PI3k inhibitors and uses thereof

Abstract

The present disclosure provides a compound represented by Structural Formula (I '): (I'), or a pharmaceutically acceptable salt or stereoisomer thereof; and their use, for example, in the treatment of diseases or conditions associated with PI3K. The disclosure also features compositions containing such compounds or pharmaceutically acceptable salts or stereoisomers thereof, as well as methods of use and preparation thereof.

Description

[0001] Related Applications

[0002] This application claims priority to International Application No. PCT / CN2023 / 101669, filed June 21, 2023. The entire contents of the foregoing application are hereby expressly incorporated herein by reference. TECHNICAL FIELD BACKGROUND

[0004] PI3Ks are members of a unique and conserved family of intracellular lipid kinases that phosphorylate the 3'-OH group on phosphatidylinositol or phosphoinositol. The PI3K family comprises 15 kinases with distinct substrate specificities, expression patterns, and modes of regulation (Katso et al., 2001). Class I PI3Ks (p110a, p110p, p110d, and p110y) are typically activated by tyrosine kinases or G protein-coupled receptors to generate PIP3, which binds downstream effectors such as those in the Akt / PDK1, mTOR, Tec family kinases, and Rho family GTPase pathways. Class II and III PI3-Ks play a key role in intracellular trafficking by synthesizing PI(3)P and PI(3,4)P2.

[0005] PI3K isoforms are implicated in, for example, a variety of human cancers and disorders. Mutations in genes encoding PI3K isoforms or mutations that lead to upregulation of PI3K isoforms are thought to occur in many human cancers. Mutations in genes encoding PI3K isoforms are point mutations, clustered within several hotspots in the helical and kinase domains. Because of the high mutation rate of PI3Ks, targeting this pathway can provide valuable therapeutic opportunities.

[0006] A variety of cancers are thought to involve genetic alterations in genes in the PI3K signaling, for example endometrial cancer, breast cancer, esophageal squamous cell carcinoma, cervical squamous cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, bladder urothelial carcinoma, glioblastoma, ovarian cancer, non-small cell lung cancer, gastroesophageal cancer, schwannoma, head and neck squamous cell carcinoma, melanoma, gastroesophageal adenocarcinoma, soft tissue sarcoma, prostate cancer, fibrolamellar carcinoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, cholangiocarcinoma, B-cell lymphoma, mesothelioma, adrenocortical carcinoma, non-clear cell kidney cancer, clear cell kidney cancer, germ cell cancer, thymoma, pheochromocytoma, mixed neuroepithelial tumor, thyroid cancer, leukemia, and ependymal glioma (Goncalves MD, Hopkins BD, Cantley LC. Phosphatidylinositoi 3-Kinase, Growth Disorders, and Cancer. N Engl J Med. 2018 Nov 22;379(21):2052-2062).

[0007] For example, the alpha (a) isoform of PI3K has been implicated in a variety of human cancers. Angiogenesis has been shown to selectively depend on the alpha isoform of PI3K in the control of endothelial cell migration. (Graupera et al., Nature 2008; 453;662-6). Mutations in the PI3Ka gene or mutations that lead to upregulation of PI3Ka are thought to occur in many human cancers, for example lung cancer, gastric cancer, endometrial cancer, ovarian cancer, bladder cancer, breast cancer, colon cancer, brain cancer, prostate cancer, and skin cancer. Mutations in the PI3Ka gene are point mutations, clustered within several hotspots in the helical domain and kinase domain, for example E542K, E545K, and H1047R. Some of these mutations have been shown to be oncogenic gain-of-function mutations. Because of the high mutation rate in PI3Ka, targeting this pathway can provide a valuable therapeutic opportunity. While other PI3K isoforms, for example PI3Kd or RI3Kg, are primarily expressed in hematopoietic cells, PI3Ka is constitutively expressed along with PI3Kb.

[0008] Due to the important role of PI3Ka in regulating organismal glucose homeostasis, PI3K inhibition in patients often causes hyperglycemia and / or hyperinsulinemia (Busaidy NL et al., Management of metabolic effects associated with anticancer agents targeting the PI3K-Akt-mTOR pathway. J. Clin. Oncol. 2012;30:2919-28). High levels of circulating insulin can have mitogenic and / or anti-apoptotic effects on cancer cells, thus counteracting the anti-proliferative effects of PI3K inhibitors (Blouin M-J et al., Abstract 4615: the hyperinsulinemia caused by PI3K inhibitors attenuates their antineoplastic efficacy, but can be minimized by co administration of metformin. Cancer Res 2013;73:4615).

[0009] In the case of cancers with mutant PI3Ka, one way to overcome the problem of compensatory production of insulin and / or blood glucose after systemic PI3Ka inhibition would be to develop inhibitors with enhanced selectivity for mutant PI3Ka relative to wild-type PI3Ka. This would expand the dosing window to selectively inhibit the pathological signaling of mutant PI3Ka in cancer cells without affecting wild-type PI3Ka controlling systemic metabolism in host tissues (Okkenhaug K, Graupera M, Vanhaesebroeck B. Targeting PI3K in Cancer: Impact on Tumor Cells, Their Protective Stroma, Angiogenesis, and Immunotherapy. Cancer Discov. 2016 Oct;6(10): 1090-1105), thereby limiting toxicity and allowing the use of higher doses and more complete inhibition of the drug target (Ariella B. Hanker et al., Challenges for the clinical development of PI3K inhibitors: Strategies to improve their impact in solid tumors. Cancer Discov. 2019 Apr; 9(4): 482-491).

[0010] Current PI3Ka inhibitors have nearly equal effects on wild-type and mutant PI3Ka. Since the PI3Ka mutation positions are far from the active site, it is difficult to develop mutant-selective inhibitors. As such, inhibitors targeting the second peripheral binding pocket near known mutations (e.g., H1047R) can provide a selective PI3Ka inhibition pathway. Thus, targeting the mutant peripheral binding pocket of PI3Ka can in turn provide a valuable therapeutic target for drug development.

[0011] Accordingly, there remains a need to develop PI3K inhibitors with novel activity profiles, particularly inhibitors that specifically or selectively target mutant PI3Ka. SUMMARY

[0012] Described herein are compounds of Formula (I’), pharmaceutically acceptable salts, or stereoisomers thereof, that inhibit PI3Ka, particularly selectively inhibit PI3Ka mutations (e.g., H1047R and H1047L).

[0013] In one aspect, the present disclosure provides a compound of Formula (I’), a pharmaceutically acceptable salt, or a stereoisomer thereof:

[0014] (I’),

[0015] wherein rings A and B and variables W, X, Y, Z, G 1 , G 2 , G 3 , R 1 , R 2 , R 4 , R 5 , R E , R Na , n, m, and o are as defined herein.

[0016] Also provided are pharmaceutical compositions comprising a compound of Formula (I) or (I’), a pharmaceutically acceptable salt, or a stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.

[0017] The present disclosure also provides a method of inhibiting PI3Kα in a patient comprising administering to the patient a compound of Formula (I’), or a pharmaceutically acceptable salt or stereoisomer thereof.

[0018] The present disclosure also provides a method of treating a disease or condition in an individual that is at least partially mediated by PI3Kα comprising administering to the individual a therapeutically effective amount of a compound of Formula (I’), a pharmaceutically acceptable salt, or a stereoisomer thereof.

[0019] The present disclosure also provides a method of treating a cancer or disorder in a patient in need thereof comprising administering to the patient an effective amount of: (1) a compound of Formula (I’), a pharmaceutically acceptable salt, or a stereoisomer thereof; or (2) a pharmaceutically acceptable composition comprising a compound of Formula (I’), a pharmaceutically acceptable salt, or a stereoisomer thereof, and a pharmaceutically acceptable carrier.

[0020] In certain embodiments, the cancer is treatable by inhibition of PI3Kα (e.g., PI3Kα mutations), for example, a cancer selected from the group consisting of breast cancer (e.g., hormone receptor positive breast cancer, HER2 negative breast cancer, HER2 positive breast cancer, and triple negative breast cancer), endometrial cancer, uterine cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, brain cancer, or prostate cancer.

[0021] In certain embodiments, the disorder is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis / osteofascial dysplasia syndrome) or PIK3CA-related overgrowth syndrome (PROS).

[0022] In certain embodiments of the methods of the disclosure, the cancer can be treated by inhibiting the activity of PI3Ka (e.g., PI3Ka mutations).

[0023] In certain embodiments of the methods of the disclosure, the compound of the disclosure is administered with a second therapeutic agent that also treats the same cancer described herein.

[0024] The disclosure also provides the use of a compound of Formula (I’), a pharmaceutically acceptable salt, or a stereoisomer thereof, or a pharmaceutical composition comprising the same, in any of the methods described herein. In one embodiment, there is provided a compound of Formula (I’), or a pharmaceutically acceptable salt, or a stereoisomer thereof, or a pharmaceutical composition comprising the same, for use in any of the methods described herein. In another embodiment, there is provided the use of a compound of Formula (I’), or a pharmaceutically acceptable salt, or a stereoisomer thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for use in any of the methods described herein. DETAILED DESCRIPTION

[0025] 1. A compound

[0026] In a first aspect, the disclosure provides a compound represented by Formula (I’):

[0027] (I’),

[0028] or a pharmaceutically acceptable salt thereof, wherein:

[0029] is a single or double bond as permitted by valence;

[0030] Ring A is or wherein ** is the point of attachment to Y;

[0031] (i) when W is C and Y is N or CR Z1 , then X is C and Z is N or CR Z1 ;

[0032] (ii) when W is C and Y is C(O), then X is C or N and Z is CR Z1 , N, NR N1 , or O;

[0033] (iii) when W is N, then Y is C(O), X is C, and Z is N or CR Z1 ;

[0034] G 1 , G 2 , and G 3 are each independently C(R G2 )2, NR N2 , or O;

[0035] n is 0, 1, 2, or 3;

[0036] m is 0, 1, 2, 3, or 4;

[0037] o is 0, 1, 2, 3, or 4;

[0038] R Na is H;

[0039] R N1 is H, C 1-6 alkyl, C 1-6 haloalkyl, -C(O)R 1a , C 3-6 cycloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein said phenyl and 5- to 6-membered heteroaryl each represented by R N1 is optionally substituted by one to three substituents selected from the group consisting of halogen, C 1-3 alkyl, and C 1-3 haloalkyl;

[0040] R Z1 is H, halogen, cyano, NO2, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, C 1-6 hydroxyalkoxy, NR N1a R N1b , -C(O)R 1a , -C(O)OR O1a , -C(O)NR N1a R N1b , -OR O1a , 3- to 12-membered carbocyclyl, phenyl, 5- or 6-membered heteroaryl, or 4- to 12-membered heterocyclyl, wherein said carbocyclyl, phenyl, 5- or 6-membered heteroaryl, or 4- to 12-membered heterocyclyl represented by R Z1 is optionally substituted by one to four R 1b ;

[0041] each R 1 is independently halogen, cyano, NO2, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, C 1-6 hydroxyalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, NR N1a R N1b , -C(O)R 1a , -C(O)OR O1a , -C(O)NRN1a R N1b -OR O1a -(CH2) 0或1 -3 to 12-membered carbon cyclogroups, -(CH2) 0或1 -4 to 12-membered heterocyclic groups, -(CH2) 0或1 -6 to 10 aryl groups or -(CH2) 0或1 -5 to 10 aryl compounds, of which R 1 The C mentioned 2-6 alkenyl, C 2-6 Alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl are each optionally surrounded by one to four R groups. 1b replace;

[0042] R 1a R O1a R N1a and R N1b Each independently represents H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4- to 6-membered heterocyclic groups;

[0043] Each R 1b Independently halogenated, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkoxy, -C(O)R 1a -C(O)OR O1a -C(O)NR N1a R N1b -SO2R 1a -NR N1a R N1b -NR N1a C(O)R 1a -NR N1a C(O)OR 1a -NR N1a SO2R 1a -NR N1a SO2NR N1a R N1b , cyano, NO2 or OR O1a ;

[0044] R N2 For H, C 1-6 Alkyl, C 1-6 Haloalkyl, -C(O)R 2a C3-6 cycloalkyl, phenyl or 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl each are optionally substituted with one to three substituents selected from halo, C N2 alkyl and C 1-3 haloalkyl; 1-3 haloalkyl;

[0045] each R G2 independently H, halo, cyano, oxo (as needed), NO2, C 1-6 alkyl, C 1-6 haloalkyl, *=CH-R 7 (as needed), C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, C 1-6 hydroxyalkoxy, -C(O)R 2a , -C(O)OR O2a , -C(O)NR N2a R N2b , OR O2a , NR N2a R N2b , SO2R 2a , -NR N2a C(O)R 2a , -NR N2a C(O)OR 2a , -NR N2a SO3R 2a , -NR N2a SO3NR N2a R N2a , -(CH2) 0或1 -3- to 12-membered carbocyclyl, -(CH2) 0或1 -4- to 12-membered heterocyclyl, -(CH2) 0或1 -6- to 10-membered aryl or -(CH2) 0或1 -5- to 10-membered heteroaryl, wherein the carbocyclyl, heterocyclyl, aryl or heteroaryl represented by R G2 each are optionally substituted with one to four halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkoxy, -C(O)R 2a , -C(O)OR O2a , -C(O)NR N2a R N2b, cyano, NO2, OR O2a , NR N2a R N2b , SO3R 2a , -NR N2a C(O)R 2a , -NR N2a C(O)OR 2a , -NR N2a SO3R 2a or -NR N2a SO3NR N2a R N2a substituted, and wherein said C2alkenyl is optionally substituted with phenyl or 5- to 6-membered heteroaryl;

[0046] each R 2 is independently halo, cyano, oxo (as needed), NO2, C 1-6 alkyl, C 1-6 haloalkyl, *=CH-R 7 (as needed), C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, C 1-6 hydroxyalkoxy, -C(O)R 2a , -C(O)OR O2a , -C(O)NR N2a R N2b , OR O2a , NR N2a R N2b , SO2R 2a , -NR N2a C(O)R 2a , -NR N2a C(O)OR 2a , -NR N2a SO3R 2a , -NR N2a SO3NR N2a R N2a , -(CH2) 0或1 -3- to 12-membered carbocyclyl, -(CH2) 0或1 -4- to 12-membered heterocyclyl, -(CH2) 0或1 -6- to 10-membered aryl, or -(CH2) 0或1 -5- to 10-membered heteroaryl, wherein said carbocyclyl, heterocyclyl, aryl, or heteroaryl represented by R 2 is each optionally substituted with one to four halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6alkoxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkoxy, -C(O)R 2a , -C(O)OR O2a , -C(O)NR N2a R N2b , cyano, NO2, OR O2a , NR N2a R N2b , SO3R 2a , -NR N2a C(O)R 2a , -NR N2a C(O)OR 2a , -NR N2a SO3R 2a or -NR N2a SO3NR N2a R N2a substituted, and wherein said C2alkenyl is optionally substituted with phenyl or 5- to 6-membered heteroaryl; or

[0047] two R 2 , two R G2 , one R 2 and one R N2 , one R 2 and one R G2 , or one R G2 and one R N2 together with the atom to which they are attached form a 3- to 12-membered carbocyclyl, 4- to 12-membered heterocyclyl, phenyl, naphthyl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one to four R 6 ;

[0048] R 2a and R O2a are each independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, or 4- to 6-membered heterocyclyl;

[0049] R N2a and R N2b are each independently H, C 1-6 alkyl, C 1-6 haloalkyl, OR O2a , or C 3-6 cycloalkyl;

[0050] * is a point of attachment to the tricyclic core ring;

[0051] R 7 is C 1-4alkyl, 3- to 12-membered carbocyclyl, 4- to 12-membered heterocyclyl, phenyl, naphthyl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one to four halo, -OH, -NH2, cyano, NO2, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, or heteroaryl;

[0052] each R 6 is independently halo, cyano, oxo (as needed), NO2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, C 1-6 hydroxyalkoxy, -C(O)R 6a , -C(O)OR O6a , -C(O)NR N6a R N6b , OR O6a , NR N6a R N6b , SO2R 6a , -NR N6a C(O)R 6a , -NR N6a C(O)OR 6a , -NR N6a SO3R 6a , -NR N6a SO3NR N6a R N6a , -(CH2) 0或1 -3- to 12-membered carbocyclyl, -(CH2) 0或1 -4- to 12-membered heterocyclyl, -(CH2) 0或1 -6- to 10-membered aryl, or -(CH2) 0或1 -5- to 10-membered heteroaryl, wherein said carbocyclyl, heterocyclyl, aryl, or heteroaryl represented by R 6 is each optionally substituted with one to four halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkoxy, -C(O)R 6a , -C(O)OR O6a , -C(O)NR N6a R N6b, cyano, NO2, OR O6a , NR N6a R N6b , SO3R 6a , -NR N6a C(O)R 6a , -NR N6a C(O)OR 6a , -NR N6a SO3R 6a or -NR N6a SO3NR N6a R N6a substituted;

[0053] or two R 6 together with the atom to which they are attached form a C 3-6 cycloalkyl ring;

[0054] R 6a and R O6a are each independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, or 4- to 6-membered heterocyclyl;

[0055] R N6a and R N6b are each independently H, cyano, C 1-6 alkyl, C 1-6 haloalkyl, OR O6a , or C 3-6 cycloalkyl;

[0056] Ring B is phenyl or 5- to 10-membered monocyclic or bicyclic heteroaryl, each of which is substituted at the ortho position to the N(R Na ) substituent with R E and is optionally substituted with one to four R 3 ;

[0057] each R 3 is independently halo, cyano, NO2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, C 1-6 hydroxyalkoxy, -C(O)R 3a , -C(O)OR O3a , -C(O)NR N3a R N3b , OR O3a , NR N3a R N3b , SO2R 3a-NR N3a C(O)R 3a -NR N3a C(O)OR 3a -NR N3a SO3R 3a -NR N3a SO3NR N3a R N3a -(CH2) 0或1 -3 to 12 membered carbocyclyl, -(CH2) 0或1 -4 to 12 membered heterocyclyl, -(CH2) 0或1 -6 to 10 membered aryl or -(CH2) 0或1 -5 to 10 membered heteroaryl, wherein said carbocyclyl, heterocyclyl, aryl or heteroaryl group represented by R 3 is each optionally substituted by one to four halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, C 1-6 hydroxyalkoxy, -C(O)R 3a -C(O)OR O3a -C(O)NR N3a R N3b -cyano, NO2, OR O3a NR N3a R N3b -SO3R 3a -NR N3a C(O)R 3a -NR N3a C(O)OR 3a -NR N3a SO3R 3a or -NR N3a SO3NR N3a R N3a ;

[0058] R E is H, cyano, C 1-4 alkyl, -C(O)R 8 -C(NH)NR N3E R N3E -S(O2)NR N3E R N3E -C(O)OR O3a -C(O)NR N3a R N3b phenyl, 5 to 10 membered heteroaryl or 4 to 12 membered heterocyclyl, wherein said C 1-4 alkyl is optionally substituted by one to four R EaThe phenyl group, the 5- to 10-membered heteroaryl group, and the 4- to 12-membered heterocyclic group are each optionally replaced by one or two R groups. Eb replace;

[0059] or R E and R 3 Together with the atoms they are attached to, they form 5- to 6-membered monocyclic heterocyclic groups;

[0060] R 8 For H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-4 Thioalkyl, C 1-4 Thiohaloalkyl or SH;

[0061] Each R Ea Independently a halogen group, cyano group, OH group, or NR group N3E R N3E ;

[0062] Each R Eb Independently oxo, =S, halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, cyano, C 1-3 Alkyl group, -OH or -C(O)NR N3E R N3E , of which R Eb The C mentioned 1-3 The alkyl group is optionally substituted with a 4- to 6-membered heterocyclic group, which is optionally C-shaped. 1-3 Alkyl substitution;

[0063] Each R N3E Independently H, OH or C 1-3 alkyl;

[0064] R 3a and R O3a Each independently represents H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4- to 6-membered heterocyclic groups, wherein R 3a or R O3a The C mentioned 1-6 Alkyl groups are optionally substituted with 4- to 6-membered heterocyclic groups;

[0065] R N3a and R N3b Each is independently H, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OR O3a -SO2C 1-4 Alkyl or C 3-6 cycloalkyl, wherein RN3a or R N3b represents the C 1-6 alkyl group is optionally substituted with C 1-3 alkoxy or 5- to 6-membered heteroaryl;

[0066] R 4 is C 1-3 alkyl; and

[0067] R 5 is H.

[0068] In a second aspect, the present disclosure provides a compound according to the first aspect, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (I):

[0069] (I),

[0070] wherein:

[0071] each R 6 is independently halo, cyano, oxo (as needed), NO2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, C 1-6 hydroxyalkoxy, -C(O)R 6a , -C(O)OR O6a , -C(O)NR N6a R N6b , OR O6a , NR N6a R N6b , SO2R 6a , -NR N6a C(O)R 6a , -NR N6a C(O)OR 6a , -NR N6a SO3R 6a , -NR N6a SO3NR N6a R N6a , -(CH2) 0或1 -3- to 12-membered carbocyclyl, -(CH2) 0或1 -4- to 12-membered heterocyclyl, -(CH2) 0或1 -6- to 10-membered aryl, or -(CH2) 0或1 -5- to 10-membered heteroaryl, wherein the carbocyclyl, heterocyclyl, aryl, or heteroaryl groups represented by R 6 are each optionally substituted with one to four halo, C 1-6 alkyl, C1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkoxy, -C(O)R 6a , -C(O)OR O6a , -C(O)NR N6a R N6b , cyano, NO2, OR O6a , NR N6a R N6b , SO3R 6a , -NR N6a C(O)R 6a , -NR N6a C(O)OR 6a , -NR N6a SO3R 6a or -NR N6a SO3NR N6a R N6a substituted;

[0072] R 7 is 3- to 12-membered carbocyclyl, 4- to 12-membered heterocyclyl, phenyl, naphthyl, or 5- to 10-membered heteroaryl, each optionally substituted with one to four halo, -OH, -NH2, cyano, NO2, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, or heteroaryl;

[0073] R E is -C(O)OR O3a or -C(O)NR N3a R N3b ;

[0074] R 3a and R O3a are each independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, or 4- to 6-membered heterocyclyl; and

[0075] R N3a and R N3b are each independently H, cyano, C 1-6 alkyl, C 1-6 haloalkyl, OR O3a , or C 3-6 cycloalkyl. The definitions of the remaining variables are provided in the first aspect.

[0076] In one aspect, R 4 is -CH3or -CH2CH3. In another aspect, R 4 is -CH3.

[0077] In a third aspect, the present disclosure provides a compound according to the first or second aspect, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (VI), (VII), or (VII’):

[0078] (VI), (VII), or

[0079] (VII’),

[0080] wherein m and n are each independently 0, 1, or 2; and o is 0 or 1. The definitions of the remaining variables are provided in the first or second aspect.

[0081] In an alternative form of the third aspect, the compound is represented by formula (VI). In another alternative form of the third aspect, the compound is represented by formula (VII). In another alternative form of the third aspect, the compound is represented by formula (VII’).

[0082] In a fourth aspect, the present disclosure provides a compound according to the third aspect, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (VIa), (VIb), (VIc), (VId), (VIe), (VIIa), (VIIb), (VIIc), or (VIIa’):

[0083] (VIa), (VIb),

[0084] (VIc), (VId),

[0085] (VIe), (VIIa), (VIIb), (VIIc), or (VIIa’),

[0086] wherein:

[0087] n and o are each independently 0 or 1;

[0088] q is 0, 1, or 2;

[0089] J 1 , J2 , J 3 and J 4 each independently N, CH or CR 6 ;

[0090] T 1 and T 5 each independently N or C;

[0091] T 2 , T 3 and T 4 each independently N, NR N6 , O, S, CH or CR 6 ;

[0092] R N6 is H, C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, phenyl or 5- to 6-membered heteroaryl, wherein said phenyl and 5- to 6-membered heteroaryl represented by R N6 each are optionally substituted with one to three halo, C 1-3 alkyl, C 1-3 haloalkyl, cyano, OH, C 1-3 alkoxy or C 1-3 haloalkoxy;

[0093] U 1 is NR N2 , CH2or O;

[0094] U 2 is absent, NR N6 , CH2or O. The definition of the remaining variables is provided in the third aspect.

[0095] In an alternative form of the fourth aspect, the compound is represented by formula (VIa). In another alternative form of the fourth aspect, the compound is represented by formula (VIb). In another alternative form of the fourth aspect, the compound is represented by formula (VIc). In another alternative form of the fourth aspect, the compound is represented by formula (VId). In another alternative form of the fourth aspect, the compound is represented by formula (VIe). In another alternative form of the fourth aspect, the compound is represented by formula (VIIa). In another alternative form of the fourth aspect, the compound is represented by formula (VIIb). In another alternative form of the fourth aspect, the compound is represented by formula (VIIc). In another alternative form of the fourth aspect, the compound is represented by formula (VIIa’).

[0096] In a fifth aspect, the present disclosure provides a compound according to the fourth aspect, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (VIa-1), (VIa-2), (VIb-1), (VIc-1), (VIc-2), (VIc-3), (VIc-4), (VId-1), (VId-2), (VIe-1), or (VIIc-1):

[0097] (VIa-1), (VIa-2), (VIb-1), (VIa-3), (VIc-1), (VIc-2), (VIc-3), (VIc-4),

[0098] (VId-1), (VId-2),

[0099] (VIe-1), (VIIc-1), or

[0100] (VIIa'-1);

[0101] wherein n is 0 or 1, and q is 0, 1, or 2. The definitions of the remaining variables are provided in the fourth aspect.

[0102] In an alternative form of the fifth aspect, the compound is represented by formula (VIa-1). In another alternative form of the fifth aspect, the compound is represented by formula (VIa-2). In another alternative form of the fifth aspect, the compound is represented by formula (VIb-1). In another alternative form of the fifth aspect, the compound is represented by formula (VIc-1). In another alternative form of the fifth aspect, the compound is represented by formula (VIc-2). In another alternative form of the fifth aspect, the compound is represented by formula (VIc-3). In another alternative form of the fifth aspect, the compound is represented by formula (VIc-4). In another alternative form of the fifth aspect, the compound is represented by formula (VId-1). In another alternative form of the fifth aspect, the compound is represented by formula (VId-2). In another alternative form of the fifth aspect, the compound is represented by formula (VIe-1).

[0103] In a sixth aspect, the present disclosure provides a compound according to the first or second aspect, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (II), (III), (IV), or (V):

[0104] (II), (III),

[0105] (IV), or (V);

[0106] wherein m and n are each independently 0, 1, or 2; o is 0 or 1. The definitions of the remaining variables are provided in the first or second aspect.

[0107] In an alternative form of the sixth aspect, the compound is represented by formula (II). In another alternative form of the sixth aspect, the compound is represented by formula (III). In another alternative form of the sixth aspect, the compound is represented by formula (IV). In another alternative form of the sixth aspect, the compound is represented by formula (V).

[0108] In a seventh aspect, the present disclosure provides a compound according to the sixth aspect, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (IIa), (IIb), (IIc), (IId), (IIIa), (IIIb), (IIIc), (IVa), (IVb), (IVc), (Va), (Vb), (Vc), or (Vd):

[0109] (IIa), (IIb),

[0110] (IIc), (IId),

[0111] (IIIa), (IIIb), (IIIc), (IVa), (IVb), (IVc), (Va), (Vb), (Vc), or (Vd);

[0112] wherein:

[0113] n and o are each independently 0 or 1 ;

[0114] q is 0, 1 or 2;

[0115] J 1 , J 2 , J 3 and J 4 are each independently N, CH or CR 6 ;

[0116] T 1 and T 5 are each independently N or C;

[0117] T 2 , T 3 and T 4 are each independently N, NR N6 , O, S, CH or CR 6 ;

[0118] R N6 is H, C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, phenyl, naphthyl or 5- to 6-membered heteroaryl, wherein said phenyl, naphthyl and 5- to 6-membered heteroaryl represented by R N6 are each optionally substituted with one to three halo, C 1-3 alkyl, C 1-3 haloalkyl, cyano, OH, C 1-3 alkoxy or C 1-3 haloalkoxy;

[0119] U 1 is NR N2 , CH2or O;

[0120] U 2 is NR N6 , CH2or O. The definition of the remaining variables is provided in the sixth aspect.

[0121] In an alternative form of the seventh aspect, the compound is represented by Formula (IIa). In another alternative form of the seventh aspect, the compound is represented by Formula (IIb). In another alternative form of the seventh aspect, the compound is represented by Formula (IIc). In another alternative form of the seventh aspect, the compound is represented by Formula (IId). In another alternative form of the seventh aspect, the compound is represented by Formula (IIIa). In another alternative form of the seventh aspect, the compound is represented by Formula (IIIb). In another alternative form of the seventh aspect, the compound is represented by Formula (IIIc). In another alternative form of the seventh aspect, the compound is represented by Formula (IVa). In another alternative form of the seventh aspect, the compound is represented by Formula (IVb). In another alternative form of the seventh aspect, the compound is represented by Formula (IVc). In another alternative form of the seventh aspect, the compound is represented by Formula (Va). In another alternative form of the seventh aspect, the compound is represented by Formula (Vb). In another alternative form of the seventh aspect, the compound is represented by Formula (Vc).

[0122] In an eighth aspect, the present disclosure provides a compound according to the seventh aspect, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (IIa-1), (IIa-2), (IIa-3), (IIa-4), (IIa-5), (IIa-6), (IIa-7), (IIb-1), (IIb-2), (IIb-3), (IIb-4), (IIb-5), (IIb-6), (IIb-7), (IIb-8), (IIb-9), (IIb-10), (IIb-11), (IIc-1), (IIIa-1), (IIIb-1), (IIIc-1), (IVc-1), (Va-1), (Va-2), (Va-3), or (Vc-1):

[0123] (IIa-1), (IIa-2), (IIa-3), (IIa-4),

[0124] (IIa-5), (IIa-6),

[0125] (IIa-7), (IIb-1),

[0126] (IIb-2), (IIb-3),

[0127] (IIb-4), (IIb-5),

[0128] (IIb-6), (IIb-7), (IIb-8), (IIb-9), (IIb-10), (IIb-11),

[0129] (IIc-1), (IIIa-1), (IIIb-1),

[0130] (IIIc-1), (IVc-1),

[0131] (Va-1), (Va-2),

[0132] (Va-3) or (Vc-1).

[0133] The definitions of the remaining variables are provided in the seventh aspect.

[0134] In an alternative form of the eighth aspect, the compound is represented by formula (IIa-1). In another alternative form of the eighth aspect, the compound is represented by formula (IIa-2). In another alternative form of the eighth aspect, the compound is represented by formula (IIa-3). In another alternative form of the eighth aspect, the compound is represented by formula (IIa-4). In another alternative form of the eighth aspect, the compound is represented by formula (IIa-5). In another alternative form of the eighth aspect, the compound is represented by formula (IIa-6). In another alternative form of the eighth aspect, the compound is represented by formula (IIa-7). In another alternative form of the eighth aspect, the compound is represented by formula (IIb-1). In another alternative form of the eighth aspect, the compound is represented by formula (IIb-2). In another alternative form of the eighth aspect, the compound is represented by formula (IIb-3). In another alternative form of the eighth aspect, the compound is represented by formula (IIb-4). In another alternative form of the eighth aspect, the compound is represented by formula (IIb-5). In another alternative form of the eighth aspect, the compound is represented by formula (IIb-6). In another alternative form of the eighth aspect, the compound is represented by formula (IIb-7). In another alternative form of the eighth aspect, the compound is represented by formula (IIb-8). In another alternative form of the eighth aspect, the compound is represented by formula (IIb-9). In another alternative form of the eighth aspect, the compound is represented by formula (IIb-10). In another alternative form of the eighth aspect, the compound is represented by formula (IIb-11). In another alternative form of the eighth aspect, the compound is represented by formula (IIc-1). In another alternative form of the eighth aspect, the compound is represented by formula (IIIa-1). In another alternative form of the eighth aspect, the compound is represented by formula (IIIb-1). In another alternative form of the eighth aspect, the compound is represented by formula (IIIc-1). In another alternative form of the eighth aspect, the compound is represented by formula (IVc-1). In another alternative form of the eighth aspect, the compound is represented by formula (Va-1). In another alternative form of the eighth aspect, the compound is represented by formula (Va-2). In another alternative form of the eighth aspect, the compound is represented by formula (Va-3). In another alternative form of the eighth aspect, the compound is represented by formula (Vc-1).

[0135] In a ninth aspect, the present disclosure provides a compound according to the first or second aspect, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (VIII):

[0136] (VIII);

[0137] wherein:

[0138] n is 0, 1, or 2;

[0139] m is 0, 1, or 2;

[0140] o is 0 or 1;

[0141] each R 1 is independently halo, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -NR N1a R N1b , -C(O)R 1a , -C(O)OR O1a , -C(O)NR N1a R N1b , OR O1a , C 3-6 cycloalkyl, phenyl, or 5- to 6-membered monocyclic heteroaryl, wherein the C 1 alkyl, cycloalkyl, phenyl, and 5- to 6-membered monocyclic heteroaryl groups represented by R 3-6 are each optionally substituted with one to three halo, C 1-3 alkyl, C 1-3 haloalkyl, OH, C 1-3 alkoxy, C 1-3 haloalkoxy, -C(O)R 1a , -C(O)OR O1a , or -C(O)NR N1a R N1b ;

[0142] each R 2 is independently halo, oxo, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -NR N2a R N2b , -C(O)R 2a , -C(O)OR O2a , -C(O)NR N2a R N2b , OR O2a , C 3-6 cycloalkyl, phenyl, or 5- to 6-membered monocyclic heteroaryl, wherein the C 2 alkyl, cycloalkyl, phenyl, and 5- to 6-membered monocyclic heteroaryl groups represented by R 3-6 are each optionally substituted with one to three halo, C 1-3 alkyl, C 1-3 haloalkyl, OH, C 1-3 alkoxy, C 1-3 haloalkoxy, -C(O)R 2a ;, -C(O)OR O2a , -C(O)NR N2a R N2b substituted;

[0143] R 2a , R O2a , R N2a and R N2b are each independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, or 4- to 6-membered heterocyclyl;

[0144] Ring B is phenyl or 5- to 6-membered monocyclic heteroaryl, each of which is substituted at the ortho position to the NH substituent with R E , and is substituted with one to three R 3 ;

[0145] each R 3 is independently halo, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -NR N3a R N3b , -C(O)R 3a , -C(O)OR O3a , -C(O)NR N3a R N3b , OR O3a , C 3-6 cycloalkyl, phenyl, or 5- to 6-membered monocyclic heteroaryl, wherein said C 3 cycloalkyl, phenyl, and 5- to 6-membered monocyclic heteroaryl represented by R 3-6 is each optionally substituted with one to three halo, C 3-3 alkyl, C 3-3 haloalkyl, OH, C 1-3 alkoxy, C 1-3 haloalkoxy, -C(O)R 3a , -C(O)OR O3a , or -C(O)NR N3a R N3b ;

[0146] R 3a , R O3a , R N3a and R N3b are each independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, or 4- to 6-membered heterocyclyl;

[0147] Ring C is 6-membered monocyclic heterocyclyl, phenyl, or 5- to 6-membered monocyclic heteroaryl, each of which is optionally substituted with one to three R 6substituted;

[0148] Q 1 and Q 2 are each independently C, CH, or N, provided that at least one of Q 1 or Q 2 is C or CH;

[0149] each R 6 is independently halo, oxo, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -NR N6a R N6b , -C(O)R 6a , -C(O)OR O6a , -C(O)NR N6a R N6b , OR O6a , C 1-6 cycloalkyl, phenyl, or 5- to 6-membered monocyclic heteroaryl, wherein said C 6 cycloalkyl, phenyl, and 5- to 6-membered monocyclic heteroaryl represented by R 1-6 are each independently substituted with one to three halo, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -C(O)R 6a , -C(O)OR O6a , or -C(O)NR N6a R N6b ;

[0150] R 6a , R O6a , R N6a , and R N6b are each independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cycloalkyl, or 4- to 6-membered heterocyclyl. The definitions of the remaining variables are provided in the first or second aspect.

[0151] In a tenth aspect, the present disclosure provides a compound according to the ninth aspect, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (VIIIa), (VIIIb), or (VIIIc):

[0152] (VIIIa), (VIIIb)

[0153] or (VIIIc);

[0154] wherein:

[0155] n is 0 or 1 ;

[0156] q is 0, 1, or 2;

[0157] U 2 is NR N6 , CH2, or O;

[0158] J 1 , J 2 , J 3 , and J 4 are each independently N or CH, wherein at least one of J 1 , J 2 , J 3 , and J 4 is CH;

[0159] T 1 and T 5 are each independently N or C;

[0160] T 2 , T 3 , and T 4 are each independently N, NR N6 , O, S, or CH;

[0161] R N6 is H, C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein said phenyl and 5- to 6-membered heteroaryl represented by R N6 are each optionally substituted with one to three halo, C 1-3 alkyl, C 1-3 haloalkyl, cyano, OH, C 1-3 alkoxy, or C 1-3 haloalkoxy. The definition of the remaining variables is provided in the ninth aspect.

[0162] In an alternative tenth aspect, the compound has formula (VIIIa). In another alternative of the tenth aspect, the compound has formula (VIIIb). In another alternative of the tenth aspect, the compound has formula (VIIIc).

[0163] In an eleventh aspect, the present disclosure provides a compound according to the first aspect, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (II-1), (III-1), (IV-1), (V-1), (VI-1), (VI-2), or (VII-1):

[0164] (II-1), (III-1),

[0165] (IV-1), (V-1),

[0166] (VI-1), (VI-2) or

[0167] (VII-1),

[0168] wherein

[0169] m, n and o are each independently 0 or 1;

[0170] U 1 is NR N2 , CH2or O;

[0171] R 7 is C 1-4 alkyl, 5- or 6-membered heterocyclyl, phenyl or 5- or 6-membered heteroaryl, wherein each of said 5- or 6-membered heterocyclyl, phenyl or 5- or 6-membered heteroaryl is optionally substituted with one to two halo, -OH, -NH2, cyano, C 1-3 alkyl, C 1-3 alkyl-OR O7a , C 3-6 cycloalkyl, C 1-3 haloalkyl or 4- to 6-membered heterocyclyl;

[0172] R O7a is H or C 1-3 alkyl. The definitions of the remaining variables are provided in the first aspect.

[0173] In alternative forms of the eleventh aspect, the compound is of Formula (II-1). In another alternative form of the eleventh aspect, the compound is of Formula (III-1). In another alternative form of the eleventh aspect, the compound is of Formula (IV-1). In another alternative form of the eleventh aspect, the compound is of Formula (V-1). In another alternative form of the eleventh aspect, the compound is of Formula (VI-1). In another alternative form of the eleventh aspect, the compound is of Formula (VI-2). In another alternative form of the eleventh aspect, the compound is of Formula (VII-1).

[0174] In a twelfth aspect, the present disclosure provides a compound according to the eleventh aspect, or a pharmaceutically acceptable salt thereof, wherein R 7 is C 1-3alkyl, phenyl, pyridinyl, isoxazolyl, pyrazolyl, imidazolyl, tetrahydrofuranyl, or tetrahydro-2H-pyranyl, wherein the phenyl, pyridinyl, isoxazolyl, pyrazolyl, imidazolyl, tetrahydrofuranyl, and tetrahydro-2H-pyranyl are each optionally substituted with one to two halo, -OH, C 1-3 alkoxy, -NH2, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkyl-OR O7a or cyclopropyl, or R 7 is morpholinyl; R O7a is H or C 1-3 alkyl. The definitions of the remaining variables are provided in the eleventh aspect.

[0175] In a thirteenth aspect, the disclosure provides a compound according to the first aspect, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (IX):

[0176] (IX).

[0177] The definitions of the remaining variables are provided in the first aspect.

[0178] In a fourteenth aspect, the disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth aspect, or a pharmaceutically acceptable salt thereof, wherein ring B is phenyl or 6-membered monocyclic heteroaryl, each of which is substituted at the NR Na substituted with R E at the ortho position of the substituent, and is further optionally substituted with one or two R 3 . The definitions of the remaining variables are provided in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth aspect.

[0179] In a fifteenth aspect, the disclosure provides a compound according to the fourteenth aspect, or a pharmaceutically acceptable salt thereof, wherein ring B is phenyl, pyrimidinyl, or pyridinyl, each of which is substituted at the NR Na substituent ortho position with R E , and is further optionally substituted with one or two R 3 . The definitions of the remaining variables are provided in the fourteenth aspect.

