Isoquinolinone derivatives and 4H-quinolidinone derivatives and their pharmaceutical compositions for the treatment of diseases

Abstract

The isoquinolin-1(2H)-one derivative of formula (I), or its stereoisomer, tautomer, or pharmaceutically acceptable salt is disclosed herein, and the variables (e.g., L 2A , R 1 , R 2A , R 3 , R 4A , R 4B , R 4C , R 4D , Q 2 , Q 3 , Q 4 ) have the values as described herein. Also disclosed are pharmaceutical compositions containing such derivatives, and methods for treating or preventing disorders or diseases responsive to inhibition of PI3Kα activity in a subject using such derivatives. TIFF2026516333000335.tif53165

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to International Application PCT / CN2023 / 093652, filed on 11 May 2023, and International Application PCT / CN2023 / 108473, filed on 20 July 2023, the disclosures of each thereof being incorporated herein by reference in their entirety.

[0002] Disclosed herein are isoquinoline-1(2H)-one derivatives and 4H-quinoridine-4-one derivatives, or their stereoisomers, or pharmaceutically acceptable salts thereof, which are useful as PI3Kα inhibitors, as well as pharmaceutical compositions containing them. Also disclosed herein are methods for treating cancer using isoquinoline-1(2H)-one derivatives, or their stereoisomers, or their pharmaceutically acceptable salts, as PI3Kα inhibitors. Further disclosed herein are methods for treating cancer using 4H-quinoridine-4-one derivatives, or their stereoisomers, or their pharmaceutically acceptable salts, as PI3Kα inhibitors. [Background technology]

[0003] Phosphoinositide 3-kinase (PI3K) signaling is one of the most frequently abnormally activated pathways in human cancers. Under physiological conditions, the PI3K pathway is activated in response to insulin, growth factors, and cytokines. Activated PI3K supports both systemic metabolic homeostasis and individual cell growth by regulating major metabolic processes, including glucose metabolism, macromolecule biosynthesis, and maintenance of redox balance. Oncogenic activation of the PI3K pathway in cancer cells reprograms cellular metabolism by enhancing the activity of nutrient transporters and metabolic enzymes, thereby supporting the anabolic needs of abnormally growing cells.

[0004] The PI3K signaling network is activated downstream of receptor tyrosine kinases (RTKs), cytokine receptors, integrins, and G protein-coupled receptors (GPCRs), playing a central role in promoting cell survival and growth (Fruman et al., 2017). Class IA PI3K exists as a heterodimer of a regulatory subunit (p85α or p85β, or shorter variants thereof) and an associated catalytic subunit (p110α, p110β, or p110δ) (Thorpe, Yuzugullu, & Zhao, 2015). Activation of PI3K at the plasma membrane stimulates the phosphorylation of its phospholipid substrate phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) to produce a second messenger, phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3). PtdIns(3,4,5)P3 accumulation in the plasma membrane and possibly other intracellular membranes recruits downstream effector proteins containing subclasses of plexutrin homology (PH) domains, including protein kinases (such as AKT and BTK), adapter proteins, and GTPase regulators, to create docking sites and regulate their activity.

[0005] Genetic events leading to growth factor-independent activation of the PI3K pathway are one of the most frequently occurring driving factors in human cancer. Among gene mutations, PIK3CA mutations are among the most frequently mutated kinase genes in solid tumors, with a mutation rate of approximately 14% across all cancers (Zhang et al., 2017). Endometrial, breast, colon, lung, and benign skin cancers are now known to be among the tumor types with the highest frequency of PIK3CA mutations (Samuels & Waldman, 2010). Oncogenic mutations in PIK3CA are particularly abundant in hotspot mutations in the helical (E542K, E545K) and kinase (H1047R) domains (Arafeh & Samuels, 2019).

[0006] Given the oncogenic function of PIK3CA mutations in cancer progression, several PI3Kα inhibitors have been developed, and one p110α-selective PI3K inhibitor, alpelisib (BYL719), has shown improved clinical response when used in combination with an estrogen receptor antagonist (Andre et al., 2019), and has therefore been approved by the FDA for the treatment of HR+Her2- metastatic breast cancer with PIK3CA mutations.

[0007] Although drugs are approved and several inhibitors are continuously being studied in clinical trials, the efficacy of p110α-selective PI3K inhibitors is moderate, partly due to on-target toxicity of hyperglycemia and / or hyperinsulinemia. Targeted inhibition of PI3Kα disrupts glucose metabolism in multiple tissues, preventing glucose uptake in skeletal muscle and adipose tissue, leading to hyperglycemia. Hyperglycemia is usually transient in the initial stages of PI3Kα inhibition, due to compensatory insulin release from the pancreas. However, hyperglycemia may worsen or become prolonged in patients with any degree of insulin resistance, in which case discontinuation of therapy may be necessary (Mayer et al., 2017). In addition, preclinical studies have reported that high levels of circulating insulin activate the PI3K-mTOR signaling axis in tumors, impairing the effects of PI3Kα inhibitors (Hopkins et al., 2018).

[0008] Therefore, it is necessary to improve the therapeutic index of PI3Kα inhibitors by identifying compounds that have higher selectivity for mutant PI3Kα than for wild-type PI3Kα. This is expected to specifically inhibit mutant PI3Kα in cancer cells while evading wild-type PI3Kα in host tissues, thus creating a larger therapeutic window, enabling sufficient targeted inhibition, and achieving improved antitumor efficacy. [Overview of the Initiative] [Means for solving the problem]

[0009] Isoquinolin-1(2H)-one derivatives of formula (I) and 4H-quinolizin-4-one derivatives of formula (VI), and methods of using them are disclosed herein.

[0010] Aspect 1. A compound of formula (I) or formula (VI),

Chemical formula

[0011] In the embodiment of the first aspect, Q 2 C(R 5 ) and Q 3 C(R 6 ) and Q 4 C(R 7 ) or N.

[0012] Appearance 2. Having formula (II), [ka] In the formula, R 1 , L 2A , R 2A , R 3 , R 4A , R 4B , R 4C ,R 4D , R 5 , R 6 , and R 7 However, the compound described in Embodiment 1, which is defined as Embodiment 1.

[0013] Appearance 3. Having formulas (III-1) to (III-9), [ka] Each R Q These independently produce hydrogen, halogen, and -C. 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OR Q1 , -SO2R Q1 -SO2NR Q2 R Q3 , -COR Q1 , -CO2R Q1 ,-CONR Q1 R Q2 , -NR Q1 R Q2 , -NR Q1 COR Q2 , -NR Q1 CONR Q2 R Q3 , or -NR Q1 CO2R Q2 and -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl each independently and optionally has at least one substituent R Q11 It has been replaced with, R Q1 , R Q2 , and R Q3 Each of them independently produces hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl, and the -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl each independently and optionally has at least one substituent R Q11 It has been replaced with, R Q11 However, hydrogen, halogen, -CN, -NO2, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 1-6Haloalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -OC 1-6 Alkyl, -COC 1-6 Alkyl, or -CO2C 1-6 It is alkyl, n Q The compound according to embodiment 1 or 2, wherein the coefficient is 0, 1, 2, 3, 4, or 5.

[0014] Embodiment 4a. The compound according to Embodiment 3, having formula (IV-a). [ka]

[0015] Embodiment 4. The compound according to Embodiment 3, having formula (IV). [ka]

[0016] In the embodiment of aspect 4, R 1 is hydrogen, deuterium, -C 1-6 Alkyl, deuterated-C 1-6 Alkyl, heterocyclyl, heteroaryl, or aryl, and said -C 1-6 Alkyl, deuterated-C 1-6 Alkyl, heterocyclyl, heteroaryl, or aryl each independently and optionally has at least one substituent R 11a It has been replaced with, Each R 11a These are independently hydrogen, halogen, oxo, and -C. 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OR 1a , -COR 1a , -CO2R 1a ,-CONR 1a R 1b , -SO2R 1a , -NR 1aR 1b , -NR 1a COR 1b , -NR 1a CONR 1b R 1c , or -NR 1a CO2R 1b And, the said -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl each independently and optionally has at least one substituent R 1d It has been replaced with, R 1a , R 1b , and R 1c Each of them is independently hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl, and said -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl each independently and optionally has at least one substituent R 1d It has been replaced with, Each R 1d These are independently hydrogen, halogen, oxo, -CN, -NO2, and -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 1-6 Haloalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -OC 1-6 Alkyl, -COC 1-6 Alkyl, or -CO2C 1-6 It is alkyl. R 3 is hydrogen, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -CN, or -NO2, and the -C1-6 Alkyl or -OC 1-6 Alkyl can be optionally hydrogen, halogen, or -C. 1-6 It is substituted with at least one substituent selected from alkyl, -CN, and -NO2. R 4A and R 4B These may be the same or different, and each can be independently hydrogen, deuterium, halogen, and -C. 1-6 Alkyl or deuterated C 1-6 It is alkyl, and the -C 1-6 Alkyl or deuterated C 1-6 Alkyl elements can be selected independently and arbitrarily from halogens and -C. 1-6 Alkyl, -C 1-6 Haloalkyl, -CN, -NO2, -OC 1-6 Alkyl, -COC 1-6 Alkyl and -CO2C 1-6 It is substituted with at least one substituent selected from alkyl groups. R 4C is hydrogen, halogen, -C 1-6 Alkyl or deuterated C 1-6 It is alkyl, and the -C 1-6 Alkyl or deuterated C 1-6 Alkyl can be optionally hydrogen, halogen, or -C. 1-6 Alkyl, -C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OC 1-6 Alkyl, -COC 1-6 Alkyl and -CO2C 1-6 It is substituted with at least one substituent selected from alkyl groups. R 5 is hydrogen, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -CN, or -NO2, and the -C 1-6 Alkyl or -OC 1-6 Alkyl can be optionally hydrogen, halogen, or -C. 1-6It is substituted with at least one substituent selected from alkyl, -CN, and -NO2. R 6 is hydrogen, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -CN, or -NO2, and the -C 1-6 Alkyl or -OC 1-6 Alkyl atoms can be independently and optionally selected from hydrogen, deuterium, halogen, and -C. 1-6 It is substituted with at least one substituent selected from alkyl, -CN, and -NO2. R 7 is hydrogen, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -CN, or -NO2, and the -C 1-6 Alkyl or -OC 1-6 Alkyl can be optionally hydrogen, halogen, or -C. 1-6 It is substituted with at least one substituent selected from alkyl, -CN, and -NO2. -L 2A - is a covalent bond, *-N(R 21a )C(O)-**,**-N(R 21a )C(O)-*, *-(CR 22a R 23a ) m -C(R 22a )=C(R 23a )-(CR 22a R 23a ) n -**,or [ka] And, * indicates the position where it is bound to isoquinoline-1(2H)-one. ** is R 2A It refers to the position where it is connected. m and n are independently 0, 1, 2, or 3. R 21a is hydrogen or -C 1-6 It is alkyl, and the -C 1-6 The alkyl group optionally has at least one substituent R211b It has been replaced with, Each R 211b These are independently hydrogen or halogen, R 22a and R 23a Each of these is independently hydrogen, halogen, or -C 1-6 It is alkyl, and the -C 1-6 Each alkyl group may independently and optionally have at least one substituent R 223a It has been replaced with, Each R 223a These are independently hydrogen or halogen, R 2A is -C 1-6 Alkyl, 3-15 member cycloalkyl, unsaturated 3-15 member heterocyclyl containing at least one carbon-carbon double bond, 5-12 member aryl, or 5-15 member heteroaryl, and said -C 1-6 Each of alkyl, 3-15 membered cycloalkyl, unsaturated 3-7 membered heterocyclyl containing at least one carbon-carbon double bond, 5-12 membered aryl, or 5-15 membered heteroaryl may optionally contain at least one R Y1 It has been replaced with, Each R Y1 These are independently hydrogen, halogen, oxo, and -C. 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, -O-heterocyclyl, -CO-heterocyclyl, aryl, heteroaryl, -P(O)(C 1-6 Alkyl)2,-OH,-CN,-OC 1-6 Alkyl, -SC 1-6 Alkyl or -NO2, and the -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -OC 1-6 Alkyl, or -SC 1-6 Each alkyl group can independently and optionally have at least one substituent R Y1aIt has been replaced with, Each R Y1a These are independently hydrogen, halogen, and -C 1-6 Alkyl, -NHC 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -OH, -CN, -CONH2, -COCH3, -OC 1-6 It is alkyl or -NO2.

[0017] Appearance 5. Having formula (V), [ka] In the formula, cyl1 and cyl2 are each independently a 5 or 6-membered cycloalkyl ring, a cycloalkenyl ring, a heterocyclyl ring, an aryl ring, or a heteroaryl ring. At least one of cyl1 and cyl2 is an aromatic ring. cyl1 and cyl2 are independently and arbitrarily selected, R Q The compound according to embodiment 1, which is substituted by...

[0018] Embodiment 6. The compound according to Embodiment 5, having formulas (V-1) to (V-11). [ka]

[0019] Appearance 7. *-L 2A -** is a covalent bond, *-N(R 21a )C(O)-**,**-N(R 21a )C(O)-*, *-(CR 22a R 23a ) m -C(R 22a )=C(R 23a )-(CR 22a R 23a ) n -**,or [ka] And, m and n are independently 0, 1, 2, 3, 4, 5, or 6. R 21a However, hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl, and the -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl each independently and optionally has at least one substituent R 211b It has been replaced with, Each R 211b These independently produce hydrogen, halogen, -CN, -NO2, and -C. 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -C 1-6 Haloalkyl, -OC 1-6 Alkyl, -COC 1-6 Alkyl, or -CO2C 1-6 It is alkyl, R 22a , and R 23a Each of them independently produces hydrogen, halogen, and -C. 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OR 222a , -COR 222a , -CO2R 222a ,-CONR 222a R 222b , -NR 222a R 222b , -NR 222a COR 222b , -NR 222a CONR 222bR 222c , or -NR 222a CO2R 222b and -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl each independently and optionally has at least one substituent R 223a It has been replaced with, R 222a , R 222b , and R 222c Each of them independently produces hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl, and the -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl each independently and optionally has at least one substituent R 223a It has been replaced with, R 223a However, hydrogen, halogen, -CN, -NO2, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 1-6 Haloalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -OC 1-6 Alkyl, -COC 1-6 Alkyl, or -CO2C 1-6 A compound according to any one of embodiments 1 to 6, which is alkyl.

