), 9.34 (d, J = 9.7 Hz, IH), 9.20 (s, IH), 7.75 (d, J = 3.1 Hz, IH), 7.68 (d, J = 9.2 Hz, IH), 7.63-7.59 (m, 3H), 7.49 (t, J = 9.7 Hz, 2H), 7.22 (d, J = 2.9 Hz, IH), 4.80 (dd, J = 12.3, 3.3 Hz, IH), 4.66 (dd, J = 12.4, 6.9 Hz, IH), 4.34 (d, J = 13.5 Hz, 2H), 4.16 (s, 2H), 3.86 (s, 2H), 3.68 (s, 3H), 3.15 (d, J = 7.9 Hz, IH), 2.98 (s, 2H), 2.34-2.25 (m, IH), 2.11-1.88 (m, 7H).

[0276] Example 20: Preparation of 4-((lR,5S)-3,8-diazabicyclo[3.2. l]octan-3-yl)-2-((S)-l- methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-l-yl)-7H-pyrrolo[2,3-h]quinazoline trifluoroacetate salt

[0277]

[0278] First Step: tert-Butyl (lR,5S)-3-(2-((S)-l-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-l-yl)- 7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2. l]octane-8-carboxylate (20-a)

[0279] Intermediate I-3 (100 mg, 0.17 mmol), cuprous iodide (17 mg, 0.09 mmol), metformin (12 mg, 0.09 mmol) and cesium carbonate (111 mg, 0.34 mmol) were dissolved in N,N-dimethylformamide (5 ml), and then 1-iodonaphthalene (216 mg, 0.85 mmol) was added. The reaction was carried out at 130°C for 16 hours. The crude product was added to 50 ml of water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified on a TLC plate (dichloromethane:methanol = 10:1) to obtain the target product tert-butyl (lR,5S)-3-(2-((S)-l-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-l-yl)-7H- pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2. l]octane-8-carboxylate (20-a, 26 mg, yield 24.76%). o + 619.4.​

[0280] Step 2: 4-((lR,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((S)-l-methylpyrrolidin-2- yl)methoxy)-7-(naphthalen-l-yl)-7H-pyrrolo[2,3-h]quinazoline trifluoroacetate (20)

[0281] Tert-butyl (lR,5S)-3-(2-((S)-l-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-l-yl)- 7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20-a, 26 mg, 0.04 mmol) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (1 ml) and reacted at room temperature for 1 hour. The solvent was removed under reduced pressure and the crude product was purified by Pre-HPLC to give compound 20: 4-((lR,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((S)-l-methylpyrrolidin-2- yl)methoxy)-7-(naphthalen-l-yl)-7H-pyrrolo[2,3-h]quinazoline trifluoroacetate (1.27 mg, 4.78% yield). MS (ESI) [M+H] + 519.4. 1 HNMR (400 MHz, DMSO-d6) δ 9.89 (s, IH), 9.17 (d, J = 10.4 Hz, IH), 9.03-8.97 (m, IH), 8.16 (dd, J = 15.8, 8.1 Hz, 2H), 7.76-7.66 (m, 3H), 7.65-7.55 (m, 2H), 7.50 (d, J = 8.0 Hz, IH), 7.28 (d, J = 2.8 Hz, IH), 7.18-7.13 (m, IH), 6.88 (d, J = 9.1 Hz, IH), 4.82 (s, IH), 4.70 (d, J = 6.7 Hz, IH), 4.28 (d, J = 12.9 Hz, 2H), 4.12 (s, 2H), 3.88 (s, IH), 3.60 (d, J = 13.8 Hz, 3H), 3.16 (d, J = 7.5 Hz, IH), 2.99 (s, 2H), 2.32 (d, J = 7.7 Hz, IH), 2.13-1.86 (m, 8H).

[0282] Example 21: Preparation of 2-(4-((lR,5S)-3,8-diazabicyclo[3.2.1]octanyl-3-yl)-2-((S)-l- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline-7-yl)benzonitrile trifluoroacetate

[0283]

[0284] First step: tert-butyl (1R, 5S)-3-(7-(2-cyanophenyl)-2-((S)-1-methylpyrrolidin-2- yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (21-a)

[0285] Intermediate I-3 (100 mg, 0.17 mmol), cuprous iodide (17 mg, 0.09 mmol), metformin (12 mg, 0.09 mmol) and cesium carbonate (111 mg, 0.34 mmol) were dissolved in N,N-dimethylformamide (5 ml), then 2-iodobenzonitrile (195 mg, 0.85 mmol) was added and reacted at 130 °C for 16 hours. The crude product was added to 50 ml of water and extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and then purified on a TLC plate (dichloromethane:methanol = 10:1) to obtain the target product tert-butyl (1R, 5S)-3-(7-(2-cyanophenyl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (21-a, 35 mg, yield 34.65%). MS (ESI) [M+H] + 594.5.

[0286] Second step: 2-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octanyl-3-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-7-yl)benzonitrile trifluoroacetate (21)

[0287] Tert-butyl (1R, 5S)-3-(7-(2-cyanophenyl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (21-a, 35 mg, 0.06 mmol) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (1 ml) and reacted at room temperature for 1 hour. The solvent was removed by distillation under reduced pressure, and the crude product was purified by Pre-HPLC to obtain compound 21: 2-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octanyl-3-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-7-yl)benzonitrile trifluoroacetate (13.91 mg, yield 38.85%). MS (ESI) [M+H] + 494.4. 1HNMR (400 MHz, DMSO-d6) δ 9.99 (s, IH), 9.32 (d, J = 9.5 Hz, IH), 9.16 (s, IH), 8.15 (d, J = 7.4 Hz, IH), 7.96 (t, J = 7.8 Hz, IH), 7.81-7.72 (m, 3H), 7.69 (d, J = 9.2 Hz, IH), 7.25 (dd, J = 14.2, 6.1 Hz, 2H), 4.81 (dd, J = 12.4, 3.4 Hz, IH), 4.67 (dd, J = 12.4, 7.0 Hz, IH), 4.32 (d, J = 12.6 Hz, 2H), 4.15 (s, 2H), 3.87 (s, IH), 3.66 (d, J = 14.2 Hz, 4H), 3.15 (d, J = 6.1 Hz, IH), 2.98 (s, 2H), 2.30 (d, J = 7.7 Hz, IH), 2.07 (d, J = 12.7 Hz, IH), 1.94 (d, J = 13.6 Hz, 6H).

[0288] Example 22: Preparation of 4-(4-((lR,5S)-3,8-diazabicyclo[3.2. l]octanyl-3-yl)-2-((S)-l- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinazolin-7-yl)aniline trifluoroacetic acid salt

[0289]

[0290] First Step: Preparation of tert-butyl (lR,5S)-3-(7-(4-((tert-butoxycarbonyl)amino)phenyl)-2- ((S)-l-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8-diazabicyclo[3.2. l]octane-8-carboxylate (22-a)

[0291] Intermediate I-3 (100 mg, 0.169 mmol), tert-butyl (4-iodophenyl)carbamate (270 mg, 0.84 mmol), cesium carbonate (110 mg, 0.338 mmol), copper iodide (16 mg, 0.084 mmol), metformin (10 mg, 0.084 mmol) were dissolved in DMF (2.5 mL), the reaction system was replaced with nitrogen and heated to 130 °C for 16 hours under nitrogen. The reaction system was cooled to room temperature, quenched with water, extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by flash column (methanol: dichloromethane = 0% ~ 10%) to obtain the target product tert-butyl (1R, 5S)-3-(7-(4-((tert-butoxycarbonyl)amino)phenyl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (22-a, 60 mg, yield 60%, black solid). MS (ESI) [M+H] + 684.88.

[0292] Second step: Preparation of 4-(4-((1R, 5S)-3, 8-diazabicyclo[3.2.1]octanyl-3-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-7-yl)aniline trifluoroacetate salt (22)

[0293] Tert-butyl (1R, 5S)-3-(7-(4-((tert-butoxycarbonyl)amino)phenyl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (22-a, 60 mg, 0.1 mmol) was dissolved in dichloromethane / trifluoroacetic acid (2 ml / 0.5 ml), the reaction solution was reacted at 20 °C for 0.5 hours. The reaction solution was separated and purified by preparative liquid chromatography to obtain compound 22: 4-(4-((1R, 5S)-3, 8-diazabicyclo[3.2.11 octanyl-3-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-7-yl)aniline trifluoroacetate salt (32 mg, yield 64.4%, brown solid) MS (ESI) [M+H] + 484.28. 1H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 9.23 (s, 1H), 9.08 (s, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.58 (s, 1H), 7.37 (d, J = 8.9 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.14 (s, 1H), 4.80 (d, J = 10.1 Hz, 1H), 4.67 (d, J = 7.0 Hz, 1H), 4.33 (d, J = 13.4 Hz, 2H), 4.15 (s, 2H), 3.85 (s, 4H), 3.16 (s, 1H), 2.98 (s, 2H), 2.84 (s, 1H), 2.65 (s, 1H), 2.31 (s, 1H), 2.01 (d, J = 41.3 Hz, 7H), 1.21 (s, 2H).

[0294] Example 23: Preparation of 4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((S)-l- methylpyrrolidin-2-yl)methoxy)-7-(4-(trifluoromethoxy)phenyl)-7H-pyrrolo[2,3- h]quinazoline trifluoroacetate

[0295]

[0296] First Step: Preparation of tert-butyl (lR,5S)-3-(2-((S)-l-methylpyrrolidin-2-yl)methoxy)-7-(4- (trifluoromethoxy)phenyl)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1] octane-8-carboxylate (23-a)

[0297] Intermediate I-3 (100 mg, 0.169 mmol), l-iodo-4-(trifluoromethoxy)benzene (243 mg, 0.845 mmol), cesium carbonate (110 mg, 0.338 mmol), copper iodide (16 mg, 0.084 mmol), metformin (11 mg, 0.084 mmol) were dissolved in DMF (2.5 mL), the reaction system was replaced with nitrogen and heated to 130 °C for 16 hours under nitrogen. The reaction system was cooled to room temperature, quenched with water, extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by flash column (methanol: dichloromethane = 0% ~ 10%) to obtain the target product tert-butyl (1R, 5S)-3-(2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(4-(trifluoromethoxy)phenyl)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (23-a, 80 mg, yield 72.7%, brown solid). MS (ESI) [M+H] + 653.88.

[0298] Second step: Preparation of 4-((1R, 5S)-3, 8-diazabicyclo[3.2.1]octan-3-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(4-(trifluoromethoxy)phenyl)-7H-pyrrolo[2,3-h]quinoline trifluoroacetate (23)

[0299] Tert-butyl (1R, 5S)-3-(2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(4-(trifluoromethoxy)phenyl)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (23-a, 80 mg, 0.122 mmol) was dissolved in dichloromethane / trifluoroacetic acid (3 ml / 0.6 ml), the reaction solution was reacted at 20 °C for 0.5 hours. The reaction solution was separated and purified by preparative liquid chromatography to obtain compound 23: 4-((1R, 5S)-3, 8-diazabicyclo[3.2.1]octan-3-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(4-(trifluoromethoxy)phenyl)-7H-pyrrolo[2,3-h]quinoline trifluoroacetate (21.17 mg, yield 31.25%, brown solid) MS (ESI) [M+H] + 553.72. 1HNMR (400 MHz, DMSO-d6) δ 7.72 (dd, J = 11.6, 3.0 Hz, 3H), 7.68 (s, IH), 7.59 (d, J = 8.5 Hz, 2H), 7.54 (s, IH), 7.27 (d, J = 3.1 Hz, IH), 4.84 - 4.74 (m, IH), 4.62 (d, J = 7.0 Hz, IH), 4.42 (d, J = 13.7 Hz, 2H), 4.11 (s, 2H), 3.87 - 3.81 (m, 2H), 3.69 (d, J = 13.7 Hz, 2H), 3.59 (s, IH), 3.13 (s, IH), 2.95 (s, 3H), 2.29 (d, J = 8.3 Hz, IH), 2.05 (s, IH), 1.93 (s, 6H).