[0180] In a sixteenth aspect, the disclosure provides a compound according to the fifteenth aspect, or a pharmaceutically acceptable salt thereof, wherein ring B and R E together with the optionally substituted R 3 are represented by:

[0181] , 、 、 、 、 、 or . The definition of the remaining variables is provided in the fifteenth aspect.

[0182] In a seventeenth aspect, the disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth aspect, or a pharmaceutically acceptable salt thereof, wherein ring B and R E together with optionally substituted R 3 is represented by: or . The definition of the remaining variables is provided in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth aspect.

[0183] In an eighteenth aspect, the disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenth aspect, or a pharmaceutically acceptable salt thereof, wherein:

[0184] R E is cyano, C 1-4 alkyl, -C(O)R 8 , -C(NH)NR N3E R N3E , -S(O2)NR N3E R N3E , -C(O)OR O3a , -C(O)NR N3a R N3b , phenyl, 5- to 6-membered heteroaryl, or 4- to 10-membered heterocyclyl, wherein the C 1-4 alkyl is optionally substituted with one to four R Ea , and the phenyl, 5- to 6-membered heteroaryl, and 4- to 10-membered heterocyclyl are each optionally substituted with one or two R Eb ;

[0185] R 8 is H, C 1-3 alkyl, C 1-3 haloalkyl, or SH;

[0186] each R Ea is independently halo, cyano, OH, or NR N3E R N3E ;

[0187] each R Ebindependently oxo, =S, halo, C 1-3 alkyl, C 1-3 haloalkyl, cyano, C 1-3 alkoxy, -OH, or -C(O)N R N3E R N3E wherein the C 1-3 alkyl is optionally substituted with 4- to 6-membered heterocyclyl optionally substituted with C 1-3 alkyl;

[0188] each R N3E is independently H, OH, or C 1-3 alkyl; R O3a is H, C 1-3 alkyl, or 4- to 6-membered monocyclic heterocyclyl, wherein the C 1-3 alkyl is optionally substituted with 4- to 6-membered monocyclic heterocyclyl;

[0189] R N3a and R N3b are each independently H, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, -OH, -S(O)2C 1-3 alkyl, or cyclopropyl, wherein the C 1-3 alkyl is optionally substituted with C 1-3 alkoxy, or 6-membered heteroaryl. The definitions of the remaining variables are provided in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenth aspects.

[0190] In a nineteenth aspect, the present disclosure provides a compound according to the eighteenth aspect, or a pharmaceutically acceptable salt thereof, wherein

[0191] R E is cyano, C 1-4 alkyl, -C(O)R 8 , -C(NH)NR N3E R N3E , -S(O2)NR N3E R N3E , -C(O)OR O3a -C(O)NR N3a R N3b , phenyl, pyridyl, pyrazolyl, oxadiazolyl, imidazolyl, thiazolyl, isothiazolyl, triazolyl, oxazolyl, thienyl, morpholinyl, piperidinyl, piperazinyl, or 7-oxa-2- azaspiro[3.5]nonanyl, wherein the C 1-4 alkyl is optionally substituted with one to four R Easubstituted, and each of the phenyl, pyridyl, pyrazolyl, oxadiazolyl, imidazolyl, thiazolyl, isothiazolyl, triazolyl, oxazolyl, thienyl, morpholinyl, piperidinyl, piperazinyl, and 7-oxa-2-azaspiro[3.5]non-1-yl is optionally substituted with one or two R Eb substituted;

[0192] R 8 is H, C 1-3 alkyl, C 1-3 haloalkyl, or SH;

[0193] each R Ea is independently halo, cyano, OH, or NR N3E R N3E ;

[0194] each R Eb is independently halo, C 1-3 alkyl, C 1-3 haloalkyl, cyano, C 1-3 alkoxy, -OH, or -C(O)NR N3E R N3E , wherein the C 1-3 alkyl is optionally substituted oxetanyl, which is substituted with C 1-3 alkyl;

[0195] each R N3E is independently H, OH, or C 1-3 alkyl;

[0196] R O3a is H, C 1-3 alkyl, or tetrahydrofuranyl, wherein the C 1-3 alkyl is optionally substituted with tetrahydrofuranyl;

[0197] R N3a and R N3b are each independently H, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, -OH, -S(O)2C 1-3 alkyl, or cyclopropyl, wherein the C 1-3 alkyl is optionally substituted with C 1-3 alkoxy or pyridyl. The definitions of the remaining variables are provided in the eighteenth aspect.

[0198] In a twentieth aspect, the present disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenth aspect, or a pharmaceutically acceptable salt thereof, wherein:

[0199] R E -C(O)OR O3a -C(O)NR N3a R N3b ;

[0200] R O3a H or C 1-3 alkyl;

[0201] R N3a and R N3b each independently H, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, -OH, or cyclopropyl. The definitions of the remaining variables are provided in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenth aspects.

[0202] In a twenty-first aspect, the present disclosure provides a compound according to the eighteenth or nineteenth aspect, or a pharmaceutically acceptable salt thereof, wherein R E -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, -C(O)OC(CH3)3, -C(O)NH2, -C(O)NHCH3, -C(O)NHS(O)2CH3, -C(O)NHCH2CH2OCH3, -C(O)N(CH3)OCH3, cyano, -C(O)H, -C(O)CH3, -C(O)CF3, -C(O)SH, -CH3, -C(CH2CN)2OH, -C(NH)NHOH, -CH2OH, -CH(OH)CF3, -S(O)2NHC(CH3)3, -S(O)2NH2, 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , or . The definition of the remaining variables is provided in the eighteenth or nineteenth aspect.

[0203] In a twenty-second aspect, the disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenth aspect, or a pharmaceutically acceptable salt thereof, wherein R E is -C(O)OH. The definition of the remaining variables is provided in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenth aspect.

[0204] In a twenty-third aspect, the disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, or twenty-second aspect, or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently halo, C 1-3 alkyl, C 1-3 haloalkyl, or 6-membered monocyclic heterocyclyl, wherein the 6-membered monocyclic heterocyclyl is optionally substituted with halo. The definition of the remaining variables is provided in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, or twenty-second aspect.

[0205] In a twenty-fourth aspect, the disclosure provides a compound according to the twenty-third aspect, or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently -Br, -Cl, -F, -CH3, -CF3, or pyridyl, wherein the pyridyl is optionally substituted with -F. The definition of the remaining variables is provided in the twenty-third aspect.

[0206] In a twenty-fifth aspect, the disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, or twenty-fourth aspect, or a pharmaceutically acceptable salt thereof, wherein each R1 independently CN, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxyalkyl or halo. The definitions of the remaining variables are provided in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, or twenty-sixth aspect.

[0207] In a twenty-sixth aspect, the present disclosure provides a compound according to the twenty-fifth aspect, or a pharmaceutically acceptable salt thereof, wherein each R 1 independently C 1-3 alkyl, C 1-3 haloalkyl or halo, preferably wherein R 1 is -CH3or -F. The definitions of the remaining variables are provided in the twenty-fifth aspect.

[0208] In a twenty-seventh aspect, the present disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, or twenty-sixth aspect, or a pharmaceutically acceptable salt thereof, wherein:

[0209] each R 6 independently oxo, halo, cyano, -OH, C 1-3 alkyl, C 1-3 alkoxy, -C(O)NH2, or -NH2;

[0210] or two R 6 together with the atom to which they are attached form a cyclopropyl group;

[0211] R N6 is H, C 1-3 alkyl, phenyl, or pyridyl, wherein the phenyl is optionally substituted with -CN. The definitions of the remaining variables are provided in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, or twenty-sixth aspect.

[0212] In a twenty-eighth aspect, the present disclosure provides a compound according to the twenty-seventh aspect, or a pharmaceutically acceptable salt thereof, wherein:

[0213] each R 6 independently oxo, -CI, -F, -OH, -CH3, -OCH3, -OCH(CH3)3, CN, -C(O)NH2, or -NH2;

[0214] R N6 is H, -CH3, or The definitions of the remaining variables are provided in the twenty-seventh aspect.

[0215] In a twenty-ninth aspect, the present disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, or twenty-eighth aspect, or a pharmaceutically acceptable salt thereof, wherein each R 2 is independently C 1-3 alkyl or C 1-3 haloalkyl. The definitions of the remaining variables are provided in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, or twenty-eighth aspect.

[0216] In a thirtieth aspect, the present disclosure provides a compound according to the first or second aspect, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (VIc-1a):

[0217] (VIc-1a),

[0218] wherein:

[0219] X is N or CH;

[0220] n is 0 or 1;

[0221] R 1 is halo or C 1-3 alkyl;

[0222] w is 0, 1, or 2;

[0223] each R 3 is independently halo or C 1-3 alkyl;

[0224] q is 0, 1, or 2; and

[0225] each R 6 is independently halo or C 1-3alkyl. The definitions of the remaining variables are provided in the first or second aspect.

[0226] In one aspect, the disclosure provides a compound according to the thirtieth aspect or a pharmaceutically acceptable salt thereof, wherein X is N. The definitions of the remaining variables are provided in the thirtieth aspect.

[0227] In a thirty-first aspect, the disclosure provides a compound according to the thirtieth aspect or a pharmaceutically acceptable salt thereof, wherein R 1 is -F or -CH3. The definitions of the remaining variables are provided in the thirtieth aspect.

[0228] In a thirty-second aspect, the disclosure provides a compound according to the thirtieth or thirty-first aspect or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently -F, -Cl, -Br, or -CH3. The definitions of the remaining variables are provided in the thirtieth or thirty-first aspect.

[0229] In one aspect, the disclosure provides a compound according to the thirtieth, thirty-first, or thirty-second aspect or a pharmaceutically acceptable salt thereof, wherein w is 1. The definitions of the remaining variables are provided in the thirtieth, thirty-first, or thirty-second aspect.

[0230] In a thirty-third aspect, the disclosure provides a compound according to the thirtieth, thirty-first, or thirty-second aspect, wherein the compound is represented by formula (VIc-1aa):

[0231] (VIc-1aa),

[0232] or a pharmaceutically acceptable salt thereof. The definitions of the remaining variables are provided in the thirtieth, thirty-first, or thirty-second aspect.

[0233] In a thirty-fourth aspect, the disclosure provides a compound according to the thirtieth, thirty-first, thirty-second, or thirty-third aspect or a pharmaceutically acceptable salt thereof, wherein each R 6 is independently C 1-3 alkyl, preferably wherein each R 6 is -CH3. The definitions of the remaining variables are provided in the thirtieth, thirty-first, thirty-second, or thirty-third aspect.

[0234] In a thirty-fifth aspect, the disclosure provides a compound according to the thirtieth, thirty-first, thirty-second, or thirty-third aspect or a pharmaceutically acceptable salt thereof, wherein q is 0. The definitions of the remaining variables are provided in the thirtieth, thirty-first, thirty-second, or thirty-third aspect.

[0235] In a thirty-sixth aspect, the present disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, or thirty-fifth aspect, or a pharmaceutically acceptable salt thereof, wherein or is . The definitions of the remaining variables are provided in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, or thirty-fifth aspect.

[0236] Additionally, in the first embodiment, the present disclosure provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof:

[0237] (I),

[0238] wherein:

[0239] is a single or double bond, as valence allows;

[0240] (i) when W is N, then Y is C(O), X is C, and Z is N or CR Z1 ;

[0241] (ii) when W is C and Y is C(O), then X is C or N, and Z is CR Z1 , N, NR N1 , or O;

[0242] (iii) when W is C and Y is N or CR Z1 , then X is C, and Z is N or CR Z1 ;

[0243] G 1 , G 2 , and G 3 are each independently C(R G2 )2, NR N2 , or O;

[0244] n is 0, 1, 2, or 3;

[0245] m is 0, 1, 2, 3, or 4;

[0246] o is 0, 1, 2, 3, or 4;

[0247] R Na is H, C 1-6 alkyl, or C 1-6 haloalkyl;

[0248] R N1 is H, C 1-6 alkyl, C 1-6 haloalkyl, -C(O)R 1a , C 3-6 cycloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein said phenyl and 5- to 6-membered heteroaryl each represented by R N1 is optionally substituted with one to three substituents selected from the group consisting of halogen, C 1-3 alkyl, and C 1-3 haloalkyl;

[0249] R Z1 is H, halogen, cyano, NO2, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, C 1-6 hydroxyalkoxy, NR N1a R N1b , -C(O)R 1a , -C(O)OR O1a , -C(O)NR N1a R N1b , -OR O1a , 3- to 12-membered carbocyclyl, phenyl, 5- or 6-membered heteroaryl, or 4- to 12-membered heterocyclyl, wherein said carbocyclyl, phenyl, 5- or 6-membered heteroaryl, or 4- to 12-membered heterocyclyl each represented by R Z1 is optionally substituted with one to four R 1b ;

[0250] each R 1 is independently halogen, cyano, NO2, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, C 1-6 hydroxyalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, NR N1a R N1b , -C(O)R 1a , -C(O)OR O1a , -C(O)NR N1a R N1b , -ORO1a -(CH2) 0或1 -3 to 12 membered carbocyclyl, -(CH2) 0或1 -4 to 12 membered heterocyclyl, -(CH2) 0或1 -6 to 10 membered aryl or -(CH2) 0或1 -5 to 10 membered heteroaryl, wherein said C 1 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with one to four R 1b ;

[0251] R 1a , R O1a , R N1a , and R N1b are each independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, or 4- to 6-membered heterocyclyl;

[0252] each R 1b is independently halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkoxy, -C(O)R 1a , -C(O)OR O1a , -C(O)NR N1a R N1b , -SO2R 1a , -NR N1a R N1b , -NR N1a C(O)R 1a , -NR N1a C(O)OR 1a , -NR N1a SO2R 1a , -NR N1a SO2NR N1a R N1b , cyano, NO2, or OR O1a ;

[0253] R N2 is H, C 1-6 alkyl, C 1-6 haloalkyl, -C(O)R 2a , C 3-6 cycloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein RN2 the phenyl and 5- to 6-membered heteroaryl groups represented by R 1-3 alkyl and C 1-3 haloalkyl groups;

[0254] each R G2 independently H, halo, cyano, oxo (as needed), NO2, C 1-6 alkyl, C 1-6 haloalkyl, *=CH-R 7 (as needed), C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, C 1-6 hydroxyalkoxy, -C(O)R 2a , -C(O)OR O2a , -C(O)NR N2a R N2b , OR O2a , NR N2a R N2b , SO2R 2a , -NR N2a C(O)R 2a , -NR N2a C(O)OR 2a , -NR N2a SO3R 2a , -NR N2a SO3NR N2a R N2a , -(CH2) 0或1 -3- to 12-membered carbocyclyl, -(CH2) 0或1 -4- to 12-membered heterocyclyl, -(CH2) 0或1 -6- to 10-membered aryl, or -(CH2) 0或1 -5- to 10-membered heteroaryl, wherein the carbocyclyl, heterocyclyl, aryl, or heteroaryl groups represented by R G2 each are optionally substituted with one to four halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkoxy, -C(O)R 2a , -C(O)OR O2a , -C(O)NR N2a R N2b , cyano, NO2, OR O2a , NRN2a R N2b SO3R 2a NR N2a C(O)R 2a NR N2a C(O)OR 2a NR N2a SO3R 2a NR N2a SO3NR N2a R N2a substituted, and wherein said C2 alkenyl is optionally substituted with phenyl or 5- to 6-membered heteroaryl;

[0255] each R 2 is independently halo, cyano, oxo (as needed), NO2, C 1-6 alkyl, C 1-6 haloalkyl, *=CH-R 7 (as needed), C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, C 1-6 hydroxyalkoxy, -C(O)R 2a , -C(O)OR O2a , -C(O)NR N2a R N2b , OR O2a , NR N2a R N2b , SO2R 2a , -NR N2a C(O)R 2a , -NR N2a C(O)OR 2a , -NR N2a SO3R 2a , -NR N2a SO3NR N2a R N2a , -(CH2) 0或1 -3- to 12-membered carbocyclyl, -(CH2) 0或1 -4- to 12-membered heterocyclyl, -(CH2) 0或1 -6- to 10-membered aryl, or -(CH2) 0或1 -5- to 10-membered heteroaryl, wherein said carbocyclyl, heterocyclyl, aryl, or heteroaryl represented by R 2 is each optionally substituted with one to four halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, C 1-6 alkoxy, C1-6 haloalkoxy, C 1-6 hydroxyalkoxy, -C(O)R 2a , -C(O)OR O2a , -C(O)NR N2a R N2b , cyano, NO2, OR O2a , NR N2a R N2b , SO3R 2a , -NR N2a C(O)R 2a , -NR N2a C(O)OR 2a , -NR N2a SO3R 2a or -NR N2a SO3NR N2a R N2a substituted, and wherein said C2alkenyl is optionally substituted with phenyl or 5- to 6-membered heteroaryl; or

[0256] two R 2 , two R G2 , one R 2 and one R N2 , one R 2 and one R G2 , or one R G2 and one R N2 together with the atom to which they are attached form a 3- to 12-membered carbocyclyl, 4- to 12-membered heterocyclyl, phenyl, naphthyl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one to four R 6 ;

[0257] R 2a and R O2a are each independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, or 4- to 6-membered heterocyclyl;

[0258] R N2a and R N2b are each independently H, C 1-6 alkyl, C 1-6 haloalkyl, OR O2a , or C 3-6 cycloalkyl;

[0259] * is a point of attachment to the tricyclic core ring;

[0260] R 7It is a 3- to 12-membered carbocyclic group, a 4- to 12-membered heterocyclic group, a phenyl group, a naphthyl group, or a 5- to 10-membered heteroaryl group, each optionally decorated with one to four halogen groups, -OH, -NH2, cyano, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Alkynyl, aryl, or heteroaryl substitutions;

[0261] Each R 6 Independently, it can be a halogen group, a cyano group, an oxo group (as needed), NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxyalkyl, C 1-6 Hydroxyalkoxy, -C(O)R 6a -C(O)OR O6a -C(O)NR N6a R N6b OR O6a NR N6a R N6b SO2R 6a -NR N6a C(O)R 6a -NR N6a C(O)OR 6a -NR N6a SO3R 6a -NR N6a SO3NR N6a R N6a -(CH2) 0或1 -3 to 12-membered carbon cyclogroups, -(CH2) 0或1 -4 to 12-membered heterocyclic groups, -(CH2) 0或1 -6 to 10 aryl groups or -(CH2) 0或1 -5 to 10 aryl compounds, of which R 6 The carbocyclic, heterocyclic, aryl, or heteroaryl groups represented are each optionally surrounded by one to four halogen groups, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkoxy, -C(O)R 6a -C(O)OR O6a -C(O)NR N6a R N6b, cyano, NO2, OR O6a NR N6a R N6b SO3R 6a -NR N6a C(O)R 6a -NR N6a C(O)OR 6a -NR N6a SO3R 6a or -NR N6a SO3NR N6a R N6a replace;

[0262] R 6a and R O6a Each independently represents H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4- to 6-membered heterocyclic groups;

[0263] R N6a and R N6b Each is independently H, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OR O6a Or C 3-6 cycloalkyl;

[0264] Ring B is a phenyl or a 5- to 10-membered monocyclic or bicyclic heteroaryl group, each of which is located in N(R) Na The adjacent position of the substituent is R E Replace, and optionally be one to four R 3 replace;

[0265] Each R 3 Independently, it can be a halogenated group, a cyano group, NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxyalkyl, C 1-6 Hydroxyalkoxy, -C(O)R 3a -C(O)OR O3a -C(O)NR N3a R N3b OR O3a NR N3a R N3b SO2R 3a -NR N3a C(O)R 3a -NR N3a C(O)OR 3a-NR N3a SO3R 3a -NR N3a SO3NR N3a R N3a -(CH2) 0或1 -3 to 12 membered carbocyclyl, -(CH2) 0或1 -4 to 12 membered heterocyclyl, -(CH2) 0或1 -6 to 10 membered aryl, or -(CH2) 0或1 -5 to 10 membered heteroaryl, wherein said carbocyclyl, heterocyclyl, aryl, or heteroaryl group represented by R 3 is each optionally substituted with one to four halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, C 1-6 hydroxyalkoxy, -C(O)R 3a -C(O)OR O3a -C(O)NR N3a R N3b cyano, NO2, OR O3a NR N3a R N3b SO3R 3a -NR N3a C(O)R 3a -NR N3a C(O)OR 3a -NR N3a SO3R 3a or -NR N3a SO3NR N3a R N3a ;

[0266] R E is -C(O)OR O3a or -C(O)NR N3a R N3b ;

[0267] R 3a and R O3a are each independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, or 4 to 6 membered heterocyclyl;

[0268] R N3a and R N3b are each independently H, C 1-6 alkyl, C 1-6 haloalkyl, OR O3a , or C 3-6 cycloalkyl;

[0269] R 4 and R 5 each independently is H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, or C 1-6 alkoxyalkyl; or

[0270] R 4 and R 5 together with the carbon to which they are attached form a C 3-6 cycloalkyl or 4- to 6-membered oxygen-only heterocyclyl.

[0271] In a second embodiment, the present disclosure provides a compound according to the first embodiment, a pharmaceutically acceptable salt thereof, wherein R Na is H. The definitions of the remaining variables are provided in the first embodiment.

[0272] In a third embodiment, the present disclosure provides a compound according to the first or second embodiment, a pharmaceutically acceptable salt thereof, wherein R 4 is C 1-3 alkyl and R 5 is H. The definitions of the remaining variables are provided in the first or second embodiment.

[0273] In a fourth embodiment, the present disclosure provides a compound according to the first, second, or third embodiment, a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (II), (III), (IV), or (V):

[0274] (II), (III),

[0275] (IV), or (V);

[0276] wherein m and n are each independently 0, 1, or 2, and o is 0 or 1. The definitions of the remaining variables are provided in the first, second, or third embodiment.

[0277] In an alternative form of the fourth embodiment, the compound has formula (II). In another alternative form of the fourth embodiment, the compound has formula (III). In another alternative form of the fourth embodiment, the compound has formula (IV). In another alternative form of the fourth embodiment, the compound has formula (V).

[0278] In a fifth embodiment, the present disclosure provides a compound according to the fourth embodiment, a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (IIa), (IIb), (IIc), (IId), (IIIa), (IIIb), (IIIc), (IVa), (IVb), (IVc), (Va), (Vb), (Vc), or (Vd):

[0279] (IIa), (IIb),

[0280] (IIc), (IId),

[0281] (IIIa), (IIIb), (IIIc), (IVa), (IVb), (IVc), (Va), (Vb),

[0282] (Vc), or (Vd);

[0283] wherein:

[0284] n and o are each independently 0 or 1;

[0285] q is 0, 1, or 2;

[0286] J 1 , J 2 , J 3 , and J 4 are each independently N, CH, or CR 6 ;

[0287] T 1 and T 5 are each independently N or C;

[0288] T 2 , T 3 , and T 4 are each independently N, NR N6 , O, S, CH, or CR 6 ;

[0289] R N6 is H, C 1-3 alkyl, C1-3 haloalkyl, C 3-6 cycloalkyl, phenyl, naphthyl, or 5- to 6-membered heteroaryl, wherein the phenyl, naphthyl, and 5- to 6-membered heteroaryl groups represented by R N6 each are optionally substituted with one to three halo, C 1-3 alkyl, C 1-3 haloalkyl, cyano, OH, C 1-3 alkoxy, or C 1-3 haloalkoxy;

[0290] U 1 is NR N2 , CH2, or O;

[0291] U 2 is NR N6 , CH2, or O. The definitions of the remaining variables are provided in the fourth embodiment.

[0292] In an alternative form of the fifth embodiment, the compound is of Formula (IIa). In another alternative form of the fifth embodiment, the compound is of Formula (IIb). In another alternative form of the fifth embodiment, the compound is of Formula (IIc). In another alternative form of the fifth embodiment, the compound is of Formula (IId). In another alternative form of the fifth embodiment, the compound is of Formula (IIIa). In another alternative form of the fifth embodiment, the compound is of Formula (IIIb). In another alternative form of the fifth embodiment, the compound is of Formula (IIIc). In another alternative form of the fifth embodiment, the compound is of Formula (IVa). In another alternative form of the fifth embodiment, the compound is of Formula (IVb). In another alternative form of the fifth embodiment, the compound is of Formula (IVc). In another alternative form of the fifth embodiment, the compound is of Formula (Va). In another alternative form of the fifth embodiment, the compound is of Formula (Vb). In another alternative form of the fifth embodiment, the compound is of Formula (Vc). In another alternative form of the fifth embodiment, the compound is of Formula (Vd).

[0293] In a sixth embodiment, the present disclosure provides a compound according to the fifth embodiment, a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (IIa-1), (IIa-2), (IIa-3), (IIa-4), (IIa-5), (IIa-6), (IIa-7), (IIb-1), (IIb-2), (IIb-3), (IIb-4), (IIb-5), (IIb-6), (IIb-7), (IIb-8), (IIb-9), (IIb-10), (IIb-11), (IIc-1), (IIIa-1), (IIIc-1), (IVc-1), (Va-1), (Va-2), (Va-3), or (Vc-1):

[0294] (IIa-1), (IIa-2),

[0295] (IIa-3), (IIa-4),

[0296] (IIa-5), (IIa-6),

[0297] (IIa-7), (IIb-1),

[0298] (IIb-2), (IIb-3),

[0299] (IIb-4), (IIb-5),

[0300] (IIb-6), (IIb-7),

[0301] (IIb-8), (IIb-9), (IIb-10), or (IIb-11),

[0302] (IIc-1), (IIIa-1),

[0303] (IIIc-1), (IVc-1),

[0304] (Va-1), (Va-2),

[0305] (Va-3), or (Vc-1). The definitions of the variables therein are provided in the fifth embodiment.

[0306] In an alternative form of the sixth embodiment, the compound is of Formula (IIa-1). In another alternative form of the sixth embodiment, the compound is of Formula (IIa-2). In another alternative form of the sixth embodiment, the compound is of Formula (IIa-3). In another alternative form of the sixth embodiment, the compound is of Formula (IIa-4). In another alternative form of the sixth embodiment, the compound is of Formula (IIa-5). In another alternative form of the sixth embodiment, the compound is of Formula (IIa-6). In another alternative form of the sixth embodiment, the compound is of Formula (IIa-7). In another alternative form of the sixth embodiment, the compound is of Formula (IIb-1). In another alternative form of the sixth embodiment, the compound is of Formula (IIb-2). In another alternative form of the sixth embodiment, the compound is of Formula (IIb-3). In another alternative form of the sixth embodiment, the compound is of Formula (IIb-4). In another alternative form of the sixth embodiment, the compound is of Formula (IIb-5). In another alternative form of the sixth embodiment, the compound is of Formula (IIb-6). In another alternative form of the sixth embodiment, the compound is of Formula (IIb-7). In another alternative form of the sixth embodiment, the compound is of Formula (IIb-8). In another alternative form of the sixth embodiment, the compound is of Formula (IIb-9). In another alternative form of the sixth embodiment, the compound is of Formula (IIb-10). In another alternative form of the sixth embodiment, the compound is of Formula (IIb-11). In another alternative form of the sixth embodiment, the compound is of Formula (IIc-1). In another alternative form of the sixth embodiment, the compound is of Formula (IIIa-1). In another alternative form of the sixth embodiment, the compound is of Formula (IIIc-1). In another alternative form of the sixth embodiment, the compound is of Formula (IVc-1). In another alternative form of the sixth embodiment, the compound is of Formula (Va-1). In another alternative form of the sixth embodiment, the compound is of Formula (Va-2). In another alternative form of the sixth embodiment, the compound is of Formula (Va-3). In another alternative form of the sixth embodiment, the compound is of Formula (Vc-1).

[0307] In a seventh embodiment, this disclosure provides a compound, a pharmaceutically acceptable salt, or a pharmaceutically acceptable salt thereof according to a first embodiment, wherein the compound is represented by formula (VIII):

[0308] (VIII);

[0309] in:

[0310] n is 0, 1, or 2;

[0311] m is 0, 1, or 2;

[0312] o is 0 or 1;

[0313] Each R 1 Independently halogenated, cyanoated, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -NR N1a R N1b -C(O)R 1a -C(O)OR O1a -C(O)NR N1a R N1b OR O1a C 3-6 Cycloalkyl, phenyl, or 5- to 6-membered monocyclic heteroaryl, wherein R 1 The C mentioned 3-6 Cycloalkyl, phenyl, and 5- to 6-membered monocyclic heteroaryl groups are each optionally surrounded by one to three halogen groups, C 1-3 Alkyl, C 1-3 Halogenated alkyl, OH, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, -C(O)R 1a -C(O)OR O1a or -C(O)NR N1a R N1b replace;

[0314] Each R 2 Independently, it can be a halogen group, an oxo group, a cyano group, or a C group. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -NR N2a R N2b -C(O)R 2a -C(O)OR O2a -C(O)NR N2a R N2b OR O2a C 3-6 Cycloalkyl, phenyl, or 5- to 6-membered monocyclic heteroaryl, wherein R2 The C mentioned 3-6 Cycloalkyl, phenyl, and 5- to 6-membered monocyclic heteroaryl groups are each optionally surrounded by one to three halogen groups, C 1-3 Alkyl, C 1-3 Halogenated alkyl, OH, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, -C(O)R 2a -C(O)OR O2a or -C(O)NR N2a R N2b replace;

[0315] R 2a R O2a R N2a and R N2b Each independently represents H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4- to 6-membered heterocyclic groups;

[0316] Ring B is a phenyl or a 5- to 6-membered monocyclic heteroaryl group, each of which is replaced by R at the ortho position of the NH substituent. E Replaced, and by one to three Rs 3 replace;

[0317] Each R 3 Independently halogenated, cyanoated, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -NR N3a R N3b -C(O)R 3a -C(O)OR O3a -C(O)NR N3a R N3b OR O3a C 3-6 Cycloalkyl, phenyl, or 5- to 6-membered monocyclic heteroaryl, wherein R 3 The C mentioned 3-6 Cycloalkyl, phenyl, and 5- to 6-membered monocyclic heteroaryl groups are each optionally surrounded by one to three halogen groups, C 3-3 Alkyl, C 3-3 Halogenated alkyl, OH, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, -C(O)R 3a -C(O)OR O3a or -C(O)NR N3a R N3b replace;

[0318] R 3a R O3a R N3a and RN3b Each independently represents H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4- to 6-membered heterocyclic groups;

[0319] The ring C is a 6-membered monocyclic heterocyclic group, a phenyl group, or a 5- to 6-membered monocyclic heteroaryl group, each optionally surrounded by one to three R groups. 6 replace;

[0320] Q 1 and Q 2 Each can be independently C, CH, or N, with the constraint Q. 1 Or Q 2 At least one of them is C or CH;

[0321] Each R 6 Independently, it can be a halogen group, an oxo group, a cyano group, or a C group. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -NR N6a R N6b -C(O)R 6a -C(O)OR O6a -C(O)NR N6a R N6b OR O6a C 1-6 Cycloalkyl, phenyl, or 5- to 6-membered monocyclic heteroaryl, wherein R 6 The C mentioned 1-6 Cycloalkyl, phenyl, and 5- to 6-membered monocyclic heteroaryl groups are each independently bound by one to three halogen groups, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -C(O)R 6a -C(O)OR O6a or -C(O)NR N6a R N6b replace;

[0322] R 6a R O6a R N6a and R N6b Each independently represents H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cycloalkyl or 4- to 6-membered heterocyclic groups. Definitions of the remaining variables are provided in the first embodiment.

[0323] In an eighth embodiment, the present disclosure provides a compound according to the seventh embodiment, a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (VIIIa), (VIIIb), or (VIIIc):

[0324] (VIIIa), (VIIIb),

[0325] or (VIIIc);

[0326] wherein:

[0327] n is 0 or 1;

[0328] q is 0, 1, or 2;

[0329] U 2 is NR N6 , CH2, or O;

[0330] J 1 , J 2 , J 3 , and J 4 are each independently N or CH, wherein at least one of J 1 , J 2 , J 3 , and J 4 is CH;

[0331] T 1 and T 5 are each independently N or C;

[0332] T 2 , T 3 , and T 4 are each independently N, NR N6 , O, S, or CH;

[0333] R N6 is H, C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl represented by R N6 are each optionally substituted with one to three halo, C 1-3 alkyl, C 1-3 haloalkyl, cyano, OH, C 1-3 alkoxy, or C 1-3 haloalkoxy. The definitions of the remaining variables are provided in the seventh embodiment.

[0334] In an alternative form of the eighth embodiment, the compound is of Formula (VIIIa). In another alternative form of the eighth embodiment, the compound is of Formula (VIIIb). In another alternative form of the eighth embodiment, the compound is of Formula (VIIIc):

[0335] In a ninth embodiment, the present disclosure provides a compound according to the first, second, or third embodiment, a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (VI) or (VII):

[0336] (VI) or (VII),

[0337] wherein m and n are each independently 0, 1, or 2; and o is 0 or 1. The definitions of the remaining variables are provided in the first, second, or third embodiment.

[0338] In an alternative form of the ninth embodiment, the compound is of Formula (VI). In another alternative form of the ninth embodiment, the compound is of Formula (VII).

[0339] In a tenth embodiment, the present disclosure provides a compound according to the ninth embodiment, a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (VIa), (VIb), (VIc), (VIIa), (VIIb), or (VIIc):

[0340] (VIa), (VIb),

[0341] (VIc), (VIIa),

[0342] (VIIb), or (VIIc),

[0343] wherein:

[0344] n and o are each independently 0 or 1;

[0345] q is 0, 1, or 2;

[0346] J 1 , J 2 , J 3 , and J 4 are each independently N, CH, or CR 6 ;

[0347] T 1 , and T 5 are each independently N or C;

[0348] T 2 T 3 and T 4 Each is independently N, NR N6 , O, S, CH or CR 6 ;

[0349] R N6 For H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein R N6 The phenyl group and the 5- to 6-membered heteroaryl group are each optionally surrounded by one to three halogen groups, C 1-3 Alkyl, C 1-3 Halogenated alkyl, cyano, OH, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups;

[0350] U 1 For NR N2 CH2 or O;

[0351] U 2 For NR N6 CH2 or O. The definitions of the remaining variables are provided in the ninth embodiment.

[0352] In an alternative form of the tenth embodiment, the compound has formula (VIa). In another alternative form of the tenth embodiment, the compound has formula (VIb). In another alternative form of the tenth embodiment, the compound has formula (VIc). In another alternative form of the tenth embodiment, the compound has formula (VIIa). In another alternative form of the tenth embodiment, the compound has formula (VIIb). In another alternative form of the tenth embodiment, the compound has formula (VIIc).

[0353] In the eleventh embodiment, this disclosure provides a compound according to the tenth embodiment, and a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (VIa-1), (VIc-1), or (VIIc-1):

[0354] (VIa-1) (VIc-1) or

[0355] (VIIc-1);

[0356] Where n is 0 or 1, and q is 0, 1, or 2. The definitions of the remaining variables are provided in the tenth embodiment.

[0357] In an alternative form of the eleventh embodiment, the compound has formula (VIa-1). In another alternative form of the eleventh embodiment, the compound has formula (VIc-a). In yet another alternative form of the eleventh embodiment, the compound has formula (VIIc-1).

[0358] In a twelfth embodiment, this disclosure provides a compound according to a first embodiment, and a pharmaceutically acceptable salt thereof, wherein the compound is of formula (II-1), (III-1), (IV-1), (V-1), (VI-1), or (VII-1):

[0359] (II-1) (III-1)

[0360] (IV-1) (V-1)

[0361] (VI-1) or (VII-1),

[0362] in

[0363] m, n, and o are each independently 0 or 1;

[0364] R 7 It is a 5- or 6-membered heterocyclic group, phenyl, or 5- or 6-membered heteroaryl group, each optionally decorated with one or two halogen groups, -OH, -NH2, cyano, C 1-3 Alkyl or C 1-3 Halogenated alkyl substitution.

[0365] In an alternative form of the twelfth embodiment, the compound has formula (II-1). In another alternative form of the twelfth embodiment, the compound has formula (III-1). In another alternative form of the twelfth embodiment, the compound has formula (IV-1). In another alternative form of the twelfth embodiment, the compound has formula (V-1). In another alternative form of the twelfth embodiment, the compound has formula (VI-1). In another alternative form of the twelfth embodiment, the compound has formula (VII-1).

[0366] In the thirteenth embodiment, this disclosure provides a compound according to the twelfth embodiment, and a pharmaceutically acceptable salt thereof, wherein R 7 It can be phenyl, pyridyl, isoxazolyl, or tetrahydro-2H-pyranyl. Definitions of the remaining variables are provided in the twelfth embodiment.

[0367] In a fourteenth embodiment, the present disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiment, a pharmaceutically acceptable salt thereof, wherein ring B is phenyl or 6-membered monocyclic heteroaryl, each of which is substituted at the NR Na position ortho to the substituent with R E , and is further optionally substituted with one or two R 3 . The definitions of the remaining variables are provided in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiment.

[0368] In a fifteenth embodiment, the present disclosure provides a compound according to the fourteenth embodiment, a pharmaceutically acceptable salt thereof, wherein ring B is phenyl or pyridyl, each of which is substituted at the NR Na position ortho to the substituent with R E , and is further optionally substituted with one R 3 . The definitions of the remaining variables are provided in the fourteenth embodiment.

[0369] In a sixteenth embodiment, the present disclosure provides a compound according to the fifteenth embodiment, a pharmaceutically acceptable salt thereof, wherein ring B and R E together with the optionally substituted R 3 are represented by: , , or . The definitions of the remaining variables are provided in the fifteenth embodiment.

[0370] In a seventeenth embodiment, the present disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenth embodiment, a pharmaceutically acceptable salt thereof, wherein R E is -C(O)OR O3a or -C(O)NR N3a R N3b ; R O3a is H or C 1-3 alkyl; and R N3a and R N3b are each independently H, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, -OH, or cyclopropyl. The definitions of the remaining variables are provided in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenth embodiment.

[0371] In an eighteenth embodiment, the present disclosure provides a compound according to the seventeenth embodiment, a pharmaceutically acceptable salt thereof, wherein R E is -C(O)OH. The definitions of the remaining variables are provided in the seventeenth embodiment.

[0372] In a nineteenth embodiment, the present disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, or eighteenth embodiment, a pharmaceutically acceptable salt thereof, wherein each R 3 is independently halo, C 1-3 alkyl, or C 1-3 haloalkyl. The definitions of the remaining variables are provided in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, or eighteenth embodiment.

[0373] In a twentieth embodiment, the present disclosure provides a compound according to the nineteenth embodiment, a pharmaceutically acceptable salt thereof, wherein each R 3 is independently -CI, -F, or -CF3. The definitions of the remaining variables are provided in the nineteenth embodiment.

[0374] In a twenty-first embodiment, the present disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, or twentieth embodiment, a pharmaceutically acceptable salt thereof, wherein each R 1 is independently CN, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxyalkyl, or halo. The definitions of the remaining variables are provided in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, or twentieth embodiment.

[0375] In a twenty-second embodiment, the present disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, or twenty-first embodiment, a pharmaceutically acceptable salt thereof, wherein each R 1 is independently C 1-3 alkyl, C 1-3haloalkyl or halo group. The definitions of the remaining variables are provided in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, or twenty-first embodiment.

[0376] In a twenty-third embodiment, the present disclosure provides a compound according to the twenty-second embodiment, a pharmaceutically acceptable salt thereof, wherein each R 1 is independently -CH3or -F. The definitions of the remaining variables are provided in the twenty-second embodiment.

[0377] In a twenty-fourth embodiment, the present disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, or twenty-third embodiment, a pharmaceutically acceptable salt thereof, wherein each R 6 is independently halo, cyano, -OH, C 1-3 alkyl, C 1-3 alkoxy, or -NH2; and R N6 is H, C 1-3 alkyl, phenyl, or pyridyl, wherein the phenyl is optionally substituted with -CN. The definitions of the remaining variables are provided in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, or twenty-third embodiment.

[0378] In a twenty-fifth embodiment, the present disclosure provides a compound according to the twenty-fourth embodiment, a pharmaceutically acceptable salt thereof, wherein each R 6 is independently -Cl, -F, -OH, -OCH3, -OCH(CH3)3, CN, or -NH2; and R N6 is H, -CH3, or . The definitions of the remaining variables are provided in the twenty-fourth embodiment.

[0379] In an aspect or embodiment, the present disclosure provides a compound selected from the compounds disclosed in Examples and Table 1, a pharmaceutically acceptable salt, or stereoisomer thereof.

[0380] Table 1

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397] 2. Definitions

[0398] The term "halo" or "halogen" as used herein refers to fluoro, chloro, bromo, or iodo.