[0020] Appearance 8. *-L 2A -** is a covalent bond, *-N(R 21a )C(O)-**,**-N(R 21a )C(O)-*, *-(CR 22a R 23a )m -C(R 22a )=C(R 23a )-(CR 22a R 23a ) n -**,or [ka] And, m and n are independently 0, 1, 2, 3, 4, 5, or 6. R 21a However, hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl or cycloalkyl, and the -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl or cycloalkyl molecules each independently and optionally have at least one substituent R 211b It has been replaced with, Each R 211b These independently produce hydrogen, halogen, -CN, -NO2, and -C. 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -C 1-6 Haloalkyl, -OC 1-6 Alkyl, -COC 1-6 Alkyl, or -CO2C 1-6 It is alkyl, R 22a , and R 23a Each of them independently produces hydrogen, halogen, and -C. 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, -CN, -NO2, -OR 222a , -COR 222a , -CO2R 222a ,-CONR 222a R 222b , -NR 222a R 222b , -NR 222a COR 222b , -NR222a CONR 222b R 222c , or -NR 222a CO2R 222b and -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl or cycloalkyl molecules each independently and optionally have at least one substituent R 223a It has been replaced with, R 222a , R 222b , and R 222c Each of them independently produces hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl or cycloalkyl, and the -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl or cycloalkyl molecules each independently and optionally have at least one substituent R 223a It has been replaced with, Each R 223a These independently produce hydrogen, halogen, -CN, -NO2, and -C. 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 1-6 Haloalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -OC 1-6 Alkyl, -COC 1-6 Alkyl, or -CO2C 1-6 The compound according to embodiment 7, which is alkyl.

[0021] Appearance 9. *-L 2A -** is a covalent bond, *-N(R 21a )C(O)-**,**-N(R 21a )C(O)-*, *-(CR 22a R 23a ) m -C(R 22a )=C(R 23a )-(CR 22a R 23a ) n- or [Chem.] and m and n are each independently 0, 1, 2, 3, 4, 5, or 6, R 21a is hydrogen, -C 1-6 alkyl, and the -C 1-6 alkyl is each independently optionally substituted with at least one substituent R 211b ; each R 211b is independently hydrogen, halogen, -CN, -NO2, -C 1-6 alkyl, -C 1-6 haloalkyl, -OC 1-6 alkyl, -COC 1-6 alkyl, or -CO2C 1-6 alkyl; R 22a , and R 23a are each independently hydrogen, halogen, -C 1-6 alkyl, -CN, -NO2, or -OR 222a ; and the -C 1-6 alkyl is each independently optionally substituted with at least one substituent R 223a ; each R 223a is independently hydrogen, halogen, -CN, -NO2, -C 1-6 alkyl, -C 1-6 haloalkyl, -OC 1-6 alkyl, -COC 1-6 alkyl, or -CO2C 1-6 alkyl; a compound according to embodiment 8.

[0022] Embodiment 10. *-L 2A -** is a covalent bond, *-N(R 21a )C(O)-**, **-N(R 21a )C(O)-*, *-(CR 22a R 23a ) m -C(R 22a )=C(R 23a )-(CR22a R 23a ) n -**,or [ka] And, m and n are independently 0, 1, 2, or 3. R 21a However, hydrogen, or -C 1-6 Alkyl, and the -C 1-6 Each alkyl group independently and optionally has at least one substituent R 211b It has been replaced with, Each R 211b These are independently hydrogen or halogen, R 22a , and R 23a Each of these independently produces hydrogen, halogen, or -C 1-6 Alkyl, and the -C 1-6 Each alkyl group independently and optionally has at least one substituent R 223a It has been replaced with, Each R 223a The compound according to embodiment 9, wherein is independently hydrogen or halogen.

[0023] Appearance 11. -L 2A The compound according to embodiment 10, wherein - is a covalent bond, *-NHC(O)-**, **-NHC(O)-*, *-CH=CH-**, or *-C≡C-**.

[0024] In the embodiment of aspect 11, -L 2A - represents a covalent bond.

[0025] Appearance 12. R 2A However, -C 1-6 Selected from alkyl, cycloalkyl, unsaturated heterocyclyl, aryl, or heteroaryl containing at least one carbon-carbon double bond, and the -C 1-6Alkyl, cycloalkyl, unsaturated heterocyclyl, aryl, or heteroaryl each independently and optionally has at least one substituent R 24a It has been replaced with, Each R 24a These independently produce hydrogen, halogen, oxo, and -C. 1-6 Alkyl, -SC 1-6 Alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -CN, -COOH, -P(O)R 241b R 241c , or -OR 241a and -C 1-6 Alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl each independently and optionally has at least one substituent R 242a It has been replaced with, Each R 242a These independently produce hydrogen, halogen, -CN, and -C. 1-6 Alkyl, -NR 241a R 241b , -COR 241a ,-CONR 241a R 241b , -OR 241a , heterocyclyl, aryl, or heteroaryl, and the -C 1-6 Alkyl, heterocyclyl, aryl, or heteroaryl each independently and optionally has at least one substituent R 243a It has been replaced with, R 241a , R 241b , and R 241c Each of these independently comprises hydrogen, cycloalkyl, heterocyclyl, or -C 1-6 Alkyl, and the -C 1-6 Each alkyl group independently and optionally has at least one substituent R 243a It has been replaced with, Each R 243a These independently produce hydrogen, halogen, -CN, -OH, -NO2, and -C. 1-6 Alkyl, -OC 1-6 Alkyl, or -C(O)C 1-6The compound according to any one of aspects 1 to 11, which is alkyl.

[0026] In an embodiment, R 2A is selected from -C <X 1-6 alkyl, cycloalkyl, an unsaturated heterocyclic ring containing at least one carbon-carbon double bond, aryl, or heteroaryl, and the -C 1-6 alkyl, cycloalkyl, unsaturated heterocyclic ring, aryl, or heteroaryl is each independently, optionally, substituted with at least one substituent R 24a and each R 24a is independently hydrogen, halogen, oxo, -C 1-6 alkyl, -SC 1-6 alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -CN, -P(O)R 241b R 241c or -OR 241a and the -C 1-6 alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl or heteroaryl is each independently, optionally, substituted with at least one substituent R 242a and each R 242a is independently hydrogen, halogen, -CN, -C 1-6 alkyl, -NR 241a R 241b -COR 241a -CONR 241a R 241b -OC 1-6 alkyl, heterocyclyl, aryl, or heteroaryl, and the -C 1-6 alkyl, heterocyclyl, aryl, or heteroaryl is each independently, optionally, substituted with at least one substituent R 243a and R <X 241a R 241b and R 241c are each independently hydrogen, cycloalkyl, heterocyclyl, or -C 1-6 alkyl, and the -C 1-6Each alkyl group may independently and optionally have at least one substituent R 243a It has been replaced with, Each R 243a These are independently hydrogen, halogen, -CN, -OH, -NO2, or -OC 1-6 It is alkyl.

[0027] Appearance 13. R 2A but, -C 1-6 alkyl; -3- to 7-membered cycloalkyl groups; -Optional, one or more independently selected F, -C 1-6 Unsaturated 3- to 7-membered heterocyclic compounds containing at least one carbon-carbon double bond, substituted with alkyl, -CN, or aryl groups; -Optional, one or more independently selected F, -C 1-6 Alkyl, -C 1-6 Alkinyl, -SC 1-6 Alkyl, -OC 1-6 Alkyl, -PO(C 1-6 Alkyl)2, -CN, -COOH, -CONH2, cycloalkyl, -COcycloalkyl, heterocyclyl, -COheterocryl, aryl, or 5-12 membered aryl (the aforementioned -C 1-6 Alkyl, cycloalkyl, heterocyclyl, or heteroaryl elements are each independently and optionally included as -OH, -CN, F, or -NHC. 1-6 Alkyl, -C 1-6 Alkyl or -OC 1-6 (substituted with alkyl), or -Optional, one or more independently selected F, -C 1-6 Alkyl, -OC 1-6 5-15 member heteroaryls substituted with alkyl, -CN, oxo, cycloalkyl, heterocyclyl, aryl, or heteroaryl (the aforementioned -C 1-6Alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each independently and optionally selected as cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, F, Cl, -OH, -CONH2, -C 1-6 Alkyl, or -OC 1-6 A compound according to any one of embodiments 1 to 11, selected from (substituted with alkyl).

[0028] Appearance 14. R 2A However, -C 1-6 Alkyl, [ka] Selected from, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 , Z 9 , Z 10 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , Y 11 , Y 12 , Y 13 , and Y 14 Each of them operates independently, C(R Y ), C(R Y’ R Y ), N(R Y ), N, O, or S, n Z However, each is independently selected from 0, 1, 2, or 3. n1 is independently selected from 0, 1, 2, or 3. R Y’ and R Y Each of them independently produces hydrogen, halogen, and -C. 1-6 Alkyl, -C 2-6Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -CN, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -P(O)(C 1-6 Alkyl)2, -OH, or -NO2, and the -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -OC 1-6 Alkyl or -SC 1-6 Each alkyl group can independently and optionally have at least one substituent R Ya It has been replaced with, Each R Ya These independently produce hydrogen, halogen, and -C. 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -OH, -CN, -OC 1-6 A compound according to any one of embodiments 1 to 11, wherein it is alkyl or -NO2.

[0029] Appearance 15. R 2A However, methyl, [ka] Selected from, Each R Y1 These independently produce hydrogen, halogen, oxo, and -C. 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, -O-heterocyclyl, -CO-heterocyclyl, aryl, heteroaryl, -P(O)(C 1-6 Alkyl)2,-OH,-CN,-OC 1-6 Alkyl, -SC 1-6 Alkyl, or -NO2, and the -C1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -OC 1-6 Alkyl, or -SC 1-6 Each alkyl group can independently and optionally have at least one substituent R Y1a It has been replaced with, Each R Y1a These independently produce hydrogen, halogen, and -C. 1-6 Alkyl, -NHC 1-6 Alkyl,-C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -OH, -CN, -CONH2, -COCH3, -OC 1-6 Alkyl, or -NO2, n Z However, each is independently selected from 0, 1, 2, or 3. The compound according to any one of embodiments 1 to 11, wherein n1 is independently selected from 0, 1, 2, or 3.

[0030] In the embodiment of aspect 15, R 2A teeth, [ka] And, X is C(R Y12 ) or N, R Y11 , R Y12 , R Y13 , R Y14 , and R Y15 Each of these is independently hydrogen, halogen, and -C. 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, -O-heterocyclyl, -CO-heterocyclyl, aryl, heteroaryl, -P(O)(C 1-6 Alkyl)2,-OH,-CN,-OC1-6 Alkyl, -SC 1-6 Alkyl or -NO2, and the -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -OC 1-6 Alkyl, or -SC 1-6 Each alkyl group can independently and optionally have at least one substituent R Y1a It is replaced with, or (R Y11 and R Y12 ), (R Y12 and R Y13 ), (R Y13 and R Y14 ), or (R Y14 and R Y15 ) together with the atom to which they are bonded, C 3-10 Cycloalkyl, C 3-10 A 4-12 membered heterocyclyl ring, a 6-12 membered aryl ring, or a 4-12 membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from cycloalkenyl, nitrogen, oxygen, and optionally oxidized sulfur, and optionally comprising at least one substituent R Y1a It has been replaced with, Each R Y1a These are independently hydrogen, halogen, and -C 1-6 Alkyl, -NHC 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -OH, -CN, -CONH2, -COCH3, -OC 1-6 It is alkyl or -NO2.

[0031] In some embodiments, R Y11 and R Y15 It is hydrogen.

[0032] In some embodiments, R Y12 , R Y13 , and R Y14 One, two, or three of these are hydrogen. In further embodiments, R Y12 , R Y13 , and R Y14 is hydrogen, halogen, -C 1-6 Alkyl, -P(O)(C 1-6 Alkyl)2,-OH,-CN,-OC 1-6 Alkyl, -SC 1-6 Selected from alkyl or -NO2. In alternative further embodiments, (R Y12 and R Y13 ) together with the atoms to which they are bonded, form a 4- to 12-membered heterocyclyl ring containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur, or a 4- to 12-membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur, and optionally, at least one substituent R Y1a It has been replaced with.

[0033] In some embodiments, R Y12 and R Y14 is hydrogen, and R Y13 is halogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, or cycloalkynyl, heterocyclyl, -O-heterocyclyl, -CO-heterocyclyl, aryl, heteroaryl, -P(O)(C 1-6 Alkyl)2,-OH,-CN,-OC 1-6 Alkyl, -SC 1-6 Alkyl or -NO2, and the -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -OC 1-6 Alkyl, or -SC 1-6Each alkyl group can independently and optionally have at least one substituent R Y1a It has been replaced with.

[0034] In the embodiment of aspect 15, R 2A teeth, [ka] And, R Y11 , R Y12 , R Y13 , R Y14 , and R Y15 Each of these is independently hydrogen, halogen, oxo, and -C. 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, -O-heterocyclyl, -CO-heterocyclyl, aryl, heteroaryl, -P(O)(C 1-6 Alkyl)2,-OH,-CN,-OC 1-6 Alkyl, -SC 1-6 Alkyl or -NO2, and the -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -OC 1-6 Alkyl, or -SC 1-6 Each alkyl group can independently and optionally have at least one substituent R Y1a It has been replaced with, (R Y11 and R Y12 ), (R Y12 and R Y13 ), (R Y13 and R Y14 ), or (R Y14 and R Y15 ) together with the atom to which they are bonded, C 3-10 Cycloalkyl, C 3-10A 4-12 membered heterocyclyl ring, a 6-12 membered aryl ring, or a 4-12 membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from cycloalkenyl, nitrogen, oxygen, and optionally oxidized sulfur, and optionally comprising at least one substituent R Y1a It has been replaced with, Each R Y1a These are independently hydrogen, halogen, and -C 1-6 Alkyl, -NHC 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -OH, -CN, -CONH2, -COCH3, -OC 1-6 It is alkyl or -NO2.

[0035] In some embodiments, R Y11 , R Y12 , R Y13 , R Y14 , and R Y15 Each of these is independently hydrogen, halogen, and -C. 1-6 Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OH, -CN, -OC 1-6 Alkyl, -SC 1-6 Alkyl or -NO2, and the -C 1-6 Alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl each independently and optionally have at least one substituent R Y1a It has been replaced with, (R Y11 and R Y12 ), (R Y12 and R Y13 ), (R Y13 and R Y14 ), or (R Y14 and R Y15) together with the atoms to which they are bonded, form a 5-6 membered heterocyclyl ring, a 6-12 membered aryl ring, or a 5-6 membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur, and optionally at least one substituent R Y1a It has been replaced with, Each R Y1a These are independently hydrogen, -CN, halogen, and -C 1-6 Alkyl, -OC 1-6 It is alkyl or -OH.

[0036] In some embodiments, R Y11 , R Y12 , R Y13 , R Y14 , and R Y15 Each of these is independently hydrogen, F, -CN, pyrazolyl, and -C. 1-6 Alkyl, cyclopropanyl, piperidinyl, or tetrahydropyranyl, wherein the pyrazolyl, -C 1-6 Alkyl, cyclopropanyl, piperidinyl, or tetrahydropyranyl each independently and optionally has at least one substituent R Y1a It has been replaced with, Each R Y1a These are independently hydrogen, -CN, F, and -C 1-6 Alkyl, -OC 1-6 It is alkyl or -OH.

[0037] In the embodiment of aspect 15, R 2A teeth, [ka] That is the case.