[0300] Example 24: Preparation of 4-((lR,5S)-3,8-diazabicyclo[3.2. l]oct-3-yl)-7-(4-(l- methyl-lH-imidazol-5-yl)phenyl)-2-((S)-l-methylpyrrolidin-2-yl)methoxy)-7H- pyrrolo[2,3-h]quinazoline trifluoroacetate

[0301]

[0302] First Step: Preparation of tert-butyl (lR,5S)-3-(7-(4-(l-methyl-lH-imidazol-5- yl)phenyl)-2-((S)-l-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-4-yl)- 3,8-diazabicyclo[3.2. l]octane-8-carboxylate (24-a)

[0303] Intermediate I-3 (100 mg, 0.169 mmol), 5-iodo-l-methyl-lH-imidazole (175 mg, 0.845 mmol), cesium carbonate (110 mg, 0.338 mmol), copper iodide (16 mg, 0.0845 mmol), 4,7-dimethoxy-l,10-phenanthroline (20 mg, 0.0845 mmol) were dissolved in DMF (2.5 mL), the reaction system was replaced with nitrogen and heated to 130 °C for 16 hours under nitrogen. The reaction system was cooled to room temperature, quenched with water, extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by flash column (methanol: dichloromethane = 0% ~ 10%) to obtain the target product tert-butyl (lR,5S)-3-(7-(4-(l-methyl-lH-imidazol-5-yl)phenyl)-2-((S)-l-methylpyrrolidin-2- yl)methoxy)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (24-a, 50 mg, yield 51.70%, yellow, solid). MS (ESI) [M+H] + 573.81.

[0304] Second Step: Preparation of 4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(4-(l- methyl-lH-imidazol-5-yl)phenyl)-2-((S)-l-methylpyrrolidin-2-yl)methoxy)-7H- pyrrolo[2,3-h]quinoline trifluoroacetate salt (24)

[0305] Tert-butyl (lR,5S)-3-(7-(4-(l-methyl-lH-imidazol-5-yl)phenyl)-2-((S)-l- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (24-a, 50 mg, 0.087 mmol) was dissolved in acetonitrile / trifluoroacetic acid (1 ml / 0.5 ml), the reaction solution was reacted at 20 °C for 0.5 hours. The reaction solution was separated and purified by preparative liquid chromatography to obtain compound 24: 4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(4-(l-methyl-lH-imidazol-5- yl)phenyl)-2-((S)-l-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline trifluoroacetate salt (11.4 mg, yield 27.62%, yellow, solid) MS (ESI) [M+H] + 473.72. 1HNMR (400 MHz, DMSO-d6) δ 10.01 (s, IH), 9.34 (d, J = 9.8 Hz, IH), 9.19 (s, IH), 7.72 (ddd, J = 30.7, 13.6, 5.8 Hz, 5H), 7.51 (d, J = 9.2 Hz, IH), 7.22 (d, J = 3.0 Hz, IH), 4.79 (dd, J = 12.4, 3.3 Hz, IH), 4.66 (dd, J = 12.4, 6.9 Hz, IH), 4.33 (d, J = 13.6 Hz, 2H), 4.16 (s, 2H), 3.76 (d, J = 72.7 Hz, 7H), 3.18 (d, J = 21.2 Hz, 2H), 2.95 (d, J = 24.0 Hz, 3H), 2.30 (d, J = 7.8 Hz, IH), 2.07 (d, J = 12.3 Hz, IH), 1.92 (d, J = 33.0 Hz, 5H), 1.21 (s, IH).

[0306] Example 25: Preparation of 4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((S)-l- methylpyrrolidin-2-yl)methoxy)-7-(4-(pyridin-3-yl)phenyl)-7H-pyrrolo[2,3-h]quinazoline trifluoroacetate

[0307]

[0308] First Step: Preparation of tert-butyl (lR,5S)-3-(2-((S)-l-methylpyrrolidin-2-yl)methoxy)-7-(4- (pyridin-3-yl)phenyl)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (25-a)

[0309] Intermediate I-3 (100 mg, 0.169 mmol), 3-iodopyridine (172 mg, 0.845 mmol), cesium carbonate (110 mg, 0.338 mmol), copper iodide (16 mg, 0.0845 mmol), metformin (10 mg, 0.0845 mmol) were dissolved in DMF (2.5 mL), the reaction system was replaced with nitrogen and heated to 130 °C for 16 hours under nitrogen. The reaction system was cooled to room temperature, quenched with water, extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by flash column (methanol: dichloromethane = 0% ~ 10%) to obtain the target product tert-butyl (1R, 5S)-3-(2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(4-(pyridin-3-yl)phenyl)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (25-a, 86.6 mg, yield 90%, yellow solid). MS (ESI) [M+H] + 570.81.

[0310] Second step: Preparation of 4-((1R, 5S)-3, 8-diazabicyclo[3.2.1]octan-3-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(4-(pyridin-3-yl)phenyl)-7H-pyrrolo[2,3-h]quinoline trifluoroacetate (25)

[0311] Tert-butyl (1R, 5S)-3-(2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(4-(pyridin-3-yl)phenyl)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (25-a, 86.6 mg, 0.152 mmol) was dissolved in dichloromethane / trifluoroacetic acid (2.5 ml / 0.6 ml), the reaction solution was reacted at 20 °C for 0.5 hours. The reaction solution was separated and purified by preparative liquid chromatography to obtain compound 25: 4-((1R, 5S)-3, 8-diazabicyclo[3.2.1]octan-3-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(4-(pyridin-3-yl)phenyl)-7H-pyrrolo[2,3-h]quinoline trifluoroacetate (62 mg, yield 86.8%, white solid) MS (ESI) [M+H] + 470.71. 1HNMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 9.34 (d, J = 9.8 Hz, 1H), 9.19 (s, 1H), 7.72 (ddd, J = 30.7, 13.6, 5.8 Hz, 6H), 7.51 (d, J = 9.2 Hz, 1H), 7.22 (d, J = 3.0 Hz, 2H), 4.79 (dd, J = 12.4, 3.3 Hz, 1H), 4.66 (dd, J = 12.4, 6.9 Hz, 1H), 4.33 (d, J = 13.6 Hz, 2H), 4.16 (s, 2H), 3.76 (d, J = 72.7 Hz, 7H), 3.18 (d, J = 21.2 Hz, 2H), 2.95 (d, J = 24.0 Hz, 3H), 2.30 (d, J = 7.8 Hz, 1H), 2.07 (d, J = 12.3 Hz, 1H), 1.92 (d, J = 33.0 Hz, 2H), 1.21 (s, 1H).

[0312] Example 26: Preparation of 4-(4-((lR,5S)-3,8-diazabicyclo[3.2. l]octanyl-3-yl)-2-((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizine-7a(5H)-yl)methoxy)-7H-pyrrolo[2,3- h]quinazolin-7-yl)benzonitrile trifluoroacetate

[0313]

[0314] First Step: tert-Butyl (lR,5S)-3-(7-(4-cyanophenyl)-2-((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-ylmethoxy)-7H-pyrrolo[2,3-h]quinazolin-4-yl)-3,8-diazabicyclo[3.2. l]octane-8-carboxylate (26-a)

[0315] Intermediate I-4 (100 mg, 0.16 mmol), cuprous iodide (15 mg, 0.08 mmol), metformin (10 mg, 0.08 mmol) and cesium carbonate (104 mg, 0.32 mmol) were dissolved in N,N-dimethylformamide (5 ml), then 4-iodobenzonitrile (183 mg, 0.8 mmol) was added and reacted at 130 °C for 16 hours. The crude product was added to 50 ml of water and extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and then purified on a TLC plate (dichloromethane:methanol = 15:1) to obtain the target product tert-butyl (1R,5S)-3-(7-(4-cyanophenyl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizidin-7a(5H)-ylmethoxy)-7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (26-a, 73 mg, yield 71.57 %). MS (ESI) [M+H] + 638.4.

[0316] Second step: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizidin-7a(5H)-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-7-yl)benzonitrile trifluoroacetate (26)

[0317] Tert-butyl (1R,5S)-3-(7-(4-cyanophenyl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizidin-7a(5H)-ylmethoxy)-7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (26-a, 73 mg, 0.11 mmol) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (1 ml) and reacted at room temperature for 1 hour. The solvent was removed by distillation under reduced pressure, and the crude product was purified by Pre-HPLC to obtain compound 26: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizidin-7a(5H)-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-7-yl)benzonitrile trifluoroacetate (7.48 mg, yield 10.39 %). MS (ESI) [M+H] + 538.4. 1HNMR (600 MHz, DMSO-d6) δ 11.04 (s, IH), 9.37 (d, J = 9.4 Hz, IH), 9.22 (s, IH), 8.10 (d, J = 8.2 Hz, 2H), 7.87 (d, J = 8.0 Hz, 3H), 7.73 (d, J = 9.2 Hz, IH), 7.61 (d, J = 9.1 Hz, IH), 7.28 (s, IH), 4.67-4.62 (m, 2H), 4.38-4.33 (m, 2H), 4.17 (s, 2H), 3.90 (s, 2H), 3.68 (dd, J = 13.4, 7.0 Hz, 4H), 3.34-3.29 (m, IH), 2.61 (dd, J = 15.5, 3.9 Hz, IH), 2.55-2.51 (m, IH), 2.37-2.33 (m, IH), 2.23-2.15 (m, 2H), 2.08 (d, J = 13.1 Hz, IH), 1.97 (s, 4H).

[0318] Example 27: Preparation of 4-((lR,5S)-3,8-diazabicyclo[3.2.1]octanyl-3-yl)-7-(4- fluorophenyl)-2-((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizidin-7a(5H)-yl)methoxy)-7H- pyrrolo[2,3-h]quinazoline trifluoroacetate

[0319]

[0320] First Step: tert-Butyl (lR,5S)-3-(7-(4-fluorophenyl)-2-((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizidin-7a(5H)-yl)methoxy)-7H-pyrrolo[2,3-h]quinazolin-4-yl)-3,8-diazabicyclo[3.2. l]octane-8-carboxylate (27-a)

[0321] Intermediate I-4 (100 mg, 0.16 mmol), cuprous iodide (15 mg, 0.08 mmol), metformin (10 mg, 0.08 mmol) and cesium carbonate (104 mg, 0.32 mmol) were dissolved in N,N-dimethylformamide (5 ml), then p-fluoroiodobenzene (222 mg, 0.8 mmol) was added and reacted at 130 °C for 16 hours. The crude product was added to 50 ml of water and extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and then purified on a TLC plate (dichloromethane:methanol = 15:1) to obtain the target product tert-butyl (1R,5S)-3-(7-(4-fluorophenyl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizidin-7a(5H)-ylmethoxy)-7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (27-a, 39 mg, yield 38.61 %). MS (ESI) [M+H] + 631.4.

[0322] Second step: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(4-fluorophenyl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizidin-7a(5H)-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline trifluoroacetate (27)

[0323] Tert-butyl (1R,5S)-3-(7-(4-fluorophenyl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizidin-7a(5H)-ylmethoxy)-7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (27-a, 39 mg, 0.06 mmol) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (1 ml) and reacted at room temperature for 1 hour. The solvent was removed by distillation under reduced pressure, and the crude product was purified by Pre-HPLC to obtain compound 27: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(4-fluorophenyl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizidin-7a(5H)-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline trifluoroacetate (4.75 mg, yield 11.93 %). MS (ESI) [M+H] + 531.2. 1HNMR (600 MHz, DMSO-d6) δ 11.04 (s, IH), 9.37 (d, J = 9.4 Hz, IH), 9.22 (s, IH), 8.10 (d, J = 8.2 Hz, 2H), 7.87 (d, J = 8.0 Hz, 3H), 7.73 (d, J = 9.2 Hz, IH), 7.61 (d, J = 9.1 Hz, IH), 7.28 (s, IH), 4.67-4.62 (m, 2H), 4.38-4.33 (m, 2H), 4.17 (s, 2H), 3.89 (d, J = 15.2 Hz, 2H), 3.68 (dd, J = 13.4, 7.0 Hz, 4H), 3.34-3.29 (m, IH), 2.61 (dd, J = 15.5, 3.9 Hz, IH), 2.55-2.51 (m, IH), 2.37-2.33 (m, IH), 2.23-2.15 (m, 2H), 2.08 (d, J = 13.1 Hz, IH), 1.97 (s, 4H).

[0324] Example 28: Preparation of 2-(4-((lR,5S)-3,8-diazabicyclo[3.2. l]octanyl-3-yl)-2-((S)-l- methylpyrrolidin-2-yl)methyloxy)-7H-pyrrolo[2,3-h]quinazolin-7-yl)-5-iodobenzonitrile trifluoroacetate salt

[0325]

[0326] First Step: tert-Butyl (lR,5S)-3-(7-(2-cyano-4-iodophenyl)-2-((S)-l- methylpyrrolidin-2-yl)methyloxy)-7H-pyrrolo[2,3-h]quinazolin-4-yl)-3,8- diazabicyclo[3.2. l]octane-8-carboxylate (28-a)

[0327] Intermediate I-3 (100 mg, 0.17 mmol), cuprous iodide (17 mg, 0.09 mmol), metformin (12 mg, 0.09 mmol) and cesium carbonate (111 mg, 0.34 mmol) were dissolved in N,N-dimethylformamide (5 ml), then 2-fluoro-5-iodobenzonitrile (210 mg, 0.85 mmol) was added and reacted at 130 °C for 16 hours. The crude product was added to 50 ml of water and extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and then purified on a TLC plate (dichloromethane:methanol = 15:1) to obtain the target product tert-butyl (1R,5S)-3-(7-(2-cyano-4-iodophenyl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (28-a, 97 mg, yield 79.31 %). MS (ESI) [M+H] + 720.3.