[0399] The term "alkyl" used alone or as part of a larger moiety, e.g., "alkoxy" or "haloalkyl," means a saturated aliphatic straight or branched chain monovalent hydrocarbon radical of the formula -C n H (2n+1) Unless otherwise indicated, alkyl groups typically have 1 to 6 carbon atoms, i.e., Ci-6alkyl. As used herein, a "Ci-6alkyl" group means a group having from 1 to 6 carbon atoms in a straight or branched arrangement. Examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, hexyl, and the like.

[0400] The term "haloalkyl" means an alkyl group optionally substituted with one or more halogen atoms. In one embodiment, the alkyl group can be substituted with one to three halogens. Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and the like.

[0401] The term "hydroxyalkyl" means an alkyl group optionally substituted with one or more hydroxyl groups. In one embodiment, the alkyl group can be substituted with one to three hydroxyl groups.

[0402] The term "alkoxy" means an alkyl group connected through an oxygen connecting atom, represented by -Oalkyl. For example, "C 1-4 alkoxy" includes methoxy, ethoxy, propoxy, and butoxy.

[0403] The term "haloalkoxy" means an alkoxy group optionally substituted with one or more halogen atoms. In one embodiment, the alkoxy group can be substituted with one to three halogens.

[0404] The term "hydroxyalkoxy" means an alkoxy group optionally substituted with one or more hydroxyl groups. In one embodiment, the alkoxy group can be substituted with one to three hydroxyl groups. In one embodiment, the alkoxy group is substituted with one hydroxyl group.

[0405] The term "alkoxyalkyl" means an alkyl group substituted with one or more alkoxy groups (e.g., C 1-4 alkoxy). In one embodiment, the alkyl group can be substituted with one to three alkoxy groups. In one embodiment, the alkyl group is substituted with one alkoxy group.

[0406] The term "alkenyl" means an alkyl group in which one or more carbon / carbon single bonds are replaced with a double bond.

[0407] The term "alkynyl" means an alkyl group in which one or more carbon / carbon single bonds are replaced with a triple bond.

[0408] The term "carbocyclyl" refers to a 3- to 12-membered non-aromatic hydrocarbon ring system and can exist in a single ring or multiple ring (e.g., including fused, spiro, or bridged carbocyclic rings or tricyclic rings) form. In one embodiment, the carbocyclyl is a 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic or tricyclic hydrocarbon ring, any of which can be saturated, partially unsaturated. Any substitutable ring atom can be substituted (e.g., with one or more substituents). Examples of these carbocyclic rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, and cyclooctadienyl. In one embodiment, carbocyclyl is intended to include bridged rings, fused rings, and spiro rings. In spiro carbocyclyl groups, one atom is shared by two different rings. An example of a spiro carbocyclyl group is spiro[3.3]heptanyl. In bridged carbocyclyl groups, each ring shares at least two shared non-adjacent atoms. Examples of bridged carbocyclyl groups include bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]hept-2-enyl, and adamantyl. In fused carbocyclic ring systems, two or more rings can be fused together such that the two rings share a common bond. Examples of bi- or tri-fused carbocyclyl groups include naphthyl, tetrahydronaphthalenyl / tetralinyl, indenyl, indanyl (dihydroindenyl), anthryl, phenanthryl, and decahydronaphthalenyl. The term "carbocyclyl" as used herein includes groups in which a carbocyclic ring is fused to one or more aryl rings, where the attachment is through a carbon of the carbocyclic ring. Non-limiting examples of these fused ring systems include:

[0409] , and .

[0410] In some embodiments, carbocyclyl refers to a 3- to 12-membered cycloalkyl.

[0411] The term "cycloalkyl" refers to cyclic, bicyclic, tricyclic, or polycyclic saturated hydrocarbon groups having 3 to 12 ring carbons. In one embodiment, the cycloalkyl group can have 3 to 7 ring carbons. Any substitutable ring atom can be substituted (e.g., with one or more substituents). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl groups can include multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyl groups include: bicyclo[l. l.0]butane, bicyclo[2. l.0]pentane, bicyclo[l. l.0]pentane, bicyclo[3. l.0]hexane, bicyclo[2. l. l]hexane, bicyclo[3.2.0]heptane, bicyclo[4. l.0]heptane, bicyclo[2.2. l]heptane, bicyclo[3. l. l]heptane, bicyclo[4.2.0]octane, bicyclo[3.2. l]octane, bicyclo[2.2.2]octane, and the like. Cycloalkyl groups also include spirocyclic (e.g., spirocyclic bicyclic, where two rings are connected by only one atom). Non-limiting examples of spirocyclic cycloalkyl groups include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like.

[0412] The term "heterocyclyl" or "heterocycle" refers to a radical of a 4- to 12-membered nonaromatic fully or partially substituted ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, quaternized nitrogen, nitrosonium (e.g., NO), oxygen, and sulfur, including sulfoxides and sulfones ("4- to 12-membered heterocyclyl"). In some embodiments, the heterocyclyl is a 3- to 7-membered nonaromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3- to 7-membered heterocyclyl"). In some embodiments, the heterocyclyl comprises 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur. Oxygen-only heterocyclyl refers to a heterocyclyl comprising 1 or 2 heteroatoms each selected only from oxygen. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom as valence allows. The heterocyclyl can be monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., a bicyclic system ("bicyclic heterocyclyl") or a tricyclic system ("tricyclic heterocyclyl"); polycyclic systems include fused, bridged, or spiro systems). The heterocyclyl polycyclic system can include heteroatoms in one or more rings of the polycyclic system, including polycyclic systems having a nonaromatic ring fused with a benzene or heteroaromatic ring. When the heterocyclyl is a polycyclic system, the ring system includes at least one nonaromatic ring. Exemplary monocyclic heterocyclyls include azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, azepinyl, oxepinyl, thiepinyl, tetrahydropyridinyl, and the like. The heterocyclyl polycyclic system can include heteroatoms in one or more rings of the polycyclic system. Substituents can be present on one or more rings of the polycyclic system.

[0413] Spiroheterocyclyl refers to a 5- to 12-membered polycyclic heterocyclyl group in which a ring is connected through a common carbon atom, referred to as a spiro atom, wherein the ring has one or more heteroatoms selected from the group consisting of nitrogen, quaternized nitrogen, nitrosonium (e.g., NO), oxygen, and sulfur (including sulfoxides and sulfones), with the remaining ring atoms being C, wherein one or more rings can contain one or more double bonds, and wherein no ring has a fully conjugated pi-electron system. Representative examples of spiroheterocyclyl groups include, but are not limited to, the following groups:

[0414] .

[0415] Fused heterocyclyl refers to a 5- to 12-membered polycyclic heterocyclyl group in which each ring in the group shares a pair of adjacent carbon atoms with another ring in the group, wherein one or more rings can contain one or more double bonds, and wherein the ring has one or more heteroatoms selected from the group consisting of nitrogen, quaternized nitrogen, nitrosonium (e.g., NO), oxygen, and sulfur (including sulfoxides and sulfones), with the remaining ring atoms being C. Representative examples of fused heterocyclyl groups include, but are not limited to, the following groups:

[0416] .

[0417] In some embodiments, fused heterocyclyl includes groups in which a non-aromatic heterocyclyl ring is fused to one or more aryl or heteroaryl groups. Non-limiting examples of such fused heterocyclyl ring systems include:

[0418]

[0419] Bridged heterocyclyl refers to 5- to 12-membered polycyclic heterocyclyl groups in which any two rings in the group share two non-adjacent atoms, the rings can have one or more double bonds but do not have a fully conjugated pi-electron system, and the rings have one or more heteroatoms as ring atoms selected from the group consisting of nitrogen, quaternized nitrogen, nitrogen oxide (e.g., NO), oxygen, and sulfur (including sulfoxide and sulfone), with the remaining ring atoms being C. Representative examples of bridged heterocyclyl groups include, but are not limited to, the following groups:

[0420]

[0421] Generally, carbocyclyl, cycloalkyl, or heterocyclyl groups can be unsubstituted or substituted with one or more substituents as valence allows, where the substituents can be independently selected from a variety of groups, such as oxo, -CN, halogen, alkyl, and alkoxy, among others, optionally, the alkyl substituents can be further substituted.

[0422] The term "aryl" refers to a 6- to 10-membered all-carbon monocyclic or polycyclic ring ("fused" ring systems mean that each ring in the system shares a pair of adjacent carbon atoms with another ring in the system) groups, and has a fully conjugated pi-electon system. The term "aryl" can be used interchangeably with the terms "aromatic ring," "carbocyclic aromatic ring," "aryl group," and "carbocyclic aromatic group." Representative examples of aryl groups are phenyl and naphthyl.

[0423] The term "heteroaryl" as used herein refers to a monocyclic or polycyclic aromatic hydrocarbon in which at least one ring carbon atom is replaced by a heteroatom independently selected from oxygen, nitrogen, and sulfur. Preferably, the heteroaryl is a C 5-10 aryl. In some embodiments, the heteroaryl comprises 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur. The heteroaryl can be attached through a ring carbon atom or, as valence allows, through a ring nitrogen atom. Generally, the heteroaryl can be unsubstituted or substituted with one or more substituents as valence allows, where the substituents are independently selected from halogen, OH, alkyl, alkoxy, and amino (e.g., NH2, NHalkyl, N(alkyl)2), optionally, the alkyl can be further substituted.

[0424] ​​​​Examples of monocyclic 5- to 6-membered heteroaryl groups include furanyl (e.g., 2-furanyl, 3-furanyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 2-oxadiazolyl, 5-oxadiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), triazolyl (e.g., 2-triazolyl, 5-triazolyl), tetrazolyl (e.g., tetrazolyl), thiophenyl (e.g., 2-thiophenyl, 3-thiophenyl), pyrimidinyl, pyridyl, and pyridazinyl. Examples of polycyclic aromatic heteroaryl groups include carbazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl, or benzoisoxazolyl. A "substituted heteroaryl" is substituted at any one or more substitutable ring atom, which is a ring carbon or ring nitrogen atom bonded to hydrogen.

[0425] As used herein, any moiety (e.g., alkyl, alkylene, cycloalkyl, aryl, heteroaryl, or heterocyclyl) can be referred to as "substituted" or "optionally substituted." When a moiety is modified by one of these terms, unless otherwise indicated, it means that any portion of the moiety that can be substituted, known to one of ordinary skill in the art, can be substituted, including one or more substituents. If there is more than one substituent present, each substituent can be selected independently. Such meaning of substitution is well known in the art and / or taught by this disclosure. An optional substituent can be any substituent suitable for attachment to the moiety.

[0426] Where no suitable substituents are specifically listed, exemplary substituents include, but are not limited to: C1-5alkyl, C1-5hydroxyalkyl, C1-5haloalkyl, C1-5alkoxy, C1-5haloalkoxy, halogen, hydroxyl, cyano, amino, -CN, -NO2, -OR c1 , -NR a1 R b1 , -S(O) i R a1 , -NR a1 S(O) i R b1 , -S(O) i NR a1 R b1, -C(=O)OR a1 , -OC(=O)OR a1 , -C(=S)OR a1 , -O(C=S)R a1 , -C(=O)NR a1 R b1 , -NR a1 C(=O)R b1 , -C(=S)NR a1 R b1 , -C(=O)R a1 , -C(=S)R a1 , NR a1 C(=S)R b1 , -O(C=O)NR a1 R b1 , -NR a1 (C=S)OR b1 , -O(C=S)NR a1 R b1 , -NR a1 (C=O)NR a1 R b1 , -NR a1 (C=S)NR a1 R b1 , phenyl or 5- to 6-membered heteroaryl. Each R a1 and each R b1 is independently selected from -H and C1-5alkyl optionally substituted with hydroxyl or C1-3alkoxy; R c1 is H, C1-5haloalkyl or C1-5alkyl, wherein C1-5alkyl is optionally substituted with hydroxyl or C1-C3alkoxy.

[0427] Unless otherwise defined, the terms used herein have their standard meanings in the art (e.g., “hydroxy” or “hydroxyl” is -OH).

[0428] Pharmaceutically acceptable salt

[0429] The term “pharmaceutically acceptable salt” refers to a pharmaceutical salt that is, within the scope of sound medical judgment, suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, and allergic response, and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in J. Pharm. Sci., 1977, 66, 1-19.

[0430] Pharmaceutically acceptable salts of the compounds of any one of the above-described formulae include acid addition salts and base salts.

[0431] The teachings of the disclosure include pharmaceutically acceptable salts of the compounds disclosed herein. Compounds having basic groups can form pharmaceutically acceptable salts with pharmaceutically acceptable acids. Pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (e.g., hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, and sulfuric acids) and organic acids (e.g., acetic, benzenesulfonic, benzoic, ethanesulfonic, methanesulfonic, and succinic acids). Compounds of the teachings of the disclosure having an acidic group (e.g., a carboxylic acid) can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. Pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts (e.g., sodium and potassium salts), and alkaline earth metal salts (e.g., magnesium and calcium salts).

[0432] Pharmaceutically acceptable salts of the compounds of any one of the above- described formulae can be prepared by one or more of three methods:

[0433] (i) reacting a compound of any one of the above-described formulae with the desired acid or base;

[0434] (ii) removing an acid- or base-labile protecting group from a suitable precursor of a compound of any one of the above-described formulae, or ring-opening a suitable cyclic precursor (e.g., an internal ester or lactam) using the desired acid or base; or

[0435] (iii) converting one salt of a compound of any one of the above-described formulae to another by reaction with the appropriate acid or base, or via use of a suitable ion exchange column.

[0436] All three reactions are typically carried out in solution. The resulting salts can be precipitated from solution and collected by filtration or can be recovered by evaporation of the solvent. The degree of ionization in the resulting salt can vary from completely ionized to almost non-ionized.

[0437] The compounds of any one of the above-described formulae and their pharmaceutically acceptable salts can exist in unsolvated and solvated forms.

[0438] Stereoisomers and other variations

[0439] The compounds of any one of the above-described formulae can exhibit one or more types of isomerism (e.g., optical, geometric, or tautomeric). Such variations are implicit in the compounds of any one of the above-described formulae defined by reference to their structural features and thus fall within the scope of the disclosure.

[0440] Compounds having one or more chiral centers can exist in various stereoisomeric forms, i.e., each chiral center can have the R or S configuration, or can be a mixture of the two configurations. Stereoisomers are compounds that differ only in the arrangement of atoms in space. Stereoisomers include all diastereomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are mirror images of one another. Diastereomers are stereoisomers that are not mirror images of one another and have two or more chiral centers.

[0441] When a compound is named by its chemical name (e.g., where the configuration is indicated in the chemical name by “R” or “S”) or by its structure (e.g., the configuration is indicated by a “wedge” bond) indicating a single enantiomer, the compound has at least 60%, 70%, 80%, 90%, 99%, or 99.9% optical purity (also known as “enantiomerically pure”) unless otherwise indicated. The optical purity is the weight of the specified or depicted enantiomer in the mixture divided by the total weight of the mixture of the two enantiomers.

[0442] When the stereochemistry of a disclosed compound is specified or depicted by structure and the specified or depicted structure encompasses more than one stereoisomer (e.g., in a pair of diastereomers), it is understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers is included. It is also understood that the stereoisomerically pure is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight of the specified or depicted stereoisomer. In this case, the stereoisomerically pure is determined by the total weight of the mixture of the specified or depicted stereoisomer divided by the total weight of the mixture of all stereoisomers.

[0443] When two stereoisomers are depicted by their chemical names or structures and the chemical names or structures are connected by “and”, it means a mixture of the two stereoisomers.

[0444] When two stereoisomers are depicted by their chemical names or structures and the names or structures are connected by “or”, it means one or the other of the two stereoisomers, but not both.

[0445] When a disclosed compound having a chiral center is depicted by structure without showing the configuration at the chiral center, the structure is intended to encompass the compound having the S configuration at the chiral center, the compound having the R configuration at the chiral center, or the compound having a mixture of R and S configurations at the chiral center. When a disclosed compound having a chiral center is depicted by its chemical name without indicating whether the configuration of the chiral center is “S” or “R”, the name is intended to encompass the compound having the S configuration at the chiral center, the compound having the R configuration at the chiral center, or the compound having a mixture of R and S configurations at the chiral center.

[0446] A racemic mixture means 50% of one enantiomer and 50% of the corresponding enantiomer. When a compound having one chiral center is named or depicted without indicating the stereochemistry of the chiral center, it should be understood that the name or structure encompasses both possible enantiomeric forms of the compound (e.g., enantiomerically pure, enantiomerically enriched, or racemic). When a compound having two or more chiral centers is named or depicted without indicating the stereochemistry of the chiral centers, it should be understood that the name or structure encompasses all possible diastereomeric forms of the compound (e.g., diastereomerically pure, diastereomerically enriched, and equimolar mixtures of one or more diastereomers (e.g., racemic mixtures)).

[0447] The term "geometric isomer" means isomers that differ in the orientation of substituent atoms about a carbon-carbon double bond, carbocyclic ring, or bridged bicyclic ring system. The substituent atoms (other than hydrogen) on either side of a carbon-carbon double bond can be in the E or Z configuration according to the Cahn-Ingold-Prelog priority rule. In the "E" configuration, the substituent with the highest priority is located opposite the carbon-carbon double bond. In the "Z" configuration, the substituent with the highest priority is oriented toward the same side of the carbon-carbon double bond.

[0448] Substituents around a carbon-carbon double bond can also be referred to as "cis" or "trans", where "cis" indicates substituents on the same side of the double bond and "trans" indicates substituents on opposite sides of the double bond. The arrangement of substituents around a carbocyclic ring can also be named "cis" or "trans". The term "cis" indicates substituents on the same side of the ring plane, and the term "trans" indicates substituents on opposite sides of the ring plane. Mixtures of compounds in which the substituents are on the same side and on opposite sides of the ring plane are named "cis / trans".

[0449] Tautomeric isomerism ("tautomerism") can occur where structural isomers can interconvert by a low energy barrier. This can manifest as proton tautomerism in compounds of any one of the formulae described above containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds containing aromatic moieties. As such, a single compound can exhibit more than one type of isomerism.

[0450] In certain instances, there are tautomeric forms of the disclosed compounds, for example, the tautomeric structures shown below:

[0451]

[0452] When a geometric isomer is shown by name or structure, it is to be understood that the named or shown isomer is present to a greater extent than the other isomer, i.e., the geometric isomer named or shown is greater than 50% by weight geometrically pure, e.g., at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight. Geometric purity is determined by dividing the weight of the named or shown geometric isomer in the mixture by the total weight of all geometric isomers in the mixture.

[0453] Cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, e.g., chromatography and fractional crystallization.

[0454] Conventional techniques for preparing / isolating individual enantiomers / diastereomers include chiral synthesis from suitable optically pure precursors or resolution of a racemic form (or salt or derivative of a racemic form) by, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, a racemic form (or racemic precursor) can be reacted with an appropriate optically active compound (for example, ethanol) or, in the case of a compound of any one of the formulae described above containing an acidic or basic moiety, with a base or acid (for example, 1-phenylethylamine or tartaric acid). The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization, and one or both of the diastereomers converted into the corresponding pure enantiomers by techniques well known to the skilled person. Chiral compounds of any one of the formulae described above (and chiral precursors thereof) can be obtained in enantiomerically enriched form using asymmetric resin chromatography (typically HPLC) with a mobile phase consisting of a hydrocarbon (typically heptane or hexane) containing 0% to 50% by volume (typically 2% to 20%) of isopropanol and 0% to 5% by volume of an alkylamine (typically 0.1% diethylamine). The eluent is concentrated to give an enriched mixture. Chiral chromatography using subcritical and supercritical fluids can be employed. Chiral chromatography methods that can be used in some embodiments of the disclosure are known in the art (see, for example, Smith, Roger M., Loughborough University, Loughborough, UK; Chromatographic Science Series (1998), 75 (Supercritical Fluid Chromatography with Packed Columns), pages 223-249 and references cited therein). Columns can be obtained from Chiral Technologies, Inc, West Chester, Pa., USA, a subsidiary of Daicel Chemical Industries, Ltd., Tokyo, Japan. ® Chemical Industries, Ltd., Tokyo, Japan.

[0455] It must be emphasized that any of the compounds described above in any one of the formulae are depicted herein in a single tautomeric form, but all possible tautomeric forms are included within the scope of the present disclosure.

[0456] 3. Administration and Dosing

[0457] Generally, the compounds of the present disclosure are administered in an amount effective to treat the conditions described herein. The compounds of the present disclosure can be administered in the form of the compound itself or, alternatively, in the form of a pharmaceutically acceptable salt. For administration and dosing purposes, the compound itself or its pharmaceutically acceptable salt will be referred to simply as the compound of the present disclosure.

[0458] The compounds of the present disclosure are administered by any suitable route in the form of a pharmaceutical composition adapted to such route, and in a dose effective for the treatment intended. The compounds of the present disclosure can be administered orally, rectally, vaginally, parenterally, or topically.

[0459] The compounds of the present disclosure can be administered orally. Oral administration can involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration can be employed, by which the compound enters the blood circulation directly from the mouth.

[0460] In another embodiment, the compounds of the present disclosure can also be administered directly into the blood circulation, into muscle, or into an internal organ. Means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intracerebroventricular, intraurethral, sternal, intracranial, intramuscular, and subcutaneous. Devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors, and infusion techniques.

[0461] In another embodiment, the compounds of the present disclosure can also be administered topically, i.e., to the skin or mucosa, either cutaneously or transdermally. In another embodiment, the compounds of the present disclosure can also be administered intranasally or by inhalation. In another embodiment, the compounds of the present disclosure can be administered rectally or vaginally. In another embodiment, the compounds of the present disclosure can also be administered directly to the eye or ear.

[0462] The dosing regimen of the compounds of the present disclosure and / or of compositions comprising said compounds is based on a variety of factors, including the type, age, weight, sex, and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Thus, dosing regimens can vary widely.

[0463] Suitable individuals in accordance with the present disclosure include mammalian individuals, including non-human mammals, such as primates, rodents (mice, rats, hamsters, rabbits, etc.). In one embodiment, humans are suitable individuals. Human individuals can be of either gender and at any stage of development.

[0464] 4. Pharmaceutical Compositions

[0465] In another embodiment, the disclosure includes pharmaceutical compositions. These pharmaceutical compositions include a compound of the disclosure as presented, a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient. Other pharmacologically active substances can also be present.

[0466] As used herein, "pharmaceutically acceptable carrier or excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, and combinations thereof, and can include isotonic agents, for example, sugars, sodium chloride and the like. Pharmaceutically acceptable substances (e.g., wetting agents) or minor amounts of auxiliary substances (e.g., wetting or emulsifying agents, preservatives or buffers) enhance the shelf life or effectiveness of the antibody or antibody portion.

[0467] Compositions of the disclosure can be in various forms. These forms include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes, and suppositories. The form is dependent on the intended mode of administration and therapeutic application.

[0468] Typical compositions are in the form of injectable or infusible solutions, such as compositions similar to those used for passive immunization of humans with antibodies. One mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). In another embodiment, the antibody is administered by intravenous infusion or injection. In yet another embodiment, the antibody is administered by intramuscular or subcutaneous injection.

[0469] Oral administration of a solid dosage form can exist, for example, as discrete units such as hard or soft capsules, pills, cachets, lozenges or tablets each containing a predetermined amount of at least one compound of the disclosure. In another embodiment, oral administration can be in the form of a powder or granules. In another embodiment, the oral dosage form is a sublingual dosage form, such as a lozenge. In these solid dosage forms, the compound of any one of the formulae described above is generally combined with one or more adjuvants. These capsules or tablets can contain a slow-release formulation. In the case of capsules, tablets and pills, the dosage form can also include a buffering agent or can be prepared with an enteric coating.

[0470] In another embodiment, oral administration can be in the form of a liquid dosage form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions can also contain adjuvants, such as wetting agents, emulsifying agents, suspending agents, flavoring agents (e.g., sweetening agents), and / or perfuming agents.

[0471] In another embodiment, the present disclosure includes parenteral dosage forms.

[0472] “Parenteral administration” includes, for example, subcutaneous injections, intravenous injections, intraperitoneal, intramuscular injections, intrasternal injections, and infusions. Injectable preparations, i.e., sterile injectable aqueous or oleaginous suspensions, can be formulated according to known techniques using suitable dispersing agents, wetting agents, and / or suspending agents.

[0473] In another embodiment, the present disclosure includes topical dosage forms.

[0474] “Topical administration” includes, for example, transdermal administration such as through a transdermal patch or iontophoresic device, intraocular administration, or intranasal or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. Topical formulations can include compounds that enhance absorption or penetration of the active ingredient through the skin or other affected areas. When the compounds of the present disclosure are administered through a transdermal device, administration will be accomplished using a reservoir with a porous membrane type or a solid matrix type of patch. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, and microemulsions. Liposomes can also be used. Typical vehicles include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers can be incorporated, see, e.g., Finnin and Morgan, J. Pharm. Sci., 88:955-958, 1999.

[0475] Formulations suitable for topical administration to the eye include, for example, eye drops, wherein the compound of the present disclosure is dissolved or suspended in a suitable carrier. Typical formulations for ophthalmic or aural administration can be in the form of drops of a micronized suspension or solution in isotonic, pH adjusted, sterile saline. Other formulations suitable for ophthalmic and aural administration include creams, biodegradable (i.e., absorbable gel sponges, collagen) and non-biodegradable (i.e., silicone) implants, wafers, lenses, and microparticle or vesicle systems, such as niosomes or liposomes. Polymers, such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers (e.g., hydroxypropyl methylcellulose, hydroxyethylcellulose, or methylcellulose), or heterosaccharide polymers (e.g., gellan gum) can be incorporated with a preservative, such as benzalkonium chloride. Such formulations can also be delivered by iontophoresis.

[0476] For intranasal administration or administration by inhalation, the compounds of the present disclosure are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or from a pressurized container or a nebulizer with a suitable propellant. Formulations suitable for intranasal administration are generally administered as a dry powder from a dry powder inhaler, as a mixture in a dry blend with a lactose or other dry diluent and then administered from an insufflator, or as an aerosol spray from a pressurized container with a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane, in either a solution or a fine suspension. For intranasal use, the powder can contain a bioadhesive agent, for example, chitosan or cyclodextrin.

[0477] In another embodiment, the present disclosure includes rectal dosage forms. Such rectal dosage forms can be in the form of suppositories, for example, for example. Cocoa butter is a traditional suppository base, but various alternatives can be used as desired.

[0478] Other carrier materials and modes of administration known in the pharmaceutical art can also be used. The pharmaceutical compositions of the present disclosure can be prepared by any of the well-known pharmaceutical techniques, such as effective formulation and administration procedures.

[0479] The above considerations regarding effective formulation and administration procedures are well-known in the art and are described in standard texts. The formulation of drugs is discussed in, for example, Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1975; Liberman et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Kibbe et al., Eds., Handbook of Pharmaceutical Excipients (3 rd Ed.), American Pharmaceutical Association, Washington, 1999.

[0480] 5. Methods of treatment

[0481] The terms “individual” or “patient” are used interchangeably and refer to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.

[0482] The terms“treatment,”“treat,” and“treating” refer to reversing, alleviating, or inhibiting the progress of a disease described herein. In some embodiments, treatment can be administered after one or more symptoms or indicators of the disease have developed or have been observed (i.e., therapeutic treatment). In other embodiments, treatment can be administered in the absence of symptoms or indicators of the disease. For example, treatment can be administered to a susceptible individual prior to the onset of symptoms (i.e., prophylactic treatment) (e.g., in light of a history of symptoms and / or in light of exposure to a pathogen). Treatment can also continue after symptoms have resolved, for example to delay or prevent recurrence.

[0483] The terms“condition,”“disease,” and“disorder” are used interchangeably.

[0484] The terms“administer,”“administering” or“administration” refer to the methods used to introduce a compound disclosed herein or a composition thereof into the body or onto the surface of a patient. These methods include, but are not limited to, intraarticular (into a joint), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhalation, transdermal, rectal, and the like. Administration techniques that can be employed with the agents and methods described herein are found, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current edition; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

[0485] Generally, an effective amount of a compound taught herein will vary depending upon a variety of factors, for example, the drug or compound given, the pharmaceutical formulation, the route of administration, the type of disease or disorder, the identity of the individual or host being treated, and the like, but can nevertheless be routinely determined by one of ordinary skill in the art. An effective amount of a compound taught by the present disclosure can be readily determined by one of ordinary skill by routine methods known in the art.

[0486] The term "therapeutically effective amount" means an amount that, when administered to a subject, results in a beneficial or intended result, including clinical results, such as inhibition, suppression, or reduction of symptoms of a condition for which the subject is being treated, as compared to a control. For example, a therapeutically effective amount can be an amount effective to detectably kill or detectably inhibit the growth or spread of cancer cells, detectably kill or detectably inhibit the size or number of tumors, or detectably kill or detectably inhibit the grade, stage, progression, or other measure of cancer. The precise amount required will vary depending on the subject, depending on the subject's species, age, and general condition, the severity of the disease, the particular anticancer agent, its mode of administration, combination treatments with other therapies, and the like.

[0487] The compounds of the present disclosure can inhibit PI3K a and are thus useful in treating diseases in which the underlying pathology is mediated, in whole or in part, by PI3K a (e.g., PI3K a mutations). These diseases include cancer and CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis / osteofascial and spinal abnormalities syndrome).

[0488] In some embodiments, the present disclosure provides a method of modulating the activity of a PI3K (e.g., PI3K a) (e.g., in vitro or in vivo), comprising contacting a cell with a therapeutically effective amount of a compound of Formula (I) or (I'), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

[0489] In some embodiments, the present disclosure provides a method of modulating the activity of a mutant PI3K a (e.g., in vitro or in vivo), comprising contacting a cell with a therapeutically effective amount of a compound of Formula (I) or (I'), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

[0490] In some embodiments, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or (I') of the present disclosure, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition.

[0491] In some embodiments, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or (I') of the present disclosure, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition.

[0492] In some embodiments, the disease or disorder is associated with PI3K (e.g., PI3K a) activity. In some embodiments, the disease or disorder is a disease or disorder in which PI3K (e.g., PI3K a) activity is implicated.

[0493] In some embodiments, the disease or disorder is associated with mutant PI3Ka activity. In some embodiments, the disease or disorder is a disease or disorder in which mutant PI3Ka activity is implicated.

[0494] In some embodiments, the disease or disorder is cancer.

[0495] In some embodiments, the cancer is selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphoma, anal cancer, astrocytic tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, osteosarcoma, malignant fibrous histiocytoma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, cancer of unknown primary origin, cardiac tumor, atypical teratoid / rhabdoid tumor, primary CNS lymphoma, cervical cancer, cholangiocarcinoma, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, mycosis fungoides, Sezary syndrome, ductal carcinoma in situ (DCIS), embryonal tumor, medulloblastoma, endometrial cancer, ependymal tumor, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic disease, hairy cell leukemia, head and neck cancer, hepatocellular cancer, Langerhans cell histiocytosis, Hodgkin lymphoma, islet cell tumor, pancreatic neuroendocrine tumor, Kaposi sarcoma, kidney cancer, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, macular tumor, melanoma, Merkel cell carcinoma, mesothelioma, mouth cancer, multiple myeloma, myelodysplastic syndrome, myeloproliferative disorder, nasal cavity cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, oral cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pituitary tumor, plasma cell neoplasm, pleuropulmonary blastoma, prostate cancer, rectal cancer, renal cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach cancer, T-cell lymphoma, testicular cancer, throat cancer, thymoma, thyroid cancer, tongue cancer, ureter cancer, urethral cancer, uterine cancer, vaginal cancer, and vulvar cancer.sarcoma), kidney cancer, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, male breast cancer, intraocular melanoma, Merkel cell carcinoma, malignant mesothelioma, metastatic cancer, metastatic squamous neck cancer with occult primary, midline carcinoma with NUT gene alterations, mouth cancer, multiple endocrine neoplasm syndrome, multiple myeloma / plasma cell neoplasm, myelodysplastic syndrome, myelodysplastic neoplasm, myeloproliferative neoplasm, chronic myelogenous neoplasm, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, lip and oral cavity cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumor (islet cell tumor), papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumor, plasma cell neoplasm, multiple myeloma, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, recurrent cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, childhood hemangioma, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell cancer of the skin, testicular cancer, throat cancer, thymoma, thymic carcinoma, thyroid cancer, tracheal and bronchial tumors, transitional cell cancer of the renal pelvis and ureter, urethral cancer, uterine sarcoma, vaginal cancer, vascular tumors, vulvar cancer, and Wilms tumor.

[0496] In some embodiments, the cancer is endometrial cancer, breast cancer, esophageal squamous cell carcinoma, cervical squamous cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, bladder urothelial carcinoma, glioblastoma, ovarian cancer, non-small cell lung cancer, gastroesophageal cancer, schwannoma, head and neck squamous cell carcinoma, melanoma, gastroesophageal adenocarcinoma, soft tissue sarcoma, prostate cancer, fibroblastic sarcoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, cholangiocarcinoma, B-cell lymphoma, mesothelioma, adrenocortical carcinoma, non-clear cell renal carcinoma, clear cell renal carcinoma, germ cell carcinoma, thymoma, pheochromocytoma, mixed neuroepithelial tumor, thyroid cancer, leukemia, or encapsulated glioma.

[0497] In some embodiments, the cancer is breast cancer, prostate cancer, or brain cancer.

[0498] In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is brain cancer.

[0499] In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, the breast cancer is ductal carcinoma in situ (DCIS). In some embodiments, the breast cancer is invasive ductal carcinoma. In some embodiments, the breast cancer is triple negative breast cancer. In some embodiments, the breast cancer is medullary carcinoma. In some embodiments, the breast cancer is tubular carcinoma. In some embodiments, the breast cancer is mucinous carcinoma. In some embodiments, the breast cancer is Paget disease of the breast or nipple. In some embodiments, the breast cancer is inflammatory breast cancer (IBC).

[0500] In some embodiments, the prostate cancer is adenocarcinoma. In some embodiments, the prostate cancer is small cell carcinoma. In some embodiments, the prostate cancer is neuroendocrine tumor. In some embodiments, the prostate cancer is transitional cell carcinoma. In some embodiments, the prostate cancer is sarcoma.

[0501] In some embodiments, the brain cancer is acoustic neuroma. In some embodiments, the brain cancer is astrocytoma. In some embodiments, the brain cancer is brain metastasis. In some embodiments, the brain cancer is choroid plexus carcinoma. In some embodiments, the brain cancer is craniopharyngioma. In some embodiments, the brain cancer is embryonal tumor. In some embodiments, the brain cancer is ependymoma. In some embodiments, the brain cancer is glioblastoma. In some embodiments, the brain cancer is glioma. In some embodiments, the brain cancer is medulloblastoma. In some embodiments, the brain cancer is meningioma. In some embodiments, the brain cancer is oligodendroglioma. In some embodiments, the brain cancer is pediatric brain tumor. In some embodiments, the brain cancer is pinealoblastoma. In some embodiments, the brain cancer is pituitary tumor.

[0502] In some embodiments, the cancer is breast cancer (e.g., hormone receptor positive breast cancer, HER2 negative breast cancer, HER2 positive breast cancer, and triple negative breast cancer), endometrial cancer, uterine cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, brain cancer, or prostate cancer.

[0503] In some embodiments, the disease or disorder associated with PI3K a (e.g., PI3K a mutation) includes, but is not limited to, CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis / osteochondro dysplasia syndrome), PIK3CA-related overgrowth syndrome (PROS), breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer.

[0504] In some embodiments, the disease or disorder associated with PI3Ka (e.g., a PI3Ka mutation) is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis / osteochondro dysplasia syndrome).

[0505] In some embodiments, the disease or disorder associated with PI3Ka (e.g., a PI3Ka mutation) is PIK3CA-related overgrowth syndrome (PROS).

[0506] In some embodiments, the disease or disorder associated with PI3Ka (e.g., a PI3Ka mutation) is breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer.

[0507] In some embodiments, the disease or disorder associated with PI3Ka (e.g., a PI3Ka mutation) is breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer.

[0508] In some embodiments, the disease or disorder associated with PI3Ka (e.g., a PI3Ka mutation) is leukemia, lymphoma, or sarcoma.

[0509] In some embodiments, the cancer is endometrial cancer, head and neck cancer, or sarcoma.

[0510] In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is sarcoma.

[0511] In some embodiments, the sarcoma is soft tissue sarcoma, osteosarcoma, chondrosarcoma, Ewing sarcoma, hemangioendothelioma, angiosarcoma, fibrosarcoma, myofibrosarcoma, chordoma, adamantinoma, liposarcoma, leiomyosarcoma, malignant peripheral nerve sheath tumor, rhabdomyosarcoma, synovial sarcoma, or malignant solitary fibrous tumor.

[0512] In some embodiments, the sarcoma is a soft tissue sarcoma. In some embodiments, if not specified, the soft tissue sarcoma is a liposarcoma, atypical lipomatous tumor, dermatofibrosarcoma protuberans, solitary fibrous tumor, inflammatory myofibroblastic tumor, low grade myofibroblastic sarcoma, fibrosarcoma, myxofibrosarcoma, low grade fibromyxoid sarcoma, soft tissue giant cell tumor, leiomyosarcoma, glomus tumor, rhabdomyosarcoma, hemangioendothelioma, angiosarcoma, extraskeletal osteosarcoma, gastrointestinal stromal tumor, malignant gastrointestinal stromal tumor (GIST), malignant peripheral nerve sheath tumor, malignant Triton tumor, malignant granular cell tumor, malignant ossifying fibromyxoid tumor, stromal sarcoma, myoepithelial carcinoma, malignant phyllodes tumor, synovial sarcoma, epithelioid sarcoma, alveolar soft part sarcoma, clear cell sarcoma of soft tissue, extraskeletal myxoid chondrosarcoma, extraskeletal Ewing sarcoma, desmoplastic small round cell tumor, extrarenal rhabdoid tumor, perivascular epithelioid cell tumor, intimal sarcoma, undifferentiated spindle cell sarcoma, undifferentiated pleomorphic sarcoma, undifferentiated round cell sarcoma, undifferentiated epithelioid sarcoma, or undifferentiated sarcoma.

[0513] In some embodiments, the present disclosure provides a method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or (I’), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition of the present disclosure.

[0514] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or (I’), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition of the present disclosure.

[0515] In some embodiments, the present disclosure provides a method of treating or preventing breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or (I’), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition of the present disclosure.

[0516] In some embodiments, the present disclosure provides a method of treating breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or (I’), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition of the present disclosure.

[0517] In some embodiments, the present disclosure provides a method of treating or preventing prostate cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or (I’), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition of the present disclosure.

[0518] In some embodiments, the present disclosure provides a method of treating prostate cancer in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Formula (I) or (I'), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition of the present disclosure.

[0519] In some embodiments, the present disclosure provides a method of treating or preventing brain cancer in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Formula (I) or (I'), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition of the present disclosure.

[0520] In some embodiments, the present disclosure provides a method of treating brain cancer in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Formula (I) or (I'), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition of the present disclosure.

[0521] In some embodiments, the present disclosure provides a compound of Formula (I) or (I'), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, for use in modulating PI3K (e.g., PI3K a) activity (e.g., in vitro or in vivo).

[0522] In some embodiments, the present disclosure provides a compound of Formula (I) or (I'), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, for use in modulating mutant PI3K a activity (e.g., in vitro or in vivo).

[0523] In some embodiments, the present disclosure provides a compound of Formula (I) or (I'), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, for use in treating or preventing a disease or disorder disclosed herein.

[0524] In some embodiments, the present disclosure provides a compound of Formula (I) or (I'), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, for use in treating a disease or disorder disclosed herein.

[0525] In some embodiments, the present disclosure provides a compound of Formula (I) or (I'), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, for use in treating or preventing cancer in an individual in need thereof.

[0526] In some embodiments, the present disclosure provides a compound of Formula (I) or (I'), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, for use in treating cancer in an individual in need thereof.

[0527] In some embodiments, the present disclosure provides a compound of Formula (I) or (I'), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, for use in treating or preventing breast cancer in an individual in need thereof.

[0528] In some embodiments, the present disclosure provides a compound of Formula (I) or (I'), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, for use in treating breast cancer in an individual in need thereof.

[0529] In some embodiments, the present disclosure provides a compound of Formula (I) or (I'), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, for use in treating or preventing prostate cancer in an individual in need thereof.

[0530] In some embodiments, the present disclosure provides a compound of Formula (I) or (I'), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, for use in treating prostate cancer in an individual in need thereof.