[0038] In the embodiment of aspect 15, R 2A teeth, [ka] And, RY11 , R Y13 , R Y14 , and R Y15 Each of these is independently hydrogen, halogen, and -C. 1-6 Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OH, -CN, -OC 1-6 Alkyl, -SC 1-6 Alkyl or -NO2, and the -C 1-6 Alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl each independently and optionally have at least one substituent R Y1a It has been replaced with, (R Y13 and R Y14 ) or (R Y14 and R Y15 ) together with the atoms to which they are bonded, form a 5-6 membered heterocyclyl ring, a 6-12 membered aryl ring, or a 5-6 membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur, and optionally at least one substituent R Y1a It has been replaced with, Each R Y1a These independently produce hydrogen, -CN, halogen, and -C. 1-6 Alkyl, -OC 1-6 It is alkyl or -OH.

[0039] In some embodiments, R Y11 , R Y13 , R Y14 , and R Y15 Each of these is independently hydrogen, F, -CN, pyrazolyl, and -C. 1-6 Alkyl, cyclopropanyl, piperidinyl, or tetrahydropyranyl, wherein the pyrazolyl, -C 1-6 Alkyl, cyclopropanyl, piperidinyl, or tetrahydropyranyl each independently and optionally has at least one substituent R Y1a It has been replaced with, Each R Y1aThese are independently hydrogen, -CN, F, and -C 1-6 Alkyl, -OC 1-6 It is alkyl or -OH.

[0040] In some embodiments, R Y11 , R Y13 , R Y14 , and R Y15 Each of these is independently hydrogen, F, -CN, pyrazolyl, and -C. 1-6 Alkyl, cyclopropanyl, piperidinyl, or tetrahydropyranyl, wherein the pyrazolyl, -C 1-6 Alkyl, cyclopropanyl, piperidinyl, or tetrahydropyranyl each independently and optionally has at least one substituent R Y1a It has been replaced with, Each R Y1a These are independently hydrogen, -CN, F, and -C 1-6 Alkyl, -OC 1-6 It is alkyl or -OH.

[0041] In the embodiment of aspect 15, R 2A teeth, [ka] Selected from.

[0042] Appearance 16. Each R Y1 These are independent of F and -C 1-6 Alkyl, aryl, heteroaryl, -P(O)(CH3)2, -OH, -CN, or -OC 1-6 Alkyl, and the -C 1-6 Alkyl, aryl, heteroaryl, or -OC 1-6 Each alkyl group can independently and optionally have at least one substituent R Y1a It has been replaced with, Each R Y1a These are independent of F and -C 1-6 Alkyl, -OH, -CN, or -OC 1-6 The compound according to embodiment 15, which is alkyl.

[0043] Appearance 17. R 2A However, methyl, [ka] [ka] [ka] A compound according to any one of embodiments 1 to 11, selected from the above.

[0044] Appearance 18(a).R 4A and R 4B However, they are different, and each is independent of hydrogen, deuterium, halogen, and -C. 1-6 Alkyl or deuterated C 1-6 It is alkyl, and carbon atom R 4A and R 4B A compound according to any one of embodiments 1 to 17, wherein the atoms bond to form an S or R configuration.

[0045] In this embodiment, R 4A is hydrogen or deuterium, and R 4B is methyl or -CD3. In the embodiment, R 4A is hydrogen, and R 4B It is methyl.

[0046] In this embodiment, R 4A is hydrogen or deuterium, and R 4B It is methyl or -CD3, and carbon atom R 4A and R 4B They combine to form an S configuration. In this embodiment, R 4A is hydrogen, and R 4B It is methyl, and carbon atom R 4A and R 4B They combine to form an S configuration.

[0047] In this embodiment, R 4A is hydrogen or deuterium, and R 4BIt is methyl or -CD3, and carbon atom R 4A and R 4B They combine to form an R configuration. In this embodiment, R 4A is hydrogen, and R 4B It is methyl, and carbon atom R 4A and R 4B They combine to form an R configuration.

[0048] Appearance 18.R 4A and R 4B However, they may be the same or different, and each can be independently hydrogen, halogen, or -C. 1-6 Alkyl, and the -C 1-6 Each alkyl group independently and optionally has at least one substituent R 44a It has been replaced with, Each R 44a These independently produce hydrogen, halogen, and -C. 1-6 Alkyl, -C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OC 1-6 Alkyl, -COC 1-6 Alkyl, or -CO2C 1-6 A compound according to any one of embodiments 1 to 17, wherein the compound is alkyl.

[0049] Appearance 19. R 4A and R 4B However, they are different, and each is independent of hydrogen, halogen, or -C. 1-6 Alkyl, and the -C 1-6 Each alkyl group independently and optionally has at least one substituent R 44a It has been replaced with, Each R 44a These independently produce hydrogen, halogen, and -C. 1-6 Alkyl, -C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OC 1-6 Alkyl, -COC 1-6 Alkyl, or -CO2C 1-6 A compound according to any one of embodiments 1 to 17, wherein the compound is alkyl.

[0050] Appearance 20. R 4A and R 4B However, they are different, and each is independent of hydrogen or -C. 1-6 Alkyl, and the -C 1-6 Each alkyl group independently and optionally has at least one substituent R 44a It has been replaced with, Each R 44a These independently produce hydrogen, halogen, and -C. 1-6 Alkyl, -C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OC 1-6 Alkyl, -COC 1-6 Alkyl, or -CO2C 1-6 A compound according to any one of embodiments 1 to 17, wherein the compound is alkyl.

[0051] Appearance 21. R 4A and R 4B However, they are different, and each is independent of hydrogen or -C. 1-6 Alkyl, and the -C 1-6 Each alkyl group independently and optionally has at least one substituent R 44a It is substituted with carbon atom R 4A and R 4B They combine to form an S or R configuration, Each R 44a These independently produce hydrogen, halogen, and -C. 1-6 Alkyl, -C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OC 1-6 Alkyl, -COC 1-6 Alkyl, or -CO2C 1-6 A compound according to any one of embodiments 1 to 17, wherein the compound is alkyl.

[0052] Appearance 22. R 4A However, it is hydrogen, R 4B However, -C 1-6 Alkyl, and the -C 1-6 Each alkyl group independently and optionally has at least one substituent R 44a It is substituted with carbon atom R 4A and R 4B They combine to form an S configuration, Each R 44a These independently produce hydrogen, halogen, and -C. 1-6 Alkyl, -C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OC 1-6 Alkyl, -COC 1-6 Alkyl, or -CO2C 1-6 A compound according to any one of embodiments 1 to 17, wherein the compound is alkyl.

[0053] Appearance 23. R 4B However, it is hydrogen, R 4A However, -C 1-6 Alkyl, and the -C 1-6 Each alkyl group independently and optionally has at least one substituent R 44a It is substituted with carbon atom R 4A and R 4B They combine to form an R configuration, Each R 44a These independently produce hydrogen, halogen, and -C. 1-6 Alkyl, -C 1-6 Haloalkyl, -C2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OC 1-6 Alkyl, -COC 1-6 Alkyl, or -CO2C 1-6 A compound according to any one of embodiments 1 to 17, wherein the compound is alkyl.

[0054] In the embodiment of aspect 23, the compound has formula (IV-1). [ka]

[0055] Appearance 24. R 4A However, hydrogen, and R 4B is-C 1-6 Alkyl, and the -C 1-6 Each alkyl group independently and optionally has at least one substituent R 44a It has been replaced with, Each R 44a These independently produce hydrogen, halogen, and -C. 1-6 Alkyl, -C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OC 1-6 Alkyl, -COC 1-6 Alkyl, or -CO2C 1-6 A compound according to any one of embodiments 1 to 17, wherein the compound is alkyl.

[0056] Appearance 25. R 4C However, hydrogen, halogen, or -C 1-6 Alkyl, and the -C 1-6 Each alkyl group independently and optionally has at least one substituent R 44d It has been replaced with, Each R 44dThese independently produce hydrogen, halogen, and -C. 1-6 Alkyl, -C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OC 1-6 Alkyl, -COC 1-6 Alkyl, or -CO2C 1-6 A compound according to any one of embodiments 1 to 24, wherein the compound is alkyl.

[0057] Appearance 26.R 4C The compound according to any one of embodiments 1 to 24, wherein the compound is hydrogen.

[0058] Appearance 27. R 4D However, the aryl or heteroaryl is an aryl or heteroaryl, and each of the aryl or heteroaryl is independently and optionally has at least one substituent R 44e It has been replaced with, Each R 44e These are independent of halogen and -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -CN, -NO2, -OR 444d , -SO2R 444d , -COR 444d , -CO2R 444d ,-CONR 444d R 444e -C(=NR 444d )NR 444e R 444f , -NR 444d R 444e , -NR 444d COR 444e , -NR 444d CONR 444e R 444f , -NR 444d CO2R 444e , -NR 444d SONR 444e R 444f -SO2NR 444e R 444f -SO2NR444e COR 444f , or -NR 444d SO2R 444e and -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Each of the alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, and heteroaryl compounds can independently and optionally have at least one substituent R N It has been replaced with, R 444d , R 444e , and R 444f Each of them independently produces hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl-C 1-6 Haloalkyl, -COC 1-6 Alkyl, or -CO2C 1-6 It is alkyl, R N However, each is independent of hydrogen, halogen, and -C. 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OC 1-6 Alkyl, -C 1-6 Haloalkyl, -COC 1-6 Alkyl, or -CO2C 1-6 A compound according to any one of embodiments 1 to 26, wherein the compound is alkyl.

[0059] Appearance 28. R 4D However, it is an aryl, and each of the aryl or heteroaryl independently optionally has at least one substituent R 44e It has been replaced with, Each R 44e These are independent of halogen and -C 1-6 Alkyl, -CN, -NO2, -OR 444d , -SO2R444d , -COR 444d , -CO2R 444d ,-CONR 444d R 444e , -NR 444d R 444e , or -SO2NR 444e R 444f and -C 1-6 Each alkyl group may independently and optionally have at least one substituent R N It has been replaced with, R 444d , R 444e , and R 444f Each of them independently produces hydrogen, halogen, and -C. 1-6 Alkyl, -CN, -NO2, -OC 1-6 Alkyl, -C 1-6 Haloalkyl, -COC 1-6 Alkyl, or -CO2C 1-6 It is alkyl, R N However, each is independent of hydrogen, halogen, and -C. 1-6 Alkyl, -CN, -NO2, -OC 1-6 Alkyl, -C 1-6 Haloalkyl, -COC 1-6 Alkyl, or -CO2C 1-6 A compound according to any one of embodiments 1 to 26, wherein the compound is alkyl.

[0060] Appearance 29. R 4D However, the phenyl is phenyl, and the phenyl optionally has at least one substituent R 44e It has been replaced with, Each R 44e These are independent of halogen and -C 1-6 Alkyl, -CN, -NO2, -OR 444d , -SO2R 444d , -COR 444d , -CO2R 444d ,-CONR 444d R 444e , -NR 444d R 444e , -SO2R 444d , or -SO2NR 444e R 444fand -C 1-6 Each alkyl group may independently and optionally have at least one substituent R N It has been replaced with, R 444d , R 444e , and R 444f Each of them independently produces hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl-C 1-6 Haloalkyl, -COC 1-6 Alkyl, or -CO2C 1-6 It is alkyl, R N However, each is independent of hydrogen, halogen, and -C. 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OC 1-6 Alkyl, -C 1-6 Haloalkyl, -COC 1-6 Alkyl, or -CO2C 1-6 A compound according to any one of embodiments 1 to 26, wherein the compound is alkyl.

[0061] Appearance 30.R 4D but, [ka] The compound according to any one of embodiments 1 to 26.

[0062] Appearance 31. R 1 However, hydrogen, -C 1-6 Alkyl, heterocyclyl, heteroaryl, or aryl, and the -C 1-6 Alkyl, heterocyclyl, heteroaryl, or aryl each independently and optionally has at least one substituent R 11a It has been replaced with, Each R 11aThese independently produce hydrogen, halogen, oxo, and -C. 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OR 1a , -COR 1a , -CO2R 1a ,-CONR 1a R 1b , -NR 1a R 1b , -NR 1a COR 1b , -NR 1a CONR 1b R 1c , or -NR 1a CO2R 1b and -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl each independently and optionally has at least one substituent R 1d It has been replaced with, R 1a , R 1b , and R 1c Each of them independently produces hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl, and the -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl each independently and optionally has at least one substituent R 1d It has been replaced with, Each R 1d These independently produce hydrogen, halogen, oxo, -CN, -NO2, and -C. 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C1-6 Haloalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -OC 1-6 Alkyl, -COC 1-6 Alkyl, or -CO2C 1-6 A compound according to any one of embodiments 1 to 30, which is alkyl.

[0063] In the embodiment of aspect 31, R 1 is -C 1-6 Alkyl, deuterated-C 1-6 Alkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, thietan 1,1-dioxydyl, pyrazolyl, isoxazolyl, oxazolyl, or thiazolyl, and the -C 1-6 Alkyl or deuterated C 1-6 Each alkyl group is independently and optionally substituted with at least one substituent selected from hydrogen, deuterium, -CN, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, thietanyl 1,1-dioxydyl, pyrazolyl, isoxazolyl, oxazolyl, and thiazolyl, wherein each of the oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, thietanyl 1,1-dioxydyl, pyrazolyl, isoxazolyl, oxazolyl, or thiazolyl is optionally substituted with -C 1-6 It is substituted with at least one substituent selected from alkyl groups.

[0064] Appearance 32.R 1 However, hydrogen, methyl, -CH2CN, -CH2OCH3, -CH2CH3, -CH2CH3CN, -CH2SO2CH3, -COCH3, -CH2OH, -CH2CH2OCH3, [ka] The compound according to any one of embodiments 1 to 30.

[0065] In the embodiment of aspect 32, R 1 This is methyl, -CD3, or -CH2CN.

[0066] In the embodiment of aspect 32, R 1 It is methyl.

[0067] In the embodiment of aspect 32, R 1 It is -CD3.

[0068] Appearance 33.R 3 The compound according to any one of embodiments 1 to 32, wherein the compound is hydrogen.

[0069] Appearance 34.R 5 The compound according to any one of embodiments 1 to 33, wherein the compound is hydrogen.

[0070] Appearance 35(a).R 6 However, hydrogen, F, and optionally -C substituted with at least one halogen. 1-6 It is an alkyl group or a methyl deuterated group, preferably R 6 The compound according to any one of embodiments 1 to 34, wherein is hydrogen, F, methyl, -CD3, -CF3, -CHF2, or -CH2F.

[0071] Appearance 35. R 6 However, -C is substituted with hydrogen, F, or at least one halogen of any choice. 1-6 It is alkyl, preferably R 6 However, it is F, -CH3, -CH2F, -CHF2, or -CF3, and more preferably R 6 The compound according to any one of embodiments 1 to 34, wherein the compound is -CH3 or -CF3.

[0072] Appearance 36.R 6 However, it is methyl deuterated, preferably R 6 The compound according to any one of embodiments 1 to 34, wherein the compound is -CD3.

[0073] In the embodiment of aspect 36, R 6 It is methyl.

[0074] In the embodiment of aspect 36, R 6 It is -CD3.

[0075] Appearance 37.R 7 The compound according to any one of embodiments 1 to 36, wherein the compound is hydrogen.