[0328] Second step: 2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octanyl-3-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-7-yl)-5-iodobenzonitrile trifluoroacetate salt (28)

[0329] Tert-butyl (1R,5S)-3-(7-(2-cyano-4-iodophenyl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (28-a, 97 mg, 0.13 mm o l) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (1 ml) and reacted at room temperature for 1 hour. The solvent was removed by distillation under reduced pressure, and the crude product was purified by Pre-HPLC to obtain compound 28: 2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octanyl-3-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-7-yl)-5-iodobenzonitrile trifluoroacetate salt

[0330] (53 mg, yield 55.79 %). MS (ESI) [M+H] + 620.2. 1HNMR (600 MHz, DMSO-d6) δ 10.03 (s, IH), 9.35 (d, J = 9.5 Hz, IH), 9.19 (s, IH), 8.54 (s, IH), 8.29 (d, J = 8.4 Hz, IH), 7.77 (d, J = 2.7 Hz, IH), 7.69 (d, J = 9.2 Hz, IH), 7.52 (d, J = 8.4 Hz, IH), 7.27 (d, J = 8.9 Hz, 2H), 4.81 (dd, J = 12.3, 2.8 Hz, IH), 4.67 (dd, J = 12.3, 6.9 Hz, IH), 4.37-4.32 (m, 2H), 4.16 (s, 2H), 3.69 (dd, J = 13.6, 6.4 Hz, 4H), 3.62 (s, IH), 3.15 (d, J = 6.9 Hz, IH), 2.98 (s, 2H), 2.33-2.27 (m, IH), 2.10-2.04 (m, IH), 1.99-1.89 (m, 6H).

[0331] Example 29: Preparation of 2-(4-((lR,5S)-3,8-diazabicyclo[3.2. l]octanyl-3-yl)-2-((S)-l- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinazolin-7-yl)-4-iodobenzonitrile trifluoroacetate salt

[0332]

[0333] First Step: tert-Butyl (lR,5S)-3-(7-(2-cyano-5-iodophenyl)-2-((S)-l- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8- diazabicyclo[3.2. l]octane-8-carboxylate (29-a)

[0334] Intermediate I-3 (100 mg, 0.17 mmol), cuprous iodide (17 mg, 0.09 mmol), metformin (12 mg, 0.09 mmol) and cesium carbonate (111 mg, 0.34 mmol) were dissolved in N,N-dimethylformamide (5 ml), then 2-fluoro-4-iodobenzonitrile (210 mg, 0.85 mmol) was added and reacted at 130 °C for 16 hours. The crude product was added to 50 ml of water and extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and then purified on a TLC plate (dichloromethane:methanol = 15:1) to obtain the target product tert-butyl (1R,5S)-3-(7-(2-cyano-5-iodophenyl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (29-a, 99.8 mg, yield 81.60 %). MS (ESI) [M+H] + 720.2.

[0335] Second step: 2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-7-yl)-4-iodobenzonitrile trifluoroacetate (29)

[0336] Tert-butyl (1R,5S)-3-(7-(2-cyano-5-iodophenyl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (29-a, 99.8 mg, 0.14 mmol) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (1 ml) and reacted at room temperature for 1 hour. The solvent was removed by distillation under reduced pressure, and the crude product was purified by Pre-HPLC to obtain compound 29: 2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-7-yl)-4-iodobenzonitrile trifluoroacetate (39.6 mg, yield 41.51 %). MS (ESI) [M+H] + 620.2. 1HNMR (600 MHz, DMSO-d6) δ 10.02 (s, IH), 9.33 (d, J = 9.6 Hz, IH), 9.19 (s, IH), 8.17 (s, IH), 8.14 (d, J = 8.2 Hz, IH), 7.88 (d, J = 8.2 Hz, IH), 7.80 (d, J = 2.9 Hz, IH), 7.71 (d, J = 9.1 Hz, IH), 7.27 (d, J = 9.4 Hz, 2H), 4.82 (d, J = 12.3 Hz, IH), 4.68 (dd, J = 12.3, 7.0 Hz, IH), 4.37-4.32 (m, 2H), 4.16 (s, 2H), 3.68 (dd, J = 13.6, 5.8 Hz, 4H), 3.62 (s, IH), 3.15 (d, J = 6.0 Hz, IH), 2.98 (s, 2H), 2.33-2.27 (m, IH), 2.10-2.05 (m, IH), 1.99-1.89 (m, 6H).

[0337] Example 30: Preparation of 4-((lR,5S)-3,8-diazabicyclo[3.2. l]octanyl-3-yl)-7-(3- chlorophenyl)-2-((S)-l-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinazoline

[0338]

[0339] First Step: Preparation of tert-butyl (lR,5S)-3-(7-(3-fluorophenyl)-2-((S)-l- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8- diazabicyclo[3.2. l]octane-8-carboxylate (30-a)

[0340] Intermediate I-3 (118 mg, 0.20 mmol) was dissolved in N,N-dimethylformamide (5 mL), 1-chloro-3-iodobenzene (238 mg, 1.00 mmol), dimethylguanidine (13 mg, 0.10 mmol), copper iodide (19 mg, 0.10 mmol) and cesium carbonate (130 mg, 0.40 mmol) were added, the reaction vessel was replaced with nitrogen and heated at 130 °C overnight. Water (20 mL) was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the target product tert-butyl (1R,5S)-3-(7-(3-chlorophenyl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30-a, 350 mg, crude) which was used directly in the next step without further purification. MS (ESI) [M+H] + 603.2

[0341] Second Step: Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octanyl-3-yl)-7-(3- chlorophenyl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline (30)

[0342] Tert-butyl (1R,5S)-3-(7-(3-chlorophenyl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H- pyrrolo[2,3-h]quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30-a, 350 mg, crude) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (500 μL) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC to give compound 30: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octanyl-3-yl)-7-(3-chlorophenyl)-2-((S)-1- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline (15 mg). MS (ESI) [M+H] + 503.2. 1H NMR (600 MHz, DMSO-d6) δ 10.09 (s, IH), 9.40 (d, J = 9.3 Hz, IH), 9.26 (s, IH), 7.82 (d, J = 2.8 Hz, IH), 7.77-7.71 (m, 2H), 7.69-7.62 (m, 2H), 7.56 (t, J = 8.5 Hz, 2H), 7.25 (d, J = 2.3 Hz, IH), 4.85-4.70 (m, 2H), 4.69 (dd, J = 12.3, 6.9 Hz, IH), 4.37 (d, J = 13.5 Hz, 3H), 4.19 (s, 3H), 3.72-3.64 (m, 3H), 3.00 (s, 3H), 2.32 (d, J = 7.8 Hz, IH), 2.12-1.89 (m, 8H).

[0343] Example 31: Preparation of 4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((S)-l- methylpyrrolidin-2-yl)methoxy)-7-(m-tolyl)-7H-pyrrolo[2,3-h]quinoline

[0344]

[0345] First Step: Preparation of tert-butyl (lR,5S)-3-(2-((S)-l-methylpyrrolidin-2-yl)methoxy)-7-(m- tolyl)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (31-a)

[0346] Intermediate I-3 (59 mg, 0.10 mmol) was dissolved in N,N-dimethylformamide (3 ml), m-iodotoluene (119 mg, 0.50 mmol), 4,7-dimethoxy-l,10-phenanthroline (12 mg, 0.05 mmol), cuprous iodide (9 mg, 0.05 mmol) and cesium carbonate (65 mg, 0.20 mmol) were added, the nitrogen was replaced and the reaction was carried out at 130 °C overnight. Water (10 ml) was added and the organic phase was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the target product tert-butyl (lR,5S)-3-(7-(3-chlorophenyl)-2-((S)-l-methylpyrrolidin-2-yl)methoxy)-7H- pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (31-a, 112 mg, crude) which was used directly in the next step without further purification. MS (ESI) [M+H] + 583.3.

[0347] Step 2: Preparation of 4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((S)-l- methylpyrrolidin-2-yl)methoxy)-7-(m-tolyl)-7H-pyrrolo[2,3-h]quinazoline (31)

[0348] tert-Butyl (lR,5S)-3-(7-(3-chlorophenyl)-2-((S)-l-methylpyrrolidin-2-yl)methoxy)- 7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (31-a, 112 mg, crude) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (500 μL) was added, and the reaction was stirred at room temperature for 3 hours. After concentration under reduced pressure, the compound 31, 4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((S)-l- methylpyrrolidin-2-yl)methoxy)-7-(m-tolyl)-7H-pyrrolo[2,3-h]quinazoline (10 mg) was purified by preparative HPLC. MS (ESI) [M+H] + 483.3. 1 HNMR (600 MHz, DMSO-d6) δ 10.26 (s, IH), 9.54 (d, J = 7.7 Hz, IH), 9.41 (s, IH), 7.81 (d, J = 2.7 Hz, IH), 7.76 (d, J = 9.2 Hz, IH), 7.62-7.56 (m, 2H), 7.51 (s, IH), 7.48 (d, J = 7.8 Hz, IH), 7.37 (d, J = 7.6 Hz, IH), 7.32-7.28 (m, IH), 4.91-4.86 (m, IH), 4.79-4.73 (m, IH), 4.43 (d, J = 13.5 Hz, 2H), 4.25 (s, 3H), 3.97-3.94 (m, 2H), 3.76 (d, J = 13.5 Hz, 3H), 3.74-3.68 (m, IH), 3.27-3.20 (m, IH), 3.07 (s, 3H), 2.56 (s, 2H), 2.43-2.35 (m, IH), 2.16 (s, IH), 2.09-1.96 (m, 6H).

[0349] Example 32: Preparation of 4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((S)-l- methylpyrrolidin-2-yl)methoxy)-7-(o-tolyl)-7H-pyrrolo[2,3-h]quinazoline

[0350]

[0351] First Step: Preparation of tert-butyl (1R, 5S)-3-(2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(o-tolyl)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (32-a)

[0352] Intermediate I-3 (50 mg, 0.10 mmol) was dissolved in N,N-dimethylformamide (2 mL), and o-iodotoluene (122 mg, 0.50 mmol), 4,7-dimethoxy-1,10-phenanthroline (12 mg, 0.05 mmol), cuprous iodide (19 mg, 0.10 mmol), and cesium carbonate (65 mg, 0.20 mmol) were added. The reaction was heated at 180 °C for 30 min in a microwave reactor. Water (10 mL) was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (dichloromethane:methanol) to give the target product tert-butyl (1R, 5S)-3-(2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(o-tolyl)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (32-a, 31 mg, 52.5 %) MS (ESI) [M+H] + 583.3

[0353] Second Step: Preparation of 4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(o-tolyl)-7H-pyrrolo[2,3-h]quinoline (32)

[0354] Tert-butyl (1R, 5S)-3-(2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(o-tolyl)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (32-a, 31 mg, 0.05 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (500 μL) was added. The reaction was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give compound 32: 4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(o-tolyl)-7H-pyrrolo[2,3-h]quinoline (2 mg, 8 % yield). MS (ESI) [M+H] + 483.3. 1HNMR (600 MHz, DMSO-d6) δ 10.05 (s, IH), 9.37-9.31 (m, IH), 9.19 (s, IH), 7.64 (d, J = 9.1 Hz, IH), 7.60 (d, J = 2.9 Hz, IH), 7.56-7.47 (m, 2H), 7.47-7.41 (m, IH), 7.38 (d, J = 7.7 Hz, IH), 7.26-7.20 (m, IH), 7.00 (d, J = 9.1 Hz, IH), 4.86-4.81 (m, IH), 4.73-4.67 (m, IH), 4.39-4.30 (m, 2H), 4.23 (d, J = 15.0 Hz, IH), 4.16 (s, 2H), 3.89 (s, 2H), 3.20-3.13 (m, IH), 3.00 (s, 2H), 2.87 (s, IH), 2.72 (s, IH), 2.38-2.27 (m, IH), 2.01 (s, 3H), 1.99-1.90 (m, 5H), 1.33-1.18 (m, 2H).