[0531] In some embodiments, the present disclosure provides a compound of Formula (I) or (I'), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, for use in treating or preventing brain cancer in an individual in need thereof.

[0532] In some embodiments, the present disclosure provides a compound of Formula (I) or (I'), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, for use in treating brain cancer in an individual in need thereof.

[0533] In some embodiments, the present disclosure provides use of a compound of Formula (I) or (I'), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in the manufacture of a medicament for modulating PI3K (e.g., PI3K a) activity (e.g., in vitro or in vivo).

[0534] In some embodiments, the present disclosure provides use of a compound of Formula (I) or (I'), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in the manufacture of a medicament for modulating mutant PI3K a activity (e.g., in vitro or in vivo).

[0535] In some embodiments, the present disclosure provides use of a compound of Formula (I) or (I'), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in the manufacture of a medicament for treating or preventing a disease or condition disclosed herein.

[0536] In some embodiments, the present disclosure provides use of a compound of Formula (I) or (I'), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in the manufacture of a medicament for treating a disease or condition disclosed herein.

[0537] In some embodiments, the present disclosure provides use of a compound of Formula (I) or (I'), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in the manufacture of a medicament for treating or preventing cancer in an individual in need thereof.

[0538] In some embodiments, the present disclosure provides use of a compound of Formula (I) or (I'), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in the manufacture of a medicament for treating cancer in an individual in need thereof.

[0539] In some embodiments, the disclosure provides use of a compound of Formula (I) or (I'), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in the manufacture of a medicament for treating or preventing breast cancer in an individual in need thereof.

[0540] In some embodiments, the disclosure provides use of a compound of Formula (I) or (I'), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in the manufacture of a medicament for treating breast cancer in an individual in need thereof.

[0541] In some embodiments, the disclosure provides use of a compound of Formula (I) or (I'), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in the manufacture of a medicament for treating or preventing prostate cancer in an individual in need thereof.

[0542] In some embodiments, the disclosure provides use of a compound of Formula (I) or (I'), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in the manufacture of a medicament for treating prostate cancer in an individual in need thereof.

[0543] In some embodiments, the disclosure provides use of a compound of Formula (I) or (I'), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in the manufacture of a medicament for treating or preventing brain cancer in an individual in need thereof.

[0544] In some embodiments, the disclosure provides use of a compound of Formula (I) or (I'), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in the manufacture of a medicament for treating brain cancer in an individual in need thereof.

[0545] The disclosure provides compounds for use as modulators (i.e., inhibitors) of PI3K activity. Accordingly, the disclosure provides a method of modulating PI3K activity in vitro or in vivo, the method comprising contacting a cell with a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof.

[0546] In some embodiments, the PI3K a modulation is PI3K a inhibition.

[0547] In some embodiments, the PI3K a inhibitor is a compound of Formula (I) or (I'), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. In some embodiments, the PI3K a inhibitor is a mutant PI3K a inhibitor. In some embodiments, the PI3K a inhibitor is a PI3K a H1047R mutant inhibitor. In some embodiments, the PI3K a inhibitor is a PI3K a H1047L mutant inhibitor.

[0548] The effectiveness of the compounds of the disclosure can be determined by industry-recognized analytical / disease models that elucidate the same in the art and based on standard practices of current general knowledge.

[0549] The present disclosure also provides a method of treating a disease or disorder involving PI3Ka activity in a patient in need of treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or (I'), as defined herein, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

[0550] The present disclosure provides a method of modulating the activity of the allosteric active site of PI3Ka, wherein the modulation is induced by targeting a peripheral site. In some embodiments, the peripheral site is targeted by an agent selected from the group consisting of a small molecule, a peptide, a peptidomimetic, a protein, a protein mimetic, a nucleic acid, an antibody, an antibody-drug conjugate, a nucleoprotein complex, an immunotherapy, or a combination thereof.

[0551] 6. Therapeutic kits

[0552] One aspect of the present disclosure relates to a kit suitable and effective for carrying out a method or use according to the present disclosure. Typically, a pharmaceutical pack or kit comprises one or more containers filled with one or more of the ingredients of a pharmaceutical composition of the present disclosure. These kits are particularly suitable for the delivery of solid oral forms, such as tablets or capsules. Such a kit preferably includes a plurality of unit dosages and can further include a card on which the dosages are arranged in the order in which they are intended to be used. Where desired, memory aids can be provided, such as numbers, letters, or other markings or the use of a calendar insert, to indicate the dates on which dosages can be administered in the treatment schedule. Such containers can optionally be accompanied by written

[0553] The following representative examples contain important additional information, exemplification, and guidance that can be adapted to the practice of the present disclosure in its various embodiments and equivalents thereof. These examples are intended to illustrate the present invention and are not intended to limit, and should not be construed as limiting, the scope thereof. Indeed, various modifications of the present disclosure and many further embodiments thereof, in addition to those shown and described herein, will readily occur to those skilled in the art upon review of the drawings and this description.

[0554] The contents of the cited references are incorporated herein by reference to aid in the understanding of the current state of the art.

[0555] Additionally, for purposes of this disclosure, chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics 75thEd. inside cover, and specific functional groups are specified in accordance with "Organic Chemistry" Thomas Sorrell, University Science Books, Sausalito: 1999; and "Organic Chemistry," Morrison & Boyd (3d Ed.). The entire contents of these references are hereby incorporated by reference.

[0556] 7. Preparation

[0557] Compounds of any one of the formulae described above can be prepared by general and specific methods described below using the general knowledge of a person skilled in the art of synthetic organic chemistry. Such general knowledge can be found in standard reference works, e.g. Comprehensive Organic Chemistry, Barton and Ollis, Eds., Elsevier; Comprehensive Organic Transformations: A Guide to Functional Group Preparations, Larock, John Wiley and Sons; and Compendium of Organic Synthetic Methods, Volumes I-XII (published by Wiley-Interscience). Starting materials used herein can be purchased or can be prepared by routine methods known in the art.

[0558] In preparing compounds of any one of the formulae described above, it will be appreciated that some of the processes described herein can require protection of remote functionality (for example, primary amines, secondary amines, carboxyl groups in precursors of any one of the formulae described above). The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation method. The selection and use of suitable protecting groups is a matter of choice and will be apparent to those skilled in the art. The need for protection will also depend on the nature and the conditions of the preparation method. The need for protection will be readily determined by one skilled in the art. The use of such protecting groups / addition of protecting groups is within the skill of those in the art. For a general description of protecting groups and their use, see Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0559] For example, certain compounds contain primary amine or carboxylic acid functional groups that, if unprotected, can interfere with reactions at other sites in the molecule. Thus, these functional groups can be protected by appropriate protecting groups that can be removed in subsequent steps. Protecting groups suitable for amine and carboxylic acid protection include those commonly used in peptide synthesis (e.g., N-tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and 9-fluorenylmethyloxycarbonyl (Fmoc) for amines and lower alkyl or benzyl ester groups for carboxylic acids), which are generally unreactive under the reaction conditions described and which can generally be removed without chemically altering another functional group in a compound of any one of the formulae described above.

[0560] The schemes / examples described below are intended to provide a general description of the methods employed in preparing the compounds of the disclosure. Some of the compounds of the disclosure can contain a single or multiple chiral centers with stereochemistry designated (R) or (S). It will be apparent to those skilled in the art that all synthetic transformations can be carried out in an analogous manner, whether the material is enantiomerically enriched or racemic. Resolution of the desired optically active material can be carried out at any desired point in the sequence using, for example, known methods described herein and in the chemical literature.

[0561] Examples

[0562] Abbreviations

[0563] rt room temperature

[0564] N2nitrogen

[0565] DCM dichloromethane

[0566] DCE 1,2-dichloroethane

[0567] DMF N,N-dimethylformamide

[0568] DMSO dimethyl sulfoxide

[0569] Et20 diethyl ether

[0570] EtOH ethanol

[0571] DME 1,2-dimethoxyethane

[0572] EtOAc ethyl acetate

[0573] THF tetrahydrofuran

[0574] CHCl3chloroform

[0575] TEA triethylamine

[0576] H2O2hydrogen peroxide

[0577] DIPEA N,N-diisopropylethylamine

[0578] HATU 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0579] BOP 1H-benzotriazol-1-yl oxytris(dimethylamino)phosphonium hexafluorophosphate

[0580] PyBOP benzotriazol-1-yl oxytripyrrolidinophosphonium hexafluorophosphate

[0581] PPh3 triphenylphosphine

[0582] DIAD diisopropyl azodicarboxylate

[0583] Pd(PPh3)2Cl2 bis(triphenylphosphine)palladium(II) chloride

[0584] Pd(PPh3)4 tetrakis(triphenylphosphine)palladium

[0585] X-phos 2-(dicyclohexylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl

[0586] Pd2(dba)3 tris(dibenzylideneacetone)dipalladium

[0587] Pd(dppf)Cl2 [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)

[0588] DIBAL-H diisobutylaluminum hydride

[0589] (NH4)2S2O8 ammonium persulfate

[0590] KF potassium fluoride

[0591] NaBH4 sodium borohydride

[0592] LiOH H2O lithium hydroxide monohydrate

[0593] LiHMDS lithium bis(trimethylsilyl)amide

[0594] Ti(OEt)4 titanium ethoxide

[0595] TiCl4 titanium tetrachloride

[0596] HCl hydrochloric acid

[0597] AcOH acetic acid

[0598] POCl3 phosphorus oxychloride

[0599] CeCl3 cerium(III) chloride

[0600] Na2SO4 sodium sulfate

[0601] NaHCO3 sodium bicarbonate

[0602] Na2S2O3 sodium thiosulfate

[0603] Cs2CO3 cesium carbonate

[0604] KOAc potassium acetate

[0605] Na2CO3 sodium carbonate

[0606] NH4Cl ammonium chloride

[0607] LC-MS liquid chromatography mass spectrometry

[0608] prep-HPLC preparative high-performance liquid chromatography

[0609] K2CO3 potassium carbonate

[0610] m-CPBA 3-chloroperbenzoic acid

[0611] MeOH methanol

[0612] ACN acetonitrile

[0613] CDI 1,1'-carbonyldiimidazole

[0614] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0615] MTBE tert-butyl methyl ether

[0616] NaCl sodium chloride

[0617] BINAP 1.1'-binaphthalene-2.2'-bisphosphine

[0618] CH3ONa sodium methoxide

[0619] AlCl3 aluminum chloride

[0620] TFAA trifluoroacetic anhydride

[0621] NaNO2 sodium nitrite

[0622] KI potassium iodide

[0623] NaH sodium hydride

[0624] NaClO sodium hypochlorite

[0625] CuI copper(I) iodide

[0626] BBr3 boron tribromide

[0627] IBX 2-iodoxybenzoic acid

[0628] POBr3 Phosphorus oxybromide

[0629] Xant-phos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0630] t-BuOK Potassium tert-butoxide

[0631] TMSCl Trimethylsilyl chloride

[0632] (Boc)2O Di-tert-butyl dicarbonate

[0633] CuBr2 Copper bromide

[0634] Fe Iron

[0635] CAN Cerium ammonium nitrate

[0636] PyClOP Chlorotripyrridinylphosphonium hexafluorophosphate

[0637] Part 1. Synthetic methods for preparing intermediates

[0638] Intermediate 1

[0639]

[0640] Step 1:

[0641] To a stirred solution of 4,6-dichlorobenzaldehyde (3 g, 17.1 mmol) in methanol (20 mL) at 0 °C was added acetic acid (511 mg, 8.5 mmol) and phenethylamine (2 g, 18.7 mmol). The mixture was stirred at 25 °C under N2for 1 h. Then, sodium cyanoborohydride (1.6 g, 25.5 mmol) was added and the mixture was stirred at 25 °C for 1 h. The mixture was diluted with water (50 mL) and extracted with DCM (100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography to give N-phenethyl-1-(4,6-dichloropyridin-3-yl)methanamine (3.8 g, crude) as a yellow solid, which was used in the next step without further purification. LC-MS: m / z 267.0 [M+H] + .

[0642] Step 2:

[0643] To a stirred solution of N-benzyl-l-(4,6-dichloropyridin-3-yl)methanamine (5 g, 18.7 mmol) and triethylamine (9.4 g, 93.5 mmol) in DCM (80 mL) was added 3-chloro-3-oxopropionic acid methyl ester (5.1 g, 36.4 mmol) at 0 °C. The mixture was stirred at 25 °C under N2atmosphere for 1 h. The mixture was diluted with water (100 mL) and extracted with DCM (100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography to give 3-(benzyl((4,6-dichloropyridin-3-yl)methyl)amino)-3-oxopropionic acid methyl ester (5 g, 72% yield) as a yellow solid. LC-MS: m / z 367.0 [M+H] + .

[0644] Step 3:

[0645] To a stirred solution of 3-(benzyl((4,6-dichloropyridin-3-yl)methyl)amino)-3- oxopropionic acid methyl ester (1.5 g, 4.1 mmol) in DMF (20 mL) was added potassium carbonate (1.7 g, 12.3 mmol) at 20 °C. The resulting mixture was stirred at 120 °C under N2atmosphere for 5 h. The mixture was diluted with water (100 mL) and extracted with DCM (100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography to give 2-benzyl-6-chloro-3-oxo-l,2,3,4-tetrahydro-2,7- naphthyridine-4-carboxylic acid methyl ester (1.2 g, 88% yield) as a yellow solid. LC-MS: m / z 331.1 [M+H] + .

[0646] Step 4:

[0647] A solution of 2-benzyl-6-chloro-3-oxo-l,2,3,4-tetrahydro-2,7-naphthyridine-4- carboxylic acid methyl ester (1 g, 3 mmol) in concentrated HCl (15 mL) was stirred at 100 °C under N2for 1 h. The pH of the mixture was adjusted to 8 with saturated aqueous NaHCO3solution. The mixture was diluted with water (50 mL) and extracted with DCM (100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give 2-benzyl-6-chloro-l,4-dihydro-2,7-naphthyridine-3(2H)-one (600 mg, 73% yield) as a yellow oil. LC-MS: m / z 273.1 [M+H] + .

[0648] Step 5:

[0649] A solution of 2-benzyl-6-chloro-l,4-dihydro-2,7-naphthyridin-3(2H)-one (700 mg, 2.5 mmol) in borane (1 M in THF, 25 mmol, 25 mL) was stirred at 70 °C under N2for 1 h. The mixture was quenched with MeOH (10 mL), followed by addition of 2 N HC1 (10 mL) and stirring for 1 h. The mixture was diluted with water (100 mL) and extracted with DCM (100 mL). The organic layer was washed with brine (100 mL), dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to give 2-benzyl-6-chloro-l,2,3,4-tetrahydro-2,7-naphthyridine (500 mg, 75% yield) as a yellow solid. LC-MS: m / z 259.1 [M+H] + .

[0650] Step 6:

[0651] To a stirred solution of 2-benzyl-6-chloro-l,2,3,4-tetrahydro-2,7-naphthyridine (500 mg, 1.9 mmol) and DIPEA (750 mg, 5.8 mmol) in DCE (10 mL) was added 1- chloroethyl chloroformate (1.1 g, 7.7 mmol) at 0 °C. The mixture was stirred at 70 °C under N2atmosphere for 2 h. The mixture was concentrated in vacuo, and then methanol (10 mL) was added. The mixture was stirred at 70 °C for 2 h. The mixture was then concentrated in vacuo to give 6-chloro-l,2,3,4-tetrahydro-2,7-naphthyridine (500 mg, crude) as a yellow oil, which was used in the next step without further purification.

[0652] Intermediate 2

[0653]

[0654] Step 1:

[0655] To a solution of 7,8-dihydro-6H-isoquinoline-5-one (1 g, 6.9 mmol) in methanol (20 mL), pyrrolidine (194.8 mg, 2.7 mmol), 3-bromo-5-fluoro-2-hydroxybenzaldehyde (1.5 g, 6.9 mmol), and H₂O (10 mL) were added. The mixture was stirred at 60 °C for 12 h. The resulting mixture was quenched by adding saturated aqueous NH₄Cl solution (5 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by rapid chromatography to give (3-bromo-5-fluoro-2-hydroxyphenyl)-(7,8-dihydroisoquinoline-6-yl) methyl ketone (700 mg, 29% yield) as a yellow solid. LC-MS: m / z 348.0 [M+H] + .

[0656] Step 2:

[0657] I₂ (500 mg, 2 mmol) was added to a solution of (3-bromo-5-fluoro-2-hydroxy-phenyl)-(7,8-dihydroisoquinoline-6-yl) methyl ketone (450 mg, 1.3 mmol) in DMSO (2 mL). The mixture was stirred at 100 °C for 8 hours. The resulting mixture was quenched by adding saturated aqueous Na₂SO₃ (20 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by rapid chromatography to give 11-bromo-9-fluoro-5,6-dihydrobenzopyrano[2,3-f]isoquinoline-7-one (170 mg, 38% yield) as a white solid. LC-MS: m / z 346.0 [M+H] + .

[0658] Intermediate 3

[0659]

[0660] Step 1:

[0661] To a solution of (3R)-3-vinylmorpholine hydrochloride (500 mg, 3.3 mmol) in DCM (10 mL) was added HATU (1.3 g, 3.3 mmol), DIPEA (1.7 g, 13.4 mmol) and but-3-enoic acid (431.5 mg, 5 mmol). The mixture was stirred at 20 °C for 12 h. The resulting mixture was quenched by the addition of saturated aqueous NH4Cl solution (5 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to give 1-[(3R)-3-vinylmorpholin-4-yl]but-3-en-1-one (480 mg, 79% yield) as a colorless oil. LC-MS: m / z 182.1 [M+H] + .

[0662] Step 2:

[0663] To a solution of 1-[(3R)-3-vinylmorpholin-4-yl]but-3-en-1-one (480 mg, 2.7 mmol) in DCM (10 mL) was added 1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium (112.4 mg, 0.1 mmol). The mixture was degassed with N2and backfilled 3 times and stirred at 20 °C for 36 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography to give (9aR)-3,4,7,9a-tetrahydro-1H-pyrido[2,1-c][1,4]oxazin-6-one (350 mg, 86% yield) as a yellow oil. LC-MS: m / z 154.0 [M+H] + .

[0664] Step 3:

[0665] To a round-bottom flask was added (9aR)-3,4,7,9a-tetrahydro-1H-pyrido[2,1-c][1,4]oxazin-6-one (350 mg, 2.3 mmol), PtO2 (20 mg, 0.1 mmol) and methanol (2 mL). The mixture was backfilled with H2three times and stirred at 20 °C for 6 h. The resulting mixture was filtered and concentrated under reduced pressure to give (9aR)-3,4,7,8,9,9a-hexahydro-1H-pyrido[2,1-c][1,4]oxazin-6-one (350 mg, 98% yield) as a black oil. LC-MS: m / z 156.0 [M+H] + .

[0666] Step 4:

[0667] To a solution of 3-bromo-5-fluoro-2-hydroxy-benzoic acid (1.6 g, 6.8 mmol) in MeOH (10 mL) was added H2SO4 (668 mg, 6.8 mmol). The mixture was stirred at 60 °C for 12 h. The resulting mixture was added to water and filtered. The filter cake was washed with water, dried under reduced pressure to give methyl 3-bromo-5-fluoro-2-hydroxy-benzoate (1.6 g, 94% yield) as a brown solid.

[0668] Step 5:

[0669] To a solution of methyl 3-bromo-5-fluoro-2-hydroxy-benzoate (1.4 g, 5.6 mmol) in THF (10 mL) was added NaH (60% dispersion in oil, 449.7 mg, 11.2 mmol, 60% purity). The mixture was stirred at 0 °C for 1 h. Then, bromo(methyloxy)methane (1.4 g, 11.2 mmol) was added to the mixture and stirred at 20 °C for 12 h. The resulting mixture was quenched by the addition of saturated aqueous NH4Cl solution (5 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give methyl 3-bromo-5-fluoro-2-(methoxymethoxy)benzoate (2.1 g, crude) as a yellow oil.

[0670] Step 6:

[0671] To a round bottom flask was added (9aR)-3,4,7,8,9,9a-hexahydro-lH-pyrido[2,l- c][l,4]oxazin-6-one (300 mg, 1.9 mmol) and THF (20 mL). The solution was degassed with N2and backfilled 3 times. Then (diisopropylamino)lithium (2.0 M, 2 mL) was added to the solution at 0 °C for 0.5 h. Then methyl 3-bromo-5-fluoro-2- (methoxymethoxy)benzoate (700 mg, 2.4 mmol) was added to the mixture at 0 °C. The mixture was allowed to warm to 20 °C and stirred at 20 °C for 12 h. The resulting mixture was quenched by the addition of saturated aqueous NH4Cl (20 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to give (9aR)-7-[3-bromo-5-fluoro-2- (methoxymethoxy)benzoyl]-3,4,7,8,9,9a-hexahydro-lH-pyrido[2,l-c][l,4]oxazin-6-one (400 mg, 50% yield) as a yellow solid. LC-MS: m / z 415.8 [M+H] + .

[0672] Step 7:

[0673] To a solution of (9aR)-7-[3-bromo-5-fluoro-2-(methoxymethoxy)benzoyl]-3,4,7,8,9,9a- hexahydro-lH-pyrido[2,l-c][l,4]oxazin-6-one (400 mg, 1 mmol) in DCM (5 mL) was added TFA (1.5 g, 13.1 mmol). The mixture was stirred at 20 °C for 1 h. The resulting mixture was quenched by the addition of saturated aqueous NaHC03(5 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give (9aR)-7-(3-bromo-5-fluoro-2-hydroxy- benzoyl)-3,4,7,8,9,9a-hexahydro-lH-pyrido[2,l-c][l,4]oxazin-6-one (350 mg, 97% yield) as a brown oil. LC-MS: m / z 372.0 [M+H] + .

[0674] Step 8:

[0675] To a solution of (9aR)-7-(3-bromo-5-fluoro-2-hydroxy-benzoyl)-3,4,7,8,9,9a- hexahydro-1H-pyrido[2,1-c][1,4]oxazin-6-one (300 mg, 0.8 mmol) in CHCl3 (20 mL) was added PPA (8.4 g, 5 mL). The mixture was stirred at 80 °C for 12 h. The resulting mixture was added to water and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to give (7R)-16-bromo-14-fluoro-5,18-dioxa-2- azatetracyclo[8.8.0.0 2, 7 .0 12,17 ]octadeca-1(10),12(17),13,15-tetraen-11-one (120 mg, 42% yield). LC-MS: m / z 354.0 [M+H] + .

[0676] Intermediate 4

[0677]

[0678] Step 1:

[0679] To a solution of (3R)-3-(hydroxymethyl)morpholine-4-carboxylic acid tert-butyl ester (5 g, 23 mmol) in DCM (20 mL) was added (1,1-diacetoxy-3-oxo-1,2-benziodoxol-1- yl)acetate (11.7 g, 27.6 mmol). The mixture was stirred at 20 °C for 12 h. The resulting mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to give (3S)-3-formylmorpholine-4-carboxylic acid tert-butyl ester (4.5 g, 90% yield) as green oil.

[0680] Step 2:

[0681] Potassium bis(trimethylsilyl)imine (1 M, 23 mL) was added dropwise to a solution of methyl(triphenyl)phosphonium bromide (8.2 g, 23 mmol) in THF (50 mL) at 0 °C. Then, tert-butyl (3S)-3-formylmorpholine-4-carboxylate (4.5 g, 20.9 mmol) was added to the mixture at 0 °C. The mixture was heated to 20 °C and stirred for 12 hours. The resulting mixture was quenched by adding saturated aqueous NH4Cl solution (50 mL) and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid chromatography to give tert-butyl (3R)-3-vinylmorpholine-4-carboxylate (900 mg, 20% yield) as a yellow oil.

[0682] Step 3:

[0683] A solution of 4 M HCl in dioxane (1 mL) was added to a solution of (3R)-3-vinylmorpholine-4-carboxylic acid tert-butyl ester (900 mg, 4.2 mmol) in DCM (5 mL). The mixture was stirred at 20 °C for 12 hours. The resulting mixture was concentrated under reduced pressure to give (3R)-3-vinylmorpholine hydrochloride (450 mg, 71% yield) as a yellow solid, which was used in the next step without further purification.

[0684] Intermediate 5

[0685]

[0686] Step 1:

[0687] Acetyl chloride (4.9 g, 62.8 mmol) was added dropwise to a stirred solution of 2-bromo-4-fluorophenol (10 g, 52.4 mmol) and pyridine (5 g, 62.8 mmol) in DCM (100 mL) at 0 °C. The mixture was stirred at 25 °C for 4 hours and quenched with water (300 mL), acidified to pH ~5 with 1 N HCl, and extracted with DCM (250 mL × 2). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under vacuum to give 2-bromo-4-fluorophenyl acetate (12.2 g, crude product) as a colorless oil, which was used directly in the next step without further purification.

[0688] Step 2:

[0689] A mixture of 2-bromo-4-fluorophenyl acetate (12.2 g, 52.4 mmol) and AICI3(20.9 g, 157 mmol) was degassed with N2and purged three times and stirred at 140 °C for 1 h. The reaction was allowed to cool, diluted with DCM (200 mL) and poured into ice water (400 mL). The mixture was filtered and the aqueous phase was extracted with DCM (300 mL x 2). The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo, the residue was purified by flash column chromatography on silica gel to give 1-(3-bromo-5-fluoro-2-hydroxy-phenyl)ethanone (11 g, 90% yield) as a white solid.

[0690] Step 3:

[0691] To a stirred solution of 1-(3-bromo-5-fluoro-2-hydroxy-phenyl)ethanone (11 g, 47.2 mmol) in THF (150 mL) at -70 °C was added LiHMDS (7.9 g, 47.2 mmol) dropwise. The mixture was allowed to warm to -5-0 °C and stirred for 0.5 h. The reaction was allowed to cool to -20 °C and methanedithione (10.8 g, 141.6 mmol) in THF (50 mL) was added dropwise at -20 °C. The mixture was then stirred at 25 °C for 16 h and quenched with water (500 mL). The mixture was acidified with 1 N HC1 to pH ~5, extracted with EtOAc (400 mL x 2). The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo to give 8-bromo-6-fluoro-2-mercapto-4H-chromen-4-one (12 g, crude) as a yellow solid which was used directly in the next step without further purification. LC-MS: m / z 274.9 [M+H] + .

[0692] Step 4:

[0693] To a mixture of 8-bromo-6-fluoro-2-mercapto-chromen-4-one (12 g, 43.6 mmol) and K2C03(7.2 g, 52.4 mmol) in acetone (150 mL) was added iodoethane (27.2 g, 174.5 mmol). The mixture was stirred at 60 °C for 4 h. The mixture was poured into water (600 mL) and extracted with DCM (400 mL x 2). The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo, the residue was purified by flash column chromatography on silica gel to give 8-bromo-2-(ethylthio)-6-fluoro-4H-chromen-4-one (12 g, 90.8% yield) as a yellow solid. LC-MS: m / z 302.9 [M+H] + .

[0694] Step 5:

[0695] To a stirred mixture of 8-bromo-2-ethylsulfonyl-6-fluoro-chromen-4-one (2 g, 6.6 mmol) in DCM (10 mL) was added m-CPBA (1.1 g, 6.6 mmol) under N2. The mixture was stirred at 20 °C for 16 h. The mixture was dissolved in water (150 mL) and extracted with EtOAc (150 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo, the residue was purified by flash column chromatography on silica gel to give 8-bromo-2-ethylsulfinyl-6-fluoro-chromen-4-one (2 g, 95% yield) as a red solid.

[0696] Step 6:

[0697] To a solution of 8-bromo-2-ethylsulfinyl-6-fluoro-chromen-4-one (2 g, 6.3 mmol) in THF (5 mL) was added NaOH (800 mg, 20 mmol) and water (1 mL). The mixture was stirred at 20 °C for 2 h. The reaction was quenched by the addition of saturated aqueous NH4Cl solution (5 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 8-bromo-6-fluoro-2-hydroxy-chromen-4-one (1.2 g, 73.9% yield) as a yellow solid. LC-MS: m / z 258.9 [M+H] + .

[0698] Step 7:

[0699] A solution of 8-bromo-6-fluoro-2-hydroxy-chromen-4-one (1.6 g, 6.3 mmol) in phosphorus oxychloride (16.5 g, 107.3 mmol) was stirred at 100 °C for 12 h. The resulting mixture was slowly added to water (20 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to give 8-bromo-2-chloro-6-fluoro-chromen-4-one (230 mg, 13.2% yield) as a yellow solid. LC-MS: m / z 276.9 [M+H] + .

[0700] Intermediate 6

[0701]

[0702] Step 1:

[0703] To a stirred solution of 6-bromo-3-chloro-2-fluoro-benzaldehyde (800 mg, 3.4 mmol) in CH3CN (10 mL) at 0 °C was added a solution of NaClO2 (457 mg, 5.1 mmol) in H2O (5 mL). The mixture was stirred at room temperature for 2 hours. The mixture was poured into saturated Na2SO3 (20 mL aqueous solution) and stirred at room temperature for 30 minutes. The mixture was diluted with water (50 mL), the pH was adjusted to 2 with 1 N HC1, extracted with DCM (300 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo, the residue was purified by silica gel flash column chromatography (eluting with 0% to 20% DCM / MeOH) to give 6-bromo-3-chloro-2-fluoro-benzoic acid (600 mg, 70% yield) as a yellow oil. LC-MS: m / z 253.1 [M+H] + .

[0704] Step 2:

[0705] To a stirred solution of 6-bromo-3-chloro-2-fluoro-benzoic acid (200 mg, 789.1 pmol) in MeOH (5 mL) at room temperature was added H2SO4 (774 mg, 7.9 mmol). The mixture was stirred at 75 °C for 15 hours. The mixture was cooled to room temperature, diluted with water (50 mL), basified to pH ~9 with saturated aqueous Na2CO3 solution, extracted with DCM (200 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo, the residue was purified by silica gel flash column chromatography (eluting with 0% to 10% DCM / MeOH) to give methyl 6-bromo-3-chloro-2-fluoro-benzoate (200 mg, 94% yield) as a yellow solid. LC-MS: m / z 267.1 [M+H] + .

[0706] Intermediate 7

[0707]

[0708] Step 1:

[0709] To a stirred solution of 4-tert-butoxycarbonylmorpholine-3-carboxylic acid (1 g, 4.3 mmol) in DCM (10 mL) and MeOH (10 mL) was added diazomethyl(trimethyl)silane (494 mg, 4.3 mmol) portionwise. The mixture was stirred at room temperature for 1 hour, and the mixture was directly concentrated to give morpholine-3,4-dicarboxylic acid 4-(tert-butyl ester) 3-methyl ester (1 g, crude).

[0710] Step 2:

[0711] To a stirred solution of morpholine-3,4-dicarboxylic acid 4-(tert-butyl ester) 3-methyl ester (1 g, 4.1 mmol) in THF (10 mL) at 0 °C was added dropwise lithium bis(trimethylsilyl)amide (682 mg, 4.1 mmol) in THF under N2. Then iodomethane (579 mg, 4.1 mmol) was added to the above mixture at 0 °C. The mixture was stirred at room temperature for 3 hours and methanol was added dropwise to quench the reaction. The mixture was poured into water, extracted with ethyl acetate, the combined organic phase was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and purified by column chromatography to give 3-methyl morpholine-3,4-dicarboxylic acid 4-(tert-butyl ester) 3-methyl ester (600 mg, 56% yield).

[0712] Step 3:

[0713] To a stirred solution of 3-methyl morpholine-3,4-dicarboxylic acid 4-(tert-butyl ester) 3-methyl ester (600 mg, 2.3 mmol) in DCM (10 mL) was added HCl solution in EtOH (4 M, 0.5 mL) under N2. The mixture was stirred at room temperature for 1 hour, and the mixture was concentrated to give 3-methyl morpholine-3-carboxylic acid methyl ester (400 mg, crude). LC-MS: m / z 160.1 [M+H] + .

[0714] Step 4:

[0715] To a stirred solution of 3-methyl morpholine-3-carboxylic acid methyl ester (400 mg, 2.5 mmol) in THF (10 mL) was added lithium aluminate (143 mg, 3.8 mmol) portionwise at 0 °C and the mixture was stirred at room temperature for 30 minutes. The reaction was quenched with EtOAc, stirred at room temperature for 0.5 hours, dried over anhydrous Na2SO4, filtered and concentrated to give crude product which was purified by column chromatography to give (3-methylmorpholin-3-yl)methanol (300 mg, 91% yield). LC-MS: m / z 132.1 [M+H] + .

[0716] Intermediate 8

[0717]

[0718] Step 1:

[0719] To a stirred solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole (200 mg, 1 mmol) in DMF (5 mL) was added 3-(iodomethyl)-3- methyl-oxetane (219 mg, 1 mmol), NaH (49 mg, 1.2 mmol, 60% dispersion in oil) at 20 °C. The mixture was stirred at 80 °C for 1 h. The mixture was diluted with water (50 mL) and extracted with DCM (50 mL x 2), the organic layer was washed with brine (50 mL), dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give l-((3-methyloxetan-3-yl)methyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole (100 mg, 35% yield) as a yellow solid.

[0720] Intermediate 9

[0721]

[0722] Step 1:

[0723] To a stirred solution of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyridin- 2-one (100 mg, 452.4 pmol) and TEA (230 mg, 2.3 mmol) in DCM (5 mL) was added iodomethane (128 mg, 904.7 pmol). The mixture was stirred at 50 °C under N2for 25 h before cooling to room temperature. The mixture was concentrated. The residue was purified by preparative HPLC to give (l-methyl-6-oxo-3-pyridyl)boronic acid (30 mg, 43.4% yield) as a white solid. LC-MS: m / z 154.1 [M+H] + .

[0724] Intermediate 10

[0725]

[0726] Step 1:

[0727] To a solution of 4-iodo-l-methyl-imidazole (200 mg, 961.5 pmol) in THF (6 mL) at 0 °C was added (isopropyl)magnesium chloride lithium chloride (209.4 mg, 1.4 mmol). The mixture was stirred at 0 °C for 1 h. Then 2-methoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (227.8 mg, 1.4 mmol) was added and the mixture was stirred at 0 °C for 1 h. The mixture was quenched with aqueous NH4CI solution (1 mL) and diluted with water (25 mL). The aqueous phase was purified by reverse phase chromatography (A: 0.05% aqueous FA, B: CH3CN, gradient: 0 ~ 10% B) to give (l-methylimidazol-4-yl)boronic acid as a light yellow solid (40 mg, 33% yield).

[0728] Intermediate 11

[0729]

[0730] Step 1:

[0731] To a sealed tube was added 2-bromo-6-chloro-pyridin-3-amine (100 mg, 482 pmol), tributyl(thiazol-4-yl)stannane (180.4 mg, 0.5 mmol), palladium(II)triphenylphosphine dichloride (67.7 mg, 0.1 mmol) and dioxane (2 mL). The mixture was backfilled with N2and stirred at 100 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography to give 6-chloro-2-thiazol-4-yl-pyridin-3-amine as a yellow oil (60 mg, 58.8% yield). LC-MS: m / z 211.9 [M+H] + .

[0732] Intermediate 12

[0733]

[0734] Step 1:

[0735] To a stirred solution of (S)-4-oxopiperidine-l,2-dicarboxylic acid 1-(tert-butyl ester) 2- methyl ester (2 g, 7.8 mmol) in DCM (20 mL) was added 2-methoxy-N-(2-methoxyethyl)-N- (trifluoro-sulfenyl)ethanamine (3.4 g, 15.6 mmol) followed by dropwise addition of ethanol (18 mg, 389 μmol) in DCM (5 mL) at 0 °C. The mixture was stirred at 20 °C under N2for 12 h. The mixture was diluted with water (50 mL) and extracted with DCM (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The mixture was purified by silica gel chromatography to give (S)-4,4-difluoropiperidine-l,2-dicarboxylic acid 1-(tert-butyl ester) 2-methyl ester (1 g, 46% yield) as a yellow oil. LC-MS: m / z 280.3 [M+H] + .

[0736] Step 2:

[0737] To a stirred solution of (S)-4,4-difluoropiperidine-l,2-dicarboxylic acid 1-(tert-butyl ester) 2- methyl ester (1.5 g, 5.4 mmol) in dioxane (10 mL) was added HCl (2 mL, 4.0 M in 1,4- dioxane) at 0 °C. The mixture was stirred at 0 °C for 30 min. The pH of the mixture was adjusted to 8 with saturated aqueous NaHC03solution, followed by dilution with water (50 mL) and extraction with DCM (100 mL x 2), the organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give (S)-4,4-difluoropiperidine-2-carboxylic acid methyl ester (900 mg, 94% yield) as a yellow oil. LC-MS: m / z 180.1 [M+H] + .

[0738] Step 3:

[0739] To a stirred solution of (S)-4,4-difluoropiperidine-2-carboxylic acid methyl ester (900 mg, 5.1 mmol) in methanol (10 mL) was added NaBH4(380 mg, 10.1 mmol) at 0 °C. The mixture was stirred at 0 °C for 10 min. Then 2 N HC1 (5 mL) was added and stirred at 20 °C for 30 min. The pH of the mixture was adjusted to 7 with saturated aqueous NaHC03solution, followed by concentration in vacuo, the residue was diluted with MeOH and filtered, the filtrate was concentrated under reduced pressure to give (S)-(4,4-difluoropiperidin-2-yl)methanol (700 mg, crude) as a yellow oil which was used in the next step without further purification.

[0740] Part 2. Synthetic methods for preparing the desired compound

[0741] Example 1

[0742]

[0743] Step 1:

[0744] 1-Iodopyrrolidine-2,5-dione (16.3 g, 72.7 mmol) was added to a stirred solution of 2-amino-5-methylbenzoic acid (10 g, 66.1 mmol) in DMF (100 mL) at 20 °C, and the mixture was stirred at 70 °C under a N2 atmosphere for 3 hours. The mixture was diluted with water (50 mL) and extracted with DCM (100 mL × 2). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (0–5% MeOH / DCM) to give 2-amino-3-iodo-5-methylbenzoic acid (15 g, 81% yield) as a yellow solid. LC-MS: m / z 278.1 [M+H] + .

[0745] Step 2:

[0746] 2-Chloro-5,6,7,8-tetrahydro-1,6-naphthidine hydrochloride (2.2 g, 10.8 mmol), HATU (4.3 g, 11.3 mmol), and TEA (5.4 g, 54.1 mmol) were added to a stirred solution of 2-amino-3-iodo-5-methyl-benzoic acid (3 g, 10.8 mmol) in DCM at 20 °C. The mixture was stirred at 20 °C for 2 hours. The mixture was then diluted with water (50 mL) and extracted with DCM (100 mL × 2). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The mixture was purified by silica gel chromatography to give (2-amino-3-iodo-5-methyl-phenyl)-(2-chloro-7,8-dihydro-5H-1,6-naphthidine-6-yl) methyl ketone (3 g, 64% yield) as a yellow solid. LC-MS: m / z 428.0 [M+H] + .

[0747] Step 3:

[0748] To a stirred solution of 3-chloro-12-iodo-10-methyl-5,6-dihydro-l,6- naphthyridino[5,6-b]quinazolin-8-one (500 mg, 1.2 mmol) in DMF was added Pd(PPh3)4 (273 mg, 236 μmol) and tributyl(l-ethoxyvinyl)stannane (554 mg, 1.5 mmol) at 20 °C. The mixture was stirred at 100 °C under N2 for 6 h. The mixture was cooled to room temperature, diluted with DCM (50 mL), then quenched with saturated aqueous KF solution (50 mL). The mixture was stirred at 20 °C under N2 for 2 h, then filtered. The filtrate was separated, and the organic layer was concentrated in vacuo. The residue was re-dissolved in acetone (30 mL) and added 2N HCl (5 mL). The mixture was stirred at 20 °C under N2 for 1 h. The mixture was then diluted with water (100 mL) and extracted with DCM (200 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to give 12-acetyl-3-chloro-10-methyl-5,6-dihydro-l,6- naphthyridino[5,6-b]quinazolin-8-one (400 mg, 99% yield) as a yellow solid. LC-MS: m / z 340.1 [M+H] + .