[0076] Appearance 38.R 1 However, deuterated C 1-6 It is alkyl, R 4A , R 4B Each of them independently produces deuterium or deuterated C 1-6 A compound that is alkyl and is described in any one of embodiments 1 to 37.

[0077] Appearance 39.R 1 However, it is -CD3, and R 4A , R 4B A compound according to any one of embodiments 1 to 37, wherein each of them is independently deuterium or -CD3.

[0078] Appearance 40.R 1 However, it is -CD3, and R 4A However, D is R 4B The compound according to any one of embodiments 1 to 37, wherein the compound is -CD3.

[0079] Embodiment 41. The compound according to any one of Embodiments 1 to 40, wherein the compound of formula (I) is selected from the following. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0080] In the embodiment of aspect 41, the compound is as follows: [ka] [ka] Alternatively, it may be selected from its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0081] Appearance 42. Compounds of the following formula, [ka] or its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0082] Embodiment 43. A pharmaceutical composition comprising a therapeutically effective amount of a compound disclosed herein (for example, a compound described in any one of Embodiments 1 to 42), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0083] Embodiment 44. A method for treating or preventing a disorder or disease in response to inhibition of PI3Kα activity in a subject (for example, a subject requiring the following treatment or prevention), comprising administering to the subject a compound disclosed herein (for example, a compound described in any one of Embodiments 1 to 42, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for example, a therapeutically effective amount of a compound disclosed herein, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof).

[0084] In one embodiment of the 44th model, the subject has PI3Kα containing at least one of the following mutations: H1047R, E542K, and E545K.

[0085] In one embodiment of aspect 44, the disorder or disease is an inflammatory disorder, an autoimmune disease, or cancer.

[0086] In one embodiment of aspect 44, the disorder or disease is cancer.

[0087] In one embodiment of aspect 44, the disorder or disease is selected from the group consisting of endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, prostate cancer, cervical cancer, glioblastoma, pancreatic cancer, bladder cancer, CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, spinal cord / skeletal abnormalities / scoliosis), and PROS syndrome (PIK3CA-associated overgrowth syndrome). [Modes for carrying out the invention]

[0088] The following terms have the meanings set forth throughout this specification.

[0089] Unless otherwise defined elsewhere in this specification, all other technical and scientific terms used herein have meanings that are generally understood by those skilled in the art to which this invention pertains.

[0090] The following terms have the meanings set forth throughout this specification:

[0091] As used herein, including in the attached claims, singular words such as "a," "an," and "the" refer to multiple objects corresponding to them unless the context clearly indicates otherwise.

[0092] The term "or" means "and / or" and is used interchangeably unless the context explicitly indicates otherwise.

[0093] The term "hydrogen" includes protium, tritium, and deuterium. Any hydrogen can be replaced by tritium or deuterium. In preferred embodiments, hydrogen is protium.

[0094] The term "alkyl" refers to a hydrocarbon group selected from linear and branched saturated hydrocarbon groups containing 1 to 18 carbon atoms, for example, 1 to 12, even 1 to 10, even 1 to 8, or 1 to 6, or 1 to 4 carbon atoms. 1-6 Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or s-butyl ("s-Bu"), 1,1-dimethylethyl or t-butyl ("t-Bu"), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl groups.

[0095] The term "propyl" refers to 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr").

[0096] The term "butyl" refers to 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or s-butyl ("s-Bu"), 1,1-dimethylethyl or t-butyl ("t-Bu").

[0097] The term "pentyl" refers to 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, and 2-methyl-1-butyl.

[0098] The term "hexyl" refers to 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl.

[0099] The term "halogen" refers to fluoro(F), chloro(Cl), bromo(Br), and iodine(I).

[0100] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by one or more halogen atoms, such as fluoro, chloro, bromo, and iodine. An example of a haloalkyl is halo C. 1-8 Alkyl, Halo C 1-6 Alkyl, or halo C 1-4 Alkyl groups are examples, but are not limited to -CF3, -CH2Cl, -CH2CF3, -CHCl2, -CF3, etc.

[0101] The term "alkenyl" refers to a hydrocarbon group selected from linear and branched hydrocarbon groups containing at least one C=C double bond and 2 to 18 carbon atoms, for example, 2 to 8 or even 2 to 6.2-6 Examples of alkenyls include, but are not limited to, ethenyl or vinyl, propa-1-enyl, propa-2-enyl, 2-methylpropa-1-enyl, buta-1-enyl, buta-2-enyl, buta-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, hexa-1-enyl, hexa-2-enyl, hexa-3-enyl, hexa-4-enyl, and hexa-1,3-dienyl groups.

[0102] The term "alkynyl" refers to a hydrocarbon group selected from linear and branched hydrocarbon groups containing at least one C≡C triple bond and 2 to 18 carbon atoms, for example, 2 to 8 or even 2 to 6. 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0103] The term "cycloalkyl" refers to hydrocarbon groups selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups.

[0104] For example, a cycloalkyl group may contain 3 to 12 carbon atoms, for example, 3 to 10, even more for example, 3 to 8, even more for example, 3 to 6, 3 to 5, or 3 to 4 carbon atoms. Furthermore, for example, a cycloalkyl group may be selected from monocyclic groups containing 3 to 12 carbon atoms, for example, 3 to 10, even more for 3 to 8, or 3 to 6 carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups. Saturated monocyclic cycloalkyl groups (e.g., C 3-8Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In preferred embodiments, the cycloalkyl group includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and consists of 3 to 6 carbon atoms (C 3-6 A monocyclic ring containing a cycloalkyl group (abbreviated as cycloalkyl). Examples of bicyclic cycloalkyl groups include those having 7 to 12 ring atoms, arranged as fused bicyclic rings selected from the [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems, or as bridging bicyclic rings selected from bicyclo[1.1.1]pentane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. Further examples of bicyclic cycloalkyl groups include those arranged as bicyclic rings selected from the [5,6] and [6,6] ring systems.

[0105] The term "condensed cycloalkyl" refers to a bicyclic cycloalkyl group as defined herein, which is saturated and formed by two or more rings sharing two adjacent atoms.

[0106] The term "crosslinked cycloalkyl" refers to a cyclic structure formed by two rings containing carbon atoms and sharing two non-adjacent atoms. The term "7-12 membered crosslinked cycloalkyl" refers to a cyclic structure formed by two rings containing 7-12 carbon atoms and sharing two non-adjacent atoms.

[0107] The term "cycloalkenyl" refers to a non-aromatic cyclic alkyl group of 3 to 10 carbon atoms having a monocyclic or polycyclic structure and at least one double bond, preferably 1 to 2 double bonds. In one embodiment, the cycloalkenyl is cyclopentenyl or cyclohexenyl, 1-cyclopento-1-enyl, 1-cyclopento-2-enyl, 1-cyclopento-3-enyl, 1-cyclohexa-1-enyl, 1-cyclohexa-2-enyl, 1-cyclohexa-3-enyl, cyclohexadienyl, or condensed cycloalkenyl, preferably cyclohexenyl.

[0108] The term "condensed cycloalkenyl" refers to a bicyclic cycloalkyl group as defined herein, which is formed by two or more rings sharing two adjacent atoms and containing at least one double bond.

[0109] The term "cycloalkynyl" refers to a non-aromatic cycloalkyl group consisting of 5 to 10 carbon atoms, having a single or multiple rings and at least one triple bond. For example, cycloalkynyls are condensed cycloalkynyls.

[0110] The term "condensed cycloalkynyl" refers to a bicyclic cycloalkyl group as defined herein, which is formed by two or more rings sharing two adjacent atoms and containing at least one triple bond.

[0111] Examples of condensed cycloalkyls, condensed cycloalkenyls, or condensed cycloalkynyls include bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[3.3.0]octyl, bicyclo[4.2.0]octyl, decalin, and benzo3- to 8-membered cycloalkyls, benzoC 4-6 Examples include, but are not limited to, cycloalkenyl, 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetralyl, and 1,4-dihydronaphthyl. Preferred embodiments are 8-9 membered condensed rings, which refer to cyclic structures containing 8-9 ring atoms in the above examples.

[0112] When used alone or in combination with other terms, the term “aryl” refers to a base selected from the following: Five- and six-membered carbon-cyclic aromatic rings, such as phenyl; Bicyclic ring systems such as 7-12 membered bicyclic ring systems, in which at least one ring is a carbon ring and an aromatic ring, for example naphthyl and indanyl and A tricyclic ring system, such as a 10-15 membered tricyclic ring system, in which at least one ring is a carbocyclic ring and an aromatic ring, and which contains a group selected from tricyclic ring systems, for example, fluorenyl.

[0113] The terms “aromatic hydrocarbon ring” and “aryl” are used interchangeably throughout this disclosure. The group can be bonded to the rest of the molecule via either ring. In some embodiments, the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C 5-10 (It is an aryl ring). Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphtho-1-yl, naphtho-2-yl, anthracenyl, phenantrenyl, etc. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphtho-1-yl or naphtho-2-yl), a phenyl ring, or a bicyclic condensed aryl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0114] Specifically, the term “bicyclic fused aryl” refers to a bicyclic aryl ring as defined herein. Typical bicyclic fused aryls are naphthalene or [ka] That is the case.

[0115] The term "heteroaryl" refers to a group selected from the following: A 5, 6, or 7-membered aromatic monocyclic ring comprising at least one heteroatom selected from nitrogen (N), sulfur (S), and oxygen (O), e.g., 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, or in some embodiments 1 to 2 heteroatoms, with the remaining ring atoms being carbon; A 7-12 membered bicyclic ring comprising at least one heteroatom selected from N, O, and S, e.g., 1-4 heteroatoms, or in some embodiments 1-3 heteroatoms, or in other embodiments 1 or 2 heteroatoms, the remaining ring atoms being carbon, at least one ring being aromatic, and at least one heteroatom present in the aromatic ring, and An 11-14 membered tricyclic ring comprising at least one heteroatom (e.g., 1-4, or in some embodiments 1-3, or in other embodiments 1 or 2) selected from N, O, and S, the remaining ring atoms being carbon, at least one ring being aromatic, and the at least one heteroatom located within an aromatic ring.

[0116] If the total number of S and O atoms in a heteroaryl group is greater than one, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in a heteroaryl group is not greater than two. In some embodiments, the total number of S and O atoms in an aromatic heterocycle is not greater than one. If a heteroaryl group contains more than one heteroatom ring member, these heteroatoms may be the same or different. Nitrogen atoms in the ring(s) of a heteroaryl group may be oxidized to form N-oxides.

[0117] For example, heteroaryls are bicyclic condensed heteroaryls or benzo-condensed heteroaryls.

[0118] More specifically, the term “bicyclic condensed heteroaryl” refers to a 7- to 12-membered, preferably 7- to 10-membered, more preferably 9 or 10-membered condensed bicyclic heteroaryl ring as defined herein. Typically, bicyclic condensed heteroaryls are 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 6-membered, or 6-membered / 7-membered bicyclic. The groups can be bonded to the rest of the molecule via either ring.

[0119] Representative examples of bicyclic condensed heteroaryl groups include the following groups: benzoisoxazolyl, benzodiazolyl, benzofuranil, benzoflazanil, benzofuryl, benzimidazolyl, benzoisothiazolyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzothiophenyl, benzotriazolyl, benzooxadiazolyl, benzoxazolyl, phlopyridinyl, phlopyrolyl, imidazopyridinyl, imidazopyridyl, imidazothiazolyl, indazolyl, indolidinyl, indolyl, isobenzofuryl, i This includes, but is not limited to, soindolyl, isoquinolinyl (or isoquinolyl), naphthilidinyl, phthalazinyl, pteridinyl, purinyl, pyrazinopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridyl, pyrazolotriazinyl, pyridazolopyridyl, pyrrolopyridinyl, quinazolinyl, quinolinyl (or quinolyl), quinoxalinyl, thiazolopyridyl, thienopyrazinyl, thienopyrazolyl, thienopyroryl, thienotienyl, or triazolopyridyl.

[0120] The term "benzo-condensed heteroaryl" is a bicyclic condensed heteroaryl in which a monocyclic heteroaryl ring with 5 to 7 members (preferably 5 or 6 members) is condensed to a benzene ring, as defined herein.

[0121] The terms “aromatic heterocycle” and “heteroaryl” are used interchangeably throughout this disclosure. The group can be bonded to the rest of the molecule via either ring. In some embodiments, a monocyclic or bicyclic aromatic heterocycle has 5, 6, 7, 8, 9, or 10 ring members, including 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O), with the remaining ring members being carbon. In some embodiments, a monocyclic or bicyclic aromatic heterocycle is a monocyclic or bicyclic ring containing 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, a monocyclic or bicyclic aromatic heterocycle is a 5- to 6-membered heteroaryl ring that is monocyclic and has 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocycle is an 8- to 10-membered heteroaryl ring that is bicyclic and has one or two heteroatom ring members independently selected from nitrogen, sulfur, and oxygen.

[0122] Examples of heteroaryl groups or monocyclic or bicyclic aromatic heterocycles include (counting from the bond position assigned priority 1) pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), synnolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, or 1,3,4-thia) Diazolyl), tetrazolyl, thienyl (e.g., thien-2-yl, thien-3-yl), triazinyl, benzothienyl, furyl or furanyl, benzofuryl, benzimidazolyl, indolyl, isoindolyl, oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, or 1,3,4-oxadiazolyl), phthalazinyl, pyrazinyl, pyridadinyl, pyrrolyl, triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl, or 1 ,3,4-triazolyl), quinolinyl, isoquinolinyl, pyrazolyl, pyrrolopyridinyl (e.g., 1H-pyrrolo[2,3-b]pyridinyl-5-yl), pyrazolopyridinyl (e.g., 1H-pyrazolo[3,4-b]pyridinyl-5-yl), benzoxazolyl (e.g., benzo[d]oxazole-6-yl), pteridinyl, purinyl, 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, 1-thia-2,3- This includes, but is not limited to, diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl, 1-thia-3,4-diazolyl, flazanyl (e.g., flazan-2-yl, flazan-3-yl), benzoflazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinil, quinoxalinil, naphthilidinil, phlopyridinil, benzothiazolyl (e.g., benzo[d]thiazole-6-yl), and indazolyl (e.g., 1H-indazole-5-yl).

[0123] "Heterocyclyl," "heterocycle," or "heterocyclic" are interchangeable and refer to a non-aromatic heterocyclyl group containing one or more heteroatoms selected from nitrogen, oxygen, silicon, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, and including monocyclic and fused rings, i.e., monocyclic heterocyclyls and fused heterocyclic groups, bridging heterocyclic groups, or spiroheterocyclic groups.

[0124] The term "unsaturated heterocyclic ring" refers to a "heterocyclyl," "heterocyclic ring," or "heterocyclic formula" that contains at least one carbon-carbon double bond. For example, a heterocyclyl is, [ka] Includes.

[0125] As used herein, the term “optionally oxidized sulfur” refers to S, SO, or SO2.