[0355] Example 33: Preparation of 4-(4-((lR,5S)-3,8-diazabicyclo[3.2. l]octanyl-3-yl)-2-((S)-l- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-7-yl)benzoic acid trifluoroacetic acid salt

[0356]

[0357] First Step: Preparation of tert-butyl (lR,5S)-3-(7-(4-(tert-butoxycarbonyl)phenyl)-2- ((S)-l-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8- diazabicyclo[3.2. l]octane-8-carboxylate (33-a)

[0358] Intermediate I-3 (50 mg, 0.084 mmol), tert-butyl 4-iodobenzoate (128 mg, 0.422 mmol), cesium carbonate (55 mg, 0.168 mmol), copper iodide (8 mg, 0.042 mmol), metformin (5.5 mg, 0.042 mmol) were dissolved in DMF (1.5 mL), the reaction system was replaced with nitrogen and heated to 130 °C for 16 hours under nitrogen. The reaction system was cooled to room temperature, quenched with water, extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by flash column (methanol: dichloromethane = 0% ~ 10%) to obtain the target product tert-butyl (1R, 5S)-3-(7-(4-(tert-butoxycarbonyl)phenyl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (33-a, 40 mg, yield 70.7%). MS (ESI) [M+H] + 669.95.

[0359] Second Step: Preparation of 4'-(4-((1R, 5S)-3, 8-diazabicyclo[3.2.1]octanyl-3-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-7-yl)-[1,1'-biphenyl]-4-carboxylic acid trifluoroacetic acid salt (33)

[0360] Tert-butyl (1R, 5S)-3-(7-(4-(tert-butoxycarbonyl)phenyl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (33-a, 40 mg, 0.0598 mmol) was dissolved in dichloromethane / trifluoroacetic acid (3 ml / 0.6 ml), the reaction solution was reacted at 20 °C for 0.5 hours. The reaction solution was separated and purified by preparative liquid chromatography to obtain compound 33: 4-(4-((1R, 5S)-3, 8-diazabicyclo[3.2.1]octanyl-3-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-7-yl)benzoic acid trifluoroacetic acid salt (24 mg, yield 78.3%, brown, solid) MS (ESI) [M+H] + 513.66. 1HNMR (600 MHz, DMSO-d6) δ 9.92 (s, IH), 9.26 (d, J = 9.3 Hz, IH), 9.11 (s, IH), 8.16 (d, J = 8.1 Hz, 2H), 7.85 (d, J = 9.2 Hz, IH), 7.61 (d, J = 9.2 Hz, IH), 7.25 (s, IH), 4.80 (d, J = 12.3 Hz, IH), 4.66 (dd, J = 12.3, 7.1 Hz, 2H), 4.34 (d, J = 13.6 Hz, 2H), 4.16 (s, 2H), 3.86 (s, IH), 3.72 - 3.59 (m, 4H), 3.15 (d, J = 8.3 Hz, 2H), 2.98 (s, 3H), 2.84 (s, IH), 2.31 (dd, J = 30.9, 22.8 Hz, IH), 2.12 - 1.87 (m, 3H), 1.24 (d, J = 29.6 Hz, 2H).

[0361] Example 34: Preparation of 4-(4-((lR,5S)-3,8-diazabicyclo[3.2. l]octanyl-3-yl)-2-((S)-l- methylpyrrolidin-2-yl)methyloxy)-7H-pyrrolo[2,3-h]quinazolin-7-yl)benzamide trifluoroacetic acid salt

[0362]

[0363] First Step: Preparation of tert-butyl (lR,5s)-3-(7-(4-carbamoylphenyl)-2-((S)-l- methylpyrrolidin-2-yl)methyloxy)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8- diazabicyclo[3.2. l]octane-8-carboxylate (34-a)

[0364] Intermediate I-3 (50 mg, 0.084 mmol), 4-iodobenzamide (104 mg, 0.422 mmol), cesium carbonate (55 mg, 0.168 mmol), copper iodide (8 mg, 0.042 mmol), 4,7-dimethoxy- 1,10-phenanthroline (10 mg, 0.042 mmol) were dissolved in DMF (2 mL), the reaction system was replaced with nitrogen and heated to 100 °C for 16 hours under nitrogen environment. The reaction system was cooled to room temperature, quenched with water, extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by flash column (methanol: dichloromethane = 0% ~ 10%) to obtain the target product tert-butyl (1R,5S)-3-(7-(4-carbamoylphenyl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (34-a, 40 mg, yield 77.44%). MS (ESI) [M+H] + 612.65.

[0365] Second step: preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octanyl-3-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-7-yl)benzamide trifluoroacetate salt (34)

[0366] Tert-butyl (1R,5S)-3-(7-(4-carbamoylphenyl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (34-a, 40 mg, 0.065 mmol) was dissolved in dichloromethane / trifluoroacetic acid (2 ml / 0.6 ml), the reaction solution was reacted at 25 °C for 0.5 hours. The reaction solution was separated and purified by preparative liquid chromatography to obtain compound 34: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octanyl-3-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-7-yl)benzamide trifluoroacetate salt (9.23 mg, yield 27.55%, white, solid) MS (ESI) [M+H] + 512.69. 1HNMR (600 MHz, DMSO-d6) δ 9.89 (s, IH), 9.23 (d, J = 9.7 Hz, IH), 9.08 (s, IH), 8.11 (d, J = 8.1 Hz, 2H), 7.81 (d, J = 2.4 Hz, IH), 7.73 - 7.67 (m, 2H), 7.58 (d, J = 9.1 Hz, IH), 4.80 (d, J = 12.3 Hz, IH), 4.66 (dd, J = 12.3, 7.0 Hz, IH), 4.34 (d, J = 13.6 Hz, 2H), 4.16 (s, 2H), 3.86 (s, IH), 3.71 - 3.59 (m, 4H), 3.16 (d, J = 7.6 Hz, IH), 2.98 (s, 3H), 2.31 (dd, J = 31.6, 23.5 Hz, 2H), 2.16 - 2.04 (m, IH), 1.94 (ddd, J = 23.0, 15.5, 9.0 Hz, 6H), 1.21 (s, IH).

[0367] Example 35: Preparation of 4-((lR,5S)-3,8-diazabicyclo[3.2. l]octan-3-yl)-7-(3,4- difluorophenyl)-2-((S)-l-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinazoline trifluoroacetate

[0368]

[0369] First Step: Preparation of tert-butyl (lR,5S)-3-(7-(3,4-difluorophenyl)-2-((S)-l- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinazolin-4-yl)-3,8- diazabicyclo[3.2. l]octane-8-carboxylate (35-a)

[0370] Intermediate I-3 (50 mg, 0.10 mmol), 1,2-difluoro-4-iodobenzene (48 mg, 0.20 mmol), N,N'-dimethylethylenediamine (3.5 mg, 0.04 mmol), copper iodide (3.8 mg, 0.02 mmol) and potassium phosphate (53 mg, 0.25 mmol) were dissolved in toluene (3.0 ml), the reaction system was replaced with nitrogen and heated to 120 °C for 16 hours under nitrogen. The reaction system was cooled to room temperature, quenched with water, extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product which was purified by thin layer chromatography on silica gel plates (methanol / dichloromethane = 10 / 1) to give (1R,5S)-3-(7-(3,4-difluorophenyl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (35-a, 8 mg, 13% yield). MS (ESI) [M+H] + 605.3

[0371] Second step: Preparation of ((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(3,4-difluorophenyl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline trifluoroacetate salt (35)

[0372] ((1R,5S)-3-(7-(3,4-difluorophenyl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (35-a, 8 mg, 0.013 mmol) was dissolved in acetonitrile / trifluoroacetic acid (1 ml / 1 ml) and the reaction was left to react at 20 °C for 2 hours. The reaction was purified by preparative liquid chromatography to give compound 35: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-7-yl)phenol trifluoroacetate salt (2.35 mg, 36% yield). MS (ESI) [M+H] + 505.3. 1HNMR (400 MHz, CD3OD) δ 8.15-8.01 (m, 2H), 7.56-7.40 (m, 2H), 7.79 (d, J = 8.4 Hz, IH), 7.71 (d, J = 9.3 Hz, IH), 7.46 (d, J = 5.3 Hz, IH), 5.06-4.95 (m, IH), 4.87-4.76 (m, 4H), 4.25 (s, 2H), 4.02-3.98 (m, 3H), 3.80 (s, IH), 3.14 (s, 3H), 2.51-2.41 (m, IH), 2.29-2.07 (m, 7H).

[0373] Example 36: Preparation of 4-((lR,5S)-3,8-diazabicyclo[3.2. l]octan-3-yl)-9-(2- fluorophenyl)-2-((S)-l-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinazoline trifluoroacetate salt

[0374]

[0375] First Step: Preparation of tert-butyl (lR,5S)-3-(2-((S)-l-methylpyrrolidin-2-yl)methoxy)- 7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8-diazabicyclo[3.2. l]octane-8-carboxylate (I-2)

[0376] Intermediate I-3 (474 mg, 0.8 mmol) was dissolved in acetic acid (9.5 mL) and the reaction was heated to 80 °C for 8 hours. The reaction was cooled to room temperature, quenched with water, extracted with dichloromethane, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by flash column (methanol:dichloromethane = 0% ~ 10%) to give the target product tert-butyl (lR,5S)-3-(2-((S)-l-methylpyrrolidin-2-yl)methoxy)-7H- pyrrolo[2,3-h]quinolin-4-yl)-3,8-diazabicyclo[3.2. l]octane-8-carboxylate (I-2, 272 mg, yield 69.04%). MS (ESI) [M+H] + 493.25.

[0377] Second Step: Preparation of tert-butyl (lR,5S)-3-(9-bromo-2-((S)-l- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8- diazabicyclo[3.2. l]octane-8-carboxylate (36-a)

[0378] tert-Butyl (1R, 5S)-3-(9-bromo-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H- pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (36-a, 50 mg, 0.0876 mmol), (2-fluorophenyl)boronic acid (18 mg, 0.13 mmol), potassium carbonate (36 mg, 0.26 mmol), tetrakis(triphenylphosphine)palladium (20 mg, 0.0016 mmol) were dissolved in dioxane: water = 20: 1 (1.5 mL), the reaction was replaced by nitrogen and reacted at 100 °C for 16 hours under nitrogen environment. The reaction system was cooled to room temperature, quenched with water, extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by flash column (methanol: dichloromethane = 0% ~ 10%) to obtain the target product tert-butyl (1R, 5S)-3-(9-(2-fluorophenyl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (36-b, 23 mg, yield 44.77%) MS (ESI) [M+H] + 572.

[0379] Third step: Preparation of tert-butyl (1R, 5S)-3-(9-(2-fluorophenyl)-2-((S)-1- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (36-b)

[0380] tert-Butyl (1R, 5S)-3-(9-bromo-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H- pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (36-a, 50 mg, 0.0876 mmol), (2-fluorophenyl)boronic acid (18 mg, 0.13 mmol), potassium carbonate (36 mg, 0.26 mmol), tetrakis(triphenylphosphine)palladium (20 mg, 0.0016 mmol) were dissolved in dioxane: water = 20: 1 (1.5 mL), the reaction was replaced by nitrogen and reacted at 100 °C for 16 hours under nitrogen environment. The reaction system was cooled to room temperature, quenched with water, extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by flash column (methanol: dichloromethane = 0% ~ 10%) to obtain the target product tert-butyl (1R, 5S)-3-(9-(2-fluorophenyl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (36-b, 23 mg, yield 44.77%) MS (ESI) [M+H] + 587.85.

[0381] Fourth Step: Preparation of 4-((lR,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-9-(2- fluorophenyl)-2-((S)-l-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3- h]quinazoline trifluoroacetate (36)

[0382] To a solution of tert-butyl (lR,5S)-3-(9-(2-fluorophenyl)-2-((S)-l- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (36-b, 23 mg, 0.039 mmol) in dioxane (2 mL) was added trifluoroacetic acid (0.6 mL) at 25 °C. The reaction was stirred for 1 h. After the reaction was completed, the solvent was removed under reduced pressure. The reaction was purified by preparative liquid chromatography to give compound 36: 4-((lR,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-9-(2- fluorophenyl)-2-((S)-l-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3- h]quinazoline trifluoroacetate (9.52 mg, 50.10% yield, white solid) MS (ESI) [M+H] + 487.88. 1 HNMR (600 MHz, DMSO-d6) δ 7.60 (d, J = 9.0 Hz, IH), 7.50 (dd, J = 19.1, 8.2 Hz, 2H), 7.45 (s, IH), 7.34 (d, J = 5.6 Hz, IH), 7.21 (d, J = 7.6 Hz, 2H), 4.22-4.05 (m, 5H), 3.99-3.92 (m, 3H), 3.51 (dd, J = 34.7, 19.1 Hz, 4H), 3.00 (d, J = 10.5 Hz, IH), 2.77 (s, 3H), 2.08-1.93 (m, 7H), 1.79 (d, J = 6.8 Hz, IH), 1.48 (d, J = 7.0 Hz, IH).