[0749] Step 4:

[0750] To a stirred solution of 3-chloro-12-iodo-10-methyl-5,6-dihydro-l,6- naphthyridino[5,6-b]quinazolin-8-one (500 mg, 1.2 mmol) in DMF was added Pd(PPh3)4 (273 mg, 236 μmol) and tributyl(l-ethoxyvinyl)stannane (554 mg, 1.5 mmol) at 20 °C. The mixture was stirred at 100 °C under N2 for 6 h. The mixture was cooled to room temperature, diluted with DCM (50 mL), then quenched with saturated aqueous KF solution (50 mL). The mixture was stirred at 20 °C under N2 for 2 h, then filtered. The filtrate was separated, and the organic layer was concentrated in vacuo. The residue was re-dissolved in acetone (30 mL) and added 2N HCl (5 mL). The mixture was stirred at 20 °C under N2 for 1 h. The mixture was then diluted with water (100 mL) and extracted with DCM (200 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to give 12-acetyl-3-chloro-10-methyl-5,6-dihydro-l,6- naphthyridino[5,6-b]quinazolin-8-one (400 mg, 99% yield) as a yellow solid. LC-MS: m / z 340.1 [M+H] + .

[0751] Step 5:

[0752] Ti(OEt)4 (2 g, 8.8 mmol) and (R)-2-methylpropane-2-sulfinamide (71 mg, 588 μmol) were added to a stirred solution of 12-acetyl-3-chloro-10-methyl-5,6-dihydro-1,6-naphtho[5,6-b]quinazolin-8-one (100 mg, 294 μmol) in THF (10 mL) at 20 °C. The mixture was stirred at 85 °C for 12 hours. After completion, the mixture was diluted with EtOAc (50 mL) and water (50 mL) was added. The mixture was filtered, and the filtrate was extracted with EtOAc (50 mL × 2). The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography to give (NE,R)-N-[1-(3-chloro-10-methyl-8-oxo-5,6-dihydro-1,6-naphtho[5,6-b]quinazolin-12-yl)ethylene]-2-methyl-propane-2-sulfinamide (120 mg, 92% yield) as a yellow solid. LC-MS: m / z 443.1 [M+H] + .

[0753] Step 6:

[0754] CeCl3 (55 mg, 225 μmol) and NaBH4 (9 mg, 225 μmol) were added to a stirred solution of (NE,R)-N-[1-(3-chloro-10-methyl-8-oxo-5,6-dihydro-1,6-naphtho[5,6-b]quinazolin-12-yl)ethylene]-2-methyl-propane-2-sulfinamide (100 mg, 225 μmol) in methanol (15 mL) and the mixture was stirred at 25 °C for 10 min. The mixture was quenched with water (50 mL) and extracted with DCM (100 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated under vacuum to obtain the crude product. Purification by silica gel chromatography yielded a yellow solid (R)-N-[(1R)-1-(3-chloro-10-methyl-8-oxo-5,6-dihydro-1,6-naphtho[5,6-b]quinazolin-12-yl)ethyl]-2-methyl-propane-2-sulfinamide (100 mg, 99% yield). LC-MS: m / z 445.1 [M+H] + .

[0755] Step 7:

[0756] To a stirred solution of (R)-N-[(lR)-l-(3-chloro-10-methyl-8-oxo-5,6-dihydro-l,6- naphthyridino[5,6-b]quinolin-12-yl)ethyl]-2-methyl-propane-2-sulfinamide (20 mg, 44 μιηοΐ) in methanol (5 mL) was added HC1 (0.5 mL, 4.0 M in ethanol) at 0 °C. The mixture was stirred at 0 °C for 30 min. The pH of the mixture was adjusted to 8 with saturated aqueous NaHC03solution. The mixture was diluted with water (50 mL) and extracted with DCM (100 mL). The organic layer was washed with brine (100 mL), dried over Na2S04, filtered, and concentrated in vacuo to give 12-[(lR)-l-aminoethyl]-3-chloro-10-methyl-5,6-dihydro-l,6- naphthyridino[5,6-b]quinolin-8-one (10 mg, 65% yield) as a yellow oil. LC-MS: m / z 341.1 [M+H] + .

[0757] Step 8:

[0758] To a stirred solution of 12-[(lR)-l-aminoethyl]-3-chloro-10-methyl-5,6-dihydro-l,6- naphthyridino[5,6-b]quinolin-8-one (10 mg, 29 μιηοΐ) in DMSO (5 mL) was added methyl 6-chloro-3-fluoro-pyridine-2-carboxylate (17 mg, 88 μιηοΐ) and potassium carbonate (16 mg, 117 μιηοΐ) at 20 °C. The mixture was stirred at 80 °C for 2 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (50 mL). The organic layer was dried over Na2S04, filtered, and concentrated in vacuo to give the crude product which was purified by silica gel chromatography to give methyl 6-chloro-3-[[(lR)-l-(3-chloro-10-methyl-8-oxo-5,6-dihydro-l,6- naphthyridino[5,6-b]quinolin-12-yl)ethyl]amino]pyridine-2-carboxylate (10 mg, 66% yield) as a yellow oil. LC-MS: m / z 510.1 [M+H] + .

[0759] Step 9:

[0760] To a stirred solution of (S)-2-methyl-N-((S)-1-(3-methoxy-10-methyl-8-oxo- 5,6-dihydro-1,6-naphthyridine-12-yl)ethyl)propane-2-sulfmamide (100 mg, 225 pmol) in methanol (15 mL) was added CeCl3 (110 mg, 450 pmol) and NaBH4 (85 mg, 2.3 mmol) at 25 °C and the mixture was stirred at 25 °C for 5 h. The mixture was diluted with water (50 mL) and extracted with DCM (100 mL). The organic layer was dried over Na2S04, filtered and concentrated in vacuo to give the crude product which was purified by silica gel chromatography to give (S)-2-methyl-N-((S)-1-(10-methyl-8-oxo-5,8-dihydro-6H- [1,6]naphthyridine-12-yl)ethyl)propane-2-sulfmamide (90 mg, 99% yield) as a yellow solid. LC-MS: m / z 411.2 [M+H] + .

[0761] The following compounds have been prepared analogously to the representative procedure described in relation to Example 1.

[0762]

[0763] Example 3

[0764]

[0765] Step 1:

[0766] To a stirred solution of (S)-2-methyl-N-((S)-1-(3-methoxy-10-methyl-8-oxo- 5,6-dihydro-1,6-naphthyridine-12-yl)ethyl)propane-2-sulfmamide (100 mg, 225 pmol) in methanol (15 mL) was added CeCl3 (110 mg, 450 pmol) and NaBH4 (85 mg, 2.3 mmol) at 25 °C and the mixture was stirred at 25 °C for 5 h. The mixture was diluted with water (50 mL) and extracted with DCM (100 mL). The organic layer was dried over Na2S04, filtered and concentrated in vacuo to give the crude product which was purified by silica gel chromatography to give (S)-2-methyl-N-((S)-1-(10-methyl-8-oxo-5,8-dihydro-6H- [1,6]naphthyridine-12-yl)ethyl)propane-2-sulfmamide (90 mg, 99% yield) as a yellow solid. LC-MS: m / z 411.2 [M+H] + .

[0767] Step 2:

[0768] To a stirred solution of (R)-2-methyl-N-((R)-l-(lO-methyl-8-oxo-5,8-dihydro-6H- [l,6]naphthyridino[5,6-b]quinolin-12-yl)ethyl)propane-2-sulfmamide (20 mg, 44 pmol) in methanol (5 mL) was added HC1 (0.5 mL, 4 M in ethanol) at 0 °C. The mixture was stirred at 0 °C for 30 min. The pH of the mixture was adjusted to ~8 with saturated aqueous NaHC03solution. The mixture was diluted with water (50 mL) and extracted with DCM (100 mL). The organic layer was washed with brine (100 mL), dried over Na2S04, filtered and concentrated in vacuo to give (R)-12-(l-aminoethyl)-10-methyl-5,6-dihydro-8H- [l,6]naphthyridino[5,6-b]quinolin-8-one (10 mg, 72% yield) as a yellow oil. LC-MS: m / z 307.1 [M+H] + .

[0769] Step 3:

[0770] To a stirred solution of (R)-12-(l-aminoethyl)-10-methyl-5,6-dihydro-8H- [l,6]naphthyridino[5,6-b]quinolin-8-one (10 mg, 33 pmol) in DMSO (5 mL) was added methyl 6-chloro-3-fluoro-pyridine-2-carboxylate (17 mg, 88 pmol) and potassium carbonate (16 mg, 117 pmol) at 20 °C. The mixture was stirred at 80 °C for 2 h. The mixture was then diluted with water (10 mL) and extracted with EtOAc (50 mL). The organic layer was dried over Na2S04, filtered, and concentrated in vacuo to give the crude product which was purified by silica gel chromatography to give methyl (R)-6-chloro-3-((l-(lO-methyl-8-oxo-5,8-dihydro-6H- [l,6]naphthyridino[5,6-b]quinolin-12-yl)ethyl)amino)pyridine-2-carboxylate (10 mg, 23% yield) as a yellow oil. LC-MS: m / z 476.1 [M+H] + .

[0771] Step 4:

[0772] To a stirred solution of (R)-6-chloro-3-((1-(10-methyl-8-oxo-5,8-dihydro-6H- [1,6]naphthyridin[5,6-b]quinazolin-12-yl)ethyl)amino)pyridine-2-carboxylic acid methyl ester (10 mg, 22 pmol) in a mixture of water and THF (8 mL, 1:3) was added lithium hydroxide monohydrate (6 mg, 260 pmol) at 20 °C and the mixture was stirred at 20 °C for 2 h. The pH of the mixture was adjusted to ~6 with saturated aqueous NH4Cl solution, followed by extraction with DCM (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by preparative HPLC to give (R)-6-chloro-3-((1-(10-methyl-8-oxo-5,8-dihydro-6H- [1,6]naphthyridin[5,6-b]quinazolin-12-yl)ethyl)amino)pyridine-2-carboxylic acid as a white solid (2.2 mg, 23% yield). LC-MS: m / z 462.1 [M+H] + .

[0773] The following compounds have been prepared analogously to the representative procedure described in relation to Example 3.

[0774]

[0775] Example 5

[0776]

[0777] Step 1:

[0778] To a stirred solution of 2-amino-3-bromo-5-fluorobenzoic acid (2 g, 8.5 mmol) and HATU (3.9 g, 10.2 mmol) in DMF (20 mL) was added 2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine (1.7 g, 10.2 mmol) and TEA (4.3 g, 42.6 mmol) at room temperature. The mixture was stirred at 25 °C for 3 h. The mixture was diluted with EtOAc (300 mL), followed by washing with brine (70 mL x 2). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography to give (2-amino-3-bromo-5-fluorophenyl)(2-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)methanone as a yellow solid (2.4 g, 80% yield). LC-MS: m / z 353.1, 355 [M+H] + .

[0779] Step 2:

[0780] To a stirred solution of (2-amino-3-bromo-5-fluorophenyl)(2-methyl-2,4,6,7- tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)methanone (1.3 g, 3.7 mmol) in DMSO (50 mL) was added (NH4)2S2O8 (3.4 g, 14.7 mmol) at room temperature. The mixture was stirred at 60 °C for 16 h. The mixture was diluted with EtOAc (300 mL) followed by washing with brine (70 mL x 2). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to give the crude product which was purified by silica gel chromatography to give 11-bromo-9-fluoro-2-methyl-4,5-dihydropyrazolo[4',3':3,4]pyrido[2,1-b]quinazolin-7(2H)-one (700 mg, 54% yield) as a yellow solid. LC-MS: m / z 349.1, 351 [M+H] + .

[0781] Step 3:

[0782] To a stirred solution of 11-bromo-9-fluoro-2-methyl-4,5-dihydropyrazolo[4',3':3,4]pyrido[2,1-b]quinazolin-7(2H)-one (700 mg, 2 mmol) and Pd(PPh3)2Cl2 (231.7 mg, 200.5 µmol) in dioxane (10 mL) was added tributyl(1-ethoxyvinyl)stannane (1.1 g, 3 mmol). The mixture was degassed with N2 flow for three times, then stirred at 100 °C for 16 h. The mixture was cooled to room temperature and quenched with 1 M HCl (aq) (1 mL). The mixture was diluted with water (200 mL) followed by washing with 10% NaHCO3 aqueous solution (15 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel chromatography to give 11-acetyl-9-fluoro-2-methyl-4,5-dihydropyrazolo[4',3':3,4]pyrido[2,1-b]quinazolin-7(2H)-one (400 mg, 64% yield) as a yellow solid. LC-MS: m / z 313 [M+H] + .

[0783] Step 4:

[0784] To a stirred solution of 11-acetyl-9-fluoro-2-methyl-4,5-dihydropyrazolo[4',3':3,4]pyrido[2,1- b]quinolin-7(2H)-one (400 mg, 1.3 mmol) in Ti(OEt)4 (6 mL) was added (R)-2-methylpropane-2- sulfinamide (310.5 mg, 2.6 mmol). The mixture was stirred at 70 °C under N2atmosphere for 5 h. The mixture was diluted with EtOAc (200 mL) followed by the addition of water (20 mL). The mixture was stirred at 20 °C for 0.5 h. The mixture was filtered, and the organic layer was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the crude product. The crude product was purified by silica gel chromatography to give (R,E)-N-(1-(9-fluoro-2-methyl-7-oxo-2,4,5,7-tetrahydropyrazolo[4',3':3,4]pyrido[2,1- b]quinolin-11-yl)ethylidene)-2-methylpropane-2-sulfinamide (200 mg, 40 % yield) as a yellow solid. LC-MS: m / z 416.1 [M+H] + .

[0785] Step 5:

[0786] To a stirred solution of (R,E)-N-(1-(9-fluoro-2-methyl-7-oxo-2,4,5,7-tetrahydropyrazolo[4',3':3,4]pyrido[2,1- b]quinolin-11-yl)ethylidene)-2-methylpropane-2-sulfinamide (200 mg, 498.1 µmol) and CeCl3 (122.8 mg, 498.2 µmol) in methanol (12 mL) was added NaBH4 (28.3 mg, 747.3 µmol). The mixture was stirred at 20 °C for 15 min. The mixture was diluted with CH2Cl2 (100 mL) followed by washing with brine (30 mL x 2). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel chromatography to give (R)-N-((R)-1-(9-fluoro-2-methyl-7-oxo-2,4,5,7-tetrahydropyrazolo[4',3':3,4]pyrido[2,1- b]quinolin-11-yl)ethyl)-2-methylpropane-2-sulfinamide (100 mg, 50 % yield). LC-MS: m / z 418.1 [M+H] + .

[0787] Step 6:

[0788] To a stirred solution of (R)-N-((R)-l-(9-fluoro-2-methyl-7-oxo-2,4,5,7- tetrahydropyrazolo[4',3':3,4]pyrrolo[2,l-b]quinazolin-l l-yl)ethyl)-2-methylpropane-2- sulfinamide (100 mg, 247.9 pmol) in methanol (10 mL) was added a solution of HC1 in EtOH (1.5 mL, 4 N). The mixture was stirred at 20 °C for 10 min. The mixture was diluted with CH2Cl2 (100 mL), then washed with 10% NaHC03(aq, 15 mL). The organic layer was dried over Na2S04, filtered and concentrated in vacuo to give (R)-l l-(l-aminoethyl)-9-fluoro-2-methyl-4,5-dihydropyrazolo[4',3':3,4]pyrrolo[2,l- b]quinazolin-7(2H)-one (50 mg, crude) as a grey solid which was used in the next step without further purification. LC-MS: m / z 314.1 [M+H] + .

[0789] Step 7:

[0790] To a stirred solution of (R)-l l-(l-aminoethyl)-9-fluoro-2-methyl-4,5- dihydropyrazolo[4',3':3,4]pyrrolo[2,l-b]quinazolin-7(2H)-one (40 mg, 127.7 pmol) in DMSO (2 mL) was added K2CO3(35.3 mg, 255.3 pmol) and methyl 6-chloro-3-fluoro- pyridine-2-carboxylate (36.3 mg, 191.5 pmol). The mixture was stirred at 100 °C for 3 h. The mixture was diluted with EtOAc (100 mL), then washed with brine (30 mL x 3). The organic layer was dried over Na2S04, filtered, and concentrated in vacuo to give crude product. The crude product was then purified by silica gel chromatography to give (R)-methyl 6-chloro-3-((l-(9-fluoro-2-methyl-7-oxo-2,4,5,7- tetrahydropyrazolo[4',3':3,4]pyrrolo[2,l-b]quinazolin-l l-yl)ethyl)amino)pyridine-2- carboxylate (20 mg, 32% yield) as a light yellow solid. LC-MS: m / z 483.1 [M+H] + .

[0791] Step 8:

[0792] To a stirred solution of (R)-6-chloro-3-((1-(9-fluoro-2-methyl-7-oxo- 2,4,5,7-tetrahydropyrazolo[4',3':3,4]pyrrolo[2,1-b]quinolin-11-yl)ethyl)amino) picolinic acid ester (20 mg, 41 µmol) in a mixture solvent of THF and water (5 mL, 4:1) was added LiOH·H2O (6.8 mg, 284.6 µmol). The mixture was stirred at 20 °C for 1 h. The mixture was adjusted to pH ~ 6 with 1 N HCl (aq), followed by extraction with CH2Cl2 (30 mL × 3). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by prep-HPLC to give (R)-6-chloro-3-((1-(9-fluoro-2-methyl-7-oxo- 2,4,5,7-tetrahydropyrazolo[4',3':3,4]pyrrolo[2,1-b]quinolin-11-yl)ethyl)amino) picolinic acid (10 mg, 52% yield) as a white solid. LC-MS: m / z 469.1 [M+H] + .

[0793] The following compounds have been prepared analogously to the representative procedure described in relation to Example 5.

[0794]

[0795]

[0796] Example 20

[0797]

[0798] Step 1:

[0799] To a stirred solution of indane-1,2-dione (712 mg, 4.8 mmol) in methanol (10 mL) at 25 °C was added saccharin (89.3 mg, 487 µmol) and 3-bromo-5-fluoro-benzene-1,2- diamine (1 g, 4.8 mmol) and the mixture was stirred at 25 °C under N2atmosphere for 1 h. The mixture was diluted with water (50 mL) and extracted with DCM (100 mL × 2). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo to give 6-bromo-8-fluoro-11H-indeno[1,2-b]quinoxaline and 9-bromo-7-fluoro-11H-indeno[1,2-b]quinoxaline (1.5 g, 97% yield) as a yellow solid. LC-MS: m / z 315.2 [M+H] + .

[0800] Step 2:

[0801] To a mixture of 6-bromo-8-fluoro-11H-indeno[1,2-b]quinoxaline and 9-bromo-7-fluoro- 11H-indeno[1,2-b]quinoxaline (1 g, 3.2 mmol) in DMF (20 mL) was added Pd(PPh3)4 (733 mg, 634 μmol) and tributyl(1-ethoxyvinyl)stannane (1.2 g, 3.2 mmol) at 20 °C. The mixture was stirred at 100 °C for 4 h. The mixture was diluted with DCM (50 mL) followed by quenching with saturated aqueous KF solution (50 mL). The mixture was stirred at room temperature for 2 h followed by filtration. The filtrate was separated and the organic layer was concentrated in vacuo. The residue was re-dissolved in acetone (30 mL) and 2 N HC1 (5 mL) was added. The mixture was stirred at 20 °C for 30 min. The mixture was then diluted with water (50 mL) and extracted with DCM (100 mL). The organic layer was dried over Na2S04, filtered, and concentrated in vacuo to give the crude product which was purified by silica gel flash column chromatography to give 1-(8-fluoro-11H-indeno[2,1-b]quinoxalin-6-yl)ethanone and 1-(7-fluoro-11H-indeno[1,2-b]quinoxalin-9-yl)ethanone (500 mg, 56% yield) as a yellow solid. LC-MS: m / z 279.1 [M+H] + .

[0802] Step 3:

[0803] To a stirred mixture of 1-(8-fluoro-11H-indeno[2,1-b]quinoxalin-6-yl)ethenone, 1-(7-fluoro- 11H-indeno[1,2-b]quinoxalin-9-yl)ethenone (mixture of both, 50 mg, 179 μmol) and 2- amino-5-fluorobenzoic acid (62 mg, 400 μmol) in DCM (2 mL) was added TiCl4 (340 mg, 1.8 mmol) at 25 °C and the resulting mixture was stirred at 25 °C for 1 h. Sodium cyanoborohydride (112 mg, 1.8 mmol) was then added and the mixture was stirred at 25 °C for 2 h. The mixture was diluted with water (30 mL) and extracted with DCM (50 mL). The organic layer was washed with brine (50 mL), dried over Na2S04, filtered and concentrated in vacuo to give the crude product which was purified by preparative HPLC to give 5-fluoro-2-[1-(8-fluoro-11H-indeno[2,1-b]quinoxalin-6-yl)ethylamino]benzoic acid and 5-fluoro-2-[1-(7-fluoro-11H-indeno[1,2-b]quinoxalin-9-yl)ethylamino]benzoic acid (2 mg, 3% yield) as a yellow solid. LC-MS: m / z 418.1 [M+H]+ .

[0804] Example 21

[0805]

[0806] Step 1:

[0807] To a stirred solution of 2,3-dibromobenzoic acid (2.5 g, 8.9 mmol) and DMF (65.3 mg, 0.9 mmol) in CH2Cl2(40 mL) was added oxalyl chloride (1.1 g, 8.9 mmol). The mixture was stirred at 20 °C for 0.5 h. The mixture was concentrated in vacuo to give 2,3-dibromobenzoyl chloride (2.6 g, 97% yield) as a light yellow solid, which was used in the next step without further purification.

[0808] Step 2:

[0809] To a stirred solution of LiHMDS (1.7 g, 10 mmol) in THF (30 mL) at -78 °C was added a solution of 3,4-dihydronaphthalen-l(2H)-one (1.5 g, 10 mmol) in THF (10 mL) under N2protection. The reaction was stirred at -78 °C for 1 h. Then a suspension of 2,3-dibromobenzoyl chloride (2.6 g, 8.7 mmol) in THF (30 mL) was added dropwise to the reaction mixture at -78 °C and the reaction was stirred at -78 °C for 1 h. The mixture was quenched with aqueous HC1 (1 N, 20 mL), diluted with water (100 mL) and extracted with CH2Cl2(100 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography to give 2-(2,3-dibromobenzoyl)-3,4-dihydronaphthalen-l(2H)-one (2.2 g, 62% yield) as a light yellow solid. LC-MS: m / z 406.9 [M+H] + .

[0810] Step 3:

[0811] To a stirred solution of 2-(2,3-dibromobenzoyl)-3,4-dihydronaphthalen-l(2H)-one (700 mg, 1.7 mmol), XPhos (163.5 mg, 343 µmol) and Cs2CO3 (1.4 g, 4.3 mmol) in dioxane (12 mL) was added Pd2(dba)3 (177.5 mg, 171.5 µmol). The mixture was degassed with N2 flow for three times, then stirred at 100 °C for 10 h. The mixture was diluted with water (50 mL) and extracted with CH2Cl2 (100 mL x 2). The combined extracts were washed with brine (50 mL) and dried over anhydrous Na2SO4. The solvent was evaporated to give the crude product. The crude product was purified by silica gel column chromatography to give 11-bromo-5,6-dihydro-7H-benzo[c]xanthene-7- one as a light yellow solid (210 mg, 37% yield). LC-MS: m / z 327.0 [M+H] + .

[0812] Step 4:

[0813] To a stirred solution of 11-bromo-5,6-dihydro-7H-benzo[c]xanthene-7-one (210 mg, 641.8 µmol) in dioxane (10 mL) was added tributyl(l-ethoxyvinyl)stannane (463.6 mg, 1.3 mmol) and Pd(PPh3)2Cl2 (90.1 mg, 128.3 µmol). The mixture was degassed with N2 flow for three times, then stirred at 100 °C for 16 h. The reaction was quenched with saturated KF solution (50 mL) and the mixture was extracted with CH2Cl2 (150 mL x 2). The combined extracts were washed with brine (50 mL) and dried over anhydrous Na2SO4. The solvent was evaporated and the crude product was re-dissolved in acetone (20 mL). HCl (5 mL, 2 N) was added to the mixture, then the solution was stirred at 20 °C for 20 min. The mixture was diluted with CH2Cl2 (150 mL) and washed with 10% NaHCO3 (aqueous) (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography to give 11-acetyl-5,6-dihydro-7H-benzo[c]xanthene-7-one as a light yellow solid (110 mg, 59% yield). LC-MS: m / z 291.1 [M+H] + .

[0814] Step 5:

[0815] To a stirred solution of 11-acetyl-5,6-dihydro-7H-benzo[c]xanthene-7-one (110 mg, 378.9 µmol) in Ti(OEt)4 (4 mL) was added (R)-2-methylpropane-2-sulfinamide (137.7 mg, 1.1 mmol). The mixture was stirred at 80 °C for 2 h under N2protection. The mixture was diluted with EtOAc (200 mL), followed by the addition of water (50 mL). The mixture was stirred at 20 °C for 0.5 h. The mixture was filtered, and the organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography to give (R,E)-2-methyl-N-(1-(7-oxo-5,7-dihydro-6H-benzo[c]xanthene-11-yl)ethylidene)propane-2-sulfinamide (160 mg, crude) as a light yellow oil. LC-MS: m / z 394.1 [M+H] + .

[0816] Step 6:

[0817] To a stirred solution of (R,E)-2-methyl-N-(1-(7-oxo-5,7-dihydro-6H-benzo[c]xanthene-11-yl)ethylidene)propane-2-sulfinamide (140 mg, 355.7 µmol) and CeCl3 (35.1 mg, 142.3 µmol) in methanol (10 mL) was added NaBH4 (29.6 mg, 782.7 µmol). The mixture was stirred at 0 °C for 5 min. The mixture was diluted with CH2Cl2 (70 mL), followed by washing with brine (30 mL x 2). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography to give (R)-2-methyl-N-((R)-1-(7-oxo-5,7-dihydro-6H-benzo[c]xanthene-11-yl)ethyl)propane-2-sulfinamide (130 mg, 92.3% yield) as a light yellow solid. LC-MS: m / z 396.1 [M+H] + .

[0818] Step 7:

[0819] To a stirred solution of (R)-2-methyl-N-((R)-1-(7-oxo-5,7-dihydro-6H- benzo[c]xanthene-11-yl)ethyl)propane-2-sulfmamide (35 mg, 88.5 pmol) in methanol (10 mL) was added a solution of HC1 in EtOH (1.5 mL, 4 N). The mixture was stirred at 20 °C for 5 min. The mixture was diluted with CH2Cl2 (100 mL), then washed with 10% aq. NaHC03solution (15 mL). The organic layer was dried over Na2S04, filtered and concentrated in vacuo to give (R)-11-(1- aminoethyl)-5,6-dihydro-7H-benzo[c]xanthen-7-one (35 mg, crude) as a white solid, which was used in the next step without further purification. LC-MS: m / z 292.1 [M+H] + .

[0820] Step 8:

[0821] To a stirred solution of (R)-11-(1-aminoethyl)-5,6-dihydro-7H- benzo[c]xanthen-7-one (35 mg, 120.1 pmol) and triethylamine (48.6 mg, 480.5 pmol) in DMSO (3 mL) was added 6-chloro-3-fluoropicolinic acid methyl ester (34.2 mg, 180.2 pmol). The mixture was stirred at 100 °C for 16 h. The mixture was diluted with EtOAc (100 mL), then washed with brine (30 mL x 3). The organic layer was dried over Na2S04, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography to give (R)-6-chloro-3-((1-(7-oxo-5,7-dihydro-6H- benzo[c]xanthen-11-yl)ethyl)amino)picolinic acid methyl ester (13 mg, 23.5% yield) as a white solid. LC-MS: m / z 461.1 [M+H] + .

[0822] Step 9:

[0823] To a stirred solution of (R)-methyl 6-chloro-3-((1-(7-oxo-5,7-dihydro-6H- benzo[c]xanthene-11-yl)ethyl)amino)pyridinecarboxylate (13 mg, 28.2 µmol) in a mixture solvent of THF, methanol (1 mL) and water (6 mL, 4:1:1) was added LiOH·H2O (5.9 mg, 141.0 µmol). The mixture was stirred at 20 °C for 20 min. The mixture was adjusted to pH ~ 5 with aqueous HC1 (1 N), then diluted with brine (20 mL) and extracted with CH2Cl2 (60 mL × 2). The combined organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by prep-HPLC (A: 0.05% aqueous formic acid, B: CH3CN, gradient: 10 ~ 75% B) to give (R)-6-chloro-3-((1-(7-oxo-5,7-dihydro-6H-benzo[c]xanthene-11- yl)ethyl)amino)pyridinecarboxylic acid (8 mg, 63.5% yield) as a white solid. LC-MS: m / z 447.1 [M+H] + .

[0824] Example 22

[0825]

[0826] Step 1:

[0827] To a stirred solution of ethyl 2-(3-bromopyridin-2-yl)acetate (2 g, 8.2 mmol) in anhydrous THF (30 mL) was added DIBAL-H (1 M in hexanes) (16.4 mL, 16.4 mmol) dropwise at -78 °C. The resulting red solution was stirred at room temperature for 12 h. The reaction was quenched with saturated potassium sodium tartrate solution (30 mL) at 0 °C and stirred at room temperature for 1 h. The resulting mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (60 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel flash column chromatography to give 2-(3-bromopyridin-2-yl)ethan-1-ol (0.9 g, 54% yield) as a brown oil. LC-MS: m / z 202.0 [M+H] + .

[0828] Step 2:

[0829] To a flask containing 2-(3-bromopyridin-2-yl)ethan-1-ol (900 mg, 4.5 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.2 g, 4.9 mmol) in dioxane (20 mL) was added KOAc (874 mg, 8.9 mmol) and Pd(dppf)Cl2 (323.2 mg, 445.4 μmol). The solution was degassed by N2balloon. The mixture was then heated to 100 °C for 16 h. The mixture was allowed to cool to room temperature and filtered through a pad of celite. The filter cake was washed with ethyl acetate (20 mL x 2). The combined solution was concentrated in vacuo to give 2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)ethan-1-ol (2.2 g, crude) as a black oil which was used in the next step without further purification. LC-MS: m / z 250.2 [M+H] + .

[0830] Step 3:

[0831] To a suspension of 4-bromo-6-methyl-2,3-dihydro-1H-inden-1-one (2 g, 8.9 mmol) in Et2O (20 mL) and concentrated HCl (20 mL) was added isopropyl nitrite (5.2 g, 44.4 mmol) dropwise at 25 °C and the mixture was stirred at 25 °C for 5 h. The solid was collected by filtration and washed with Et2O to give (E)-4-bromo-2-(hydroxyimino)-6-methyl-2,3-dihydro-1H-inden-1-one (1.8 g, 80% yield) as a white solid. LC-MS: m / z 253.9 [M+H] + .

[0832] Step 4:

[0833] To a suspension of (E)-4-bromo-2-(hydroxyimino)-6-methyl-2,3-dihydro-lH-inden- 1-one (1.8 g, 7.1 mmol) in CHCl3(36 mL) at 25 °C was added slowly PCl5(2.2 g, 10.6 mmol) and the mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in 4 M HC1 in dioxane (25 mL). The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated in vacuo. The residue was diluted with CH2Cl2(50 mL) and washed with water (60 mL) and saturated NaHC03(30 mL). The suspension was then filtered, and the aqueous layer was extracted with CH2Cl2:MeOH = 10:1 (V:V) (80 mL x 2). The combined organic phase was washed with brine (100 mL) and dried over anhydrous Na2S04, filtered and concentrated in vacuo, and the combined crude product was washed with Et20 to give 5-bromo-3-chloro-7-methylisoquinolin-l(2H)-one (1.9 g, 98% yield) as an off-white solid. LC-MS: m / z 271.9 [M+H] + .

[0834] Step 5:

[0835] To a mixture of 5-bromo-3-chloro-7-methylisoquinolin-l(2H)-one (1.9 g, 7 mmol) and tributyl(l-ethoxyvinyl)stannane (3 g, 8.4 mmol) in dioxane (40 mL) was added Pd(PPh3)2Cl2(489.4 mg, 697.2 μmol) and the resulting mixture was purged with nitrogen three times. The reaction mixture was stirred at 100 °C under nitrogen for 16 h. The reaction mixture was cooled to room temperature, poured into 1 N HC1 (aqueous) (40 mL), and stirred for 1 h. The mixture was neutralized to about pH ~ 8 using 10% Na2C03(aq). The mixture was diluted with CH2Cl2:MeOH = 10:1 (100 mL, V:V) and the phases were separated. The aqueous layer was extracted with a mixed solvent of CH2Cl2and MeOH (100 mL x 3, V:V = 10:1). The combined organic layers were dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The crude product was purified by silica gel flash column chromatography to give 5-acetyl-3-chloro-7-methylisoquinolin-l(2H)-one (1.3 g, 79% yield) as a tan solid. LC-MS: m / z 236.0 [M+H] + .

[0836] Step 6:

[0837] To a microwave tube containing 5-acetyl-3-chloro-7-methylisoquinolin-l(2H)-one (150 mg, 636.5 μmol), 2-(3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)ethan-l-ol (1.4 g, 5.7 mmol) in a mixture solvent of DME, EtOH and water (10 mL, 3: 1: 1), sodium carbonate (134.9 mg, 1.3 mmol) and Pd(dppf)Cl2 (46.2 mg, 63.7 μmol) were added. The mixture was degassed by N2balloon. The tube was then sealed and heated to 120 °C with microwave irradiation for 2 hours. The mixture was allowed to cool to room temperature, filtered through a pad of celite, washed with ethyl acetate (20 mL x 3). The combined solution was concentrated in vacuo to give the crude product, which was purified by silica gel flash column chromatography to give a black solid, which was purified by preparative HPLC to give 5-acetyl-3-(2-(2-hydroxyethyl)pyridin-3-yl)-7-methylisoquinolin-l(2H)-one (40 mg, 19.5% yield) as an off-white solid. LC-MS: m / z 323.1 [M+H] + .

[0838] Step 7:

[0839] To a stirred solution of 5-acetyl-3-(2-(2-hydroxyethyl)pyridin-3-yl)-7-methylisoquinolin-l(2H)-one (40 mg, 124.1 μmol) and PPh3 (48.8 mg, 186.1 μmol) in anhydrous THF (8 mL) at 0 °C under N2atmosphere was added a solution of DIAD (37.6 mg, 186.1 μmol) in THF (0.5 ml). The reaction mixture was allowed to warm to room temperature and stirred for 20 hours. The reaction mixture was heated to 60 °C for 2 hours, cooled to room temperature, then a solution of PPh3 (97.6 mg, 372.3 μmol), DIAD (75.3 mg, 372.3 μmol) in THF (5 ml) was added. The reaction mixture was then stirred for 3 hours. The mixture was concentrated in vacuo and the residue was purified by silica gel flash column chromatography to give 12-acetyl-10-methyl-5,6-dihydro-8H-isoquinoline[3,2-f][l,6]naphthyridin-8-one (200 mg, crude) as a light yellow solid. LC-MS: m / z 305.1 [M+H] + .

[0840] Step 8:

[0841] To a stirred solution of 12-acetyl-10-methyl-5,6-dihydro-8H-isoquinoline[3,2- f][l,6]naphthyridin-8-one (200 mg, 657.2 μmol) in THF (6 mL) was added (R)-2- methylpropane-2-sulfmamide (199.1 mg, 1.6 mmol) followed by Ti(OEt)4 (1.5 g, 6.6 mmol). The mixture was stirred at 80 °C for 21 h. Upon completion, the reaction mixture was allowed to cool to 5 °C, quenched with ice water (20 mL) and diluted with ethyl acetate (30 mL). The reaction mixture was stirred vigorously for 0.5 h, filtered through a pad of celite, and the filter cake was washed with ethyl acetate (30 mL). The filtrate was separated and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers were washed with water (50 mL x 2) and saturated aqueous sodium chloride (50 mL), dried over sodium sulfate and concentrated in vacuo to give (R,E)-2-methyl-N-(l-(10-methyl-8-oxo-5,8-dihydro-6H- isoquinoline[3,2-f][l,6]naphthyridin-12-yl)ethylidene)propane-2-sulfmamide (210 mg, 78.4% yield) as off-white solid. LC-MS: m / z 408.2 [M+H] + .

[0842] Step 9:

[0843] To a stirred solution of (R,E)-2-methyl-N-(l-(10-methyl-8-oxo-5,8-dihydro-6H- isoquinoline[3,2-f][l,6]naphthyridin-12-yl)ethylidene)propane-2-sulfmamide (210 mg, 515.3 μmol) and CeCl3 (76.2 mg, 309.2 μmol) in MeOH (8 mL) was added NaBH4 (21.4 mg, 566.8 μmol) at room temperature. The reaction mixture was stirred at room temperature for 30 min. Upon completion, the mixture was quenched with NH4CI (aqueous) (30 mL) and filtered. The filter cake was washed with ethyl acetate (20 mL x 2) and the aqueous layer was extracted with ethyl acetate (40 mL x 2). The combined organic phases were washed with brine (50 mL) and dried over anhydrous Na2S04, filtered and concentrated in vacuo. The crude product was purified by silica gel flash column chromatography, which was purified by preparative HPLC to give (R)-2-methyl-N-((R)-l-(10-methyl-8-oxo-5,8-dihydro-6H- isoquinoline[3,2-f][l,6]naphthyridin-12-yl)ethyl)propane-2-sulfmamide (17 mg, 8% yield) as a white solid. LC-MS: m / z 410.2 [M+H] + .

[0844] Step 10:

[0845] To a stirred solution of (R)-2-methyl-N-((R)-l-(lO-methyl-8-oxo-5,8-dihydro-6H- isoquinoline[3,2-f][l,6]naphthyridin-12-yl)ethyl)propane-2-sulfmamide (17 mg, 41.5 μmol) in EtOH (2.0 mL) was added 4 M HC1 in EtOH (1 mL) and the reaction mixture was stirred at room temperature for 15 min. The mixture was concentrated in vacuo to give (R)-12-(l-aminoethyl)- 10-methyl-5,6-dihydro-8H-isoquinoline[3,2-f][l,6]naphthyridin-8-one as amorphous crystalline solid (15 mg, crude). LC-MS: m / z 306.2 [M+H] + .

[0846] Step 11:

[0847] To a stirred solution of (R)-12-(l-aminoethyl)-lO-methyl-5,6-dihydro-8H- isoquinoline[3,2-f][l,6]naphthyridin-8-one (15 mg, 43.9 μmol) in DMSO (2 mL) was added DIPEA (28.4 mg, 219.4 μmol) followed by methyl 6-chloro-3-fluoropyridine- carboxylate (12.5 mg, 65.8 μmol). The mixture was stirred at 100 °C for 15 h. The reaction mixture was cooled to room temperature, poured into water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with water (20 mL) and saturated aqueous sodium chloride solution (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash column chromatography to give methyl (R)-6-chloro-3-((l-(lO-methyl-8-oxo-5,8-dihydro-6H- isoquinoline[3,2-f][l,6]naphthyridin-12-yl)ethyl)amino)pyridine-2-carboxylate as a brown oil (20 mg, crude). LC-MS: m / z 475.2 [M+H] + .

[0848] Step 12:

[0849] To a stirred solution of (R)-6-chloro-3-((1-(10-methyl-8-oxo-5,8-dihydro-6H- isoquinoline[3,2-f][1,6]naphthyridin-12-yl)ethyl)amino)picolinic acid methyl ester (20 mg, 42.1 μmol) in THF (2 mL) and water (1 mL) was added LiOH H2O (5 mg, 210.6 μmol) at room temperature. The mixture was then stirred at room temperature for 2 hours. The mixture was cooled to 0-5 °C and diluted with water (5 mL), acidified to pH = 2-3 with 2 N HCl and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with water (15 mL) and saturated aqueous sodium chloride solution (15 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (0.1% formic acid) to give (R)-6-chloro-3-((1-(10-methyl-8-oxo-5,8-dihydro-6H-isoquinoline[3,2- f][1,6]naphthyridin-12-yl)ethyl)amino)picolinic acid as an off-white solid (3.5 mg, 18% yield). LC-MS: m / z 461.1 [M+H] + .

[0850] The following compounds have been prepared analogously to the representative procedure described in relation to Example 22.

[0851]

[0852] Example 23

[0853]

[0854] Step 1:

[0855] To a stirred solution of 5-bromo-7-fluoro-3-iodoquinoline (2 g, 5.7 mmol) in AcOH (40 mL) was added H2O2 (2.5 mL). The mixture was stirred at 85 °C for 16 hours. LC-MS showed formation of product. The mixture was poured into saturated NaHCO3(aq) (300 mL) and saturated Na2S2O3(aq) (50 mL), extracted with DCM (200 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography to give 5-bromo-7-fluoro-3-iodoquinoline 1-oxide as a white solid (1.3 g, 60% yield). LC-MS: m / z 367.8, 369.8 [M+H] + .