[0126] The term "monocyclic heterocyclyl" refers to a monocyclic group in which at least one ring member (e.g., 1 to 3 heteroatoms, 1 or 2 heteroatoms (or more)) is a heteroatom selected from nitrogen, oxygen, silicon, or optionally oxidized sulfur. The heterocycle can be saturated or partially saturated (i.e., it does not form a fully conjugated pi-electron system).

[0127] Examples of monocyclic 4- to 9-membered heterocyclyl groups include pyrrolidine-1-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, imidazolidine-2-yl, imidazolidine-4-yl, pyrazolidine-2-yl, pyrazolidine-3-yl, piperidine-1-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, 2,5-piperazinyl, pyranyl, morpholinyl, morpholino, morpholin-2-yl, morpholin-3-yl, oxylanil, and aziridine. -1-yl, aziridin-2-yl, azocan-1-yl, azocan-2-yl, azocan-3-yl, azocan-4-yl, azocan-5-yl, thyranil, azetidine-1-yl, azetidine-2-yl, azetidine-3-yl, oxetanil, thietanil, 1,2-dithietanil, 1,3-dithietanil, dihydropyridinil, tetrahydropyridinil, thiomorpholinil, thioxanil, piperazinil, homopiperazinil, homopiperidinil, azepan-1-yl , azepan-2-yl, azepan-3-yl, azepan-4-yl, oxepanil, thiepanil, 1,4-oxathianil, 1,4-dioxepanil, 1,4-oxathiepanil, 1,4-oxazepanil, 1,4-dithiepanil, 1,4-thiazepanil, and 1,4-diazepanil, 1,4-dithianil, 1,4-azathanil, oxazepinyl, diazepinyl, thiazepinyl, dihydrothienyl, dihydropyranil, dihydrofuranil, tetrahydrofuranil, tetrahydro This includes, but is not limited to, dorothienyl, tetrahydropyranil, tetrahydrothiopyranil, 1-pyrrolinil, 2-pyrrolinil, 3-pyrrolinil, indolinyl, 2H-pyranil, 4H-pyranil, 1,4-dioxanil, 1,3-dioxolanil, pyrazolinil, pyrazolidinil, dithianil, dithiolanil, pyrazolidinil, imidazolinil, pyrimidinol, 1,1-dioxo-thiomorpholinil, oxazolidinil, or oxazolidine-4-yl.

[0128] The term "condensed heterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclyl group, where each ring in the system contains one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, and shares adjacent atom pairs (carbon and carbon, or carbon and nitrogen atoms) with another ring whose remaining ring members are carbon. One or more rings of the condensed heterocyclic group may contain one or more double bonds, but the condensed heterocyclic group does not have a fully conjugated pi electron system. Preferably, condensed heterocyclyls are 6- to 14 members, more preferably 7- to 12 members, or 7- to 10 members. Depending on the number of member rings, condensed heterocyclyls are divided into bicyclic, tricyclic, tetracyclic, or polycyclic condensed heterocyclyls. The group can be bonded to the rest of the molecule via any of the rings.

[0129] More specifically, the term “bicyclic condensed heterocyclyl” refers to a 7- to 12-membered, preferably 7- to 10-membered, more preferably 9 or 10-membered condensed heterocyclyl as defined herein, comprising two condensed rings and containing 1 to 4 heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members. Typically, bicyclic condensed heterocyclyls are 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 6-membered, or 6-membered / 7-membered bicyclic condensed heterocyclyls. Representative examples of (bicyclic) condensed heterocycles include the following groups: octahydrocyclopenta[c]pyrrole, octahydropyrrolo[3,4-c]pyrrolyl, octahydroisoindolyl, isoindlinyl, octahydro-benzo[b][1,4]dioxin, indlinyl, isoindlinyl, benzopyranil, dihydrothiazolopyrimidinyl, tetrahydroquinolyl, tetrahydroisoquinolyl (or tetrahydroisoquinolinyl), dihydrobenzofuranil, dihydrobenzoxazinyl, dihydrobenzimidazolyl, tetrahydrobenzothienyl, tetrahydrobenzof This includes, but is not limited to, lanyl, benzodioxolyl, benzodioxonyl, chromanyl, clomenyl, octahydroclomenyl, dihydrobenzodioxynyl, dihydrobenzoxedinyl, dihydrobenzodioxypinyl, dihydrothienodiooxynyl, dihydrobenzoxazepinyl, tetrahydrobenzoxazepinyl, dihydrobenzoazepinyl, tetrahydrobenzoazepinyl, isochromanyl, chromanyl, or tetrahydropyrazolopyrimidinyl (e.g., 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl).

[0130] The term "benzo-condensed heterocyclyl" is a polycyclic (e.g., bicyclic) condensed heterocyclyl obtained by condensing a monocyclic or polycyclic (e.g., bicyclic) 4- to 14-membered heterocyclyl (e.g., 4- to 9-membered heterocyclyl, preferably 5- or 6-membered heterocyclyl) with a benzene ring, as defined herein.

[0131] The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic alkyl group, where each of the two rings in the system shares two cleaved atoms, with one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, and the remaining ring members being carbon. More specifically, a bridge with two bridgeheads contains 1 to 6 atoms selected from carbon, oxygen, nitrogen, and sulfur, with two heteroatoms (oxygen, nitrogen, and sulfur) not bonded to each other. One or more rings of the bridged heterocyclyl group may contain one or more double bonds, but none of the rings have a fully conjugated pi electron system. Preferably, bridged heterocyclyls are 6- to 14-membered, or 7- to 12-membered, more preferably 7- to 10-membered. Depending on the number of member rings, cross-linked heterocyclils are classified into bicyclic, tricyclic, tetracyclic, or polycyclic cross-linked heterocyclils, preferably bicyclic, tricyclic, or tetracyclic cross-linked heterocyclils, and more preferably bicyclic or tricyclic cross-linked heterocyclils. Typical examples of cross-linked heterocyclils include, but are not limited to, 2-azabicyclo[2.2.1]heptyl, azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.2.2]octyl, and 2-azabicyclo[3.3.2]decyl.

[0132] A "spiroheterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclyl having a ring bonded via one common carbon atom (referred to as a spiro atom), wherein the ring has one or more heteroatoms selected from the group consisting of N, O, S, SO, or SO2 heteroatoms as ring atoms, and the remaining ring atoms are C. Preferably, spiroheterocyclyls are 6- to 14 members, more preferably 7- to 10 members. Depending on the typical number of spiro atoms, spiroheterocyclyls are divided into monospiroheterocyclyls, dispiroheterocyclyls, or polyspiroheterocyclyls, preferably monospiroheterocyclyls or dispiroheterocyclyls, and more preferably 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocyclyls. Representative examples of spiroheterocyclils include, but are not limited to, 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[3.5]nonyl, 5-oxaspiro[2.4]heptyl, and 2-oxa-6-azaspiro[3.3]heptyl.

[0133] As disclosed herein, “N-linked heterocyclyl” refers to a heterocyclyl group that is linked to the rest of the molecule by a bond from the nitrogen atom of the heterocyclyl ring. “N-linked heterocyclyl containing 0, 1, or 2 additional heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members” refers to a heterocyclyl group that is linked to the rest of the molecule by a bond from the nitrogen atom of the heterocyclyl ring and contains 0, 1, or 2 additional heteroatoms in addition to the nitrogen atom linked to the rest of the molecule.

[0134] As disclosed herein, “C-linked heterocyclyl” refers to a heterocyclyl group that is bonded to the rest of the molecule by a bond from the carbon atoms of the heterocyclyl ring. As disclosed herein, “Si-linked heterocyclyl” refers to a heterocyclyl group that is bonded to the rest of the molecule by a bond from the silicon atoms of the heterocyclyl ring.

[0135] The term “at least one substituent” as disclosed herein includes, for example, 1 to 3 substituents, or even 1 to 4 substituents, as long as the theory of valence is satisfied. For example, “at least one substituent R” as disclosed herein d " refers to the R disclosed herein. d It includes 1 to 3 substituents selected from the list, and 1 to 4 substituents, such as 1 or 2.

[0136] The compounds disclosed herein may have chiral centers and therefore may exist as enantiomers. “Enantiomer” refers to two stereoisomers of a compound that are mirror images of each other and cannot be superimposed. If a compound disclosed herein has two or more chiral centers, they may also exist as diastereomers. Enantiomers and diastereomers belong to a broader classification of stereoisomers. All such possible stereoisomers are intended to be included, such as substantially pure decomposed enantiomers, their racemic mixtures, and mixtures of diastereomers. All stereoisomers of the compounds disclosed herein and / or their pharmaceutically acceptable salts are intended to be included. Unless otherwise specified, a reference to one isomer applies to any of the possible isomers. Whenever the isomer composition is not specified, all possible isomers are included.

[0137] The compounds disclosed herein also include deuterated compounds. The term “deuterated compound” refers to a compound in which one or more carbon-bonded hydrogens are replaced by one or more deuterium atoms. Similarly, the term “deuterated” is used herein to modify a chemical structure or organic group or radical in which one or more carbon-bonded hydrogens are replaced by one or more deuterium atoms, such as “deuterated alkyl,” “deuterated cycloalkyl,” “deuterated heterocycloalkyl,” “deuterated aryl,” “deuterated morpholinyl,” etc. For example, the term “deuterated alkyl” as defined above refers to an alkyl group as defined herein, in which at least one hydrogen atom bonded to carbon is replaced by deuterium. In a deuterated alkyl group, at least one carbon atom is bonded to deuterium, and it is possible for one carbon atom to be bonded to multiple deuterium atoms, and for multiple carbon atoms of an alkyl group to be bonded to deuterium atoms. “Deuterated” can be monosubstituted, disubstituted, polysubstituted, or complete substituted.

[0138] As used herein, the term “substantially pure” means that the target stereoisomer contains any other stereoisomer(s) in an amount of 35% by weight or less, e.g., 30% by weight or less, further e.g., 25% by weight or less, e.g., even further 20% by weight or less. In some embodiments, the term “substantially pure” means that the target stereoisomer contains any other stereoisomer(s) in an amount of 10% by weight or less, e.g., 5% by weight or less, e.g., 1% by weight or less.

[0139] Where a compound disclosed herein contains an olefinic double bond, unless otherwise specified, such double bond is intended to include both E and Z geometric isomers.

[0140] Where a compound disclosed herein includes a disubstituted cyclic ring system, the substituents found in such a ring system may adopt cis and trans configurations. Cis configuration means that both substituents are found on the upper side of the arrangement of the two substituents on the carbon, while trans configuration means they are on opposite sides. For example, a disubstituted cyclic ring system may be a cyclohexyl or cyclobutyl ring.

[0141] It may be advantageous to separate reaction products from each other and / or from the starting materials. The desired products from each step or series of steps are separated and / or purified to a desired degree of homogeneity (hereinafter, separated) by techniques common in the art. Typically, such separations include multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can include any number of methods, such as reversed-phase and normal-phase, size exclusion, ion exchange, high, medium, and low-pressure liquid chromatography methods and apparatus, small-scale analysis, simulated moving bed ("SMB") and preparative thin-layer or thick-layer chromatography, as well as small-scale thin-layer and flash techniques. Those skilled in the art will apply the technique that is most likely to achieve the desired separation.

[0142] A "diastereomer" refers to a stereoisomer of a compound that has two or more chiral centers, but these centers are not mirror images of each other. A mixture of diastereomers can be separated into their individual diastereomers based on their physicochemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional recrystallization. Enantiomers can be separated by converting the enantiomer mixture into a diastereomer mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Moscher acid chloride), separating the diastereomers, and converting the individual diastereoisomers into their corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers can also be separated by the use of a chiral HPLC column.

[0143] A single stereoisomer, for example, a substantially pure enantiomer, can be obtained by the resolution of a racemic mixture using methods such as the formation of a diastereomer with an optically active resolving agent (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, CH, et al. "Chromatographic resolution of enantiomers: Selective review." J. Chromatogr., 113(3)(1975): pp.283-302). The racemic mixture of the chiral compound of the present invention can be separated and isolated by any preferred method including (1) the formation of an ionic diastereomer salt using the chiral compound and separation by fractional crystallization or other methods; (2) the formation of a diastereomer compound using a chiral derivatization reagent, separation of the diastereomer, and conversion to a pure stereoisomer; and (3) the direct separation of substantially pure or concentrated stereoisomers under chiral conditions. Reference: Wainer, Irving W., Ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

[0144] The arrangement of diastereomers or enantiomer isomers can be determined by techniques including, but not limited to, the following: 1D- or 2D-NMR spectroscopy of the compound or its derivatives (e.g., Moscher esters), optical rotation and dispersion, circular dichroism spectroscopy, X-ray diffraction, and in silico calculations (e.g., QM or MMGBSA).

[0145] Some of the compounds disclosed herein may exist at different hydrogen bonding sites, known as tautomers. For example, compounds containing a carbonyl-CH2C(O)- group (keto form) may undergo tautomerism to form a hydroxyl-CH=C(OH) (enol form). Where applicable, both keto and enol forms are intended to be included individually and as mixtures thereof. For example, [ka] It undergoes tautomerism. [ka] This can form a compound, where A* and B* indicate the positions where substituents are attached to the pyrazole.

[0146] A "pharmaceutically acceptable salt" means a salt that, within the bounds of sound medical judgment, is suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, or allergic reactions, and that corresponds to a reasonable benefit / risk ratio. Pharmacologically acceptable salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting free base functional groups with suitable organic acids or acidic groups with suitable bases.

[0147] In addition, when the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid acid. Conversely, when the product is a free base, addition salts such as pharmaceutically acceptable addition salts can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, following conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize a variety of synthetic methods that can be used without excessive experimentation to prepare non-toxic, pharmaceutically acceptable addition salts.

[0148] As defined herein, “a pharmaceutically acceptable salt of the compound” includes salts of at least one compound of formula (I), and salts of stereoisomers of the compound of formula (I), such as salts of enantiomers and / or salts of diastereomers.

[0149] In this specification, the terms “administer,” “administer,” “treat,” and “treat” mean, when applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, the contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with an animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of cells includes the contact of a reagent with cells, as well as the contact of a reagent with a fluid, where the fluid comes into contact with the cells. The terms “administer” and “treat” also mean in vitro and ex vivo treatment, for example, with cells, reagents, diagnostics, conjugate compounds, or with another cell. In this specification, the term “subject” includes any living organism, preferably an animal, more preferably a mammal (e.g., rats, mice, dogs, cats, and rabbits), most preferably a human.

[0150] The terms “effective dose” or “therapeutic dose” refer to the amount of an active ingredient, such as a compound, that is sufficient to influence such treatment for a disease, disorder, or symptom when administered to a subject to treat a disease, or at least one of the clinical symptoms of a disease or disorder. “Therapeutic dose” may vary with the compound, the disease, disorder, and / or symptoms of the disease or disorder, the severity of the disease, disorder, and / or symptoms of the disease or disorder, the age of the subject being treated, and / or the weight of the subject being treated. An appropriate amount in any given case may be obvious to those skilled in the art or can be determined by customary experiment. In some embodiments, “therapeutic dose” is the amount of at least one compound disclosed herein and / or at least one stereoisomer thereof, and / or at least one pharmaceutically acceptable salt thereof, which is effective for “treatment” of a disease or disorder in a subject, as defined herein. In the case of combination therapy, “therapeutic dose” refers to the total amount of the combination substance for effective treatment of a disease, disorder, or condition.