[0383] Example 37: Preparation of 4-((lR,5S)-3,8-diazabicyclo[3.2.1]octyl-3-yl)-7-(3- chlorophenyl)-2-((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizidin-7a(5H)- ylmethoxy)-7H-pyrrolo[2,3-h]quinazoline trifluoroacetate

[0384]

[0385] Step 1: Preparation of 4-((lR,5S)-3,8-diazabicyclo[3.2.1]octanyl-3-yl)-7-(3- chlorophenyl)-2-((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizidin-7a(5H)-ylmethoxy)- 7H-pyrrolo[2,3-h]quinazoline (37-a)

[0386] Intermediate I-4 (30 mg, 0.047 mmol), 1-chloro-3-iodobenzene (56 mg, 0.235 mmol), cesium carbonate (30.6 mg, 0.094 mmol), copper(I) iodide (4.5 mg, 0.0235 mmol), metformin (3 mg, 0.0235 mmol) were dissolved in DMF (2 mL), the reaction system was replaced by nitrogen and heated to 130 °C for 16 hours under nitrogen environment. The reaction system was cooled to room temperature, quenched with water, extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash column (methanol: dichloromethane = 0% ~ 10%) to obtain the target product tert-butyl (lR,5S)-3-(7-(3-chlorophenyl)-2-((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizidin-7a(5H)-ylmethoxy)-7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (37-a, 20 mg, yield 65.64%). MS (ESI) [M+H] + 647.35.

[0387] Step 2: Preparation of 4-((lR,5S)-3,8-diazabicyclo[3.2.1]octanyl-3-yl)-7-(3- chlorophenyl)-2-((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizidin-7a(5H)-ylmethoxy)- 7H-pyrrolo[2,3-h]quinazoline trifluoroacetate (37)

[0388] Tert-butyl (1R,5S)-3-(7-(3-chlorophenyl)-2-((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizine-7a(5H)-ylmethoxy)-7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8-diazabicyclo[3.2.1] octane-8-carboxylate (37-a, 20 mg, 0.031 mmol) was dissolved in dichloromethane / trifluoroacetic acid (3 ml / 0.6 ml) and the reaction was stirred at 25 °C for 1 hour. The reaction was purified by preparative liquid chromatography to give compound 37: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(3-chlorophenyl)-2-((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizine-7a(5H)-ylmethoxy)-7H-pyrrolo[2,3-h]quinoline trifluoroacetate salt (3.76 mg, 22.25% yield, gray, solid) MS (ESI) [M+H] + 547.35. 1 HNMR (600 MHz, DMSO-d6) δ 10.81 (s, 1H), 9.20 (s, 1H), 9.04 (s, 1H), 7.80 (d, J = 2.8 Hz, 1H), 7.75-7.69 (m, 1H), 7.64 (dt, J = 15.2, 7.8 Hz, 1H), 7.57-7.51 (m, 1H), 7.21 (s, 1H), 5.59 (d, J = 52.7 Hz, 2H), 4.69-4.57 (m, 2H), 4.40-4.27 (m, 2H), 4.16 (s, 2H), 3.94-3.57 (m, 2H), 2.65-2.53 (m, 2H), 2.35 (d, J = 10.4 Hz, 1H), 2.18 (d, J = 18.8 Hz, 2H), 2.02 (d, J = 54.7 Hz, 5H), 1.43 (s, 1H), 1.21 (s, 3H).

[0389] Example 38: Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((S)-1- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-7-yl)phenol

[0390]

[0391] First Step: Preparation of tert-butyl (1R,5S)-3-(7-(4-(ethoxymethoxy)phenyl)-2-((S)-1- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8-diazabicyclo[3.2.1] octane-8-carboxylate (38-a)

[0392] Intermediate I-3 (118 mg, 0.20 mmol) was dissolved in N,N-dimethylformamide (3 mL), and 1-(ethoxymethoxy)-4-iodobenzene (278 mg, 1.00 mmol), 4,7-dimethoxy- 1,10-phenanthroline (24 mg, 0.10 mmol), copper(I) iodide (19 mg, 0.10 mmol), and cesium carbonate (130 mg, 0.40 mmol) were added. The reaction was stirred at 130 °C overnight. Water (10 mL) was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (dichloromethane:methanol) to give the target product tert-butyl (1R,5S)-3-(7-(4-(ethoxymethoxy)phenyl)-2-((S)-1- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1] octane-8-carboxylate (38-a, 53 mg, 41.7 %) MS (ESI) [M+H] + 643.4

[0393] Second Step: Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octanyl-3-yl)-2-((S)-1- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-7-yl)phenol (38)

[0394] Tert-butyl (1R,5S)-3-(7-(4-(ethoxymethoxy)phenyl)-2-((S)-1- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1] octane-8-carboxylate (38-a, 30 mg, 0.05 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (500 μL) was added. The reaction was stirred at room temperature overnight. After concentration under reduced pressure, the compound 38: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octanyl-3-yl)-2-((S)-1- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-7-yl)phenol (1 mg, 4.4 % yield) was purified by preparative HPLC. MS (ESI) [M+H] + 485.3. 1HNMR (600 MHz, DMSO-d6) δ 10.29 (s, IH), 9.53 (s, IH), 9.37 (s, IH), 7.68 (dd, J = 15.2, 5.9 Hz, 2H), 7.42 (d, J = 9.1 Hz, IH), 7.38 (t, J = 7.7 Hz, 2H), 7.25 (s, IH), 6.99 (d, J = 8.1 Hz, 2H), 4.87 - 4.82 (m, IH), 4.72 (dd, J = 12.0, 7.0 Hz, IH), 4.46 (s, 2H), 4.43 (s, 3H), 4.18 (s, 3H), 3.77 (d, J = 13.5 Hz, 2H), 2.99 (d, J = 18.6 Hz, 3H), 2.33 (d, J = 8.0 Hz, IH), 2.13 - 2.06 (m, IH), 1.97 (s, 6H).

[0395] Example 39: Preparation of 4-((lR,5S)-3,8-diazabicyclo[3.2. l]octan-3-yl)-2-((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizidin-7a(5H)-ylmethoxy)-7-(4-(trifluoromethyl)phenyl)-7H-pyrrolo[2,3-h]quinazoline trifluoroacetate

[0396]

[0397] First Step: Preparation of tert-butyl (lR,5S)-3-(2-((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizidin-7a(5H)-yl)methoxy)-7-(4-(trifluoromethyl)phenyl)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2. l]octane-8-carboxylate (39-a)

[0398] Intermediate I-4 (60.0 mg, 0.094 mmol), 1-iodo-4-(trifluoromethyl)benzene (127.8 mg, 0.470 mmol), cesium carbonate (61.25 mg, 0.188 mmol), copper iodide (8.95 mg, 0.047 mmol), 4,7-dimethoxy-1,10-phenanthroline (11.3 mg, 0.047 mmol) were dissolved in N,N-dimethylformamide (1.5 mL) and reacted at 130 °C overnight. Water (20 mL) was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the target product tert-butyl (1R,5S)-3-(2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(4-(trifluoromethyl)phenyl)-7H-pyrrolo[2,3-h]quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (39-a, 70 mg, crude, 109.4% yield). MS (ESI) [M+H]+684.75.

[0399] Second Step: Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-ylmethoxy)-7-(4-(trifluoromethyl)phenyl)-7H-pyrrolo[2,3-h]quinazoline trifluoroacetate (39)

[0400] Tert-butyl (1R,5S)-3-(2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(4-(trifluoromethyl)phenyl)-7H-pyrrolo[2,3-h]quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (39-a, 70 mg, 0.103 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added. The mixture was reacted at room temperature for 3 hours. Concentration under reduced pressure and purification by preparative HPLC (FA, 0.1%) gave compound 39: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-ylmethoxy)-7-(4-(trifluoromethyl)phenyl)-7H-pyrrolo[2,3-h]quinazoline trifluoroacetate (7.71 mg, 12.92% yield). MS (ESI) [M+H]+581.63. + 581.63. 1H NMR (600 MHz, CD3OD) δ 7.95 (d, J = 8.1 Hz, 2H), 7.83 (d, J = 8.0 Hz, 2H), 7.80 (d, J = 9.3 Hz, IH), 7.75 (s, IH), 7.68 (d, J = 9.2 Hz, IH), 7.41 (s, IH), 5.63 (d, J = 51.6 Hz, IH), 4.79 (s, 2H), 4.74 (d, J = 14.0 Hz, 2H), 4.26 (d, J = 25.0 Hz, 2H), 4.11-4.02 (m, IH), 3.99-3.85 (m, 4H), 3.54-3.47 (m, IH), 2.77 (dd, J = 39.8, 15.7 Hz, IH), 2.69-2.60 (m, IH), 2.51 (d, J = 9.4 Hz, IH), 2.40 (d, J = 7.2 Hz, 2H), 2.26 (d, J = 6.6 Hz, IH), 2.15 (s, 4H).

[0401] Example 40: Preparation of l-(4-((lR,5S)-3,8-diazabicyclo[3.2. l]octanyl-3-yl)-2-((S)-l- methylpyrrolidin-2-yl)methyloxy)-7H-pyrrolo[2,3-h]quinazolin-7-yl)-2-methylpropan-2- ol trifluoroacetate

[0402]

[0403] First Step: Preparation of (lR,5S)-3-(7-(2-hydroxy-2-methylpropyl)-2-((S)-l- methylpyrrolidin-2-yl)methyloxy)-7H-pyrrolo[2,3-h]quinazolin-4-yl)-3,8- diazabicyclo[3.2. l]octane-8-carboxylic acid tert-butyl ester (40-a)

[0404] Intermediate I-2 (50 mg, 0.10 mmol) was dissolved in dry N,N-dimethylformamide (1.0 ml), sodium hydride (15 mg, 0.30 mmol, 60% in oil) was added slowly, followed by 2,2-dimethyloxirane (15 mg, 0.2 mmol). The reaction was purged with nitrogen and heated to 50 °C under nitrogen for 16 hours. The reaction was cooled to room temperature, quenched with water, extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (lR,5S)-3-(7-(2-hydroxy-2-methylpropyl)-2-((S)-l- methylpyrrolidin-2-yl)methyloxy)-7H-pyrrolo[2,3-h]quinazolin-4-yl)-3,8- diazabicyclo[3.2. l]octane-8-carboxylic acid tert-butyl ester (40-a, 55 mg, 97% yield). MS (ESI) [M+H]+ 565.3

[0405] Step 2: Preparation of (1R,5S)-3-(7-(2-hydroxy-2-methylpropyl)-2-((S)-1- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (40-a)

[0406] Step 2: Preparation of (1R,5S)-3-(7-(2-hydroxy-2-methylpropyl)-2-((S)-1- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (40-a) + 465.4. 1 HNMR (600 MHz, CD3OD) δ 7.74 (s, 2H), 7.51 (s, IH), 7.22 (s, IH), 4.98 (d, J = 12.2 Hz, IH), 4.84-4.81 (m, IH), 4.27 (s, 2H), 4.25 (s, 2H), 4.01 (t, J = 13.4 Hz, 3H), 3.80 (s, IH), 3.30 (s, 3H), 3.13 (s, 3H), 2.49-2.42 (m, IH), 2.26-2.05 (m, 7H), 1.22 (s, 6H).

[0407] Example 41: Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2- ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizidin-7a(5H)-yl)methoxy)-7H- pyrrolo[2,3-h]quinolin-7-yl)aniline trifluoroacetate salt

[0408]

[0409] Step 1: Preparation of tert-butyl (1R, 5S)-3-(7-(4-aminophenyl)-2-((2R, 7aS)-2- fluorotetrahydro-lH-pyrrolizine-7a(5H)-ylmethoxy)-7H-pyrrolo[2,3-h]quinolin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (41-a)

[0410] Intermediate I-4 (50 mg, 0.0786 mmol), tert-butyl (4-iodophenyl)carbamate (125 mg, 0.393 mmol), cesium carbonate (51 mg, 0.157 mmol), cuprous iodide (7.5 mg, 0.039 mmol), metformin (3 mg, 0.039 mmol) were dissolved in DMF (2 mL), the reaction system was replaced by nitrogen and heated to 130 °C for 16 hours under nitrogen environment. The reaction system was cooled to room temperature, quenched with water, extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by flash column (methanol: dichloromethane = 0% ~ 10%) to obtain the target product tert-butyl (1R, 5S)-3-(7-(4-aminophenyl)-2-((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizine- 7a(5H)-ylmethoxy)-7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (41-a, 40 mg, yield 81.14%, pink, oily substance). MS (ESI) [M+H] + 628.52.