[0856] Step 2:

[0857] To a stirred mixture of 5-bromo-7-fluoro-3-iodoquinoline 1-oxide (1.3 g, 3.4 mmol) in CHCl3 (30 mL) was added POCl3 (2.6 g, 17 mmol). The mixture was stirred at 80 °C for 1.5 h. LC-MS showed the formation of product. The mixture was poured into saturated NaHCO3 (aqueous) (100 mL) and extracted with DCM (100 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to give 5-bromo-2-chloro-7-fluoro-3-iodoquinoline as a white solid (700 mg, 53% yield).

[0858] Step 3:

[0859] To a stirred solution of 5-bromo-2-chloro-7-fluoro-3-iodoquinoline (700 mg, 1.8 mmol) and (R)-3-(hydroxymethyl)morpholine-4-carboxylic acid tert-butyl ester (984 mg, 4.5 mmol) in THF (15 mL) was added sodium hydride (217.4 mg, 5.4 mmol, 60% purity) under N2. The mixture was stirred at 20 °C for 0.5 h. LC-MS showed the reaction was complete. The mixture was quenched with water (1 mL) to give (R)-3-(((5-bromo-7-fluoro-3-iodoquinolin-2-yl)oxy)methyl)morpholine-4-carboxylic acid tert-butyl ester (1 g, crude), which was used directly in the next step without further purification. LC-MS: m / z 567.0, 569.0 [M+H] + .

[0860] Step 4:

[0861] To a stirred solution of (R)-3-(((5-bromo-7-fluoro-3-iodoquinolin-2-yl)oxy)methyl)morpholine-4-carboxylic acid tert-butyl ester (1 g, 1.8 mmol) in THF (15 mL) was added 4 M HCl solution in EtOH (30 mL). The mixture was stirred at 40 °C for 1 h. LC-MS showed the formation of product. The mixture was poured into saturated NaHCO3 (aqueous) (250 mL) and extracted with EtOAc (200 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to give (R)-3-(((5-bromo-7-fluoro-3-iodoquinolin-2-yl)oxy)methyl)morpholine as a colorless oil (840 mg, 99% yield). LC-MS: m / z 466.9, 468.9 [M+H] + .

[0862] Step 5:

[0863] To a stirred mixture of (R)-3-(((5-bromo-7-fluoro-3-iodoquinolin-2-yl)oxy)methyl)morpholine (840 mg, 1.8 mmol) in dioxane (30 mL) was added t-BuOK (403.6 mg, 3.6 mmol) and [2-(2-aminophenyl)phenyl]-chloro-palladium; (5-diphenylphosphino-9,9-dimethyl-xanthlen-4-yl)-diphenyl-phosphine (239.7 mg, 269.8 μmol) at room temperature. The mixture was stirred at 95 °C under N2for 16 h. LC-MS showed the formation of product. The mixture was quenched with water (150 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash column chromatography to give (S)-11-bromo-9-fluoro-1,2,4a,5-tetrahydro-4H-[1,4]oxazino[4',3':4,5][1,4]oxazino[2,3-b]quinoline as a white solid (75 mg, 12% yield). LC-MS: m / z 339.0, 341.0 [M+H] + .

[0864] Step 6:

[0865] To a stirred mixture of (S)-11-bromo-9-fluoro-1,2,4a,5-tetrahydro-4H-[1,4]oxazino[4',3':4,5][1,4]oxazino[2,3-b]quinoline (130 mg, 383.3 μmol) in dioxane (5 mL) was added Pd(PPh3)2Cl2 (45.5 mg, 57.5 μmol) and tributyl(1-ethoxyvinyl)stannane (180 mg, 498.3 μmol) under N2. The mixture was stirred at 105 °C for 3 h. LC-MS showed the reaction was complete. Then 3 M HC1 (2 mL) was added and the resulting mixture was stirred at 20 °C for 0.5 h. The mixture was diluted with water (40 mL), basified to pH ~ 9 with saturated NaHC03(aq), and extracted with DCM (40 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography to give (S)-1-(9-fluoro-1,2,4a,5-tetrahydro-4H-[1,4]oxazino[4',3':4,5][1,4]oxazino[2,3-b]quinolin-11-yl)ethan-1-one as a yellow solid (110 mg, 95% yield). LC-MS: m / z 303.1 [M+H] + .

[0866] Step 7:

[0867] A mixture of (S)-l-(9-fluoro-l,2,4a,5-tetrahydro-4H- [l,4]oxazino[4',3':4,5][l,4]oxazino[2,3-b]quinolin-l l-yl)ethan-l-one (120 mg, 400 pmol) and (R)-2-methylpropane-2-sulfinamide (144.3 mg, 1.2 mmol) in THF (4 mL) and Ti(OEt)4 (2 mL) was stirred at 85 °C for 7 h. LC-MS showed the reaction was complete. The mixture was cooled to 20 °C, diluted with DCM (150 mL) and water (30 mL), and filtered. The filtrate was separated, and the organic layer was dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to give (R)-N-((E)-l-((S)-9-fluoro-l,2,4a,5-tetrahydro-4H- [l,4]oxazino[4',3':4,5][l,4]oxazino[2,3-b]quinolin-l l-yl)ethenyl)-2-methylpropane-2- sulfinamide (150 mg, 93% yield) as a yellow solid. LC-MS: m / z 406.1 [M+H] + .

[0868] Step 8:

[0869] To a stirred mixture of (R)-N-((E)-l-((S)-9-fluoro-l,2,4a,5-tetrahydro-4H- [l,4]oxazino[4',3':4,5][l,4]oxazino[2,3-b]quinolin-l l-yl)ethenyl)-2-methylpropane-2- sulfinamide (150 mg, 369.9 pmol) and CeCl3 (54.7 mg, 222 pmol) in MeOH (5 mL) was added NaBH4 (28 mg, 740 pmol) in portions at room temperature. The mixture was stirred at 20 °C for 5 min. LC-MS showed the formation of product. The mixture was quenched with water (50 mL) and extracted with DCM (40 mL x 2). The combined organic layer was dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to give (R)-N-((R)-l-((S)-9-fluoro-l,2,4a,5-tetrahydro-4H- [l,4]oxazino[4',3':4,5][l,4]oxazino[2,3-b]quinolin-l l-yl)ethyl)-2-methylpropane-2- sulfinamide (90 mg, 60% yield) as a white solid. LC-MS: m / z 408.1 [M+H] + .

[0870] Step 9:

[0871] To a stirred solution of (R)-N-((R)-1-((S)-9-fluoro-1,2,4a,5-tetrahydro-4H- [1,4]oxazino[4',3':4,5][1,4]oxazino[2,3-b]quinolin-11-yl)ethyl)-2-methylpropane-2- sulfinamide (90 mg, 220.9 μmol) in EtOH (3 mL) was added 4 M HC1 in EtOH (1 mL). The mixture was stirred at 20 °C for 0.5 h. LC-MS showed the reaction was complete. The mixture was basified with saturated NaHC03(aq) to pH ~ 9, and extracted with DCM (40 mL x 2). The combined organic layer was dried over Na2S04, filtered, and concentrated in vacuo to give (R)-1-((S)-9-fluoro-1,2,4a,5-tetrahydro-4H- [1,4]oxazino[4',3':4,5][1,4]oxazino[2,3-b]quinolin-11-yl)ethan-1-amine (65 mg, 97% yield) as off-white solid, which was used directly in the next step without further purification. LC-MS: m / z 304.1 [M+H] + .

[0872] Step 10:

[0873] To a stirred mixture of (R)-1-((S)-9-fluoro-1,2,4a,5-tetrahydro-4H- [1,4]oxazino[4',3':4,5][1,4]oxazino[2,3-b]quinolin-11-yl)ethan-1-amine (45 mg, 148.4 μmol) and methyl 6-chloro-3-fluoropicolinic acid (70.3 mg, 370.9 μmol) in DMSO (3 mL) was added K2C03(51.3 mg, 370.9 μmol) at room temperature. The mixture was then stirred at 110 °C for 4 h. LC-MS showed the formation of product. The mixture was purified by reverse phase chromatography to give methyl 6-chloro-3-(((R)-1-((S)-9-fluoro-1,2,4a,5-tetrahydro-4H- [1,4]oxazino[4',3':4,5][1,4]oxazino[2,3-b]quinolin-11-yl)ethyl)amino)picolinic acid (10 mg, 14% yield) as yellow solid. LC-MS: m / z 473.1 [M+H] + .

[0874] Step 11:

[0875] To a mixture of methyl 6-chloro-3-(((R)-1-((S)-9-fluoro-1,2,4a,5-tetrahydro-4H- [1,4]oxazino[4 3:4,5][1,4]oxazino[2,3-b]quinolin-11-yl)ethyl)amino)picolinate (10 mg, 21.2 μmol) in a mixture of THF and water (4 mL, 3:1) was added LiOH H2O (2.6 mg, 105.7 μmol). The mixture was stirred at 20 °C for 1 h. LC-MS showed the reaction was complete. The mixture was acidified with HC1 (1 M) to pH ~ 5 and concentrated in vacuo. The residue was purified by prep-HPLC to give 6-chloro-3-(((R)-1-((S)-9-fluoro-1,2,4a,5-tetrahydro-4H- [1,4]oxazino[4 3:4,5][1,4]oxazino[2,3-b]quinolin-11-yl)ethyl)amino)picolinic acid as an off-white solid (3.8 mg, 39% yield). LC-MS: m / z 459.1 [M+H] + .

[0876] The following compounds have been prepared analogously to the representative procedure described in relation to Example 23.

[0877]

[0878] Examples 25 and 26

[0879]

[0880] Step 1:

[0881] A mixture of 3-bromo-5-methyl-benzene-1,2-diamine (7 g, 34.8 mmol) and oxalic acid (6.3 g, 69.6 mmol) in 3 M aqueous HC1 (100 mL) was stirred at 100 °C for 24 h. The mixture was then filtered and the filter cake was dried in vacuo to give 5-bromo-7-methyl-1,4-dihydroquinoxaline-2,3-dione as a black solid (6 g, 68% yield). LC-MS: m / z 254.9 [M+H] + .

[0882] Step 2:

[0883] A mixture of 5-bromo-7-methyl-1,4-dihydroquinoxaline-2,3-dione (6.4 g, 25.1 mmol), POCl3 (38.5 g, 250.9 mmol, 23.4 mL) and DMF (91.7 mg, 1.3 mmol) in DCE (80 mL) was stirred at 90 °C for 14 hours. Upon completion, the mixture was concentrated in vacuo and the residue was basified with saturated NaHCO3 and extracted with DCM (100 mL x 3). The combined organic layers were concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-10% MeOH / DCM to give 5-bromo-2,3-dichloro-7-methyl-quinoxaline as a dark solid (6 g, 82% yield).

[0884] Step 3:

[0885] A mixture of 5-bromo-2,3-dichloro-7-methyl-quinoxaline (1 g, 3.4 mmol), (R)- morpholin-3-ylmethanol hydrochloride (631.35 mg, 4.11 mmol) and K2CO3 (1.4 g, 10.3 mmol) in DMSO (30 mL) was stirred at 100 °C for 16 hours. Upon completion, the mixture was diluted with EtOAc (80 mL) and washed with water (30 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-5% EtOAc / DCM to give a mixture of (S)-11-bromo-9-methyl-1,2,4a,5-tetrahydro-4H- [1,4]oxazino[4',3':4,5][1,4]oxazino[2,3-b]quinoxaline and (S)-8-bromo-10-methyl-1,2,4a,5- tetrahydro-4H-[1,4]oxazino[4',3':4,5][1,4]oxazino[2,3-b]quinoxaline as a yellow solid (861 mg, 75% yield). LC-MS: m / z 336.0 [M+H] + .

[0886] Step 4:

[0887] A mixture of (S)-11-bromo-9-methyl-1,2,4a,5-tetrahydro-4H- [1,4]oxazino[4',3':4,5][1,4]oxazino[2,3-b]quinoxazin and (S)-8-bromo-10-methyl- 1,2,4a,5-tetrahydro-4H-[1,4]oxazino[4',3':4,5][1,4]oxazino[2,3-b]quinoxazin (861 mg, 2.6 mmol), tributyl(1-ethoxyvinyl)stannane (1.4 g, 3.8 mmol) and Pd(PPh3)4 (296 mg, 256.1 μmol) in DMF (10 mL) was stirred at 90 °C under microwave irradiation for 3 h. Upon completion, 3 M HC1 (2 mL) was added and the resulting mixture was stirred at room temperature for 30 min to hydrolyze the ether intermediate to ketone. The mixture was then basified with saturated NaHC03, diluted with EtOAc (80 mL) and washed with water (40 mL x 3). The organic layer was dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-20% EtOAc / DCM to give a mixture of (S)-1-(9-methyl-1,2,4a,5-tetrahydro-4H- [1,4]oxazino[4',3':4,5][1,4]oxazino[2,3-b]quinoxazin-11-yl)ethan-1-one and (S)-1-(10-methyl-1,2,4a,5-tetrahydro-4H-[1,4]oxazino[4',3':4,5][1,4]oxazino[2,3-b]quinoxazin-8-yl)ethan-1-one as a yellow solid (532 mg, 69% yield). LC-MS: m / z 300.1 [M+H] + .

[0888] Step 5:

[0889] A mixture of (S)-1-(9-methyl-1,2,4a,5-tetrahydro-4H-[1,4]oxazino[4',3':4,5][1,4]oxazino[2,3- b]quinoxalin-11-yl)ethan-1-one and (S)-1-(10-methyl-1,2,4a,5-tetrahydro-4H-[1,4]oxazino[4',3':4,5][1,4]oxazino[2,3- b]quinoxalin-8-yl)ethan-1-one (532 mg, 1.8 mmol), (R)-2-methylpropane-2-sulfinamide (430.8 mg, 3.6 mmol), and Ti(OEt)4 (3 mL) in THF (4 mL) was stirred at 80 °C for 16 h. Upon completion, the mixture was quenched with water and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-60% EtOAc / DCM to give a mixture of (R)-2-methyl-N-((E)-1-((S)-9-methyl-1,2,4a,5-tetrahydro-4H-[1,4]oxazino[4',3':4,5][1,4]oxazino[2,3- b]quinoxalin-11-yl)ethenyl)propane-2-sulfinamide and (R)-2-methyl-N-((E)-1-((S)-10-methyl-1,2,4a,5-tetrahydro-4H-[1,4]oxazino[4',3':4,5][1,4]oxazino[2,3- b]quinoxalin-8-yl)ethenyl)propane-2-sulfinamide as a yellow solid (691 mg, 96% yield). LC-MS: m / z 403.2 [M+H] + .

[0890] Step 6:

[0891] To a stirred mixture of (R)-2-methyl-N-((E)-1-((S)-9-methyl-1,2,4a,5-tetrahydro-4H- [1,4]oxazino[4',3':4,5][1,4]oxazino[2,3-b]quinoxalin-11-yl)ethenyl)propane-2-sulfmamide and (R)-2-methyl-N-((E)-1-((S)-10-methyl-1,2,4a,5-tetrahydro-4H- [1,4]oxazino[4',3':4,5][1,4]oxazino[2,3-b]quinoxalin-8-yl)ethenyl)propane-2-sulfmamide (691 mg, 1.7 mmol) and CeCl3 (423.1 mg, 1.7 mmol) in MeOH (5 mL) was added NaBH4 (129.9 mg, 3.4 mmol) in portions and the resulting mixture was stirred at room temperature for 10 min. Upon completion, the mixture was quenched with water (20 mL) and extracted with DCM (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a mixture of (R)-2-methyl-N-((R)-1-((S)-9-methyl-1,2,4a,5-tetrahydro-4H- [1,4]oxazino[4',3':4,5][1,4]oxazino[2,3-b]quinoxalin-11-yl)ethyl)propane-2-sulfmamide and (R)-2-methyl-N-((R)-1-((S)-10-methyl-1,2,4a,5-tetrahydro-4H- [1,4]oxazino[4',3':4,5][1,4]oxazino[2,3-b]quinoxalin-8-yl)ethyl)propane-2-sulfmamide as a yellow solid (620 mg, crude), which was used in the next step without further purification. LC-MS: m / z 405.2 [M+H] + .

[0892] Step 7:

[0893] To a stirred solution of (R)-2-methyl-N-((R)-1-((S)-9-methyl-1,2,4a,5-tetrahydro- 4H-[1,4]oxazino[4',3':4,5][1,4]oxazino[2,3-b]quinoxalin-11-yl)ethyl)propane-2- sulfinamide and (R)-2-methyl-N-((R)-1-((S)-10-methyl-1,2,4a,5-tetrahydro-4H- [1,4]oxazino[4',3':4,5][1,4]oxazino[2,3-b]quinoxalin-8-yl)ethyl)propane-2-sulfinamide (632 mg, 1.6 mmol) in MeOH (3 mL) was added 4 M HC1 in dioxane (0.5 mL) dropwise and the resulting mixture was stirred at room temperature for 10 minutes. Upon completion, the mixture was basified with saturated NaHC03and extracted with DCM (30 mL x 3). The combined organic layers were dried over anhydrous Na2S04, filtered, and concentrated in vacuo to give a mixture of (R)-1-((S)-9-methyl-1,2,4a,5-tetrahydro-4H- [1,4]oxazino[4',3':4,5][1,4]oxazino[2,3-b]quinoxalin-11-yl)ethan-1-amine and (R)-1-((S)-10- methyl-1,2,4a,5-tetrahydro-4H-[1,4]oxazino[4',3':4,5][1,4]oxazino[2,3-b]quinoxalin-8- yl)ethan-1-amine as a yellow solid (590 mg, crude), which was used in the next step without further purification. LC-MS: m / z 301.1 [M+H] + .

[0894] Step 8:

[0895] A mixture of (R)-1-((S)-9-methyl-1,2,4a,5-tetrahydro-4H- [1,4]oxazino[4',3':4,5][1,4]oxazino[2,3-b]quinoxolin-11-yl)ethan-1-amine and (R)-1-((S)-10-methyl-1,2,4a,5-tetrahydro-4H- [1,4]oxazino[4',3':4,5][1,4]oxazino[2,3-b]quinoxolin-8-yl)ethan-1-amine (115 mg, 382.9 μmol) and K2CO3 (52.9 mg, 382.9 μmol) in DMSO (2 mL) was stirred at 100 °C under microwave irradiation for 1 h. Upon completion, the mixture was diluted with EtOAc (30 mL) and washed with water (15 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a mixture of methyl 6-chloro-3-(((R)-1-((S)-9-methyl-1,2,4a,5-tetrahydro-4H- [1,4]oxazino[4',3':4,5][1,4]oxazino[2,3-b]quinoxalin-11-yl)ethyl)amino)picolinic acid methyl ester and methyl 6-chloro-3-(((R)-1-((S)-10-methyl-1,2,4a,5-tetrahydro-4H- [1,4]oxazino[4',3':4,5][1,4]oxazino[2,3-b]quinoxalin-8-yl)ethyl)amino)picolinic acid methyl ester (179.9 mg, crude), which was used in the next step without further purification. LC-MS: m / z 470.1 [M+H] + .

[0896] Step 9:

[0897] A mixture of methyl 6-chloro-3-(((R)-l-((S)-9-methyl-l,2,4a,5-tetrahydro-4H- [l,4]oxazino[4',3':4,5][l,4]oxazino[2,3-b]quinoxalin-l l-yl)ethyl)amino)picolinate and methyl 6-chloro-3-(((R)-l-((S)-lO-methyl-l,2,4a,5-tetrahydro-4H- [l,4]oxazino[4',3':4,5][l,4]oxazino[2,3-b]quinoxalin-8-yl)ethyl)amino)picolinate (179.9 mg, 382.8 μmol) and LiOH H2O (9.2 mg, 382.8 μmol) in a mixture of THF and H2O (3 mL, 2: 1) was stirred at 70 °C under microwave irradiation for 20 min. Upon completion, the mixture was acidified with 1 M HC1, followed by concentration in vacuo. The residue was purified by preparative HPLC to give two products, which were arbitrarily assigned as methyl 6-chloro-3-(((R)-l-((S)-9-methyl-l,2,4a,5-tetrahydro-4H- [l,4]oxazino[4',3':4,5][l,4]oxazino[2,3-b]quinoxalin-l l-yl)ethyl)amino)picolinate (22.7 mg, 13% yield, white solid) and methyl 6-chloro-3-(((R)-l-((S)-lO-methyl-l,2,4a,5-tetrahydro-4H- [l,4]oxazino[4',3':4,5][l,4]oxazino[2,3-b]quinoxalin-8-yl)ethyl)amino)picolinate (15.7 mg, 9% yield, white solid). LC-MS: m / z 456.1 [M+H] + .

[0898] The following compounds have been prepared analogously to the representative procedures described in relation to Examples 25 and 26.

[0899]

[0900]

[0901]

[0902] Example 66

[0903]

[0904] Step 1:

[0905] To a solution of 1-bromo-2,5-difluoro-3-nitro-benzene (250 g, 1 mol) and DIPEA (474.3 g, 3.7 mol) in THF (2 L) was added ethyl 2-aminoacetate hydrochloride (204.4 g, 1.5 mol). The mixture was stirred at 65 °C for 16 hours before cooling to room temperature. The mixture was diluted with DCM (4 L) followed by washing with brine (1 L x 2). The organic phase was dried over Na2S04, filtered and concentrated to give ethyl 2-(2-bromo-4-fluoro-6-nitro-anilino)acetate (270 g, crude) as a yellow solid. LC-MS: m / z 321.0 [M+H] + .

[0906] Step 2:

[0907] A mixture of ethyl 2-(2-bromo-4-fluoro-6-nitro-anilino)acetate (270 g, 841.1 mmol) and Fe (235.5 g, 4.2 mol) in AcOH (2 L) was stirred at 85 °C under N2for 10 hours. The mixture was cooled to room temperature before being concentrated under reduced pressure to give a residue. The residue was suspended in DCM (3 L) followed by filtration. The organic phase was washed with aqueous NaHC03solution (400 mL). The organic phase was dried over Na2S04, filtered and concentrated to give 5-bromo-7-fluoro-3,4-dihydro-1H- quinoxalin-2-one (175 g, crude) as a light yellow solid. LC-MS: m / z 244.9 [M+H] + .

[0908] Step 3:

[0909] To a solution of 5-bromo-7-fluoro-3,4-dihydro-1H-quinoxalin-2-one (175 g, 714.2 mmol) in aqueous NaOH (1 N, 1500 mL) and methanol (1500 mL) was added hydrogen peroxide (283.3 g, 2.5 mol, 30% purity). The mixture was stirred at 85 °C for 10 hours before cooling to room temperature. The mixture was concentrated and the pH was adjusted to 3 with 1 N HC1 (aqueous). The mixture was filtered and the filter cake was washed with water (500 mL). The filter cake was purified by trituration with CH3OH (300 mL) to give 5-bromo-7-fluoro-1H-quinoxalin-2-one (87 g, 50% yield) as a yellow solid. LC-MS: m / z 242.8 [M+H] + .

[0910] Step 4:

[0911] To a solution of 5-bromo-7-fluoro-lH-quinoxalin-2-one (26.5 g, 109 mmol) in CH3CN (400 mL) was added CAN (179.3 g, 327.1 mmol) and tert-butyl (3R)-3-(hydroxymethyl)morpholine-4-carboxylate (47.4 g, 218.1 mmol). The mixture was stirred at 75 °C for 2 h. The mixture was concentrated, then diluted with EtOAc (3 L). The mixture was adjusted to pH 7 with 10% NaHCO3(aq). The suspension was filtered. The aqueous phase was extracted with EtOAc (1.5 L x 3) and a mixture solvent of CH2Cl2(500 mL) and CH3OH (50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to give the crude product, which was combined with the filter cake to give 5-bromo-7-fluoro-3-[[(3S)-morpholin-3-yl]methoxy]-lH-quinoxalin-2-one (300 g, crude) as a yellow solid. LC-MS: m / z 359.8 [M+H] + .

[0912] Step 5:

[0913] A solution of 5-bromo-7-fluoro-3-[[(3S)-morpholin-3-yl]methoxy]-lH-quinoxalin-2-one (103.3 g, 288.4 mmol) in methanol (1.2 L) was stirred at 70 °C for 16 h. The mixture was filtered. The filter cake was suspended in CH3OH (3 L) and the mixture was stirred at 20 °C for 0.5 h. The mixture was filtered and the filter cake was washed with CH3OH (500 mL) to give the crude product. The crude material was purified by silica gel column chromatography to give 5-bromo-7-fluoro-3-[(3R)-3-(hydroxymethyl)morpholin-4-yl]-lH-quinoxalin-2-one (33.8 g) as a yellow solid. LC-MS: m / z 357.8 [M+H] + .

[0914] Step 6:

[0915] TEA (34.7 g, 343.4 mmol) and PyClOP (28.9 g, 68.7 mmol) were added to a solution of 5-bromo-7-fluoro-3-[(3R)-3-(hydroxymethyl)morpholin-4-yl]-1H-quinoxalin-2-one (16.4 g, 45.8 mmol) in dioxane (167 mL). The mixture was degassed three times with N2 and then stirred at 127 °C for 16 h. The mixture was concentrated, diluted with DCM (1.6 L), and washed with brine (400 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to give (7S)-16-bromo-14-fluoro-5,9-dioxa-2,11,18-triazatetracyclo[8.8.0.0] as a yellow solid. 2,7 .0 12,17 Octadecto-1(18),10,12(17),13,15-pentaenes (30.7 g, 98.5% yield). LC-MS: m / z 339.8 [M+H] + .

[0916] Step 7:

[0917] To (7S)-16-bromo-14-fluoro-5,9-dioxa-2,11,18-triazatetracyclo[8.8.0.0] 2,7 .0 12,17 A solution of octadec-1(18),10,12(17),13,15-pentaene (14.8 g, 43.6 mmol) in dioxane was supplemented with tributyl(1-ethoxyvinyl)stanane (23.6 g, 65.4 mmol) and Pd(PPh3)2Cl2 (6.1 g, 8.7 mmol). The mixture was degassed three times with N2 and then stirred at 100 °C for 16 h. The mixture was quenched with KF solution (150 mL) and filtered. The filter cake was suspended in DCM (1.5 L) and stirred at 20 °C for 0.5 h. The mixture was filtered. The filtrate was washed with water (300 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. The crude substance was purified by silica gel column chromatography to obtain a yellow solid, (7S)-16-(1-ethoxyvinyl)-14-fluoro-5,9-dioxa-2,11,18-triazatetracyclo[8.8.0.0]. 2, 7 .0 12,17 Octadecto-1(18),10,12(17),13,15-pentaenes (30.3 g, crude). LC-MS: m / z 331.9 [M+H] + .

[0918] Step 8:

[0919] To (7S)-16-(1-ethoxyvinyl)-14-fluoro-5,9-dioxa-2,11,18-triazatetracyclo[8.8.0.0] 2,7 .0 12,17 30.3 g, 91.4 mmol] of octadec-1(18),10,12(17),13,15-pentaene (2 N HCl, 90 mL aqueous solution) was added to a solution of acetone (300 mL). The mixture was stirred at 20 °C for 5 min, diluted with DCM (1.5 L), and washed with 10% NaHCO3 (300 mL aqueous solution). The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain a yellow solid of 1-[(7S)-14-fluoro-5,9-dioxa-2,11,18-triazatetracyclo[8.8.0.0] 2,7 .0 12,17 [Octadec-1(18),10,12(17),13,15-pentaen-16-yl]acetone (26 g, 93.7% yield). LC-MS: m / z 303.9 [M+H] + .

[0920] Step 9:

[0921] To 1-[(7S)-14-fluoro-5,9-dioxa-2,11,18-triazatetracyclo[8.8.0.0] 2,7 .0 12,17 [18,10,12,17,13,15-pentaen-16-yl]acetone (10 g, 32.9 mmol) was added to a solution of ethyl titanate (70 mL) and THF (80 mL) with (R)-2-methylpropane-2-sulfinamide (11.9 g, 98.9 mmol). The mixture was stirred at 80 °C under N2 for 16 hours. The mixture was diluted with EtOAc (1.2 L) and water (360 mL). The mixture was stirred at 20 °C for 0.5 hours, filtered, and the organic layer was washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude substance was purified by silica gel column chromatography to obtain (R)-N-((E)-1-((S)-9-fluoro-1,2,4a,5-tetrahydro-4H-[1,4]oxazino[4',3':4,5][1,4]oxazino[2,3-b]quinoxaloline-11-yl)ethylene)-2-methylpropane-2-sulfinamide (25.7 g, 95.8% yield), as a yellow solid. LC-MS: m / z 406.9 [M+H] + .

[0922] Step 10:

[0923] To a solution of (R)-N-((E)-l-((S)-9-fluoro-l,2,4a,5-tetrahydro-4H- [l,4]oxazino[4',3':4,5][l,4]oxazino[2,3-b]quinoxalin-l l-yl)ethenyl)-2-methylpropane-2- sulfinamide (12.8 g, 31.5 mmol) and CeCl3 (3.1 g, 12.6 mmol) in methanol (160 mL) was added NaBH4 (1.8 g, 47.2 mmol) at 5-15 °C. The mixture was then stirred at 5-15 °C for 20 min, diluted with DCM (1.2 L) and washed with brine (200 mL x 2). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product. The crude material was purified by silica gel column chromatography to give (R)-N-[(lR)-l-[(7S)-14-fluoro-5,9-dioxa-2,11,18- triazatetracyclo[8.8.0.0 2, 7 .0 12,17 ]octadeca-l(18),10,12(17),13,15-pentaen-16-yl]ethyl]-2-methyl-propane-2- sulfinamide (22 g, 85.5% yield). LC-MS: m / z 406.9 [M+H] + .

[0924] Step 11:

[0925] To a solution of (R)-N-[(lR)-l-[(7S)-14-fluoro-5,9-dioxa-2,11,18-triazatetracyclo[8.8.0.0 2, 7 .0 12,17 ]octadeca-l(18),10,12(17),13,15-pentaen-16-yl]ethyl]-2-methyl-propane-2- sulfinamide (16 g, 39.1 mmol) in methanol (170 mL) was added HCl solution in EtOH (4 N, 15 mL). The mixture was stirred at 20 °C for 5 min. The mixture was diluted with water (150 mL), adjusted to pH 7 with 10% NaHC03(aq) and extracted with DCM (500 mL x 3). The combined organic layer was dried over Na2SO4, filtered and concentrated to give (lR)-l-[(7S)-14-fluoro-5,9-dioxa-2,11,18-triazatetracyclo[8.8.0.0 2,7 .0 12,17Octadeca-1(18), 10, 12(17), 13, 15-pentaen-16-yl]ethylamine (12.4 g, crude). LC-MS: m / z 304.9 [M+H] + .

[0926] Step 12:

[0927] To a solution of (1R)-1-[(7S)-14-fluoro-5,9-dioxa-2,11,18-triazatetracyclo[8.8.0.0 2,7 .0 12,17 ]octadeca-1(18), 10, 12(17), 13, 15-pentaen-16-yl]ethylamine (6.2 g, 20.3 mmol) and TEA (5.4 g, 52.9 mmol) in DMSO (60 mL) was added methyl 6-chloro-3-fluoro-pyridine-2-carboxylate (5.8 g, 30.6 mmol). The mixture was stirred at 100 °C for 16 h. The mixture was diluted with EtOAc (700 mL) and washed with brine (150 mL x 4). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product. The crude material was purified by silica gel column chromatography to give methyl 6-chloro-3-(((R)-1-((S)-9-fluoro-1,2,4a,5-tetrahydro-4H- [1,4]oxazino[4',3':4,5][1,4]oxazino[2,3-b]quinoxalin-11-yl)ethyl)amino)pyridinecarboxylate (15.7 g, 81.3% yield) as a yellow solid. LC-MS: m / z 473.8 [M+H] + .

[0928] Step 13:

[0929] To a stirred solution of methyl 6-chloro-3-(((R)-1-((S)-9-fluoro-1,2,4a,5-tetrahydro-4H- [1,4]oxazino[4 3:4,5][1,4]oxazino[2,3-b]quinoxalin-11-yl)ethyl)amino)picolinic acid (7.5 g, 15.8 mmol) in THF (150 mL), methanol (30 mL) and water (30 mL) was added LiOH H2O (3.3 g, 79.1 mmol). The mixture was stirred at 20 °C for 50 min. The mixture was adjusted to pH = 5 with 1 N HC1 (aq), diluted with brine (150 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated to give the crude product. The crude material was purified by reverse phase chromatography to give 6-chloro-3-[[(1R)-1-[(7S)-14-fluoro-5,9-dioxa-2,11,18- triazatetracyclo[8.8.0.0 2,7 .0 12,17 ]octadeca-1(18),10,12(17),13,15-pentaen-16-yl]ethyl]amino]pyridine-2-carboxylic acid (10.2 g, 70.1% yield). LC-MS: m / z 459.8 [M+H] + .

[0930] Example 29

[0931]

[0932] Step 1:

[0933] To a stirred mixture of 2-amino-3-bromo-5-methyl-benzoic acid (920.2 mg, 4 mmol), tert-butyl 2-(2-aminoethyl)piperidine-1-carboxylate (1 g, 4.4 mmol) and HATU (2.3 g, 6 mmol) in dry DMF (15 mL) was added DIPEA (1.0 g, 8.0 mmol) and the resulting mixture was stirred at room temperature for 1 h. Upon completion, the mixture was diluted with EtOAc (50 mL) and washed with water (25 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to give tert-butyl 2-[2-[(2-amino-3-bromo-5-methyl-benzoyl)amino]ethyl]piperidine-1-carboxylate (1.5 g, 85% yield) as a white solid. LC-MS: m / z 440.1 [M+H] + .

[0934] Step 2:

[0935] To a stirred mixture of tert-butyl 2-[2-[(2-amino-3-bromo-5-methyl- benzoyl)amino]ethyl]piperidine-l-carboxylate (1.5 g, 3.4 mmol) and DIPEA (2.2 g, 17.1 mmol, 3 mL) in DCM (20 mL) was added a solution of triphosgene (506 mg, 1.7 mmol) in DCM (2 mL) dropwise at 0 °C and the resulting mixture was stirred at 0 °C for 1 h. The mixture was then quenched with water, followed by treatment with 6 M HC1 at 60 °C for 1 h to remove the Boc protection. Upon completion, the mixture was basified with saturated NaHC03and extracted with DCM (50 mL x 3). The combined organic layers were dried over anhydrous Na2S04, filtered, and concentrated in vacuo to afford 8-bromo-6-methyl-3-(2-(piperidin-2- yl)ethyl)quinazoline-2,4(lH,3H)-dione (300 mg, 24% yield) as a white solid. LC-MS: m / z 366.0 [M+H] + .

[0936] Step 3:

[0937] A mixture of 8-bromo-6-methyl-3-(2-(piperidin-2-yl)ethyl)quinazoline-2,4(lH,3H)- dione (300 mg, 0.8 mmol), lH-benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (470 mg, 1.1 mmol), and DBU (187 mg, 1.2 mmol) in MeCN (15 mL) was stirred at room temperature for 2 h. The mixture was then concentrated in vacuo. The residue was purified by silica gel chromatography to afford 12-bromo-10-methyl-2,3,4,4a,5,6-hexahydro-lH,8H-pyrido[l',2':3,4]pyrimido[2,l- b]quinazolin-8-one (150 mg, 54% yield) as a white solid. LC-MS: m / z 348.0 [M+H] + .

[0938] Step 4:

[0939] A mixture of 12-bromo-10-methyl-2,3,4,4a,5,6-hexahydro-1H,8H-pyrido[1',2':3,4]pyrimidino[2,1-b]quinazolin-8-one (50 mg, 143.6 μmol), Pd(PPh3)4 (16.6 mg, 14.4 μmol), and KF (25 mg, 430.7 μmol) in DMF (4 mL) was stirred at 100 °C under microwave irradiation for 1 hour. Then, 6 M HCl (1 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The mixture was alkalized with saturated NaHCO3 and extracted with EtOAc (15 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography to give 12-acetyl-10-methyl-2,3,4,4a,5,6-hexahydro-1H,8H-pyrido[1',2':3,4]pyrimidino[2,1-b]quinazolin-8-one (40 mg, 89% yield) as a colorless foam. LC-MS: m / z 312.1 [M+H] + .

[0940] Step 5:

[0941] TiCl4 (2 mL) was added to a stirred mixture of methyl 2-aminobenzoate (750.00 mg, 4.96 mmol), 12-acetyl-10-methyl-2,3,4,4a,5,6-hexahydro-1H,8H-pyrido[1',2':3,4]pyrimidino[2,1-b]quinazolin-8-one (30 mg, 96.4 μmol) in anhydrous DCM (4 mL) at 0 °C, and the mixture was stirred at room temperature for 1 hour. Then, NaBH3CN (121 mg, 1.9 mmol) was added fractionally, and the mixture was stirred at room temperature for 1 hour. After completion, water (20 mL) was added to quench the reaction mixture, and the mixture was extracted with EtOAc (30 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography to give methyl 2-((1-(10-methyl-8-oxo-2,3,4,4a,5,6-hexahydro-1H,8H-pyrido[1',2':3,4]pyrimidino[2,1-b]quinazolin-12-yl)ethyl)amino)benzoate (28 mg, 65% yield) as a colorless foam. LC-MS: m / z 447.2 [M+H] + .

[0942] Step 6:

[0943] A mixture of methyl 2-((l-(lO-methyl-8-oxo-2,3,4,4a,5,6-hexahydro- lH,8H-pyrido[l',2':3,4]pyrimido[2,l-b]quinazolin-12-yl)ethyl)amino)benzoate (28 mg, 62.8 μmol) and LiOH H2O (15 mg, 0.6 mmol) in a mixture of THF and H2O (2 mL, 2: 1) was stirred at 70 °C under microwave irradiation for 1 hour. Upon completion, the mixture was concentrated in vacuo and the residue was purified by preparative HPLC to give 2-((l-(lO-methyl-8-oxo-2,3,4,4a,5,6-hexahydro-lH,8H-pyrido[l',2':3,4]pyrimido[2,l-b]quinazolin-12-yl)ethyl)amino)benzoic acid (5 mg, 18% yield) as a white solid. LC-MS: m / z 433.2 [M+H] + .

[0944] The following compounds have been prepared analogously to the representative procedure described in relation to Example 29.

[0945]

[0946] Example 31

[0947]

[0948] Step 1:

[0949] To a stirred mixture of 12-acetyl-10-methyl-2,3,4,4a,5,6-hexahydro-lH,8H- pyrido[l',2':3,4]pyrimido[2,l-b]quinazolin-8-one (50 mg, 161 μmol) and NH4OAc (123.8 mg, 1.6 mmol) in MeOH (3 mL) was added sodium cyanoborohydride (100.9 mg, 1.6 mmol) in portions at 60 °C and the resulting mixture was stirred at 60 °C for 1 hour. Upon completion, the reaction was quenched with water and the mixture was extracted with DCM (15 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 12-(l-aminoethyl)-10-methyl-2,3,4,4a,5,6-hexahydro-lH,8H-pyrido[l',2':3,4]pyrimido[2,l-b]quinazolin-8-one (50 mg, crude) as a white solid which was used in the next step without further purification. LC-MS: m / z 313.2 [M+H] + .

[0950] Step 2:

[0951] A mixture of 12-(1-aminoethyl)-10-methyl-2,3,4,4a,5,6-hexahydro-1H,8H- pyrido[1',2':3,4]pyrimido[2,1-b]quinolin-8-one (20 mg, 64 μmol), ethyl 6-chloro-3- fluoropyridinecarboxylate (26 mg, 128 μmol), and K2CO3 (17.7 mg, 128 μmol) in DMSO (1 mL) was stirred at 60 °C for 8 hours. After completion of the first step, a solution of LiOH H2O (7.4 mg, 320 μmol) in H2O (1 mL) was added and the mixture was stirred at room temperature overnight. The mixture was then acidified with 3.0 M HCl and the mixture was concentrated in vacuo. The residue was purified by preparative HPLC to give 6-chloro-3-((1-(10-methyl-8-oxo-2,3,4,4a,5,6-hexahydro-1H,8H- pyrido[1',2':3,4]pyrimido[2,1-b]quinolin-12-yl)ethyl)amino)pyridinecarboxylic acid (2 mg, 7% yield) as a white solid. LC-MS: m / z 467.2 [M+H] + .