[0151] Pharmaceutical compositions containing the compounds disclosed herein may be administered to subjects requiring them via oral, inhalation, rectal, parenteral, or topical administration. For oral administration, the pharmaceutical composition may be a conventional solid formulation such as tablets, powders, granules, or capsules; a liquid formulation such as water or oil suspension; or other liquid formulations such as syrups, solutions, or suspensions. For parenteral administration, the pharmaceutical composition may be a solution, aqueous solution, oil suspension concentrate, or lyophilized powder. Preferably, the formulation of the pharmaceutical composition is selected from tablets, coated tablets, capsules, suppositories, nasal sprays, or injections, more preferably tablets or capsules. The pharmaceutical composition may be a single dose in a precise dosage. In addition, the pharmaceutical composition may further contain additional active ingredients.

[0152] All formulations of the pharmaceutical compositions disclosed herein can be manufactured by conventional methods in the pharmaceutical field. For example, the active ingredient can be mixed with one or more excipients to produce the desired formulation. "Pharmacologically acceptable excipients" refers to conventional pharmaceutical carriers suitable for the desired pharmaceutical formulation, such as diluents, vehicles, such as water and various organic solvents; excipients, such as starch and sucrose; binders, such as cellulose derivatives, arginate, gelatin, and polyvinylpyrrolidone (PVP); wetting agents, such as glycerol; disintegrants, such as agar, calcium carbonate, and sodium bicarbonate; absorption enhancers, such as quaternary ammonium compounds; surfactants, such as hexadecanol; absorption carriers, such as kaolin and soap clay; and lubricants, such as talc, calcium stearate, magnesium stearate, and polyethylene glycol. In addition, the pharmaceutical composition further comprises other pharmaceutically acceptable excipients such as dispersants, stabilizers, thickeners, complexing agents, buffers, permeation enhancers, polymers, aromatic compounds, sweeteners, and dyes.

[0153] The term “disease” refers to any illness, discomfort, disorder, symptom, or adaptation, and may be interchangeable with the terms “disorder” or “condition.”

[0154] Throughout this specification and the following claims, unless contextually required, the term “comprise,” and variations such as “comprises” and “comprising,” are intended to identify the presence of a subsequent feature, but not to exclude the presence or addition of one or more other features. As used herein, the term “comprising” may be replaced by the terms “containing,” “including,” or, in some cases, “having.”

[0155] Throughout this specification and the following claims, "C n-m The term "C" indicates a range including the endpoint, where n and m are integers and represent the number of carbon atoms. For example, C 1-8 , C 1-6 This includes things like:

[0156] Unless otherwise defined elsewhere in this specification, all other technical and scientific terms used herein have meanings that are generally understood by those skilled in the art to which this invention pertains.

[0157] General synthesis The compounds and salts disclosed herein can be prepared using known organic synthesis techniques and can be synthesized according to any of a number of possible synthetic routes.

[0158] The reactions for preparing the compounds disclosed herein may be carried out in suitable solvents that can be readily selected by those skilled in the art of organic synthesis. Suitable solvents may be substantially inactive with the starting materials, intermediates, or products at the temperature in which the reaction is carried out, for example, at temperatures varying from the boiling point of the solvent. A given reaction may be carried out in one solvent or a mixture of solvents.

[0159] The selection of an appropriate protective group can be easily determined by those skilled in the art.

[0160] The reaction can be monitored according to any suitable method known in the art, such as NMR, UV, HPLC, LC-MS, and TLC. The compound can be purified by various methods, including HPLC and normal-phase silica chromatography.

[0161] Chiral analysis HPLC was used to analyze the retention time of various chiral examples, and the conditions were divided into the following methods according to the column, mobile phase, and solvent ratio used.

[0162] [ka] The compound of formula (I) can be prepared as shown in scheme I, where R 1 , L 2A , R 2A , R 3 , R 4A , R 4B , R 4C , R 4D , R 5 , R 6 , and R 7 This is as described herein (for example, in formula (I), or any embodiment thereof, for example, in formula (IV)), and X and X ’ Each of these is independently -F, -Cl, -Br, -I, or -OTf.

[0163] [ka] The compound of formula (VI) can be prepared as shown in scheme II, where R 1 , L 2A , R 2A , R 3 , R 4A , R 4B , R 4C , R 4D , R 5 , R 6 , and R 7 X is as described herein (for example, in formula (VI)), where X is -F, -Cl, -Br, -I, or -OTf. [Examples]

[0164] The following examples are for illustrative purposes only and should not be considered limiting in any way. While efforts have been made to ensure accuracy with respect to the numbers used (e.g., quantities, temperatures, etc.), some experimental error and deviation should be assumed. Unless otherwise indicated, temperatures are in degrees Celsius. Reagents were purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI and used without further purification unless otherwise instructed.

[0165] Unless otherwise specified, the reactions described below were carried out in anhydrous solvent under positive pressure of nitrogen or argon, or using a drying tube, with the reaction flask fitted with a rubber partition for introducing the substrate and reagents by syringe, and the glassware was dried in an oven and / or heated.

[0166] Unless otherwise specified, the reactions described below were carried out in anhydrous solvent under positive pressure of nitrogen or argon, or using a drying tube, with the reaction flask fitted with a rubber partition for introducing the substrate and reagents by syringe, and the glassware was dried in an oven and / or heated.

[0167] Unless otherwise specified, column chromatography purification was performed using a Biotage system (manufacturer: Dyax Corporation) with silica gel columns or silica SepPak cartridges (Waters), or a Teledyne Isco Combiflash® purification system using pre-packed silica gel cartridges.

[0168] 1 The 1H NMR spectrum was recorded using a Varian instrument operating at 400 MHz. 1¹H-NMR spectra were obtained using CDCl3, CD2Cl2, CD3OD, D2O, d6-DMSO, d6-acetone, or (CD3)2CO as solvents, and tetramethylsilane (0.00 ppm) or residual solvent (CDCl3: 7.25 ppm, CD3OD: 3.31 ppm, D2O: 4.79 ppm, d6-DMSO: 2.50 ppm, d6-acetone: 2.05, (CD3)2CO: 2.05) as reference standards. When peak multiplicity is reported, the following abbreviations are used: s (singular), d (double), t (tripular), q (quadular), qn (quintular), sx (hexatular), m (multiple), br (spread), dd (double double), dt (double triple). Given coupling constants are reported in Hertz (Hz). Compound names other than those for reagents were generated by ChemDraw version 12.0. The chiral purity of the compounds was determined by chiral HPLC or chiral SFC. Abbreviation: [Table 4-1] [Table 4-2]

[0169] Preparation of the intermediate 5-acetyl-3-chloro-2,7-dimethylisoquinoline-1(2H)-one [ka] Step 1: 3-(2-bromo-4-methylphenyl)propanoic acid [ka] A mixture of 2-bromo-4-methylbenzaldehyde (100.0 g, 502.40 mmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (87.0 g, 602.88 mmol) was mixed with TEA (100 mL) at 0°C. After stirring for 10 minutes, formic acid (100 mL) was added dropwise at 0°C. The mixture was then heated to 100°C and stirred for 2 hours. LC-MS indicated that the reaction was complete. Water (50 mL) was slowly added, and a yellow solid was crushed out. The solid was collected by filtration, slurryed with EA (200 mL), and filtered to obtain the desired product (90.0 g, 74%). MS(ESI)m / e[M+1] + =243,245.

[0170] Step 2: 3-(2-bromo-4-methylphenyl)propanoyl chloride [ka] To a solution of 3-(2-bromo-4-methylphenyl)propanoic acid (90.0 g, 370.22 mmol) in DCM (900 mL), (COCl)2 (94.0 g, 740.45 mmol) was slowly added at 0°C. Then, DMF (2.85 mL, 37.02 mmol) was added, and the mixture was stirred at 20°C for 2 hours. TLC showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain the desired product (95.0 g, crude), which was used directly in the next step.

[0171] Step 3: 4-bromo-6-methyl-2,3-dihydro-1H-inden-1-one [ka] To a solution of 3-(2-bromo-4-methylphenyl)propanoyl chloride (95.0 g, crude) in DCM (1000 mL), AlCl3 (96.9 g, 726.46 mmol) was gradually added at 0°C. The mixture was stirred at 20°C for 2 hours. LC-MS indicated that the reaction was complete. The mixture was slowly poured into ice water (1000 mL) and stirred for 30 minutes. The aqueous phase was extracted with DCM (1000 mL x 3). The combined organic phases were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was slurryed with ELISA (150 mL) and filtered to obtain the desired product (75.0 g, 92%). MS(ESI)m / e[M+1] + = 225, 227.

[0172] Step 4: 4-Bromo-2-(hydroxyimino)-6-methyl-2,3-dihydro-1H-inden-1-one [ka] To a solution of 4-bromo-6-methyl-2,3-dihydro-1H-inden-1-one (30.0 g, 133.29 mmol) in 2-isopropoxypropane (300 mL) and HCl (150 mL), isoamyl nitrite (17.2 g, 146.61 mmol) was added. The mixture was stirred at 20°C for 3 hours. LC-MS indicated that the reaction was complete. The mixture was diluted with PE, and the solid was collected by filtration. The filtration cake was dried under reduced pressure to obtain the desired product (30.0 g, 89%). MS(ESI)m / e[M+1] + =254,256.

[0173] Step 5: 5-Bromo-3-chloro-7-methylisoquinoline-1(2H)-one [ka] To a solution of 4-bromo-2-(hydroxyimino)-6-methyl-2,3-dihydro-1H-inden-1-one (10.0 g, 39.36 mmol) in CHCl3 (200 mL), PCl5 (13.1 g, 62.97 mmol) was gradually added. The mixture was stirred at 20°C for 10 hours. The reaction mixture was concentrated under vacuum and redissolved in HCl / siRNA (100 mL). The resulting mixture was stirred at 20°C for 2 hours. LC-MS indicated that the reaction was complete. The mixture was concentrated under reduced pressure. The crude product was slurryed with siRNA (50 mL) and filtered to obtain the desired product (6.0 g, 56%). MS(ESI)m / e[M+1] + =272.

[0174] Step 6: 5-Bromo-3-chloro-2,7-dimethylisoquinoline-1(2H)-one [ka] A mixture of 5-bromo-3-chloro-7-methylisoquinoline-1(2H)-one (10.0 g, 36.69 mmol), CH3I (10.4 g, 73.39 mmol), and K2CO3 (10.1 g, 73.39 mmol) in DMF (100 mL) was stirred at 20°C for 2 hours. LC-MS indicated that the reaction was complete. Water (50 mL) was added, and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was slurryed with Depositphotos (50 mL), filtered, and the desired product (6.5 g, 62%) was obtained. MS(ESI)m / e[M+1] + =286.

[0175] Step 7: 3-Chloro-5-(1-ethoxyvinyl)-2,7-dimethylisoquinoline-1(2H)-one [ka] To a solution of 5-bromo-3-chloro-2,7-dimethylisoquinoline-1(2H)-one (6.5 g, 22.68 mmol) in dioxane (70 mL), tributyl(1-ethoxyvinyl) stannane (9.0 g, 24.95 mmol) and dichloropalladium;triphenylphosphan (1.7 g, 2.50 mmol) were added under an N2 atmosphere. The mixture was stirred at 60°C for 16 hours. LC-MS indicated that the reaction was complete. The reaction was quenched with aqueous KF solution (50 mL) and stirred at 20°C for 0.5 hours. The mixture was filtered, and the filtrate was extracted with  (100 mL × 3). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the desired product (6.0 g, 95%), which was used directly in the next step. MS(ESI)m / e[M+1] + =278.

[0176] Step 8: 5-Acetyl-3-chloro-2,7-dimethylisoquinoline-1(2H)-one [ka] A mixture of dioxane (60 mL) and 3-chloro-5-(1-ethoxyvinyl)-2,7-dimethylisoquinoline-1(2H)-one (6.0 g, 21.60 mmol) in HCl (3 M, 20 mL) was stirred at 20°C for 0.5 hours. LC-MS indicated that the reaction was complete. The resulting mixture was extracted with DCM (100 mL x 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by recrystallization with MTBE (30 mL) to obtain the desired product (2.5 g, 46%). 1 H NMR(400 MHz,CDCl3)δ ppm 8.40(s,1H),7.93(d,J=1.59 Hz,1H),7.74(s,1H),3.76(s,3H),2.69(s,3H),2.53(s,3H).MS(ESI)m / e[M+1] + =250.

[0177] Example 1: 2-((1-(2,7-dimethyl-1-oxo-3-phenyl-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Step 1: 5-Acetyl-2,7-dimethyl-3-phenylisoquinoline-1(2H)-one [ka] A mixture of 5-acetyl-3-chloro-2,7-dimethylisoquinoline-1(2H)-one (130 mg, 0.52 mmol), phenylboronic acid (95 mg, 0.78 mmol), Pd(PPh3)4 (30 mg, 0.03 mmol), and K3PO4 (331 mg, 1.56 mmol) in dioxane (10 mL) and H2O (1 mL) was stirred at 100°C for 6 hours under N2. The mixture was poured into H2O and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography of silica gel eluted with 40%-45% ethyl acetate in petroleum ether to obtain the desired product (120 mg, 79%). MS(ESI)m / e[M+1] + =292.

[0178] Step 2: 5-(1-aminoethyl)-2,7-dimethyl-3-phenylisoquinoline-1(2H)-one [ka] To a solution of 5-acetyl-2,7-dimethyl-3-phenylisoquinoline-1(2H)-one (50 mg, 0.17 mmol) and ammonium acetate (66 mg, 0.86 mmol) in 5 mL of ethanol, NaBH3CN (14 mg, 0.22 mmol) was added. The resulting solution was stirred overnight at 90°C. After cooling to room temperature, the solution was concentrated under vacuum, and the residue was purified by CombiFlash®, a silica gel eluted with 8%-10% MeOH in DCM, to obtain the desired product (45 mg, 90%). MS(ESI)m / e[M+1] +=293.

[0179] Step 3: 2-((1-(2,7-dimethyl-1-oxo-3-phenyl-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] To a solution of 5-(1-aminoethyl)-2,7-dimethyl-3-phenylisoquinoline-1(2H)-one (45 mg, 0.15 mmol), 2-iodobenzoic acid (57 mg, 0.23 mmol), and K2CO3 (64 mg, 0.46 mmol) in 3 mL of DMSO, CuI (3 mg, 0.02 mmol) and L-proline (4 mg, 0.03 mmol) were added. The resulting solution was stirred overnight at 100°C under N2. After cooling to room temperature, the solution was concentrated under vacuum. The residue was redissolved in H2O and acidified to pH 5-6 with HCl (2 M in water). The mixture was filtered, and the filtered cake was purified by preparative HPLC to obtain the desired product (12 mg, 19%). 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.75(s,1H),8.37(s,1H),8.00(s,1H),7.80(d,J=7.4 Hz,1H),7.62-7.45(m,6H),7.21-7.13(m,1H),6.83(s,1H),6.56-6.47(m,1H),6.34(d,J=8.1 Hz,1H),5.20(s,1H),3.33(s,3H),2.37(s,3H),1.51(d,J=3.7 Hz,7H).MS(ESI)m / e[M+1] + =413.