[0411] Step 2: Preparation of 4-(4-((1R, 5S)-3, 8-diazabicyclo[3.2.1]octan-3-yl)-2-((2R, 7aS)-2- fluorotetrahydro-lH-pyrrolizine-7a(5H)-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-7-yl)aniline trifluoroacetate (41)

[0412] Tert-butyl (1R,5S)-3-(7-(4-aminophenyl)-2-((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizine-7a(5H)-ylmethoxy)-7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8-diazabicyclo[3.2.1] octane-8-carboxylate (41-a, 40 mg, 0.064 mmol) was dissolved in dichloromethane / trifluoroacetic acid (3 ml / 0.6 ml) and the reaction was stirred at 25 °C for 1 hour. The reaction was purified by preparative liquid chromatography to give compound 41: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-7- yl)aniline trifluoroacetate salt (13.54 mg, 37.50% yield, white solid) MS (ESI) [M+H] + 528.55. 1 HNMR (600 MHz, DMSO-d6) δ 11.02 (s, 2H), 9.24 (d, J = 95.8 Hz, 1H), 7.70-7.55 (m, 2H), 7.38 (d, J = 9.0 Hz, 1H), 7.24 (d, J = 7.5 Hz, 1H), 7.15 (s, 1H), 6.81 (d, J = 7.3 Hz, 2H), 5.59 (d, J = 52.2 Hz, 2H), 4.70-4.59 (m, 3H), 4.35 (s, 3H), 4.16 (s, 3H), 3.39-3.23 (m, 3H), 2.57 (dd, J = 52.1, 18.0 Hz, 3H), 2.39-2.31 (m, 1H), 2.27-2.13 (m, 3H), 2.08 (d, J = 10.1 Hz, 2H), 1.96 (s, 2H), 1.21 (s, 1H).

[0413] Example 42: Preparation of 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-7- yl)benzonitrile

[0414]

[0415] First Step: Preparation of tert-butyl (1R,5S)-3-(7-(3-cyanophenyl)-2-((2R,7as)-2- fluorotetrahydro-1H-pyrrolizine-7a(5H)-ylmethoxy)-7H-pyrrolo[2,3-h]quinolin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (42-a)

[0416] Intermediate I-3 (60.0 mg, 0.094 mmol), 3-(trifluoromethyl)benzonitrile (107.6 mg, 0.47 mmol), cesium carbonate (61.25 mg, 0.188 mmol), cuprous iodide (8.95 mg, 0.047 mmol), 4,7-dimethoxy-1,10-phenanthroline (11.3 mg, 0.047 mmol) were dissolved in N,N-dimethylformamide (1.5 mL) and reacted at 130 °C overnight. Water (20 mL) was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the target product tert-butyl (1R,5S)-3-(7-(3-cyanophenyl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-ylmethoxy)-7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (42-a, 80 mg, crude, 116.8% yield). MS (ESI) [M+H]+638.76.

[0417] Second Step: Preparation of 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-7-yl)benzonitrile (42)

[0418] Tert-butyl (1R,5S)-3-(2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(4-(trifluoromethyl)phenyl)-7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (42-a, 80 mg, 0.125 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added. The mixture was reacted at room temperature for 3 hours. Concentration under reduced pressure and purification by preparative HPLC (FA, 0.1%) gave compound 42: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-7-yl)benzonitrile (6.45 mg, 9.6% yield). MS (ESI) [M+H]+ + 537.64.

[0419] Example 43: Preparation of 4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizidin-7a(5H)-ylmethoxy)-7-(m-tolyl)-7H-pyrrolo[2,3- h]quinoline

[0420]

[0421] First step: Preparation of tert-butyl (lR,5S)-3-(2-((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizidin- 7a(5H)-yl)methoxy)-7-(m-tolyl)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (43-a)

[0422] Intermediate I-4 (50 mg, 0.09 mmol) was dissolved in N,N-dimethylformamide (2 ml), m-iodotoluene (100 mg, 0.09 mmol), 4,7-dimethoxy-l,10-phenanthroline (11 mg, 0.05 mmol), cuprous iodide (9 mg, 0.05 mmol) and cesium carbonate (60 mg, 0.19 mmol) were added and the reaction was carried out at 130 °C overnight. Water (10 ml) was added and the organic phase was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure and purified on a Flash column (dichloromethane:methanol) to give the target product tert-butyl (lR,5S)-3-(2-((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizidin-7a(5H)-yl)methoxy)-7-(m-tolyl)- 7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (43-a, 41 mg, 70.6%) MS (ESI) [M+H] + 627.4

[0423] Second step: Preparation of 4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizidin-7a(5H)-ylmethoxy)-7-(m-tolyl)-7H-pyrrolo[2,3- h]quinoline (43)

[0424] Tert-butyl (1R,5S)-3-(2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-7-(m-tolyl)-7H-pyrrolo[2,3-h]quinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (43-a, 41 mg, 0.05 mmol) was dissolved in acetonitrile (2 mL), and trifluoroacetic acid (200 μL) was added. The reaction was stirred at room temperature overnight. After concentration under reduced pressure, the compound 43: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-ylmethoxy)-7-(m-tolyl)-7H-pyrrolo[2,3-h]quinazoline) (7 mg, yield 20.6%) was purified by preparative HPLC. MS (ESI) [M+H] + 527.2. 1 HNMR (400 MHz, DMSO-d6) δ 9.54 (d, J = 9.5 Hz, 1H), 9.39 (s, 1H), 7.83 (d, J = 3.2 Hz, 1H), 7.78 (d, J = 9.2 Hz, 1H), 7.59 (dd, J = 15.2, 8.2 Hz, 2H), 7.52 (s, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.38 (d, J = 7.5 Hz, 1H), 7.33 (d, J = 3.0 Hz, 1H), 5.75 (s, 1H), 5.62 (s, 1H), 4.74 (s, 2H), 4.55 - 4.42 (m, 2H), 4.25 (s, 2H), 3.97 (dd, J = 18.6, 14.9 Hz, 3H), 3.49 - 3.30 (m, 2H), 2.67 (dd, J = 32.8, 10.1 Hz, 2H), 2.57 (dd, J = 6.6, 4.9 Hz, 4H), 2.51 - 2.49 (m, 2H), 2.33 - 2.21 (m, 2H), 2.04 (s, 3H).

[0425] Example 44: Preparation of 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-7H-pyrrolo[2,3-h]quinazolin-7-yl)phenol

[0426]

[0427] Step 1: Preparation of tert-butyl(1R,5S)-3-(7-(4-(ethoxymethoxy)phenyl)-2-((S)-1-methylpyrrolidine-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinazolin-4-yl)-3,8-diazacyclic[3.2.1]octane-8-carboxylic acid ester (44-a)

[0428] Intermediate I-4 (50 mg, 0.09 mmol) was dissolved in N,N-dimethylformamide (2 ml), and 1-(ethoxymethoxy)-3-iodobenzene (130 mg, 1.00 mmol), 4,7-dimethoxy-1,10-phenanthroline (11 mg, 0.05 mmol), cuprous iodide (9 mg, 0.05 mmol) and cesium carbonate (60 mg, 0.19 mmol) were added. The mixture was reacted overnight at 130 °C. Add water (10 ml), extract with ethyl acetate, wash the organic phase with saturated brine, dry with anhydrous magnesium sulfate, filter, concentrate the filtrate under reduced pressure, and purify by Flash column chromatography (dichloromethane:methanol) to obtain the target product tert-butyl(1R,5S)-3-(7-(4-(ethoxymethoxy)phenyl)-2-((S)-1-methylpyrrolidine-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinazolin-4-yl)-3,8-diazacyclic[3.2.1]octane-8-carboxylic acid ester (44-a, 40 mg, 62.8%) MS (ESI) [M+H] + 687.4

[0429] Step 2: Preparation of 3-(4-((1R,5S)-3,8-diazacyclic[3.2.1]octyl-3-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7H-pyrrolo[2,3-h]quinazolin-7-yl)phenol (44)

[0430] tert-butyl(1R,5S)-3-(7-(4-(ethoxymethoxy)phenyl)-2-((S)-1-methylpyrrolidine-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinazolin-4-yl)-3,8-diazacyclic[3.2.1]octane-8-carboxylic acid ester (44-a, 40 mg, 0.05 mmol) was dissolved in acetonitrile (2 ml), and trifluoroacetic acid (200 μL) was added. The mixture was reacted overnight at room temperature. After concentration under reduced pressure, compound 44 was obtained by preparative HPLC purification: 3-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7H-pyrrolo[2,3-h]quinazolin-7-yl)phenol (10 mg, yield 32.5%). MS (ESI) [M+H] + 529.2. 1H NMR (400 MHz, DMSO-d6) δ 9.54 (d, J = 9.5 Hz, 1H), 9.39 (s, 1H), 7.83 (d, J = 3.2 Hz, 1H), 7.78 (d, J = 9.2 Hz, 1H), 7.59 (dd, J = 15.2, 8.2 Hz, 2H), 7.52 (s, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.38 (d, J = 7.5 Hz, 1H), 7.33 (d, J = 3.0 Hz, 1H), 5.75 (s, 1H), 5.62 (s, 1H), 4.74 (s, 2H), 4.55 - 4.42 (m, 2H), 4.25 (s, 2H), 3.97 (dd, J = 18.6, 14.9 Hz, 3H), 3.49 - 3.30 (m, 2H), 2.67 (dd, J = 32.8, 10.1 Hz, 2H), 2.57 (dd, J = 6.6, 4.9 Hz, 4H), 2.51 - 2.49 (m, 2H), 2.33 - 2.21 (m, 2H), 2.04 (s, 3H).

[0431] Example 45: Preparation of 4-((lR,5S)-3,8-diazabicyclo[3.2. l]octan-3-yl)-9-(2- fluorophenyl)-7,7-dimethyl-2-((S)-l-methylpyrrolidin-2-yl)methoxy)-7H- pyrrolo[2,3-h]quinazoline trifluoroacetate

[0432]

[0433] First step: 4-((lR,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2. l]octan-3-yl)- 9-(2-fluorophenyl)-7,7-dimethyl-2-((S)-l-methylpyrrolidin-2-yl)methoxy)-7H- pyrrolo[2,3-h]quinazoline-7-dimethyl-2-((S)-l-methylpyrrolidin-2-yl)methoxy)-7H- pyrrolo[2,3-h]quinazoline (45-a)

[0434] To a solution of tert-butyl (1R,5S)-3-(9-(2-fluorophenyl)-2-((S)-1- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (36-b, 40 mg, 0.068 mmol), methyl iodide (14.5 mg, 0.102 mmol), potassium carbonate (14 mg, 0.102 mmol) in tetrahydrofuran (1.5 mL) was stirred at 25 °C for 2 hours. After the reaction was completed, water was added, and the reaction mixture was extracted with ethyl acetate. The organic phase was collected and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (methanol:dichloromethane = 0%~10%) to give the target product 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-9-(2- fluorophenyl)-7,7-dimethyl-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H- pyrrolo[2,3-h]quinoline-7-dimethyl-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H- pyrrolo[2,3-h]quinoline (45-a, 7.14 mg, yield 17.41%, white solid). MS (ESI) [M+H] + 616.55.

[0435] Second step: Preparation of the target product 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-9-(2-fluorophenyl)-7,7-dimethyl-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline trifluoroacetate salt (45)

[0436] To a solution of 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-9-(2-fluorophenyl)-7,7-dimethyl-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline-7-dimethyl-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline (45-a, 7.14 mg, 0.012 mmol) in dichloromethane / trifluoroacetic acid (1.5 ml / 0.3 ml) was stirred at 25 °C for 1 hour. The reaction mixture was purified by preparative liquid chromatography to give compound 45: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-9-(2-fluorophenyl)-7,7-dimethyl-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline trifluoroacetate salt (3.14 mg, yield 52.5%, white solid). MS (ESI) [M+H]+ 516.25. 1 HNMR (400 MHz, CD3Cl) δ 7.74 (d, J = 9.1 Hz, IH), 7.62-7.54 (m, 2H), 7.41-7.34 (m, 2H), 7.28-7.17 (m, 2H), 4.49-4.14 (m, 6H), 4.05-3.79 (m, 4H), 3.73-3.47 (m, 5H), 3.04-2.88 (m, 3H), 2.37-2.07 (m, 5H), 1.78 (dt, J = 13.7, 9.9 Hz, 2H), 1.29 (s, 2H).