[0952] Example 32

[0953]

[0954] Step 1:

[0955] A mixture of 12-acetyl-10-methyl-2,3,4,4a,5,6-hexahydro-1H,8H-pyrido[1',2':3,4] pyrimido[2,1-b]quinolin-8-one (250 mg, 0.8 mmol), (R)-2-methylpropane-2- sulfinamide (194 mg, 1.6 mmol), and Ti(OEt)4 (2 mL) in THF (2 mL) was stirred at 80 °C for 16 hours. After completion, the reaction was quenched with water and the mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give (R)-2-methyl-N-((E)-1-(10-methyl-8-oxo-2,3,4,4a,5,6-hexahydro-1H,8H- pyrido[1',2':3,4]pyrimido[2,1-b]quinolin-12-yl)ethenyl)propane-2-sulfinamide (331 mg, crude), which was used in the next step without further purification. LC-MS: m / z 415.2 [M+H] + .

[0956] Step 2:

[0957] To a stirred mixture of (NE, R)-2-methyl-N-[l-(14-methyl-l l-oxo-2,10,18- triazatetracyclo[8.8.0.0 2, 7 .0 12,17 To a stirred mixture of (NE, R)-2-methyl-N-[l-(14-methyl-l l-oxo-2,10,18- triazatetracyclo[8.8.0.0 + .

[0958] Step 3:

[0959] To a stirred mixture of (NE, R)-2-methyl-N-[l-(14-methyl-l l-oxo-2,10,18- triazatetracyclo[8.8.0.0 + .

[0960] Step 4:

[0961] A mixture of 6-chloro-3-fluoro-pyridine-2-carboxylic acid ethyl ester (20.3 mg, 100 μmol), 12-((R)-1-aminoethyl)-10-methyl-2,3,4,4a,5,6-hexahydro-1H,8H-pyrido[1',2':3,4]pyrimido[2,1-b]quinolin-8-one (30 mg, 96 μmol), and K2CO3 (56 mg, 400 μmol) in DMSO (2 mL) was stirred at 60 °C for 9 h. Upon completion, a solution of LiOH H2O (50 mg, 2.2 mmol) in water (1 mL) was added and the resulting mixture was stirred at 60 °C for 2 h. The mixture was then acidified with 3 M HC1 and extracted with DCM (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to give 6-chloro-3-(((1R)-1-(10-methyl-8-oxo-2,3,4,4a,5,6-hexahydro-1H,8H-pyrido[1',2':3,4]pyrimido[2,1-b]quinolin-12-yl)ethyl)amino)picolinic acid (3.2 mg, 7% yield) as a white solid. LC-MS: m / z 468.1 [M+H] + .

[0962] Example 33

[0963]

[0964] Step 1:

[0965] A mixture of CuI (5.3 mg, 28 μmol) and sarcosine (2.7 mg, 30 μmol) in DMSO (1 mL) was stirred at room temperature for 15 min. Then, 12-((R)-1-aminoethyl)-10-methyl-2,3,4,4a,5,6-hexahydro-1H,8H-pyrido[1',2':3,4]pyrimidino[2,1-b]quinazolin-8-one (35 mg, 112 μmol), 5-fluoro-2-iodobenzoic acid (297 mg, 1.1 mmol), and K₂CO₃ (55 mg, 400 μmol) were added, and the mixture was stirred at 60 °C for 36 h. The mixture was then acidified with 3 M HCl and extracted with DCM (20 mL × 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC to give 5-fluoro-2-(((1R)-1-(10-methyl-8-oxo-2,3,4,4a,5,6-hexahydro-1H,8H-pyrido[1',2':3,4]pyrimidino[2,1-b]quinazolin-12-yl)ethyl)amino)benzoic acid (7.1 mg, 14% yield) as a white solid. LC-MS: m / z 451.2 [M+H] + .

[0966] Example 34

[0967]

[0968] Step 1:

[0969] A mixture of 2-amino-3-bromo-5-methylbenzoic acid (1.65 g, 7.2 mmol), 5-chloroisoindoline (1 g, 6.5 mmol), HATU (3.7 g, 9.8 mmol), and TEA (2 g, 19.5 mmol) in DMF (20 mL) was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc (80 mL) and washed with water (30 mL × 3). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography to give (2-amino-3-bromo-5-methylphenyl)(5-chloroisoindoline-2-yl) methyl ketone (1.6 g, 67% yield) as a white solid. LC-MS: m / z 365.0 [M+H] + .

[0970] Step 2:

[0971] A mixture of (2-amino-3-bromo-5-methylphenyl)(5-chloroisoindolin-2-yl)methanone (1.6 g, 4.4 mmol) and (NH4)2S2O8 (4 g, 17.5 mmol) in DMSO (30 mL) was stirred at 60 °C for 2 hours. The mixture was diluted with water (60 mL) and the precipitate was collected by filtration. The filter cake was dried under vacuum to give a mixture of 6-bromo-2-chloro-8-methylisoindolo[l,2-b]quinazolin-10(12H)-one and 6-bromo-3-chloro-8-methylisoindolo[l,2-b]quinazolin-10(12H)-one (total 1.4 g, 88% yield) which was used as a mixture until the last step. LC-MS: m / z 360.9 [M+H] + .

[0972] Step 3:

[0973] A mixture of 6-bromo-2-chloro-8-methylisoindolo[l,2-b]quinazolin-10(12H)-one, 6-bromo-3-chloro-8-methylisoindolo[l,2-b]quinazolin-10(12H)-one (mixture of both, 720 mg, 2 mmol), tributyl(l-ethoxyvinyl)stannane (1.1 g, 3 mmol), Pd(PPh3)4 (231 mg, 200 μmol) and KF (232 mg, 4 mmol) in DMF (15 mL) was stirred at 90 °C for 16 hours. Upon completion, 3 M HC1 (5 mL) was added to hydrolyze the ether intermediate to the ketone product. Upon completion, the mixture was basified with saturated NaHC03 and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-5% MeOH / DCM to give a mixture of 6-acetyl-2-chloro-8-methylisoindolo[l,2-b]quinazolin-10(12H)-one and 6-acetyl-3-chloro-8-methylisoindolo[l,2-b]quinazolin-10(12H)-one (total 412 mg, 63% yield). LC-MS: m / z 325.0 [M+H] + .

[0974] Step 4:

[0975] A mixture of 6-acetyl-2-chloro-8-methylisoindolo[l,2-b]quinolin-l0(l2H)-one and 6-acetyl-3-chloro-8-methylisoindolo[l,2-b]quinolin-l0(l2H)-one (mixture of both, 412 mg, 1.3 mmol), (R)-2-methylpropane-2-sulfmamide (307 mg, 2.5 mmol), and ethyl titanate (IV) (6 mL) in THF (6 mL) was stirred at 80 °C for 16 h. The reaction was quenched with water (30 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to give a mixture of (R,E)-N-(l-(2-chloro-8-methyl-10-oxo-10,12-dihydroisoindolo[l,2-b]quinolin-6- yl)ethylidene)-2-methylpropane-2-sulfmamide and (R,E)-N-(l-(3-chloro-8-methyl-10-oxo- 10,12-dihydroisoindolo[l,2-b]quinolin-6-yl)ethylidene)-2-methylpropane-2-sulfmamide (mixture of both, 131 mg, 24% yield). LC-MS: m / z 428.1 [M+H] + .

[0976] Step 5:

[0977] To a stirred mixture of (R,E)-N-(l-(2-chloro-8-methyl-10-oxo-10,12- dihydroisoindolo[l,2-b]quinazolin-6-yl)ethylidene)-2-methylpropane-2- sulfinamide and (R,E)-N-(l-(3-chloro-8-methyl-10-oxo-10,12- dihydroisoindolo[l,2-b]quinazolin-6-yl)ethylidene)-2-methylpropane-2- sulfinamide (mixture of both, 131 mg, 306 μmol) and CeCl3 (75 mg, 306 μmol) in MeOH (5 mL) was added NaBH4 (23 mg, 612 μmol) in portions. The resulting mixture was stirred at room temperature for 30 min. The mixture was quenched with water (15 mL) and extracted with DCM (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a mixture of (R)-N-((R)-l-(2-chloro-8-methyl-10-oxo-10,12- dihydroisoindolo[l,2-b]quinazolin-6-yl)ethyl)-2-methylpropane-2-sulfinamide and (R)-N-((R)-l-(3-chloro-8-methyl-10-oxo-10,12- dihydroisoindolo[l,2-b]quinazolin-6-yl)ethyl)-2-methylpropane-2-sulfinamide (mixture of both, 130 mg), which was used in the next step without further purification. LC-MS: m / z 430.1 [M+H] + .

[0978] Step 6:

[0979] To a stirred mixture of (R)-N-((R)-1-(2-chloro-8-methyl-10-oxo-10,12- dihydroisoindolo[1,2-b]quinolin-6-yl)ethyl)-2-methylpropane-2-sulfonamide and (R)-N- ((R)-1-(3-chloro-8-methyl-10-oxo-10,12-dihydroisoindolo[1,2-b]quinolin-6-yl)ethyl)-2- methylpropane-2-sulfonamide (mixture of both, 130 mg, 0.3 mmol) in MeOH was added 4 M HC1 in dioxane (1 mL) dropwise and the resulting mixture was stirred at room temperature for 20 min. The mixture was basified with saturated NaHC03and extracted with DCM (30 mL x 3). The combined organic layers were dried over anhydrous Na2S04, filtered, and concentrated in vacuo to give a mixture of (R)-6-(1- aminoethyl)-2-chloro-8-methylisoindolo[1,2-b]quinolin-10(12H)-one and (R)-6-(1- aminoethyl)-3-chloro-8-methylisoindolo[1,2-b]quinolin-10(12H)-one (mixture of both, 100 mg) which was used in the next step without further purification. LC-MS: m / z 326.1 [M+H] + .

[0980] Step 7:

[0981] A mixture of (R)-6-(1-aminoethyl)-2-chloro-8-methylisoindolo[1,2-b]quinolin-10(12H)- one, (R)-6-(1-aminoethyl)-3-chloro-8-methylisoindolo[1,2-b]quinolin-10(12H)-one (mixture of both, 50 mg, 153 μmol) and methyl 6-chloro-3-fluoro-pyridine-2-carboxylate (58.2 mg, 306.9 μmol) in DMSO (2 mL) was stirred at 120 °C under microwave irradiation for 1 h. The mixture was diluted with EtOAc (20 mL) and washed with water (10 mL x 3). The organic layer was dried over anhydrous Na2S04, filtered, and concentrated in vacuo to give a crude mixture of (R)-methyl 6-chloro-3-((1-(2-chloro-8-methyl-10-oxo-10,12-dihydroisoindolo[1,2-b]quinolin-6-yl)ethyl)amino)pyridine-2-carboxylate and (R)-methyl 6-chloro-3-((1-(3-chloro-8-methyl-10-oxo-10,12-dihydroisoindolo[1,2-b]quinolin-6-yl)ethyl)amino)pyridine-2-carboxylate which was used in the next step without further purification. LC-MS: m / z 495.0 [M+H] + .

[0982] Step 8:

[0983] A mixture of (R)-6-chloro-3-((l-(2-chloro-8-methyl-10-oxo-10,12- dihydroisoindolo[l,2-b]quinazolin-6-yl)ethyl)amino)picolinic acid methyl ester, (R)-6-chloro-3-((l-(3-chloro-8-methyl-10-oxo-10,12-dihydroisoindolo[l,2-b]quinazolin-6- yl)ethyl)amino)picolinic acid methyl ester (mixture of both, 10 mg, 20 pmol) and LiOH H2O (9.7 mg, 404 pmol) in a mixture of THF and water (2 mL, 2: 1) was stirred at 70 °C under microwave irradiation for 15 min. The mixture was acidified with 1 N HC1, followed by concentration in vacuo. The residue was purified by preparative HPLC eluting with 20-95% MeCN / water to give a mixture of (R)-6-chloro-3-((l-(2-chloro-8-methyl-10-oxo-10,12- dihydroisoindolo[l,2-b]quinazolin-6-yl)ethyl)amino)picolinic acid and (R)-6-chloro-3-((l-(3-chloro-8-methyl-10-oxo-10,12-dihydroisoindolo[l,2-b]quinazolin-6- yl)ethyl)amino)picolinic acid as a white solid (mixture of both, 1.7 mg, 18% yield). LC-MS: m / z 481.0 [M+H] + .

[0984] Example 35

[0985]

[0986] Step 1:

[0987] A mixture of 2-amino-3-bromo-5-methyl-benzoic acid (2.3 g, 10.0 mmol) and 5-methoxy-3,4-dihydro-2H-pyrrole (3 g, 30 mmol) in toluene (30 mL) was stirred at 110 °C for 16 hours. The mixture was concentrated in vacuo and the residue was purified by silica gel chromatography eluting with 0-10% EtOAc / DCM to give 5-bromo-7-methyl-2,3-dihydro-lH-pyrrolo[2,l- b]quinazolin-9-one as a yellow solid (700 mg, 25% yield). LC-MS: m / z 279.0 [M+H] + .

[0988] Step 2:

[0989] A mixture of 5-bromo-7-methyl-2,3-dihydro-lH-pyrrolo[2,l-b]quinolin-9-one (350 mg, 1.3 mmol), tributyl(l-ethoxyvinyl)stannane (679 mg, 1.9 mmol), and Pd(PPh3)4 (1.5 g, 1.3 mmol) in DMF (10 mL) was stirred at 90 °C under microwave irradiation for 3 h. Upon completion, the reaction was quenched with 3 M HC1 (4 mL) and the mixture was stirred at room temperature for 2 h to hydrolyze the ether intermediate to the ketone. Upon completion, the mixture was basified with saturated NaHC03and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-10% EtOAc / DCM to give 5-acetyl-7-methyl-2,3-dihydro-lH-pyrrolo[2,l-b]quinolin-9-one (200 mg, 66% yield) as a yellow solid. LC-MS: m / z 243.1 [M+H] + .

[0990] Step 3:

[0991] A mixture of 5-acetyl-7-methyl-2,3-dihydro-lH-pyrrolo[2,l-b]quinolin-9-one (200 mg, 826 μmol), (R)-2-methylpropane-2-sulfmamide (200 mg, 1.7 mmol), and ethyl titanate (IV) (2 mL) in THF (4 mL) was stirred at 80 °C for 16 h. Upon completion, the mixture was quenched with water (20 mL) and extracted with EtOAc (50 mL x 4). The combined organic layers were dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-80% EtOAc / DCM to give (R,E)-2-methyl-N-(l-(7-methyl-9-oxo-l,2,3,9-tetrahydropyrrolo[2,l-b]quinolin-5-yl)ethylidene)propane-2-sulfmamide (250 mg, 87% yield) as a yellow solid. LC-MS: m / z 346.1 [M+H] + .

[0992] Step 4:

[0993] To a stirred mixture of (R,E)-2-methyl-N-(l-(7-methyl-9-oxo-l,2,3,9- tetrahydropyrrolo[2,l-b]quinazolin-5-yl)ethenyl)propane-2-sulfmamide (250 mg, 0.7 mmol) and CeCl3(250 mg, 1.0 mmol) in MeOH (5 mL) was added NaBH4(77 mg, 2.0 mmol) in portions and the resulting mixture was stirred at room temperature for 10 min. Upon completion, the mixture was quenched with water (10 mL) and extracted with DCM (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford (R)-2-methyl-N-((R)-l-(7-methyl-9-oxo-l,2,3,9- tetrahydropyrrolo[2,l-b]quinazolin-5-yl)ethyl)propane-2-sulfmamide (297 mg, crude), which was used in the next step without further purification. LC-MS: m / z 348.1 [M+H] + .

[0994] Step 5:

[0995] To a stirred mixture of (R)-2-methyl-N-((R)-l-(7-methyl-9-oxo-l,2,3,9- tetrahydropyrrolo[2,l-b]quinazolin-5-yl)ethyl)propane-2-sulfmamide (297 mg, 854 μmol) in MeOH (4 mL) was added 4 M HC1 in 1,4-dioxane (1 mL) and the resulting mixture was stirred at room temperature for 10 min. Upon completion, the mixture was quenched with saturated NaHC03(10 mL) and extracted with DCM (20 mL x 3). The combined organic layers were dried over anhydrous Na2S04, filtered, and concentrated in vacuo to afford (R)-5-(l-aminoethyl)-7-methyl-2,3-dihydropyrrolo[2,l- b]quinazolin-9(lH)-one (227 mg, crude), which was used in the next step without further purification. LC-MS: m / z 244.1 [M+H] + .

[0996] Step 6:

[0997] A mixture of methyl 6-chloro-3-fluoropicolinate (129 mg, 678 pmol), (R)-5-(l- aminoethyl)-7-methyl-2,3-dihydropyrrolo[2,l-b]quinazolin-9(lH)-one (110 mg, 452 pmol) and K2CO3 (62.5 mg, 452 pmol) in DMSO (2 mL) was stirred at 100 °C under microwave irradiation for 1 h. Upon completion, 2 M LiOH H2O (aq. 1 mL) was added and the mixture was stirred at 70 °C under microwave irradiation for 10 min to hydrolyze the ether intermediate. The reaction was then quenched with 6 M HC1 (0.5 mL) and the mixture was directly purified by preparative HPLC eluting with 10-90% MeCN / water to give 6-chloro-3-[[(lR)-l-(7-methyl-9-oxo-2,3-dihydro-lH-pyrrolo[2,l- b]quinazolin-5-yl)ethyl]amino]pyridine-2-carboxylic acid (50 mg, 27.8% yield) as a white solid. LC-MS: m / z 399.1 [M+H] + .

[0998] Example 36

[0999]

[1000] Step 1:

[1001] To a stirred mixture of 2-amino-3-bromo-5-methylbenzoic acid (600 mg, 2.6 mmol) in DCM (20 mL) was added HATU (1.29 g, 3.4 mmol), triethylamine (527.8 mg, 5.2 mmol) and tert-butyl 3-(2-aminoethyl)-4-morpholinecarboxylate (600.6 mg, 2.6 mmol). The mixture was stirred at 20 °C for 1 h. LC-MS showed the formation of the product. The mixture was dissolved in water (50 mL) and extracted with DCM (40 mL x 2). The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by silica gel flash column chromatography eluting with 0-30% EtOAc / petroleum ether to give tert-butyl 3-(2-(2-amino-3-bromo-5-methylbenzamido)ethyl)morpholine-4-carboxylate (1.1 g, 91% yield) as a white solid. LC-MS: m / z 442.1, 444.1 [M+H] + .

[1002] Step 2:

[1003] Triethylamine (2.40 g, 23.7 mmol) was added to a stirred mixture of 3-[2-[(2-amino-3-bromo-5-methylbenzoyl)amino]ethyl]morpholine-4-carboxylic acid tert-butyl ester (1.05 g, 2.4 mmol) in THF (25 mL). Then, THF (5 mL) containing triphosgene (493.1 mg, 1.7 mmol) was added dropwise at 0 °C. The mixture was stirred at 20 °C for 1 hour. LC-MS showed complete consumption of the starting material. The mixture was poured into saturated NaHCO3 (80 mL) and extracted with EtOAc (80 mL × 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give 3-(2-(8-bromo-2-hydroxy-6-methyl-4-oxoquinazoline-3(4H)-yl)ethyl)morpholine-4-carboxylic acid tert-butyl ester (1.1 g, 99% yield) as a brown solid. LC-MS: m / z 368.0, 370.0 [M+H] + .

[1004] Step 3:

[1005] A solution of HCl in dioxane (4 M, 6 mL) was added to a stirred solution of 3-[2-(8-bromo-2-hydroxy-6-methyl-4-oxo-quinazolin-3-yl)ethyl]morpholin-4-carboxylic acid tert-butyl ester (1.1 g, 2.4 mmol) in DCM (20 mL). The mixture was stirred at 20 °C for 1 hour. LC-MS showed that the reaction was complete. The mixture was alkalized with saturated NaHCO3 and extracted with DCM (30 mL × 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give 8-bromo-2-hydroxy-6-methyl-3-(2-morpholin-3-ylethyl)quinazolin-4-one (850 mg, 98% yield) as a yellow solid. LC-MS: m / z 368.0, 370.0 [M+H] + .

[1006] Step 4:

[1007] To a stirred mixture of 8-bromo-2-hydroxy-6-methyl-3-(2-morpholin-3- ylethyl)quinazolin-4-one (850 mg, 2.3 mmol) in MeCN (20 mL) was added BOP (1.5 g, 3.5 mmol) and DBU (702.8 mg, 4.6 mmol). The mixture was stirred at 20 °C for 0.5 h, then at 80 °C for 2.5 h. LC-MS showed the formation of product. The mixture was dissolved in water (100 mL) and extracted with DCM (100 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography to give 12-bromo-10-methyl-1,2,4,4a,5,6-hexahydro-8H- [1,4]oxazino[4',3':3,4]pyrimido[2,1-b]quinazolin-8-one (600 mg, 74% yield) as a yellow solid. LC-MS: m / z 350.0, 352.0 [M+H] + .

[1008] Step 5:

[1009] To a stirred mixture of 12-bromo-10-methyl-1,2,4,4a,5,6-hexahydro-8H- [1,4]oxazino[4',3':3,4]pyrimido[2,1-b]quinazolin-8-one (600 mg, 1.7 mmol) and tributyl(1-ethoxyvinyl)stannane (804.4 mg, 2.23 mmol) in dioxane (12 mL) was added Pd(PPh3)2Cl2 (180.4 mg, 257 μmol) under N2. The mixture was stirred at 105 °C for 5 h. LC-MS showed the formation of product. The mixture was cooled to 20 °C. Then HCl (8 mL, 1 M) was added to the mixture, which was stirred at 20 °C for 0.5 h. LC-MS showed the reaction was complete. The mixture was diluted with water (60 mL), basified to pH ~9 with saturated aqueous NaHCO3solution, and extracted with DCM (50 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography to give 12-acetyl-10-methyl-1,2,4,4a,5,6-hexahydro-8H- [1,4]oxazino[4',3':3,4]pyrimido[2,1-b]quinazolin-8-one (350 mg, 65% yield) as a yellow solid. LC-MS: m / z 314.1 [M+H] + .

[1010] Step 6:

[1011] A mixture of 12-acetyl-10-methyl-l,2,4,4a,5,6-hexahydro-8H- [l,4]oxazino[4',3':3,4]pyrimido[2,l-b]quinolin-8-one (350 mg, 1.1 mmol) and (R)-2-methylpropane-2-sulfinamide (270.7 mg, 2.2 mmol) in Ti(OEt)4 (4 mL) and THF (8 mL) was stirred at 80 °C for 16 h. LC-MS showed the reaction was complete. The mixture was diluted in DCM (150 mL) and water (30 mL), then filtered. The filtrate was separated and the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography to give (R)-2-methyl-N-((E)-l-(10-methyl-8-oxo-l,2,4,4a,5,6-hexahydro-8H- [l,4]oxazino[4',3':3,4]pyrimido[2,l-b]quinolin-12-yl)ethyldene)propane-2-sulfinamide (350 mg, 75% yield) as a yellow solid. LC-MS: m / z 417.1 [M+H] + .

[1012] Step 7:

[1013] To a mixture of (R)-2-methyl-N-((E)-l-(10-methyl-8-oxo-l,2,4,4a,5,6-hexahydro-8H- [l,4]oxazino[4',3':3,4]pyrimido[2,l-b]quinolin-12-yl)ethyldene)propane-2-sulfinamide (350 mg, 840.2 μmol) and CeCl3 (124.3 mg, 504.2 μmol) in MeOH (10 mL) was added NaBH4 (63.6 mg, 1.7 mmol) in portions. The mixture was stirred at 20 °C for 10 min. LC-MS showed the product was formed. The reaction was quenched with water (50 mL) and the mixture was extracted with DCM (40 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography to give (R)-2-methyl-N-((lR)-l-(10-methyl-8-oxo-l,2,4,4a,5,6-hexahydro-8H- [l,4]oxazino[4',3':3,4]pyrimido[2,l-b]quinolin-12-yl)ethyl)propane-2-sulfinamide (280 mg, 80% yield) as a white solid. LC-MS: m / z 419.1 [M+H] + .

[1014] Step 8:

[1015] To a stirred solution of (R)-2-methyl-N-((1R)-1-(10-methyl-8-oxo-1,2,4,4a,5,6- hexahydro-8H-[1,4]oxazino[4',3':3,4]pyrimido[2,1-b]quinazolin-12-yl)ethyl)propane-2- sulfonamide (80 mg, 191.1 μmol) in EtOH (3 mL) was added 4 M HC1 in EtOH (1 mL). The mixture was stirred at 20 °C for 0.5 h. LC-MS showed the reaction was complete. The mixture was basified with saturated NaHC03to pH ~ 9, followed by extraction with DCM (40 mL x 2). The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo to give 12-((R)-1-aminoethyl)-10-methyl-1,2,4,4a,5,6- hexahydro-8H-[1,4]oxazino[4',3':3,4]pyrimido[2,1-b]quinazolin-8-one (60 mg, 100% yield) as a yellow solid, which was used directly in the next step without further purification. LC-MS: m / z 315.2 [M+H] + .

[1016] Step 9:

[1017] To a stirred mixture of 12-((R)-1-aminoethyl)-10-methyl-1,2,4,4a,5,6-hexahydro-8H- [1,4]oxazino[4',3':3,4]pyrimido[2,1-b]quinazolin-8-one (60 mg, 190.9 μmol) and methyl 6-chloro-3-fluoropicolinic acid (90.5 mg, 477.1 μmol) in DMSO (3 mL) was added K2C03(79.1 mg, 572.6 μmol). The mixture was then stirred at 105 °C for 2 h. LC-MS showed the formation of product. The mixture was purified by reverse phase chromatography to give methyl 6-chloro-3-(((1R)-1-(10-methyl-8-oxo-1,2,4,4a,5,6-hexahydro-8H- [1,4]oxazino[4',3':3,4]pyrimido[2,1-b]quinazolin-12-yl)ethyl)amino)picolinic acid (70 mg, 76% yield) as a white solid. LC-MS: m / z 484.1 [M+H] + .

[1018] Step 10:

[1019] To a mixture of methyl 6-chloro-3-(((1R)-1-(10-methyl-8-oxo-1,2,4,4a,5,6- hexahydro-8H-[1,4]oxazino[4',3':3,4]pyrimido[2,1-b]quinazolin-12-yl)ethyl)amino) picolinate (70 mg, 144.6 μmol) in THF (3 mL) and water (1 mL) was added LiOH H2O (17.3 mg, 723.2 μmol). The mixture was stirred at 50 °C for 1 h. LC-MS showed the reaction was complete. The mixture was acidified with HC1 (1 M) to pH ~ 5, then concentrated in vacuo. The residue was purified by prep-HPLC to give 6-chloro-3-[[(1R)-1-(14-methyl-11-oxo-5-oxa- 2,10,18-triazatetracyclo[8.8.0.0 2,7 .0 12,17 ]octadeca-1(18),12(17),13,15-tetraen-16-yl)ethyl]amino]pyridine-2-carboxylic acid (25.6 mg, 38% yield). LC-MS: m / z 470.1 [M+H] + .

[1020] Example 37

[1021]

[1022] Step 1:

[1023] To a stirred solution of tert-butyl 2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5- carboxylate (4 g, 17.9 mmol) in methanol (40 mL) was added 4 M HC1 in EtOH (40 mL). The mixture was stirred at 20 °C for 16 h. The mixture was concentrated in vacuo to give 4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine dihydrochloride (3 g, crude) as a yellow solid, which was used in the next step without further purification.

[1024] Step 2:

[1025] Method 1:

[1026] To a stirred solution of 2-amino-3-bromo-5-methyl-benzoic acid (1.4 g, 6.1 mmol), HATU (2.7 g, 7.3 mmol) and N,N-diethylethanamine (2.1 g, 21.3 mmol) in DMF was added 4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine (971.3 mg, 6.1 mmol). The mixture was stirred at 20 °C for 2 h. The mixture was poured into water (150 mL) and precipitated out yellow solid. The mixture was filtered, and the aqueous phase was extracted with EtOAc (200 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the product as a yellow oil. The crude material was purified by silica gel column chromatography eluting with CH2Cl2:CH3OH = 20: 1 to give the product (2-amino-3-bromo-5-fluoro-phenyl)-(2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)methanone (820 mg, 40% yield) as a light yellow solid. LC-MS: m / z 337.0 [M+H] + .

[1027] Method 2:

[1028] To a stirred solution of 2-amino-3-bromo-5-methyl-benzoic acid (2.4 g, 10.4 mmol), N,N-diethylethanamine (3.1 g, 31.3 mmol) and PyBOP (6.5 g, 12.5 mmol) in DMF (40 mL) was added 4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine (1.2 g, 8.0 mmol). The mixture was stirred at 20 °C for 1.5 h. The mixture was poured into water (150 mL) followed by filtration. The filtrate was extracted with EtOAc (100 mL x 3) and the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product. The residue was purified by silica gel column chromatography eluting with CH2Cl2: CH3OH = 20: 1 to give the product (2-amino-3-bromo-5-methyl-phenyl)-(2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)methanone (2.3 g, 66% yield) as a light yellow solid. LC-MS: m / z 337.0 [M+H] + .

[1029] Step 3:

[1030] To a stirred solution of (2-amino-3-bromo-5-methyl-phenyl)-(2,4,6,7- tetrahydropyrazolo[4,3-c]pyridin-5-yl)methanone (3.1 g, 9.2 mmol) in DMSO (50 mL) was added (NH4)2S2O8 (8.4 g, 36.9 mmol). The mixture was stirred at 60 °C for 10 h. The mixture was poured into water (150 mL) and precipitated out as a yellow solid. The mixture was filtered, and the filter cake was dried under vacuum to give the product as a yellow solid. The crude product was purified by silica gel column chromatography eluted with CH2Cl2: CH3OH = 20: 1 to give the product as a yellow solid. 7-Bromo-5-methyl-1,9,13,14-tetraazatetracyclo[8.7.0.0 3,8 .0 11 ,15 ]heptadeca-3(8),4,6,9,11,14-hexaen-2-one (950 mg, 31% yield). LC-MS: m / z 331.0 [M+H] + .

[1031] Step 4:

[1032] To a stirred solution of 7-bromo-5-methyl-1,9,13,14-tetraazatetracyclo[8.7.0.0 3,8 .0 11,15 ]heptadeca-3(8),4,6,9,11,14-hexaen-2-one (950 mg, 2.8 mmol) in dioxane (20 mL) was added tributyl(1-ethoxyvinyl)stannane (1.5 g, 4.3 mmol) and Pd(PPh3)2Cl2 (402.7 mg, 573.7 µmol). The mixture was degassed with N2 flow for three times, then stirred at 100 °C for 16 h. The mixture was quenched with KF solution (50 mL) and extracted with CH2Cl2 (150 mL x 2). The combined extracts were washed with brine (50 mL) and dried over anhydrous Na2SO4. The solvent was evaporated to give the crude product. The crude material was purified by silica gel column chromatography eluted with CH2Cl2: CH3OH = 20: 1 to give the product as a yellow solid. 7-(1-ethoxyvinyl)-5-methyl-1,9,13,14-tetraazatetracyclo[8.7.0.0 3,8 .0 11,15 ]heptadeca-3(8),4,6,9,11,14-hexaen-2-one (500 mg, 54% yield). LC-MS: m / z 323.1 [M+H] + To a stirred solution of 7-(1-ethoxyvinyl)-5-methyl-1,9,13,14-tetraazatetracyclo[8.7.0.0 3,8 .011,15 ] Heptadecano-3(8),4,6,9,11,14-hexaden-2-one (500 mg, 1.5 mmol) was added to a stirred solution of acetone (20 mL) with 2 M HCl (5 mL). The mixture was stirred at 20 °C for 0.5 h. The mixture was diluted with CH2Cl2 (120 mL), washed with saturated NaHCO3 (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product. The crude product was purified by silica gel column chromatography by elution with CH2Cl2: CH3OH = 20: 1 to give the product 7-acetyl-5-methyl-1,9,13,14-tetraazatetracyclo[8.7.0.0] as a yellow solid. 3,8 .0 11,15 Heptadec-3(8),4,6,9,11,14-hexaden-2-one (450 mg, 98% yield).

[1033] Step 5:

[1034] To 7-acetyl-5-methyl-1,9,13,14-tetraazatetracyclo[8.7.0.0] 3,8 .0 11,15 (R)-2-methylpropane-2-sulfinamide (555.9 mg, 4.6 mmol) was added to a stirred solution of heptadecane-3(8),4,6,9,11,14-hexane-2-one (450 mg, 1.5 mmol) in ethyl titanate (4 mL). The mixture was stirred at 80 °C under N2 protection for 5 hours. The mixture was diluted with EtOAc (200 mL), followed by the addition of water (50 mL). The mixture was stirred at 20 °C for 0.5 hours. The mixture was filtered, and the organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product. The crude product was purified by silica gel column chromatography with elution of CH2Cl2: CH3OH = 20: 1 to give the product (NZ,R)-2-methyl-N-[1-(5-methyl-2-oxo-1,9,13,14-tetraazatetracyclo[8.7.0.0]] as a yellow solid. 3,8 .0 11,15 [Heptadecano-3(8),4,6,9,11,14-hexaden-7-yl)ethylidene]propane-2-sulfinamide (430 mg, 71% yield). LC-MS: m / z 398.2 [M+H] +

[1035] Step 6:

[1036] To (NZ,R)-2-methyl-N-[1-(5-methyl-2-oxo-1,9,13,14-tetraazatetracyclo[8.7.0.0]3, 8 .0 11,15 To a stirred solution of (R)-2-methyl-N-[(1R)-1-(5-methyl-2-oxo-1,9,13,14- tetraazatetracyclo[8.7.0.0 3,8 .0 11,15 To a stirred solution of (R)-2-methyl-N-[(1R)-1-(5-methyl-2-oxo-1,9,13,14- tetraazatetracyclo[8.7.0.0 + .

[1037] Step 7:

[1038] To a stirred solution of (R)-2-methyl-N-[(1R)-1-(5-methyl-2-oxo-1,9,13,14- tetraazatetracyclo[8.7.0.0 3, 8 .0 11,15 To a stirred solution of (R)-2-methyl-N-[(1R)-1-(5-methyl-2-oxo-1,9,13,14- tetraazatetracyclo[8.7.0.0 3,8 .0 11 ,15[Heptadecano-3(8),4,6,9,11,14-hexaden-7-yl]ethyl]propane-2-sulfinamide (60 mg, 91% yield). LC-MS: m / z 477.2 [M+H] + .

[1039] Step 8:

[1040] To (R)-2-methyl-N-[(1R)-1-[5-methyl-2-oxo-13-(2-pyridyl)-1,9,13,14-tetraazatetracyclo[8.7.0.0] 3,8 .0 11,15 Heptadecyl-3(8),4,6,9,11,14-hexaden-7-yl]ethyl]propane-2-sulfinamide (60 mg, 125.8 µmol) was added to a stirred solution of methanol (6 mL) with EtOH (0.5 mL) containing 4 M HCl. The mixture was stirred at 20 °C for 5 minutes. The mixture was diluted with CH2Cl2 (100 mL) and washed with saturated NaHCO3 (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum to give a crude product, 7-[(1R)-1-aminoethyl]-5-methyl-13-(2-pyridyl)-1,9,13,14-tetraazatetracyclo[8.7.0.0], as a white solid. 3,8 .0 11,15 Heptadec-3(8),4,6,9,11,14-hexaden-2-one (50 mg, crude). LC-MS: m / z 373.2 [M+H] + .

[1041] Step 9:

[1042] To 7-[(1R)-1-aminoethyl]-5-methyl-13-(2-pyridyl)-1,9,13,14-tetraazatetracyclo[8.7.0.0] 3,8 .0 11,15 Methyl 6-chloro-3-fluoro-pyridine-2-carboxylate (34.1 mg, 180.2 µmol) was added to a stirred solution of heptadec-3(8),4,6,9,11,14-hexen-2-one (50 mg, 134.2 µmol) and triethylamine (48.6 mg, 480.5 µmol) in DMSO (3 mL). The mixture was stirred at 100 °C for 16 hours. The mixture was diluted with EtOAc (100 mL) and washed with brine (30 mL × 3). The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product. The crude product was purified by silica gel column chromatography by elution with CH2Cl2: CH3OH = 20: 1 to obtain...

[1043] The product is a white solid, 6-chloro-3-[[(1R)-1-[5-methyl-2-oxo-13-(2-pyridyl)-1,9,13,14-tetraazatetracyclo[8.7.0.0]. 3,8 .0 11,15 Methyl heptadec-3(8),4,6,9,11,14-hexaden-7-yl]ethyl]amino]pyridine-2-carboxylate (30 mg, 46% yield). LC-MS: m / z 542.2 [M+H] + .

[1044] Step 10:

[1045] To 6-chloro-3-[[(1R)-1-[5-methyl-2-oxo-13-(2-pyridyl)-1,9,13,14-tetraazatetracyclo[8.7.0.0] 3,8 .0 11,15 Methyl heptadecyl-3(8),4,6,9,11,14-hexaden-7-yl]ethyl]amino]pyridine-2-carboxylate (30 mg, 55.3 µmol) was added to a stirred solution of LiOH (11.6 mg, 276.7 µmol) in a mixed solvent of THF, methanol, and water (6 mL, 4:1:1). The mixture was stirred at 20 °C for 20 min. The mixture was alkalized to pH 5 with saturated NaHCO3, diluted with brine (20 mL), and extracted with CH2Cl2 (60 mL × 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product. The crude substance was purified by preparative HPLC (A: 0.05% FA / water, B: CH3CN, gradient: 10 ~ 85% B) to obtain a white solid product, 6-chloro-3-[[(1R)-1-[5-methyl-2-oxo-13-(2-pyridyl)-1,9,13,14-tetraazatetracyclo[8.7.0.0]]. 3,8 .0 11,15 [Heptadecano-3(8),4,6,9,11,14-hexaden-7-yl]ethyl]amino]pyridine-2-carboxylic acid (10.2 mg, 35% yield). LC-MS: m / z 528.2 [M+H] + .

[1046] The following compounds have been prepared using a similar procedure to that described with respect to Example 37.

[1047]

[1048] Example 39:

[1049]

[1050] Step 1:

[1051] Malonyl dichloro(3.5 g, 25.1 mmol) was added to a stirred solution of 3-bromo-5-fluoro-pyridin-2-amine (4.0 g, 20.9 mmol) in DCM (80 mL) at 0 °C. The mixture was then stirred at 20 °C for 12 hours. The pale yellow precipitate was collected by filtration, washed with dichloromethane (3 × 100 mL) and water (50 mL), and dried under vacuum to give 9-bromo-7-fluoro-2-hydroxy-pyridano[1,2-a]pyrimidin-4-one (3.0 g, 55% yield) as a yellow solid. LC-MS: m / z 258.9 [M+H] + .

[1052] Step 2:

[1053] NBS (1.3 g, 7.7 mmol) was added to a stirred solution of 9-bromo-7-fluoro-2-hydroxy-pyrido[1,2-a]pyrimidin-4-one (2.0 g, 7.7 mmol) in DMF (20 mL) at 0 °C, and the mixture was stirred at 0 °C under N2 for 5 min. The mixture was diluted with water (100 mL) and extracted with DCM (2 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with 0–5% methanol / dichloromethane, to give 3,9-dibromo-7-fluoro-2-hydroxy-pyrido[1,2-a]pyrimidin-4-one (2.4 g, 92% yield) as a yellow solid. LC-MS: m / z 336.8 [M+H] + .

[1054] Step 3:

[1055] PyClOP (1.8 g, 4.4 mmol) and TEA (2.7 g, 26.6 mmol) were added to a stirred solution of 3,9-dibromo-7-fluoro-2-hydroxypyrido[1,2-a]pyrimidin-4-one (1.5 g, 4.4 mmol) in dioxane (10 mL) at 20 °C. The mixture was stirred under microwave irradiation at 100 °C for 30 min, followed by the addition of 2-piperidinylmethanol (1.5 g, 13.3 mmol), and the mixture was stirred at 100 °C under N2 for 2 h. The mixture was diluted with water (50 mL) and extracted with DCM (100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel chromatography with 0-5% methanol / dichloromethane elution to give 1.2 g (62% yield) of 3,9-dibromo-7-fluoro-2-[2-(hydroxymethyl)-1-piperidinyl]pyrido[1,2-a]pyrimidin-4-one as a yellow solid. LC-MS: m / z 433.9 [M+H] + .