[0180] Example 2: 2-((1-(2,7-dimethyl-1-oxo-3-(o-tolyl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Step 1: 5-acetyl-2,7-dimethyl-3-(o-tolyl)isoquinoline-1(2H)-one [ka] A mixture of 5-acetyl-3-chloro-2,7-dimethylisoquinoline-1(2H)-one (120 mg, 0.48 mmol), o-trilboronic acid (98 mg, 0.72 mmol), Pd(PPh3)4 (28 mg, 0.02 mmol), and K3PO4 (306 mg, 1.44 mmol) in dioxane (10 mL) and H2O (1 mL) was stirred at 100°C for 15 hours under N2. The mixture was poured into H2O and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel to obtain the desired product (141 mg, 95%). MS(ESI)m / e[M+1] + =306.

[0181] Step 2: 5-(1-hydroxyethyl)-2,7-dimethyl-3-(o-tolyl)isoquinoline-1(2H)-one [ka] A solution of 5-acetyl-2,7-dimethyl-3-(o-tolyl)isoquinoline-1(2H)-one (141 mg, 0.46 mmol) in DCM (10 mL) and MeOH (10 mL) was treated little by little with NaBH4 (35 mg, 0.92 mmol) at 0°C. The resulting solution was stirred at room temperature for 1 hour. The mixture was diluted with H2O (10 mL) and extracted with DCM (30 mL x 2). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel to obtain the desired product (140 mg, 99%). MS(ESI)m / e[M+1] + =308.

[0182] Step 3: 5-(1-bromoethyl)-2,7-dimethyl-3-(o-tolyl)isoquinoline-1(2H)-one [ka] To a solution of 5-(1-hydroxyethyl)-2,7-dimethyl-3-(o-tolyl)isoquinoline-1(2H)-one (140 mg, 0.45 mmol) in DCM (5 mL), PBr3 (366 mg, 1.35 mmol) was added dropwise at 0°C. The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (20 mL) at 0°C, and the pH was adjusted to 8 with saturated NaHCO3 aqueous solution. The mixture was extracted with DCM (10 mL x 2). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the desired product (80 mg, 48%). MS(ESI)m / e[M+1] + =370.

[0183] Step 4: Methyl 2-((1-(2,7-dimethyl-1-oxo-3-(o-tolyl)-1,2-dihydroisoquinoline-5-yl)ethyl)aminobenzoate [ka] DIEA (84 mg, 0.65 mmol) was added to a solution of 5-(1-bromoethyl)-2,7-dimethyl-3-(o-tolyl)isoquinoline-1(2H)-one (80 mg, 0.22 mmol) and methyl 2-aminobenzoate (48 mg, 0.32 mmol) in DMF (3 mL). The resulting solution was stirred at 90°C for 15 hours. After cooling to room temperature, the reaction mixture was diluted with water (30 mL) and extracted with  (30 mL x 2). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel to obtain the desired product (35 mg, 37%). MS(ESI)m / e[M+1] + =441.

[0184] Step 5: 2-((1-(2,7-dimethyl-1-oxo-3-(o-tolyl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Lithium hydroxide monohydrate (18 mg, 0.37 mmol) was added to a solution of methyl 2-((1-(2,7-dimethyl-1-oxo-3-(o-tolyl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate (35 mg, 0.07 mmol) in methanol (4 mL), H2O (2 mL), and THF (4 mL). The resulting solution was stirred at 50°C for 4 hours. The solution was concentrated under vacuum. The residue was redissolved in H2O and acidified to pH 5-6 with HCl (2 M in water). The mixture was filtered, and the filtered cake was purified by preparative HPLC to obtain the desired product (13 mg, 38%). 1 H NMR(399 MHz,DMSO-d6)δ ppm 12.72(brs,1H),8.38(brs,1H),8.00(s,1H),7.84-7.75(m,1H),7.53-7 .29(m,5H),7.21-7.09(m,1H),6.83-6.73(m,1H),6.55-6.46(m,1H),6. 40-6.27(m,1H),5.24-5.10(m,1H),3.16(s,3H),2.55-2.46(m,3H),2.4 0-2.31(m,3H),2.24-2.12(m,3H),1.53-1.44(m,3H).MS(ESI)m / e[M+1] + = 427.

[0185] Example 3: 2-((1-(3-(3-cyanophenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] The desired product (7.7 mg) was obtained following the same procedure as in Example 1. 1H NMR(399 MHz,DMSO-d6)δ ppm 12.73(brs,1H),8.36(s,1H),8.13(s,1H),8.04-7.89(m,3H),7.84-7.61(m,2H) ,7.46(s,1H),7.21-7.08(m,1H),6.91(s,1H),6.55-6.40(m,1H),6.31(d,J=8.2 Hz,1H),5.23(s,1H),3.30(s,3H),2.33(s,3H),1.49(brs,3H).MS(ESI)m / e[M+1] + = 437.

[0186] Example 4: 2-((1-(3-(4-cyanophenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] The desired product (10 mg) was obtained by following the same procedure as in Example 1. 1 H NMR(399 MHz,DMSO-d6)δ ppm 12.72(brs,1H),8.36(s,1H),8.04-7.92(m,3H),7.85-7.71(m,3H),7.47 (s,1H),7.22-7.08(m,1H),6.90(s,1H),6.57-6.45(m,1H),6.31(d,J=8.4 Hz,1H),5.21(s,1H),3.30(s,3H),2.33(s,3H),1.48(brs,3H).MS(ESI)m / e[M+1] + = 437.

[0187] Example 5: 2-((1-(3-(3-(2-cyanopropan-2-yl)phenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] The desired product (10.5 mg) was obtained following the same procedure as in Example 1. 1H NMR(399 MHz,DMSO-d6)δ ppm 12.69(brs,1H),8.33(s,1H),7.98(s,1H),7.78(d,J=7.6 Hz,1H),7.74-7.63(m,2H),7.60-7.51(m,2H),7.47(s,1H),7.23-7.09(m,1H),6.85(s,1H),6.56-6.42(m,1H),6.34(d,J=8.4 Hz,1H),5.22(s,1H),3.30(s,3H),2.36(s,3H),1.72(s,6H),1.49(d,J=4.1 Hz,3H).MS(ESI)m / e[M+1] + =480.

[0188] Example 6: 2-((1-(3-(2-fluorophenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Step 1: 1-(1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)-2H-benzo[d][1,3]oxazine-2,4(1H)-dione [ka] DIAD (60 mg, 0.30 mmol) was added at 0°C to a solution of 3-chloro-5-(1-hydroxyethyl)-2,7-dimethylisoquinoline-1(2H)-one (50 mg, 0.20 mmol), PPh3 (79 mg, 0.30 mmol), and 2H-benzo[d][1,3]oxazine-2,4(1H)-dione (49 mg, 0.30 mmol) in THF (1 mL). The mixture was stirred at 0°C for 1 hour. The mixture was concentrated under vacuum, and the residue was purified by preparative TLC to obtain the desired product (28 mg, 35%). MS(ESI)m / e[M+Na] + =419.

[0189] Step 2: 2-((1-(3-(2-fluorophenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] To a solution of methyl 2-((1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate (28 mg, 0.07 mmol), (3-fluorophenyl)boronic acid (13 mg, 0.10 mmol), and Na2CO3 (22 mg, 0.20 mmol) in 3 mL of dioxane and 1 mL of H2O, Pd(PPh3)4 (12 mg, 0.01 mmol) was added under a nitrogen atmosphere. The resulting solution was stirred overnight at 100°C. After cooling to room temperature, the mixture was poured into H2O and extracted with siRNA. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC to obtain the desired product (12 mg, 39%). 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.74(brs,1H),8.37(s,1H),8.01(s,1H),7.78(d,J=6.7 Hz,1H),7.68-7.56(m,2H),7.50(s,1H),7.47-7.36(m,2H),7.25-7.11(m,1H),6.96(d,J=10.5 Hz,1H),6.58-6.45(m,1H),6.42-6.26(dd,J=10.5,6.7 Hz,1H),5.30-5.13(m,1H),3.33(s,3H),2.38(s,3H),1.60-1.41(m,3H).MS(ESI)m / e[M+Na] + =453.

[0190] Example 7: 2-((1-(3-(3-fluorophenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] The desired product (24 mg) was obtained by following the same procedure as in Example 2. 1H NMR(400 MHz,DMSO-d6)δ ppm 12.74(s,1H),8.37(d,J=4.0 Hz,1H),7.99(s,1H),7.80(d,J=7.1 Hz,1H),7.62-7.42(m,4H),7.36(t,J=8.4 Hz,1H),7.17(t,J=4.8 Hz,1H),6.88(s,1H),6.52(t,J=7.2 Hz,1H),6.34(d,J=8.4 Hz,1H),5.27-5.18(m,1H),3.33(s,3H),2.35(s,3H),1.51(d,J=4.8 Hz,3H).MS(ESI)m / e[M+1] + =431

[0191] Example 8: 2-((1-(3-(4-fluorophenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] The desired product (21 mg) was obtained by following the same procedure as in Example 2. 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.74(brs,1H),8.37(d,J=4.8 Hz,1H),7.99(s,1H),7.79(d,J=7.8 Hz,1H),7.68-7.62(m,2H),7.47(s,1H),7.36(t,J=7.8 Hz,2H),7.17(t,J=7.2 Hz,1H),6.83(s,1H),6.51(t,J=6.4 Hz,1H),6.33(d,J=8.4 Hz,1H),5.24-5.15(m,1H),3.32(s,3H),2.36(s,3H),1.50(d,J=4.8 Hz, 3H).MS(ESI)m / e[M+1] + =431

[0192] Example 9: 2-((1-(3-(3,4-difluorophenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] The desired product (27 mg) was obtained by following the same procedure as in Example 2. 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.75(s,1H),8.65-8.27(m,1H),7.99(s,1H),7.86-7.70(m,2H),7.64-7.57(m,1H),7.51-7.44(m,2H),7.15(t,J=4.2 Hz,1H),6.89(s,1H),6.51(t,J=6.8 Hz,1H),6.32(d,J=8.0 Hz,1H),5.25-5.15(m,1H),3.34(s,3H),2.37(s,3H),1.50(d,J=4.8 Hz,3H).MS(ESI)m / e[M+1] + =439

[0193] Example 10: 2-((1-(3-(3,5-difluorophenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Step 1: 3-Chloro-5-(1-hydroxyethyl)-2,7-dimethylisoquinoline-1(2H)-one [ka] A solution of 5-acetyl-3-chloro-2,7-dimethylisoquinoline-1(2H)-one (200 mg, 0.80 mmol) in THF (10 mL) was mixed with NaBH4 (76 mg, 2.00 mmol) at 0°C. The mixture was stirred at room temperature for 2 hours. The mixture was poured into H2O and extracted with siRNA. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel to obtain the desired product (120 mg, 60%). MS(ESI)m / e[M+1] + =252.

[0194] Step 2: 5-(1-bromoethyl)-3-chloro-2,7-dimethylisoquinoline-1(2H)-one [ka] To a solution of 3-chloro-5-(1-hydroxyethyl)-2,7-dimethylisoquinoline-1(2H)-one (120 mg, 0.48 mmol) in DCM (10 mL), PBr3 (540 mg, 2.00 mmol) was added at 0°C. The mixture was stirred at room temperature for a further 12 hours. The mixture was poured into H2O and extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum to obtain the desired product (100 mg, 67%). MS(ESI)m / e[M+1] + =314.

[0195] Step 3: Methyl 2-((1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)aminobenzoate [ka] A solution of 5-(1-bromoethyl)-3-chloro-2,7-dimethylisoquinoline-1(2H)-one (100 mg, 0.32 mmol), methyl 2-aminobenzoate (150 mg, 1.0 mmol), and DIEA (258 mg, 2.0 mmol) in DMSO (160 mL) was stirred at 90°C for 12 hours. The mixture was poured into H2O and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel to obtain the desired product (30 mg, 25%). MS(ESI)m / e[M+Na] + =407.

[0196] Step 4: Methyl 2-((1-(3-(3,5-difluorophenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate [ka] To a solution of 3 mL of dioxane and 1 mL of H2O containing methyl 2-((1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate (30 mg, 0.08 mmol), (3,5-difluorophenyl)boronic acid (15 mg, 0.10 mmol), and Na2CO3 (22 mg, 0.20 mmol), Pd(PPh3)4 (12 mg, 0.01 mmol) was added under a nitrogen atmosphere. The resulting solution was stirred overnight at 100°C. After cooling to room temperature, the solution was concentrated under vacuum, and the residue was purified by preparative TLC to obtain the desired product (15 mg, 42%). MS(ESI)m / e[M+Na] + = 485.

[0197] Step 5: 2-((1-(3-(3,5-difluorophenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] A solution of methyl 2-((1-(3-(3,5-difluorophenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate (15 mg, 0.03 mmol) in methanol (0.5 mL) and THF (0.5 mL) was mixed with 1 mL of 1 N NaOH aqueous solution. The resulting solution was stirred at 25 °C for 12 hours. The solution was concentrated under vacuum. The residue was redissolved in H₂O and acidified to pH 5-6 with HCl (2 M in water). The resulting mixture was extracted with ELISA (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC to obtain the desired product (6 mg, 41%). 1H NMR(400 MHz,DMSO-d6)δ ppm 12.78(s,1H),8.42(s,1H),8.00(s,1H),7.81(d,J=7.8 Hz,1H),7.55-7.36(m,4H),7.22-7.10(m,1H),6.94(s,1H),6.58-6.46(m,1H),6.34(d,J=7.8 Hz,1H),5.24(m,1H),3.30(s,3H),2.37(s,3H),1.56-1.44(m,3H).MS(ESI)m / e[M+Na] + =471

[0198] Example 11: 2-((1-(3-(2,4-difluorophenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] The desired product (23 mg) was obtained by following the same procedure as in Example 1. 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.74(s,1H),8.65-8.27(m,1H),8.00(s,1H),7.79(d,J=7.2 Hz,1H),7.74-7.63(m,1H),7.59-7.45(m,2H),7.31(t,J=7.2 Hz,1H),7.22-7.16(m,1H),6.97(d,J=7.6 Hz,1H),6.52(s,1H),6.39-6.27(m,1H),5.26-5.14(m,1H),3.28(s,3H),2.38(s,3H),1.49(d,J=6.8 Hz,3H).MS(ESI)m / e[M+1] + =439

[0199] Example 12: 2-((1-(3-(2,3-difluorophenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] The desired product (6 mg) was obtained by following the same procedure as in Example 11. 1H NMR(400 MHz,DMSO-d6)δ ppm 12.71(s,1H),8.35(s,1H),8.00(s,1H),7.83-7.70(m,1H),7.71-7.54(m,1H),7.49(s,1H),7.46-7.33(m,2H),7.21-7.09(m,1H),7. 01(s,1H),6.57-6.43(m,1H),6.38-6.25(m,1H),5.27-5.11(m,1H),3.27(s,3H),2.36(s,3H),1.56-1.41(m,3H).MS(ESI)m / e[M+Na] + =471

[0200] Example 13: 2-((1-(3-(3-methoxyphenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Step 1: 5-Acetyl-3-(3-methoxyphenyl)-2,7-dimethylisoquinoline-1(2H)-one [ka] A mixture of 5-acetyl-3-chloro-2,7-dimethylisoquinoline-1(2H)-one (100 mg, 0.40 mmol), phenylboronic acid (91 mg, 0.60 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol), and K3PO4 (254 mg, 1.20 mmol) in dioxane (10 mL) and H2O (1 mL) was stirred at 100°C for 15 hours under N2. The mixture was poured into H2O and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel to obtain the desired product (110 mg, 86%). MS(ESI)m / e[M+1] + =322.