[0437] Example 46: Preparation of l-((lR,5S)-3-(2-((S)-l-methylpyrrolidin-2-yl)methoxy)-7-(4- (trifluoromethoxy)phenyl)-7H-pyrrolo[2,3-h]quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8- yl)prop-2-en-l-one trifluoroacetate salt

[0438]

[0439] First Step: Preparation of the target product l-((lR,5S)-3-(2-((s)-l-methylpyrrolidin-2- yl)methoxy)-7-(4-(trifluoromethoxy)phenyl)-7H-pyrrolo[2,3-h]quinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octan-8-yl)prop-2-en-l-one trifluoroacetate salt (46)

[0440] Dissolve 4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((S)-l-methylpyrrolidin-2-yl)methoxy)- 7-(4-(trifluoromethoxy)phenyl)-7H-pyrrolo[2,3-h]quinazoline (23, 15 mg, 0.027 mmol), acryloyl chloride (3.7 mg, 0.041 mmol), DIPEA (5 mg, 0.041 mmol) in tetrahydrofuran (2 ml), and react at -20 °C for 1 hour. Purify the reaction mixture by preparative liquid chromatography to obtain compound 46: l-((lR,5S)-3-(2-((S)-l-methylpyrrolidin-2-yl)methoxy)-7-(4- (trifluoromethoxy)phenyl)-7H-pyrrolo[2,3-h]quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8- yl)prop-2-en-l-one trifluoroacetate salt (2.47 mg, 15.02% yield, white solid) MS (ESI) [M+H] + 607.35. 1HNMR (400 MHz, CD3CI) δ 7.79 (d, J = 9.3 Hz, IH), 7.72 (d, J = 8.8 Hz, IH), 7.67 (d, J = 3.3 Hz, IH), 7.57 (t, J = 8.4 Hz, 2H), 7.36 (t, J = 10.4 Hz, IH), 6.80 (dd, J = 16.7, 10.5 Hz, IH), 6.38 (dd, J = 16.7, 1.5 Hz, IH), 5.88-5.82 (m, IH), 5.33 (dd, J = 12.5, 7.9 Hz, IH), 5.05-4.93 (m, 2H), 4.81-4.61 (m, 4H), 4.00 (d, J = 7.7 Hz, 2H), 3.85-3.51 (m, 5H), 3.16 (d, J = 11.7 Hz, 2H), 2.55-2.38 (m, 2H), 1.16 (dd, J = 17.6, 10.6 Hz, 2H), 0.89 (t, J = 6.7 Hz, 2H).

[0441] Example 47: Preparation of (S)-2-((l-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-l- yl)-7-(4-(trifluoromethyl)phenyl)-7H-pyrrolo[2,3-h]quinazoline trifluoroacetate salt

[0442]

[0443] First Step: 4-(2-Chloro-7H-pyrrolo[2,3-h]quinazolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (47-a)

[0444] Dissolve 2,4-dichloro-7H-pyrrolo[2,3-h]quinazoline (I-1g, 350 mg, 1.47 mmol) in N,N-dimethylformamide (5 ml), add piperazine-1-carboxylic acid tert-butyl ester (274 mg, 1.47 mmol) and N,N-diisopropyl ethylamine (570 mg, 4.41 mmol) successively at room temperature, and react at room temperature for 1 hour. Add 100 ml of water to the reaction solution, extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the target product 4-(2-chloro-7H-pyrrolo[2,3-h]quinazolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (48-a, 470 mg, yield 82.46 %). MS (ESI) [M+H] + 388.2.

[0445] Second Step: 4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)-2-fluoro-7H-pyrrolo[2,3-h]quinazoline-7-carboxylic acid tert-butyl ester (47-b)

[0446] 4-(2-chloro-7H-pyrrolo[2,3-h]quinazolin-4-yl)piperazine-l-carboxylic acid tert-butyl ester (47-a, 470 mg, 1.21 mmol) and 4-dimethylaminopyridine (15 mg, 0.12 mmol) were dissolved in acetonitrile (5 ml), and di-tert-butyl dicarbonate (317 mg, 1.45 mmol) was slowly added. The reaction was allowed to proceed at room temperature for 2 hours. A small amount of water was added to quench the reaction, and the solvent was removed under reduced pressure. The crude product was added to 100 ml of water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target product, 4-(4-(tert-butoxycarbonyl)piperazin-l-yl)-2-chloro-7H-pyrrolo[2,3-h]quinazoline-7-carboxylic acid tert-butyl ester (47-b, 223 mg, 37.80% yield). The product was used directly in the next step.

[0447] Third Step: Preparation of tert-butyl (S)-4-(4-(tert-butoxycarbonyl)piperazin-l-yl)-2-((l-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinazoline-7-carboxylate (47-c)

[0448] tert-butyl 4-(4-(tert-butoxycarbonyl)piperazin-l-yl)-2-chloro-7H-pyrrolo[2,3-h]quinazoline-7-carboxylate (47-b, 223 mg, 0.46 mmol), cesium carbonate (300 mg, 0.92 mmol), and (S)-(l-methylpyrrolidin-2-yl)methanol (106 mg, 0.92 mmol) were dissolved in toluene (20 ml), and palladium acetate (20 mg, 0.09 mmol), and 1,1'-binaphthalene-2,2'-diphenylphosphine (56 mg, 0.09 mmol) were added under nitrogen protection. The reaction was allowed to proceed at 130°C for 16 hours. The solvent was removed under reduced pressure, and the crude product was purified by flash (dichloromethane:methanol=10:1:1) to obtain the target product, tert-butyl (S)-4-(4-(tert-butoxycarbonyl)piperazin-l-yl)-2-((l-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinazoline-7-carboxylate (47-c, 160 mg, 74.42% yield). MS (ESI) [M+H] + 567.5.

[0449] Fourth Step: Preparation of tert-butyl (S)-4-(2-((l-methylpyrrolidin-2-yl)methoxy)-7-(4-(trifluoromethyl)phenyl)-7H-pyrrolo[2,3-h]quinazolin-4-yl)piperazine-l-carboxylate (47-d)

[0450] To a solution of tert-butyl (S)-4-(4-(tert-butoxycarbonyl)piperazin-l-yl)-2-((l- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline-7-carboxylate (47-c, 160 mg, 0.28 mmol), cuprous iodide (27 mg, 0.14 mmol), metformin (18 mg, 0.14 mmol) and cesium carbonate (182 mg, 0.56 mmol) in N,N-dimethylformamide (10 ml) was added l-iodo-4-(trifluoromethyl)benzene (381 mg, 1.5 mmol) at 130 °C for 16 h. The crude product was added to 50 ml of water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by TLC plate (dichloromethane:methanol = 15: 1) to give the target product tert-butyl (S)-4-(2-((l-methylpyrrolidin-2-yl)methoxy)-7-(4- (trifluoromethyl)phenyl)-7H-pyrrolo[2,3-h]quinolin-4-yl)piperazine-1-carboxylate (47-d, 72.7 mg, yield 42.51%). MS (ESI) [M+H] + 611.5.

[0451] Fifth step: (S)-2-((l-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-l-yl)-7-(4- (trifluoromethyl)phenyl)-7H-pyrrolo[2,3-h]quinoline trifluoroacetate (47)

[0452] To a solution of tert-butyl (S)-4-(2-((l-methylpyrrolidin-2-yl)methoxy)-7-(4- (trifluoromethyl)phenyl)-7H-pyrrolo[2,3-h]quinolin-4-yl)piperazine-l-carboxylate (47-d, 72.7 mg, 0.12 mmol) in dichloromethane (3 ml) and trifluoroacetic acid (1 ml) was added at room temperature for 1 h. The solvent was removed under reduced pressure. The crude product was purified by Pre-HPLC to give compound 47: (S)-2-((l-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-l-yl)-7-(4- (trifluoromethyl)phenyl)-7H-pyrrolo[2,3-h]quinoline trifluoroacetate (47 mg, yield 62.67%). MS (ESI) [M+H] + 511.4. 1HNMR (400 MHz, DMSO-d6) δ 9.99 (s, IH), 9.11 (s, 2H), 7.99 (d, J = 8.5 Hz, 2H), 7.91-7.80 (m, 3H), 7.74 (d, J = 9.2 Hz, IH), 7.60 (d, J = 9.1 Hz, IH), 7.26 (d, J = 3.1 Hz, IH), 4.81 (dd, J = 12.4, 3.3 Hz, IH), 4.67 (dd, J = 12.4, 6.9 Hz, IH), 3.85 (s, 5H), 3.34 (s, 5H), 3.14 (s, 3H), 2.97 (s, 3H), 2.30 (dd, J = 18.2, 10.7 Hz, IH), 2.08 (dd, J = 12.9, 6.7 Hz, IH), 1.98-1.88 (m, 2H).

[0453] Example 48: Preparation of (S)-1-(4-(2-((1-methylpyrrolidin-2-yl)methoxy)-7-(4- (trifluoromethyl)phenyl)-7H-pyrrolo[2,3-h]quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

[0454]

[0455] First Step: (S)-1-(4-(2-((1-methylpyrrolidin-2-yl)methoxy)-7-(4-(trifluoromethyl)phenyl)- 7H-pyrrolo[2,3-h]quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one (48)

[0456] (S)-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)-7-(4-(trifluoromethyl)phenyl)- 7H-pyrrolo[2,3-h]quinazoline trifluoroacetate (47, 35.6 mg, 0.06 mmol) was dissolved in dichloromethane (2 ml), and triethylamine (12 mg, 0.12 mmol) and acryloyl chloride (5.4 mg, 0.06 mmol) were added successively at 0 °C. The reaction was carried out at 0 °C for 0.5 hours. The solvent was removed by distillation under reduced pressure, and the crude product was purified by Pre-HPLC to obtain compound 48: (S)-1-(4-(2-((1-methylpyrrolidin-2-yl)methoxy)-7-(4-(trifluoromethyl)phenyl)-7H- pyrrolo[2,3-h]quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one (16.1 mg, yield 47.63 %). MS (ESI) [M+H] + 565.4. 1HNMR (400 MHz, DMSO-d6) δ 7.98 (d, J = 8.5 Hz, 2H), 7.93 - 7.81 (m, 3H), 7.78 (d, J = 9.2 Hz, IH), 7.62 (d, J = 9.2 Hz, IH), 7.31 (d, J = 2.9 Hz, IH), 6.82 (dd, J = 16.6, 10.5 Hz, IH), 6.15 (dd, J = 16.7, 2.1 Hz, IH), 5.73 (dd, J = 10.5, 2.0 Hz, IH), 4.83 (dd, J = 12.3, 3.1 Hz, IH), 4.68 (dd, J = 12.4, 6.9 Hz, IH), 3.85 (d, J = 10.9 Hz, 5H), 3.76 (s, 2H), 3.63 (s, 2H), 3.19 - 3.12 (m, 2H), 2.97 (s, 3H), 2.33 - 2.25 (m, IH), 2.06 (d, J = 16.8 Hz, 3H), 1.95 (dd, J = 15.5, 6.4 Hz, 2H).

[0457] Example 49: Preparation of 8-(4-((lR,5S)-3,8-diazabicyclo[3.2. l]octanyl-3-yl)-2-((S)-l- methylpyrrolidin-2-yl)methyloxy)-7H-pyrrolo[2,3-h]quinazolin-7-yl)naphthalen-2-ol trifluoroacetate salt

[0458]

[0459] First Step: Preparation of tert-butyl (lR,5S)-3-(7-(methyloxy)naphthalen-l-yl)-2-((S)-l- methylpyrrolidin-2-yl)methyloxy)-7H-pyrrolo[2,3-h]quinazolin-4-yl)-3,8- diazabicyclo[3.2. l]octane-8-carboxylate (49-a)

[0460] Intermediate I-3 (100 mg, 0.169 mmol), l-iodo-7-(methyloxy)naphthalene (83 mg, 0.253 mmol), cesium carbonate (110 mg, 0.338 mmol), copper iodide (16 mg, 0.0845 mmol), 4,7-dimethoxy- 1,10-phenanthroline (20 mg, 0.0845 mmol) were dissolved in DMF (2 mL), the reaction system was replaced with nitrogen and heated to 130 °C for 16 hours under nitrogen. The reaction system was cooled to room temperature, quenched with water, extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by flash column (methanol: dichloromethane = 0% ~ 10%) to obtain the target product tert-butyl (1R,5S)-3-(7-(7-(methyloxy)naphthalen-1-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (49-a, 44 mg, yield 37.61%, brown, oily substance). MS (ESI) [M+H] + 679.55.