[1056] Step 4:

[1057] t-BuOK (413 mg, 3.6 mmol) was added to a stirred solution of 3,9-dibromo-7-fluoro-2-[2-(hydroxymethyl)-1-piperidinyl]pyrido[1,2-a]pyrimidin-4-one (800 mg, 1.8 mmol) in i-PrOH (40 mL). The mixture was stirred at 50 °C under N2 for 30 min. The mixture was quenched with saturated NH4Cl (10 mL), diluted with water (100 mL), and extracted with DCM (2 × 100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel chromatography with 0-5% methanol / dichloromethane elution to give a yellow solid of 16-bromo-14-fluoro-9-oxa-2,12,18-triazatetracyclo[8.8.0.02,7.012,17]octadec-1(10),13,15,17-tetraen-11-one (130 mg, 20% yield). LC-MS: m / z 354.0 [M+H] + .

[1058] Step 5:

[1059] Pd(PPh3)4 (84 mg, 73 μmol) and tributyl(1-ethoxyvinyl)stanane (159 mg, 440 μmol) were added to a stirred solution of 16-bromo-14-fluoro-9-oxa-2,12,18-triazatetracyclo[8.8.0.02,7.012,17]octadec-1(10),13,15,17-tetraen-11-one (130 mg, 367 μmol) in DMF (3 mL). The mixture was stirred under microwave irradiation at 100 °C for 2 hours. The mixture was diluted with DCM (50 mL) and then quenched with a saturated aqueous solution of KF (50 mL). The mixture was stirred at 20 °C for 1 hour and then filtered. The filtrate was separated, and the organic layer was concentrated under vacuum, then dissolved in acetone (30 mL) and dioxane containing 4 M HCl (3 mL) was added. The mixture was stirred at 20 °C for 30 minutes. The mixture was then diluted with water (50 mL) and extracted with DCM (100 mL). The organic layer was dried over brine (50 mL) and concentrated under vacuum. The residue was purified by silica gel chromatography with elution of methanol / dichloromethane (0-10%) to give a yellow solid of 16-acetyl-14-fluoro-9-oxa-2,12,18-triazatetracyclo[8.8.0.02,7.012,17]octadec-1(10),13,15,17-tetraen-11-one (110 mg, 94% yield). LC-MS: m / z 318.1 [M+H] + .

[1060] Step 6:

[1061] Ti(OEt)4 (2.2 mL) and (R)-2-methylpropane-2-sulfinamide (126 mg, 1.0 mmol) were added to a stirred solution of 16-acetyl-14-fluoro-9-oxa-2,12,18-triazatetracyclo[8.8.0.02,7.012,17]octadec-1(10),13,15,17-tetraen-11-one (110 mg, 347 μmol) in THF (10 mL) and stirred at 20 °C for 12 hours. The mixture was diluted with EA (200 mL) and quenched with water (50 mL). The mixture was then filtered, and the filtrate was washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by silica gel chromatography with elution of 0-100% EA / PE to give (NE,R)-N-[1-(14-fluoro-11-oxo-9-oxa-2,12,18-triazatetracyclo[8.8.0.02,7.012,17]octadec-1(10),13,15,17-tetraen-16-yl)ethylene]-2-methyl-propane-2-sulfinamide (100 mg, 69% yield) as a yellow solid. LC-MS: m / z 421.1 [M+H] + .

[1062] Step 7:

[1063] NaBH4 (18 mg, 476 μmol) was added fractionally to a stirred mixture of (NE,R)-N-[1-(14-fluoro-11-oxo-9-oxa-2,12,18-triazatetracyclo[8.8.0.02,7.012,17]octadec-1(10),13,15,17-tetraen-16-yl)ethylene]-2-methyl-propane-2-sulfinamide (100 mg, 238 μmol) and CeCl3 (58.6 mg, 238 μmol) in MeOH (10 mL), and the mixture was stirred at 25 °C for 10 min. The reactants were quenched with water (50 mL) and the mixture was extracted with DCM (2 × 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography with elution of 0-5% methanol / dichloromethane to give N-((1R)-1-(10-fluoro-7-oxo-1,2,3,4,4a,5-hexahydro-7H-pyrido[1,2-d]pyrido[1',2':1,2]pyrimidino[5,4-b][1,4]oxazin-12-yl)ethyl)-2-methylpropane-2-sulfinamide (80 mg, 80% yield) as a yellow solid. LC-MS: m / z 423.1 [M+H] +.

[1064] Step 8:

[1065] The mixture was added dropwise to a stirred solution of N-((1R)-1-(10-fluoro-7-oxo-1,2,3,4,4a,5-hexahydro-7H-pyrido[1,2-d]pyrido[1',2':1,2]pyrimidino[5,4-b][1,4]oxazin-12-yl)ethyl)-2-methylpropane-2-sulfinamide (80 mg, 189.34 μmol) in MeOH (5 mL) and stirred at 0 °C for 30 min. The mixture was diluted with EA (30 mL) and extracted with water (2 × 50 mL). The aqueous phase was alkalized to pH = 8 with saturated NaHCO3 and extracted with DCM (2 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum to give a yellow oily substance, 12-((R)-1-aminoethyl)-10-fluoro-1,2,3,4,4a,5-hexahydro-7H-pyrido[1,2-d]pyrido[1',2':1,2]pyrimidino[5,4-b][1,4]oxazin-7-one (40 mg, 66% yield). LC-MS: m / z 319.1 [M+H] + .

[1066] Step 9:

[1067] A mixture of 12-((R)-1-aminoethyl)-10-fluoro-1,2,3,4,4a,5-hexahydro-7H-pyrido[1,2-d]pyrido[1',2':1,2]pyrimidino[5,4-b][1,4]oxazin-7-one (30 mg, 94 μmol), 6-chloro-3-fluoro-pyridin-2-carboxylate (26.8 mg, 141 μmol), and K₂CO₃ (26 mg, 188 μmol) in DMSO (3 mL) was stirred at 100 °C under microwave irradiation for 1 hour. The mixture was diluted with water (20 mL) and extracted with EA (50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to obtain a yellow oily substance, 6-chloro-3-[[(1R)-1-(14-fluoro-11-oxo-9-oxa-2,12,18-triazatetracyclo[8.8.0.0]]. 2,7 .0 12,17 Methyl 1-(10),13,15,17-tetraen-16-yl)ethyl]amino]pyridine-2-carboxylate (20 mg, 43% yield). LC-MS: m / z 488.1 [M+H] + .

[1068] Step 10:

[1069] 6-Chloro-3-[[(1R)-1-(14-fluoro-11-oxo-9-oxa-2,12,18-triazatetracyclo[8.8.0.0] 2, 7 .0 12,17 A mixture of methyl 1-octadecyl-1(10),13,15,17-tetraen-16-yl)ethyl]amino]pyridine-2-carboxylate (20 mg, 41 μmol) and LiOH (9.8 mg, 410 μmol) in a mixed solvent of THF and water (6 mL, 5:1) was stirred at 25 °C for 2 hours. Afterward, the mixture was acidified to pH = 6 with saturated NH4Cl, followed by extraction with DCM (2 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC to give a white solid of 6-chloro-3-[[(1R)-1-(14-fluoro-11-oxo-9-oxa-2,12,18-triazatetracyclo[8.8.0.0]]. 2,7 .0 12,17 Octadecto-1(10),13,15,17-tetraen-16-yl)ethyl]amino]pyridine-2-carboxylic acid (2 mg, 10% yield). LC-MS: m / z 474.1 [M+H] + .

[1070] Example 40

[1071]

[1072] Step 1:

[1073] POCl3 (30 mL) was added dropwise to a stirred mixture of pyrrolidone-2-one (3.4 g, 40 mmol) and 2-amino-3-bromo-5-fluorobenzoic acid (4.7 g, 20 mmol) at 0 °C, and the mixture was stirred at 105 °C for 16 hours. After completion, the mixture was concentrated under vacuum and then poured into ice water. The mixture was alkalized with concentrated NaOH aqueous solution and extracted with DCM (3 × 80 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with 0–50% EA / DCM, to give 5-bromo-7-fluoro-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one (4.3 g, 76% yield) as a yellow solid. LC-MS: m / z 282.9 [M+H] + .

[1074] Step 2:

[1075] A mixture of 5-bromo-7-fluoro-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one (1 g, 3.5 mmol), benzaldehyde (1.1 g, 10.6 mmol), and KOtBu (396 mg, 3.5 mmol) in THF (20 mL) was stirred at 70 °C for 1 hour. Afterward, the mixture was diluted with water and extracted with EA (3 × 80 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with 0–50% EA / DCM, to give 3-benzylmethyl-5-bromo-7-fluoro-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one (600 mg, 46% yield) as a yellow solid. LC-MS: m / z 371.0 [M+H] + .

[1076] Step 3:

[1077] A mixture of 3-benzyl-5-bromo-7-fluoro-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one (600 mg, 1.6 mmol), tributyl(1-ethoxyvinyl)stanane (1.2 g, 3.2 mmol), and Pd(PPh3)4 (187 mg, 161 μmol) in DMF (10 mL) was stirred at 100 °C under microwave irradiation for 1 hour. After completion, the mixture was treated with 3 M HCl (2 mL) to hydrolyze the ether intermediate to the ketone. After completion, the mixture was alkalized with saturated NaHCO3, diluted with EA (80 mL), and washed with water (3 × 40 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography with elution using 0–80% EA / DCM to give 263 mg (49% yield) of 5-acetyl-3-benzyl-7-fluoro-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one as a yellow solid. LC-MS: m / z 335.1 [M+H] + .

[1078] Step 4:

[1079] A mixture of 5-acetyl-3-benzyl-7-fluoro-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one (220 mg, 658 μmol), NH4OAc (254 mg, 3.3 mmol), and NaBH3CN (207 mg, 3.3 mmol) in MeOH (5 mL) was stirred at 70 °C for 1 hour. Afterward, the mixture was quenched with water (20 mL) and extracted with DCM (3 × 30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give crude 5-(1-aminoethyl)-3-benzyl-7-fluoro-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one (200 mg), which was used in the next step without further purification. LC-MS: m / z 336.1 [M+H] + .

[1080] Step 5:

[1081] A mixture of methyl 6-chloro-3-fluoro-pyridin-2-carboxylate (68 mg, 358 μmol), 5-(1-aminoethyl)-3-benzyl-7-fluoro-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one (60 mg, 179 μmol), and K₂CO₃ (49 mg, 358 μmol) in DMSO (2 mL) was stirred at 100 °C under microwave irradiation for 3 hours. After completion, the mixture was diluted with EA (30 mL) and washed with water (3 × 15 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purifi...

Claims

1. A compound of Formula (I’): (I')， or a pharmaceutically acceptable salt thereof, wherein: R1is selected from the group consisting of H, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl Ring A is or wherein ** is the point of attachment to Y; (i) when W is C and Y is N or CR Z1 then X is C, and Z is N or CR Z1 ; (ii) when W is C and Y is C(O), then X is C or N, and Z is CR Z1 , N, NR N1 or O; (iii) when W is N, then Y is C(O), X is C, and Z is N or CR Z1 ; G 1 , G 2 , and G 3 are each independently C(R G2 )2, NR N2 , or O; n is 0, 1, 2, or 3; m is 0, 1, 2, 3, or 4; o is 0, 1, 2, 3, or 4; R Na is H; R N1 For H, C 1-6 Alkyl, C 1-6 Haloalkyl, -C(O)R 1a C 3-6 Cycloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein R N1 The phenyl group and the 5- to 6-membered heteroaryl group are each optionally surrounded by one to three groups selected from halogens, C 1-3 Alkyl and C 1-3 Substituents of haloalkyl groups; R Z1 H, halogen, cyano, NO2, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, C 1-6 hydroxyalkoxy, NR N1a R N1b , -C(O)R 1a , -C(O)OR O1a , -C(O)NR N1a R N1b , -OR O1a , 3- to 12-membered carbocyclyl, phenyl, 5- or 6-membered heteroaryl, or 4- to 12-membered heterocyclyl, wherein said carbocyclyl, phenyl, 5- or 6-membered heteroaryl, or 4- to 12-membered heterocyclyl represented by R Z1 is optionally substituted by one to four R 1b ; Each R 1 Independently halogen, cyano, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxyalkyl, C 1-6 Hydroxyalkoxy, C 2-6 alkenyl, C 2-6 acetylenic, NR N1a R N1b -C(O)R 1a -C(O)OR O1a -C(O)NR N1a R N1b -OR O1a -(CH2) 0或1 -3 to 12-membered carbon cyclogroups, -(CH2) 0或1 -4 to 12-membered heterocyclic groups, -(CH2) 0或1 -6 to 10 aryl groups or -(CH2) 0或1 -5 to 10 aryl compounds, of which R 1 The C mentioned 2-6 alkenyl, C 2-6 Alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl are each optionally surrounded by one to four R groups. 1b replace; R 1a , R O1a , R N1a , and R N1b are each independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, or 4- to 6-membered heterocyclyl; each R 1b independently halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkoxy, -C(O)R 1a , -C(O)OR O1a , -C(O)NR N1a R N1b , -SO2R 1a , -NR N1a R N1b , -NR N1a C(O)R 1a , -NR N1a C(O)OR 1a , -NR N1a SO2R 1a , -NR N1a SO2NR N1a R N1b , cyano, NO2, or OR O1a ; R N2 is H, C 1-6 alkyl, C 1-6 haloalkyl, -C(O)R 2a , C 3-6 cycloalkyl, phenyl or 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl each represented by R N2 are optionally substituted by one to three substituents selected from the group consisting of halogen, C 1-3 alkyl and C 1-3 haloalkyl; each R G2 independently H, halo, cyano, oxo (as needed), NO2, C 1-6 alkyl, C 1-6 haloalkyl, *=CH-R 7 (as needed), C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, C 1-6 hydroxyalkoxy, -C(O)R 2a , -C(O)OR O2a , -C(O)NR N2a R N2b , OR O2a , NR N2a R N2b , SO2R 2a , -NR N2a C(O)R 2a , -NR N2a C(O)OR 2a , -NR N2a SO3R 2a , -NR N2a SO3NR N2a R N2a , -(CH2) 0或1 -3- to 12-membered carbocyclyl, -(CH2) 0或1 -4- to 12-membered heterocyclyl, -(CH2) 0或1 -6- to 10-membered aryl, or -(CH2) 0或1 -5- to 10-membered heteroaryl, wherein said carbocyclyl, heterocyclyl, aryl, or heteroaryl groups represented by R G2 are each optionally substituted by one to four halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkoxy, -C(O)R 2a , -C(O)OR O2a , -C(O)NR N2a R N2b , cyano, NO2, OR O2a , NR N2a R N2b , SO3R 2a , -NR N2a C(O)R 2a , -NR N2a C(O)OR 2a , -NR N2a SO3R 2a or -NR N2a SO3NR N2a R N2a substituted, and wherein said C2 alkenyl is optionally substituted with phenyl or 5- to 6-membered heteroaryl; each R 2 independently halo, cyano, oxo (as needed), NO2, C 1-6 alkyl, C 1-6 haloalkyl, *=CH-R 7 (as needed), C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, C 1-6 hydroxyalkoxy, -C(O)R 2a , -C(O)OR O2a , -C(O)NR N2a R N2b , OR O2a , NR N2a R N2b , SO2R 2a , -NR N2a C(O)R 2a , -NR N2a C(O)OR 2a , -NR N2a SO3R 2a , -NR N2a SO3NR N2a R N2a , -(CH2) 0或1 -3- to 12-membered carbocyclyl, -(CH2) 0或1 -4- to 12-membered heterocyclyl, -(CH2) 0或1 -6- to 10-membered aryl, or -(CH2) 0或1 -5- to 10-membered heteroaryl, wherein each of the carbocyclyl, heterocyclyl, aryl, or heteroaryl groups represented by R 2 is optionally substituted by one to four halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkoxy, -C(O)R 2a , -C(O)OR O2a , -C(O)NR N2a R N2b , cyano, NO2, OR O2a , NR N2a R N2b , SO3R 2a , -NR N2a C(O)R 2a , -NR N2a C(O)OR 2a , -NR N2a SO3R 2a or -NR N2a SO3NR N2a R N2a substituted, and wherein said C2alkenyl is optionally substituted with phenyl or 5- to 6-membered heteroaryl; or two R 2 , two R G2 , one R 2 and one R N2 , one R 2 and one R G2 , or one R G2 and one R N2 together with the atom to which they are attached form a 3- to 12-membered carbocyclyl, 4- to 12-membered heterocyclyl, phenyl, naphthyl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one to four R 6 ; R 2a and R O2a each independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 4- to 6-membered heterocyclyl; R N2a and R N2b each independently is H, C 1-6 alkyl, C 1-6 haloalkyl, OR O2a or C 3-6 cycloalkyl; * is a point of attachment to the tricyclic core ring; R 7 is C 1-4 alkyl, 3- to 12-membered carbocyclyl, 4- to 12-membered heterocyclyl, phenyl, naphthyl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one to four halo, -OH, -NH2, cyano, NO2, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, or heteroaryl; each R 6 independently halo, cyano, oxo (as needed), NO2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, C 1-6 hydroxyalkoxy, -C(O)R 6a , -C(O)OR O6a , -C(O)NR N6a R N6b , OR O6a , NR N6a R N6b , SO2R 6a , -NR N6a C(O)R 6a , -NR N6a C(O)OR 6a , -NR N6a SO3R 6a , -NR N6a SO3NR N6a R N6a , -(CH2) 0或1 -3- to 12-membered carbocyclyl, -(CH2) 0或1 -4- to 12-membered heterocyclyl, -(CH2) 0或1 -6- to 10-membered aryl, or -(CH2) 0或1 -5- to 10-membered heteroaryl, wherein each of the carbocyclyl, heterocyclyl, aryl, or heteroaryl groups represented by R 6 is optionally substituted by one to four halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkoxy, -C(O)R 6a , -C(O)OR O6a , -C(O)NR N6a R N6b , cyano, NO2, OR O6a , NR N6a R N6b , SO3R 6a , -NR N6a C(O)R 6a , -NR N6a C(O)OR 6a , -NR N6a SO3R 6a or -NR N6a SO3NR N6a R N6a substituted; or two R 6 with the atom to which it is attached to form C 3-6 cycloalkyl; R 6a and R O6a each independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 4- to 6-membered heterocyclyl; R N6a and R N6b each independently is H, cyano, C 1-6 alkyl, C 1-6 haloalkyl, OR O6a or C 3-6 cycloalkyl; Ring B is phenyl or 5- to 10-membered monocyclic or bicyclic heteroaryl, each of which is substituted at the ortho position to the N(R Na ) substituent with R E , and optionally substituted with one to four R 3 ; each R 3 independently halo, cyano, NO2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, C 1-6 hydroxyalkoxy, -C(O)R 3a , -C(O)OR O3a , -C(O)NR N3a R N3b , OR O3a , NR N3a R N3b , SO2R 3a , -NR N3a C(O)R 3a , -NR N3a C(O)OR 3a , -NR N3a SO3R 3a , -NR N3a SO3NR N3a R N3a , -(CH2) 0或1 -3- to 12-membered carbocyclyl, -(CH2) 0或1 -4- to 12-membered heterocyclyl, -(CH2) 0或1 -6- to 10-membered aryl, or -(CH2) 0或1 -5- to 10-membered heteroaryl, wherein said carbocyclyl, heterocyclyl, aryl, or heteroaryl groups represented by R 3 are each optionally substituted by one to four halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, C 1-6 hydroxyalkoxy, -C(O)R 3a , -C(O)OR O3a , -C(O)NR N3a R N3b , cyano, NO2, OR O3a , NR N3a R N3b , SO3R 3a , -NR N3a C(O)R 3a , -NR N3a C(O)OR 3a , -NR N3a SO3R 3a , or -NR N3a SO3NR N3a R N3a substituted; R E is H, cyano, C 1-4 alkyl, -C(O)R 8 , -C(NH)NR N3E R N3E , -S(O2)NR N3E R N3E , -C(O)OR O3a , -C(O)NR N3a R N3b , phenyl, 5- to 10-membered heteroaryl, or 4- to 12-membered heterocyclyl, wherein the C 1-4 alkyl is optionally substituted with one to four R Ea , and the phenyl, 5- to 10-membered heteroaryl, and 4- to 12-membered heterocyclyl are each optionally substituted with one or two R Eb ; or R E and R 3 with the atom to which it is attached to form a 5- to 6-membered monocyclic heterocyclyl; R 8 is H, C 1-3 alkyl, C 1-3 haloalkyl, C 1-4 thioalkyl, C 1-4 thiohaloalkyl or SH; each R is independently halo, cyano, OH, or NR Ea independently halo, cyano, OH, or NR N3E R N3E ; each R Eb independently oxo, =S, halo, C 1-3 alkyl, C 1-3 haloalkyl, cyano, C 1-3 alkoxy, -OH, or -C(O)NR N3E R N3E wherein the C Eb represented by R 1-3 alkyl is optionally substituted with 4- to 6-membered heterocyclyl optionally substituted with C 1-3 alkyl; each R is independently H, OH, or C N3E is independently H, OH, or C 1-3 alkyl; R 3a and R O3a each independently is H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, or 4- to 6-membered heterocyclyl, wherein the C 3a alkyl represented by R O3a or R 1-6 is optionally substituted with 4- to 6-membered heterocyclyl; R N3a and R N3b each independently H, cyano, C 1-6 alkyl, C 1-6 haloalkyl, OR O3a , -SO2C 1-4 alkyl or C 3-6 cycloalkyl, wherein the C N3a alkyl represented by R N3b or R 1-6 is optionally substituted with C 1-3 alkoxy or 5- to 6-membered heteroaryl; R 4 is C 1-3 alkyl; and R 5 is H.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (I): (I)， wherein: each R 6 independently halo, cyano, oxo (as needed), NO2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, C 1-6 hydroxyalkoxy, -C(O)R 6a , -C(O)OR O6a , -C(O)NR N6a R N6b , OR O6a , NR N6a R N6b , SO2R 6a , -NR N6a C(O)R 6a , -NR N6a C(O)OR 6a , -NR N6a SO3R 6a , -NR N6a SO3NR N6a R N6a , -(CH2) 0或1 -3- to 12-membered carbocyclyl, -(CH2) 0或1 -4- to 12-membered heterocyclyl, -(CH2) 0或1 -6- to 10-membered aryl, or -(CH2) 0或1 -5- to 10-membered heteroaryl, wherein said carbocyclyl, heterocyclyl, aryl, or heteroaryl groups represented by R 6 are each optionally substituted by one to four halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkoxy, -C(O)R 6a , -C(O)OR O6a , -C(O)NR N6a R N6b , cyano, NO2, OR O6a , NR N6a R N6b , SO3R 6a , -NR N6a C(O)R 6a , -NR N6a C(O)OR 6a , -NR N6a SO3R 6a or -NR N6a SO3NR N6a R N6a substituted; R 7 is 3- to 12-membered carbocyclyl, 4- to 12-membered heterocyclyl, phenyl, naphthyl, or 5- to 10-membered heteroaryl, each optionally substituted with one to four halo, -OH, -NH2, cyano, NO2, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, or heteroaryl; R E -C(O)OR O3a -C(O)NR N3a R N3b ; R 3a and R O3a each independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, or 4- to 6-membered heterocyclyl; and R N3a and R N3b each independently is H, cyano, C 1-6 alkyl, C 1-6 haloalkyl, OR O3a or C 3-6 cycloalkyl.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (VI), (VII), or (VII’): (VI), (VII) or (VII'), wherein m and n are each independently 0, 1, or 2; and o is 0 or 1.

4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (VIa), (VIb), (VIc), (VId), (VIe), (VIIa), (VIIb), (VIIc), or (VIIa’): (VIa), (VIb), (VIc), (VId), (VIe), (VIIa), (VIIb), (VIIc) or (VIIa'), wherein: n and o are each independently 0 or 1; q is 0, 1, or 2; J 1 , J 2 , J 3 and J 4 are each independently N, CH or CR 6 ; T 1 and T 5 each independently N or C; T 2 , T 3 , and T 4 are each independently N, NR N6 , O, S, CH, or CR 6 ; R N6 is H, C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, phenyl or 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl each represented by R N6 are optionally substituted by one to three halo, C 1-3 alkyl, C 1-3 haloalkyl, cyano, OH, C 1-3 alkoxy or C 1-3 haloalkoxy; U 1 for NR N2 , CH2or O; U 2 is absent, NR N6 , CH2or O.

5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (VIa-1), (VIa-2), (VIb-1), (VIc-1), (VIc-2), (VIc-3), (VIc-4), (VId-1), (VId-2), (VIe-1), or (VIIc-1): (Via-1), (VIa-2), (VIb-1), (VIa-3), (VIc-1), (VIc-2), (VIc-3)、 (VIc-4)、 (VId-1), (VId-2), (VIe-1), (VIIc-1) or (VIIa'-1); wherein n is 0 or 1, and q is 0, 1, or 2.

6. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (II), (III), (IV), or (V): (I), (II), (III), (IV) or (V); wherein m and n are each independently 0, 1, or 2; and o is 0 or 1.

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (IIa), (IIb), (IIc), (IId), (IIIa), (IIIb), (IIIc), (IVa), (IVb), (IVc), (Va), (Vb), (Vc), or (Vd): (IIa), (IIb), (IIc)、 (IId), (IIIa), (IIIb), (IIIc), (IVa), (IVb), (IVc), (Will)、 (Vb)、 (Vc) or (Vd); wherein: n and o are each independently 0 or 1; q is 0, 1, or 2; J 1 , J 2 , J 3 and J 4 are each independently N, CH or CR 6 ; T 1 and T 5 each independently N or C; T 2 , T 3 , and T 4 are each independently N, NR N6 , O, S, CH, or CR 6 ; R N6 H, C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, phenyl, naphthyl or 5- to 6-membered heteroaryl, wherein the phenyl, naphthyl and 5- to 6-membered heteroaryl groups represented by R N6 each are optionally substituted with one to three halo, C 1-3 alkyl, C 1-3 haloalkyl, cyano, OH, C 1-3 alkoxy or C 1-3 haloalkoxy; U 1 for NR N2 , CH2or O; U 2 is NR N6 , CH2or O.

8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (IIa-1), (IIa-2), (IIa-3), (IIa-4), (IIa-5), (IIa-6), (IIa-7), (IIb-1), (IIb-2), (IIb-3), (IIb-4), (IIb-5), (IIb-6), (IIb-7), (IIb-8), (IIb-9), (IIb-10), (IIb-11), (IIc-1), (IIIa-1), (IIIb-1), (IIIc-1), (IVc-1), (Va-1), (Va-2), (Va-3), or (Vc-1): (IIa-1), (IIa-2), (IIa-3), (IIa-4), (IIa-5), (IIa-6), (IIa-7), (IIb-1), (IIb-2), (IIb-3), (IIb-4), (IIb-5), (IIb-6), (IIb-7), (IIb-8), (IIb-9), (IIb-10), (IIb-11), (IIc-1), (IIIa-1), (IIIb-1), (IIIc-1), (IVc-1), (Va-1), (Va-2), (Va-3) or (Vc-1).

9. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (VIII): (VIII); wherein: n is 0, 1, or 2; m is 0, 1, or 2; o is 0 or 1; each R 1 independently halo, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -NR N1a R N1b , -C(O)R 1a , -C(O)OR O1a , -C(O)NR N1a R N1b , OR O1a , C 3-6 cycloalkyl, phenyl, or 5- to 6-membered monocyclic heteroaryl, wherein the C 1 cycloalkyl, phenyl, and 5- to 6-membered monocyclic heteroaryl of R 3-6 each is optionally substituted with one to three halo, C 1-3 alkyl, C 1-3 haloalkyl, OH, C 1-3 alkoxy, C 1-3 haloalkoxy, -C(O)R 1a , -C(O)OR O1a , or -C(O)NR N1a R N1b ; Each R 2 Independently, it can be a halogen group, an oxo group, a cyano group, or a C group. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -NR N2a R N2b -C(O)R 2a -C(O)OR O2a -C(O)NR N2a R N2b OR O2a C 3-6 Cycloalkyl, phenyl, or 5- to 6-membered monocyclic heteroaryl, wherein R 2 The C mentioned 3-6 Cycloalkyl, phenyl, and 5- to 6-membered monocyclic heteroaryl groups are each optionally surrounded by one to three halogen groups, C 1-3 Alkyl, C 1-3 Halogenated alkyl, OH, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, -C(O)R 2a -C(O)OR O2a or -C(O)NR N2a R N2b replace; R 2a , R O2a , R N2a , and R N2b are each independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, or 4- to 6-membered heterocyclyl; Ring B is phenyl or 5- to 6-membered monocyclic heteroaryl, each of which is substituted at the ortho position to the NH substituent with R E substituted, and is substituted with one to three R 3 substituted; Each R 3 Independently halogenated, cyanoated, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -NR N3a R N3b -C(O)R 3a -C(O)OR O3a -C(O)NR N3a R N3b OR O3a C 3-6 Cycloalkyl, phenyl, or 5- to 6-membered monocyclic heteroaryl, wherein R 3 The C mentioned 3-6 Cycloalkyl, phenyl, and 5- to 6-membered monocyclic heteroaryl groups are each optionally surrounded by one to three halogen groups, C 3-3 Alkyl, C 3-3 Halogenated alkyl, OH, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, -C(O)R 3a -C(O)OR O3a or -C(O)NR N3a R N3b replace; R 3a , R O3a , R N3a , and R N3b are each independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, or 4- to 6-membered heterocyclyl; The ring C is a 6-membered monocyclic heterocyclic group, a phenyl group, or a 5- to 6-membered monocyclic heteroaryl group, each optionally surrounded by one to three R groups. 6 replace; Q 1 and Q 2 each independently C, CH or N, with the proviso that at least one of Q 1 or Q 2 is C or CH; each R 6 independently halo, oxo, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -NR N6a R N6b , -C(O)R 6a , -C(O)OR O6a , -C(O)NR N6a R N6b , OR O6a , C 1-6 cycloalkyl, phenyl, or 5- to 6-membered monocyclic heteroaryl, wherein the C 6 cycloalkyl, phenyl, and 5- to 6-membered monocyclic heteroaryl represented by R 1-6 are each independently substituted with one to three halo, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -C(O)R 6a , -C(O)OR O6a , or -C(O)NR N6a R N6b ; R 6a , R O6a , R N6a and R N6b are each independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cycloalkyl or 4- to 6-membered heterocyclyl.

10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (Villa), (Vlllb), or (Vlllc): (VIIIa) (VIIIb) or (VIIIc); wherein: n is 0 or 1; q is 0, 1, or 2; U 2 is NR N6 , CH2or O; J 1 , J 2 , J 3 , and J 4 are each independently N or CH, wherein at least one of J 1 , J 2 , J 3 , and J 4 is CH; T 1 and T 5 each independently N or C; T 2 , T 3 and T 4 are each independently N, NR N6 , O, S or CH; R N6 is H, C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, phenyl or 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl each represented by R N6 are optionally substituted by one to three halo, C 1-3 alkyl, C 1-3 haloalkyl, cyano, OH, C 1-3 alkoxy or C 1-3 haloalkoxy.

11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (II-1), (III-1), (IV-1), (V-1), (VI-1), (VI-2), or (VII-1): (II-1), (III-1), (IV-1), (V-1), (VI-1)、 (VI-2) (VII-1), wherein m, n, and o are each independently 0 or 1; U 1 for NR N2 , CH2or O; R 7 is C 1-4 alkyl, 5- or 6-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl, wherein each of the 5- or 6-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl is optionally substituted with one to two halo, -OH, -NH2, cyano, C 1-3 alkyl, C 1-3 alkyl-OR O7a , C 3-6 cycloalkyl, C 1-3 haloalkyl, or 4- to 6-membered heterocyclyl; R O7a is H or C 1-3 alkyl.

12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein R 7 is C 1-3 alkyl, phenyl, pyridyl, isoxazolyl, pyrazolyl, imidazolyl, tetrahydrofuranyl, or tetrahydro-2H-pyranyl, wherein the phenyl, pyridyl, isoxazolyl, pyrazolyl, imidazolyl, tetrahydrofuranyl, and tetrahydro-2H-pyranyl are each optionally substituted with one to two halo, -OH, C 1-3 alkoxy, -NH2, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkyl-OR O7a or cyclopropyl, or R 7 is morpholinyl; R O7a is H or C 1-3 alkyl.

13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (IX): (IX).

14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein Ring B is phenyl or 6-membered monocyclic heteroaryl, each of which is substituted at the ortho position with NR Na substituted with R E , and further optionally substituted with one or two R 3 .

15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein Ring B is phenyl, pyrimidinyl, or pyridyl, each of which is optionally substituted at the NR Na adjacent position with R E and further optionally substituted with one or two R 3 .

16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein ring B and R E and optionally substituted R 3 is represented by: , , , , , , or .

17. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein ring B and R E and optionally substituted R 3 is represented by: or .

18. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein: R E is cyano, C 1-4 alkyl, -C(O)R 8 , -C(NH)NR N3E R N3E , -S(O2)NR N3E R N3E , -C(O)OR O3a , -C(O)NR N3a R N3b , phenyl, 5- to 6-membered heteroaryl, or 4- to 10-membered heterocyclyl, wherein the C 1-4 alkyl is optionally substituted with one to four R Ea , and the phenyl, 5- to 6-membered heteroaryl, and 4- to 10-membered heterocyclyl are each optionally substituted with one or two R Eb ; R 8 is H, C 1-3 alkyl, C 1-3 haloalkyl or SH; each R is independently halo, cyano, OH, or NR Ea independently halo, cyano, OH, or NR N3E R N3E ; each R Eb independently oxo, =S, halo, C 1-3 alkyl, C 1-3 haloalkyl, cyano, C 1-3 alkoxy, -OH, or -C(O)NR N3E R N3E wherein the C 1-3 alkyl is optionally substituted with 4- to 6-membered heterocyclyl optionally substituted with C 1-3 alkyl; each R is independently H, OH, or C N3E is independently H, OH, or C 1-3 alkyl; R O3a is H, C 1-3 alkyl or 4- to 6-membered monocyclic heterocyclyl, wherein the C 1-3 alkyl is optionally substituted with 4- to 6-membered monocyclic heterocyclyl; R N3a and R N3b each independently is H, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, -OH, -S(O)2C 1-3 alkyl or cyclopropyl, wherein said C 1-3 alkyl is optionally substituted with C 1-3 alkoxy or 6-membered heteroaryl.

19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein: R E is cyano, C 1-4 alkyl, -C(O)R 8 , -C(NH)NR N3E R N3E , -S(O2)NR N3E R N3E , -C(O)OR O3a , -C(O)NR N3a R N3b , phenyl, pyridyl, pyrazolyl, oxadiazolyl, imidazolyl, thiazolyl, isothiazolyl, triazolyl, oxazolyl, thienyl, morpholinyl, piperidinyl, piperazinyl, or 7-oxa-2- azaspiro[3.5]nonyl, wherein the C 1-4 alkyl is optionally substituted with one to four R Ea , and the phenyl, pyridyl, pyrazolyl, oxadiazolyl, imidazolyl, thiazolyl, isothiazolyl, triazolyl, oxazolyl, thienyl, morpholinyl, piperidinyl, piperazinyl, and 7-oxa-2- azaspiro[3.5]nonyl are each optionally substituted with one or two R Eb ; R 8 is H, C 1-3 alkyl, C 1-3 haloalkyl or SH; each R is independently halo, cyano, OH, or NR Ea independently halo, cyano, OH, or NR N3E R N3E ; each R is independently halo, C Eb independently halo, C 1-3 alkyl, C 1-3 haloalkyl, cyano, C 1-3 alkoxy, -OH, or -C(O)NR N3E R N3E wherein the C 1-3 alkyl is optionally substituted oxetanyl, which is substituted with C 1-3 alkyl; each R is independently H, OH, or C N3E independently H, OH, or C 1-3 alkyl; R O3a is H, C 1-3 alkyl or tetrahydrofuryl, wherein the C 1-3 alkyl is optionally substituted with tetrahydrofuryl; R N3a and R N3b each independently is H, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, -OH, -S(O)2C 1-3 alkyl or cyclopropyl, wherein said C 1-3 alkyl is optionally substituted with C 1-3 alkoxy or pyridyl.

20. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R E is -C(O)OR O3a or -C(O)NR N3a R N3b ; R O3a is H or C 1-3 alkyl; and R N3a and R N3b are each independently H, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, -OH, or cyclopropyl.

21. The compound of claim 18 or 19, or a pharmaceutically acceptable salt thereof, wherein R E -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, -C(O)OC(CH3)3, -C(O)NH2, -C(O)NHCH3, -C(O)NHS(O)2CH3, -C(O)NHCH2CH2OCH3, -C(O)N(CH3)OCH3, cyano, -C(O)H, -C(O)CH3, -C(O)CF3, -C(O)SH, -CH3, -C(CH2CN)2OH, -C(NH)NHOH, -CH2OH, -CH(OH)CF3, -S(O)2NHC(CH3)3, -S(O)2NH2, 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 .

22. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 16, wherein R E is -C(O)OH.

23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently halo, C 1-3 alkyl, C 1-3 haloalkyl, or 6-membered monocyclic heterocyclyl, wherein the 6-membered monocyclic heterocyclyl is optionally substituted with halo.

24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently -Br, -CI, -F, -CH3, -CF3, or pyridyl, wherein the pyridyl is optionally substituted with -F.

25. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein each R 1 independently CN, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxyalkyl, or halo.

26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein each R 1 is independently C 1-3 alkyl, C 1-3 haloalkyl or halo, preferably wherein R 1 is -CH3 or -F.

27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein: each R is independently oxo, halo, cyano, -OH, C 6 independently oxo, halo, cyano, -OH, C 1-3 alkyl, C 1-3 alkoxy, -C(O)NH2, or -NH2; or two R 6 with the atom to which it is attached form a cyclopropyl group; R N6 is H, C 1-3 alkyl, phenyl or pyridyl, wherein the phenyl is optionally substituted with -CN.

28. The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein: Each R 6 It can be independently an oxo group, -Cl, -F, -OH, -CH3, -OCH3, -OCH(CH3)3, CN, -C(O)NH2 or -NH2; R N6 H, -CH3, or .

29. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 28, wherein each R 2 is independently halo, C 1-3 alkyl or C 1-3 haloalkyl.

30. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (Vlc-la): (VIc-1a), wherein: X is N or CH; n is 0 or 1; R 1 halo or C 1-3 alkyl; w is 0, 1, or 2; each R is independently halo or C 3 independently halo or C 1-3 alkyl; q is 0, 1, or 2; and each R is independently halo or C 6 independently halo or C 1-3 alkyl.

31. The compound of claim 30, or a pharmaceutically acceptable salt thereof, wherein R 1 is -F or -CH3.

32. The compound or pharmaceutically acceptable salt thereof of claim 30 or 31, wherein each R 3 is independently -F, -CI, -Br, or -CH3.

33. The compound of any one of claims 30-32, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (Vlc-la): (VIc-1aa).

34. The compound or pharmaceutically acceptable salt thereof of any one of claims 30-33, wherein each R 6 is independently C 1-3 alkyl, preferably wherein each R 6 is -CH3.

35. The compound of any one of claims 30-33, or a pharmaceutically acceptable salt thereof, wherein q is 0.

36. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 35, wherein or is .

37. A pharmaceutical composition comprising a compound of any one of claims 1-36, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

38. A method of treating a disease or disorder associated with the modulation of a phosphoinositide 3-kinase alpha (alpha) isoform (PI3K a), comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-36, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 37.

39. The method of claim 38, wherein the PI3K a associated with the disease or disorder has, or is characterized by, a mutation.

40. The method of claim 38 or 39, wherein the PI3K a associated with the disease or disorder has, or is characterized by, a H1047R or H1047L mutation.

41. The method of any one of claims 38-40, wherein the disease or disorder is a cancer.

42. The method of claim 41, wherein the cancer is breast cancer (e.g., hormone receptor positive breast cancer, HER2 negative breast cancer, HER2 positive breast cancer, and triple negative breast cancer), endometrial cancer, uterine cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, brain cancer, or prostate cancer.

43. The method of claim 41 or 42, wherein the disease or disorder is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis / osteochondro dysplasia syndrome) or PIK3CA-related overgrowth syndrome (PROS).

44. A method of inhibiting phosphoinositide 3-kinase, alpha (alpha) isoform (PI3Ka), comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-36, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 37.

45. A method of treating a cancer or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-36, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 37.

46. The method of claim 45, wherein the cancer is breast cancer (e.g., hormone receptor positive breast cancer, HER2 negative breast cancer, HER2 positive breast cancer, and triple negative breast cancer), endometrial cancer, uterine cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, brain cancer, or prostate cancer.

47. The method of claim 45, wherein the disorder is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis / osteochondro dysplasia syndrome) or PIK3CA-related overgrowth syndrome (PROS).

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