[0461] Second Step: Preparation of 8-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-7-yl)naphthalen-2-ol trifluoroacetate salt (49)

[0462] Tert-butyl (1R,5S)-3-(7-(methyloxy)naphthalen-1-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (49-a, 44 mg, 0.065 mmol) was dissolved in acetonitrile / trifluoroacetic acid (3 ml / 0.6 ml), the reaction solution was reacted at 25 °C for 1 hour. The reaction solution was separated and purified by preparative liquid chromatography to obtain compound 49: 8-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinolin-7-yl)naphthalen-2-ol trifluoroacetate salt (18.92 mg, yield 55.73%, gray solid) MS (ESI) [M+H] + 535.26. 1HNMR (400 MHz, DMSO-d6) δ 10.06 (s, 1H), 9.90 (s, 1H), 9.31 (d, J = 10.0 Hz, 1H), 9.15 (s, 1H), 7.99 (dd, J 322.4, 8.6 Hz, 1H), 7.70 (d, J = 3.1 Hz, 1H), 7.57 (t, J = 8.9 Hz, 1H), 7.49-7.40 (m, 1H), 7.27 (d, J = 2.9 Hz, 1H), 7.15 (dd, J = 8.9, 2.2 Hz, 1H), 6.88 (d, J = 9.1 Hz, 1H), 6.37 (s, 1H), 4.86-4.64 (m, 3H), 4.29 (d, J = 14.0 Hz, 2H), 4.13 (s, 2H), 3.88 (s, 2H), 3.17 (s, 2H), 2.99 (s, 3H), 2.31 (d, J = 8.0 Hz, 1H), 1.96 (d, J = 9.8 Hz, 4H), 1.67 (d, J = 57.5 Hz. 3H).

[0463] Example 50: Preparation of 4-((S)-2-methylpiperazin-l-yl)-2-((S)-l- methylpyrrolidin-2-yl)methoxy)-7-(4-(trifluoromethyl)phenyl)-7H-pyrrolo[2,3- h]quinazoline trifluoroacetate salt

[0464]

[0465] First Step: Preparation of tert-butyl (S)-4-(2-chloro-7H-pyrrolo[2,3- h]quinazolin-4-yl)-3-methylpiperazine-1-carboxylate (50-a)

[0466] To a solution of 2,4-dichloro-7H-pyrrolo[2,3-h]quinazoline (I-1g, 100 mg, 0.42 mmol), (S)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (93 mg, 0.46 mmol), DIPEA (71 mg, 0.55 mmol) in DMF (2 mL) was stirred at 25 °C for 21 h. After the reaction was completed, water was added, and the reaction mixture was extracted with ethyl acetate. The organic phase was collected and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate: petroleum ether = 0%~20%) to give the target product tert-butyl (S)-4-(2-chloro-7H-pyrrolo[2,3-h]quinazolin-4-yl)-3-methylpiperazine-1-carboxylate (50-a, 120 mg, yield 71.2%, white solid). MS (ESI) [M+H] + 402.51.

[0467] Step 2: Preparation of tert-butyl-4-(4-(tert-butoxycarbonyl)-2-methylpiperazin-l-yl)- 2-chloro-7H-pyrrolo[2,3-h]quinoline-7-carboxylate (50-b)

[0468] To a solution of tert-butyl (S)-4-(2-chloro-7H-pyrrolo[2,3-h]quinolin-4-yl)-3- methylpiperazine-l-carboxylate (50-a, 90 mg, 0.224 mmol), Boc anhydride (59 mg, 0.269 mmol), 4-dimethylaminopyridine (2.5 mg, 0.0224 mmol) in acetonitrile (10 ml) was stirred at 25 °C for 2 h. After the reaction was completed, water was added, and the mixture was extracted with ethyl acetate. The organic phase was collected and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate: petroleum ether = 0% to 15%) to give tert-butyl-4-(4-(tert-butoxycarbonyl)-2-methylpiperazin-l-yl)-2-chloro-7H- pyrrolo[2,3-h]quinoline-7-carboxylate (50-b, 76 mg, 67.6% yield, white solid). MS (ESI) [M+H] + 502.22.

[0469] Step 3: Preparation of tert-butyl 4-((S)-4-(tert-butoxycarbonyl)-2-methylpiperazin-l-yl)- 2-((S)-l-methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline-7-carboxylate (50-c)

[0470] To a solution of tert-butyl-4-(4-(tert-butoxycarbonyl)-2-methylpiperazin-l-yl)-2- chloro-7H-pyrrolo[2,3-h]quinoline-7-carboxylate (50-b, 76 mg, 0.151 mmol), S-(l- methylpyrrolidin-2-yl)methanol (35 mg, 0.303 mmol), cesium carbonate (74 mg, 0.227 mmol), BINAP (18.6 mg, 0.03 mmol) and palladium acetate (7 mg, 0.03 mmol) in toluene (2 ml) was stirred at 110 °C for 16 h. After the reaction was completed, the mixture was cooled to room temperature, quenched with water, and extracted with ethyl acetate. The organic phase was collected and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate: petroleum ether = 0% to 10%) to give tert-butyl 4-((S)-4-(tert-butoxycarbonyl)-2-methylpiperazin-l-yl)-2-((S)-l- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline-7-carboxylate (50-c, 80 mg, 90.91% yield, yellow oil). MS (ESI) [M+H] + 581.25

[0471] Fourth Step: Preparation of tert-butyl (S)-3-methyl-4-(2-((S)-l-methylpyrrolidin-2- yl)methoxy)-7-(4-(trifluoromethyl)phenyl)-7H-pyrrolo[2,3-h]quinoline-4-yl)piperazine- 1-carboxylate (50-d)

[0472] Tert-butyl 4-((S)-4-(tert-butoxycarbonyl)-2-methylpiperazin-l-yl)-2-((S)-l- methylpyrrolidin-2-yl)methoxy)-7H-pyrrolo[2,3-h]quinoline-7-carboxylate (51-c, 70 mg, 0.121 mmol), l-iodo-4-(trifluoromethyl)benzene (164 mg, 0.603 mmol), cesium carbonate (78 mg, 0.242 mmol), copper iodide (11.5 mg, 0.06 mmol), metformin (7.8 mg, 0.06 mmol) were dissolved in DMF (7 mL), the reaction system was replaced by nitrogen and heated to 130 °C under nitrogen for 16 hours. The reaction system was cooled to room temperature, quenched with water, extracted with ethyl acetate, the organic phase was collected and backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash column (methanol: dichloromethane = 0% ~ 10%) to obtain the target product tert-butyl (S)-3-methyl-4-(2-((S)-l-methylpyrrolidin-2-yl)methoxy)-7-(4- (trifluoromethyl)phenyl)-7H-pyrrolo[2,3-h]quinoline-4-yl)piperazine-l-carboxylate (50-d, 34.5 mg, yield 40.11%, brown, oily substance). MS (ESI) [M+H] + 625.78.

[0473] Fifth Step: Preparation of 4-((S)-2-methylpiperazin-l-yl)-2-((S)-l- methylpyrrolidin-2-yl)methoxy)-7-(4-(trifluoromethyl)phenyl)-7H-pyrrolo[2,3-h]quinoline trifluoroacetate (50)

[0474] Tert-butyl(S)-3-methyl-4-(2-((S)-1-methylpyrrolidine-2-yl)methoxy)-7-(4-(trifluoromethyl)phenyl)-7H-pyrrolo[2,3-h]quinazoline-4-yl)piperazine-1-carboxylic acid ester (50-d, 34.5 mg, 0.055 mmol) was dissolved in acetonitrile / trifluoroacetic acid (3.5 ml / 0.3 ml), and the reaction solution was reacted at 25 °C for 1 hour. The reaction solution was purified by preparative liquid chromatography to obtain compound 50: 4-((S)-2-methylpiperazine-1-yl)-2-((S)-1-methylpyrrolidine-2-yl)methoxy)-7-(4-(trifluoromethyl)phenyl)-7H-pyrrolo[2,3-h]quinazoline trifluoroacetate salt (19.79 mg, yield 68.35%, white, solid) MS (ESI) [M+H + 525.35. 1 HNMR (400MHz, DMSO-d6) δ10.06 (s, 1H), 9.31 (d, J=10.0Hz, 1H), 9.15 (s, 1H), 7.99 (dd, J=22.4, 8.6 Hz, 1H), 7.70 (d, J=3.1Hz, 1H), 7.57 (t, J=8.9Hz, 1H), 7.49-7.40 (m, 1H), 7.27 (d, J=2.9Hz, 1H), 6.8 8 (d, J=9.1Hz, 1H), 6.37 (s, 1H), 4.86-4.64 (m, 3H), 4.29 (d, J=14.0Hz, 2H), 4.13 (s, 2H), 3.88 (s, 2 H), 3.17 (s, 2H), 2.99 (s, 3H), 2.31 (d, J = 8.0Hz, 3H), 1.96 (d, J = 9.8Hz, 4H), 1.67 (d, J = 57.5Hz, 2H).

[0475] Test Example 1: Phosphorylation-ERK1 / 2 (THR202 / TYR204) HTRF Test

[0476] A427 cells expressing the KRAS G12D mutation were cultured in MEM medium (Gibco) containing 10% fetal bovine serum (FBS). Once the cells reached the logarithmic growth phase, the A427 cells were resuspended in serum-free medium at a density of 3.125 × 10⁶ cells / year. 5Cells were seeded at 25,000 cells / well in 96-well cell culture plates in 80 μl / well of cell culture medium at a density of 25,000 cells / ml and incubated overnight in a cell culture incubator (37°C, 5% C02). The next day, 20 μl of compound diluted in serum-free medium was added to each well. After 4 hours of incubation in a cell culture incubator (37°C, 5% C02), the culture medium was removed from the 96-well plates and 50 μl / well of 1 x cell lysis buffer (Cisbio) was added. The plates were incubated for 30 min at room temperature with shaking. 16 μl of cell lysate was transferred to a 384-well plate (Greiner) and 4 μl / well of pre-mixed antibodies (Cisbio 64AERPEH) was added. The plates were incubated overnight at room temperature and then the HTRF signal was read in a Tecan Spark multimode plate reader. Data were analyzed using a 4-parameter logistic model to calculate IC50values. The results of the phosphorylation-ERK1 / 2 (THR202 / TYR204) HTRF test are shown in the following table:

[0477] For IC 50 values, where “+++” means IC 50 < 10 nM; “++” means IC 50 between 10 nM and 100 nM; “+” means IC 50 between 100 nM and 1 μM.

[0478] Table 1

[0479]

[0480]

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: In the formula, R1 is selected from R2 is selected from hydrogen, halogen, -C 1-3 Alkyl, 5- to 6-membered monocyclic heteroaryl, C 6-10 Aryl, -C 1-3 Alkyl-C 6-10 Aryl, -C 6-10 Aryl-C 1-3 Alkyl, -C 6-10 Aryl-C 1-3 Alkoxy, -C 1-3 Alkyl-C 6-10 Aryl-C 1-3 alkoxy groups; and the -C 1-3 Alkoxy, -C 1-3 Alkyl, 5- to 6-membered monocyclic heteroaryl, C 6-10 The aryl group is optionally substituted by one, two or three substituents independently selected from halogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, cyano, amino, -N(CH3)2, hydroxyl, carboxyl, -C(O)NH2; R2' is selected from hydrogen or methyl; R3 is selected from hydrogen; Alternatively, R2 and R2' are selected from hydrogen or methyl; R3 is selected from C. 6-10 Aryl; and the C 6-10 The aryl group is optionally substituted by one, two or three substituents independently selected from halogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, cyano, amino, -N(CH3)2, hydroxyl, carboxyl, -C(O)NH2; R4 is selected from R5 is selected from hydrogen, -C(O)C 1-3 Alkyl, -C(O)C 1-3 alkenyl, -C(O)C 1-3 alkynyl group; R6 is selected from hydrogen, halogens, and -C. 1-6 Alkyl, -C 1-6 Alkoxy; The monocyclic heteroaryl group has at least one heteroatom selected from N, O and S as a ring atom.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R2 is selected from hydrogen, methyl, or the following structures:

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R1 is selected from 4. The compound according to claim 1, its pharmaceutically acceptable salt, solvate, or prodrug, wherein, R2 and R2' are selected from hydrogen or methyl; R3 is selected from hydrogen or...

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, The compounds are shown as those of formula (Ⅲa), (Ⅲb), or (Ⅲc): In the formula, R1, R2, and R3 are each defined as described in claim 1.

6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein, The compounds are selected from the group consisting of:

7. A pharmaceutical composition, characterized in that, The composition comprises the compound according to any one of claims 1-6 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

8. Use of the compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 7, in the preparation of a medicament for treating cancer or immune diseases.

9. The use according to claim 8, wherein, The intended use is in the preparation of a medicament for treating diseases associated with KRAS mutations.

10. The use according to claim 8, wherein, The cancers mentioned are selected from pancreatic cancer, colorectal cancer, lung cancer, bile duct cancer, endometrial cancer, and ovarian cancer.

11. The use according to claim 8, wherein, The cancers mentioned are selected from pancreatic cancer, colorectal cancer, colon cancer, lung adenocarcinoma, non-small cell lung cancer and small cell lung cancer, biliary tract cancer, small bowel cancer, endometrial cancer and ovarian cancer.

12. Use of the compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 7, in the preparation of a KRAS inhibitor.

13. Use of the compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 7, in the preparation of a KRAS G12D inhibitor.

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