[0201] Step 2: 5-(1-aminoethyl)-3-(3-methoxyphenyl)-2,7-dimethylisoquinoline-1(2H)-one [ka] To a solution of 5-acetyl-3-(3-methoxyphenyl)-2,7-dimethylisoquinoline-1(2H)-one (100 mg, 0.31 mmol), formic acid (29 mg, 0.62 mmol), and ammonium formate (59 mg, 0.93 mmol) in 5 mL of methanol, Cp*Ir[N-[4-(trifluoromethyl)phenyl]-2-pyridinecarboxamidate]-Cl (10 mg, 0.02 mmol) was added under N2 conditions. The resulting solution was stirred at 60°C for 8 hours. After cooling to room temperature, the solution was concentrated under vacuum, and the residue was purified using CombiFlash® silica gel to obtain the desired product (95 mg, 95%). MS(ESI)m / e[M+1] + =323.

[0202] Step 3: 2-((1-(3-(3-methoxyphenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] To a solution of 5-(1-aminoethyl)-3-(3-methoxyphenyl)-2,7-dimethylisoquinoline-1(2H)-one (95 mg, 0.29 mmol), 2-iodobenzoic acid (146 mg, 0.59 mmol), and K2CO3 (122 mg, 0.88 mmol) in 5 mL of DMSO, CuI (6 mg, 0.03 mmol) and L-proline (7 mg, 0.06 mmol) were added. The resulting solution was stirred overnight at 100°C under N2. After cooling to room temperature, the solution was concentrated under vacuum. The residue was redissolved in H2O and acidified to pH 5-6 with HCl (2 M in water). The mixture was filtered, and the filtered cake was purified by preparative HPLC to obtain the desired product (29 mg, 22%). 1H NMR(400 MHz,DMSO-d6)δ ppm 12.73(brs,1H),8.34(s,1H),7.97(s,1H),7.78(d,J=7.6 Hz,1H),7.43(m,2H),7.14(m,3H),7.05(d,J=7.7 Hz,1H),6.81(s,1H),6.50(t,J=7.1 Hz,1H),6.33(d,J=8.3 Hz,1H),5.18(m,1H),3.80(s,3H),3.32(s,3H),2.35(s,3H),1.49(d,J=5.2 Hz,3H).MS(ESI)m / e[M+1] + =443.

[0203] Example 14: 2-((1-(3-(4-methoxyphenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] The desired product (28 mg) was obtained by following the same procedure as in Example 1. 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.76(brs,1H),8.36(s,1H),8.02-7.89(m,1H),7.79(s,1H),7.62-7.32(m,3H),7.21-6.96(m,2H),6.82-6.68(m,1H) ,6.56-6.40(m,1H),6.32(s,1H),5.16(s,1H),3.81(s,3H),3.31(s,3H),2.35(s,3H),1.49(brs,3H).MS(ESI)m / e[M+1] + =443.

[0204] Example 15: 2-((1-(3-(6-methoxypyridine-3-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] The desired product (21 mg) was obtained by following the same procedure as in Example 1. 1H NMR(399 MHz,DMSO-d6)δ ppm 12.73(brs,1H),8.45-8.29(m,2H),8.02-7.90(m,2H),7.78(d,J=7.6 Hz,1H),7.46(s,1H),7.21-7.09(m,1H),7.01-6.82(m,2H),6.56-6.41(m,1H),6.32(d,J=7.9 Hz,1H),5.21(s,1H),3.91(s,3H),3.33(s,3H),2.35(s,3H),1.48(s,3H).MS(ESI)m / e[M+1] + =444.

[0205] Example 16: 2-((1-(3-(1-(5-carbamoylpyridine-2-yl)-1H-pyrazole-4-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Step 1: Methyl 2-((1-(3-(1-(5-cyanopyridine-2-yl)-1H-pyrazole-4-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate [ka] Pd(PPh3)4 (15 mg, 0.01 mmol) was added under N2 to a solution of methyl 2-((1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate (50 mg, 0.13 mmol), 6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-yl)nicotinonitrile (77 mg, 0.26 mmol), and K3PO4 (83 mg, 0.39 mmol) in dioxane (8 mL) and H2O (1 mL). The resulting solution was stirred at 100°C for 15 hours. The mixture was poured into H2O and extracted with ethyl acetate. The combined organic extract was washed with brine (20 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel to obtain the desired product (50 mg, 75%). MS(ESI)m / e[M+1] + = 519.

[0206] Step 2: 2-((1-(3-(1-(5-Carbamoylpyridine-2-yl)-1H-pyrazole-4-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Lithium hydroxide monohydrate (20 mg, 0.48 mmol) was added to a solution of methyl 2-((1-(3-(1-(5-cyanopyridine-2-yl)-1H-pyrazole-4-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate (50 mg, 0.10 mmol) in methanol (4 mL), H2O (2 mL), and THF (4 mL). The resulting solution was stirred at 45°C for 6 hours. The solution was concentrated under vacuum. The residue was redissolved in H2O and acidified to pH 5-6 with HCl (2 M in water). The mixture was filtered, and the filtered cake was purified by preparative HPLC to obtain the desired product (8 mg, 16%). 1H NMR(399 MHz,DMSO-d6)δ ppm 9.10(s,1H),8.94(d,J=1.9 Hz,1H),8.58(brs,1H),8.42(dd,J=8.6,2.1 Hz,1H),8.27(s,1H),8.21(s,1H),8.04(d,J=8.6 Hz,1H),7.93(s,1H),7.78(d,J=7.7 Hz,1H),7.64(s,1H),7.44(s,1H),7.15-7.03(m,2H),6.46(t,J=7.5 Hz,1H),6.30(d,J=8.4 Hz,1H),5.25(d,J=5.7 Hz,1H),3.56(s,3H),2.32(s,3H),1.48(d,J=6.4 Hz,3H).MS(ESI)m / e[M+1] + = 523.

[0207] Example 17: 2-((1-(3-(benzo[d]thiazole-2-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] The desired product (18 mg) was obtained by following the same procedure as in Example 2. 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.85(brzs,1H),8.65-8.27(m,1H),8.24(d,J=7.2 Hz,1H),8.18(d,J=6.8 Hz,1H),8.05(s,1H),7.85-7.78(m,1H),7.68-7.54(m,3H),7.45(s,1H),7.22-7.10(m,1H),6.55-6.47(m,1H),6.37(d,J=4.4 Hz,1H),5.34-5.22(m,1H),3.68(s,3H),2.41(s,3H),1.53(brs,3H).MS(ESI)m / e[M+1] + =470

[0208] Example 18: 2-((1-(2,7-dimethyl-3-(2-methylbenzo[d]thiazole-6-yl)-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Step 1: 2-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole [ka] A mixture of 6-bromo-2-methylbenzo[d]thiazole (2.0 g, 8.80 mmol), bis(pinacolate)diborone (4.4 g, 17.50 mmol), Pd(dppf)Cl2 (290 mg, 0.40 mmol), and potassium acetate (1.7 g, 17.50 mmol) in dioxane (30 mL) was stirred at 110 °C for 12 hours under N2. The mixture was poured into H2O and extracted with SiO2. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by CombiFlash® chromatography on silica gel to obtain the desired product (1.8 g, 75%). MS(ESI)m / e[M+1] + =276

[0209] Step 2: Methyl 2-((1-(2,7-dimethyl-3-(2-methylbenzo[d]thiazole-6-yl)-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate [ka] A mixture of methyl 2-((1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate (50 mg, 0.13 mmol), 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (54 mg, 0.2 mmol), Pd(PPh3)4 (12 mg, 0.01 mmol), and K3PO4 (83 mg, 0.39 mmol) in dioxane (5 mL) and H2O (0.5 mL) was stirred at 100°C for 5 hours under N2. The mixture was poured into H2O and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative TLC to obtain the desired product (55 mg, 85%). MS(ESI)m / e[M+1] + =498

[0210] Step 3: 2-((1-(2,7-dimethyl-3-(2-methylbenzo[d]thiazole-6-yl)-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] A solution of methyl 2-((1-(2,7-dimethyl-3-(2-methylbenzo[d]thiazole-6-yl)-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate (55 mg, 0.11 mmol) in methanol (3 mL) was mixed with NaOH (3 M in water, 1 mL). The resulting solution was stirred at 60°C for 15 hours. The solution was concentrated under vacuum. The residue was redissolved in H2O and acidified to pH 5-6 with HCl (2 M in water). The mixture was filtered, and the solid was purified by preparative HPLC to obtain the desired product (25 mg, 47%). 1H NMR(399 MHz,DMSO-d6)δ ppm 12.76(brs,1H),8.40(s,1H),8.26(s,1H),8.08-7.95(m,2H),7.78(s,1H),7. 67(s,1H),7.47(s,1H),7.14(s,1H),6.90(s,1H),6.49(s,1H),6.34(d,J=6.1 Hz,1H),5.20(s,1H),3.33(s,3H),2.83(s,3H),2.35(s,3H),1.49(brs,3H).MS(ESI)m / e[M+1] + = 484.

[0211] Example 19: 2-((1-(2,7-dimethyl-3-(2-methyl-2H-indazole-5-yl)-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Step 1: Methyl 2-((1-(2,7-dimethyl-3-(2-methyl-2H-indazole-5-yl)-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate [ka] A mixture of methyl 2-((1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate (25 mg, 0.065 mmol), (2-methyl-2H-indazole-5-yl)boronic acid (14 mg, 0.078 mmol), Pd(PPh3)4 (7.5 mg, 0.0065 mmol), and K3PO4 (41 mg, 0.195 mmol) in dioxane and H2O (5:1) (2 mL) was stirred at 90°C for 16 hours. The mixture was concentrated under vacuum. The residue was purified by preparative TLC to obtain the desired product (30 mg, 96%). MS(ESI)m / e[M+1] + =481.

[0212] Step 2: 2-((1-(2,7-dimethyl-3-(2-methyl-2H-indazole-5-yl)-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] A solution of methyl 2-((1-(2,7-dimethyl-3-(2-methyl-2H-indazole-5-yl)-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate in MeOH (1 mL) and THF (0.5 mL) was mixed with 4N NaOH (0.2 mL). The reaction mixture was stirred at 50°C for 16 hours. The mixture was adjusted to pH 5 with 1N HCl and concentrated under vacuum. The residue was purified by preparative HPLC to obtain the desired product (17 mg, 59%). 1 H NMR(500 MHz,DMSO-d6)δ ppm 12.73(brs,1H),8.46(s,1H),8.40(s,1H),8.00(s,1H),7.91(s,1H),7.81(d,J=6.5 Hz,1H),7.70(d,J=9.0 Hz,1H),7.49(s,1H),7.39(dd,i=9.0,1.5 Hz,1H),7.17(t,J=8.0 Hz,1H),6.87(s,1H),6.52(t,J=7.5 Hz,1H),6.35(d,J=8.5 Hz,1H),5.20(s,1H),4.22(s,3H),3.36(s,3H),2.38(s,3H),1.52(d,J=6.5 Hz,3H).MS(ESI)m / e[M+1] + =467.

[0213] Example 20: 2-((1-(2-methyl-1-oxo-3-phenyl-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Step 1: 4-Bromo-2-(hydroxyamino)-2,3-dihydro-1H-inden-1-one [ka] To a solution of 4-bromo-1-indanone (10.5 g, 50.00 mmol) in diethyl ether (100 mL) in concentrated HCl (32%, 50 mL), isopentyl nitrite (7.7 g, 75.00 mmol) was added dropwise over 1 hour. The resulting solution was vigorously stirred at room temperature for 3 hours. The precipitated solid was collected by filtration and washed with ether (20 mL x 2) to obtain the desired product (8.0 g, 67%). MS(ESI)m / e[M+1] + =240.

[0214] Step 2: 5-Bromo-3-chloroisoquinoline-1(2H)-one [ka] To a solution of 4-bromo-2-(hydroxyimino)-2,3-dihydro-1H-inden-1-one (2.5 g, 10.42 mmol) in CCl4 (50 ml), PCl5 (3.2 g, 15.63 mmol) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under vacuum, and the residue was dissolved in 4 M HCl (100 ml) in dioxane. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under vacuum and redissolved in water. The precipitated solid was collected by filtration and ground with petroleum ether / siRNA (10:1) to obtain the desired product (1.6 g, 59%). MS(ESI)m / e[M+1] + =258.

[0215] Step 3: 5-Bromo-3-chloro-2-methylisoquinoline-1(2H)-one [ka] To a solution of 5-bromo-3-chloroisoquinoline-1(2H)-one (1.4 g, 5.28 mmol) and K2CO3 (2.2 g, 15.84 mmol) in DMF (8 mL), CH3I (750 mg, 5.28 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 1 hour. The mixture was poured into H2O (30 mL) and extracted with EA (20 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography to obtain the desired product (1.2 g, 83%). MS(ESI)m / e[M+1] + =272.

[0216] Step 4: 5-Acetyl-3-chloro-2-methylisoquinoline-1(2H)-one [ka] To a solution of 5-bromo-3-chloro-2-methylisoquinoline-1(2H)-one (900 mg, 3.30 mmol) and tributyl(1-ethoxyvinyl) stannane (1.2 g, 3.30 mmol) in dioxane (30 mL), bis(triphenylphosphine)palladium(II) chloride (232 mg, 0.33 mmol) was added under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 15 hours under N2. After cooling to room temperature, 10 mL of 1 M aqueous HCl was added to the reaction solution and stirred for 30 minutes. The mixture was quenched with saturated aqueous KF (50 mL), stirred for 30 minutes, and filtered. The filtrate was extracted with 10% MeOH in DCM (20 ml x 3). The combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain the desired product (447 mg, 57%). MS(ESI)m / e[M+1] + =236.

[0217] Step 5: 5-Acetyl-2-methyl-3-phenylisoquinoline-1(2H)-one [ka] A mixture of 5-acetyl-3-chloro-2-methylisoquinoline-1(2H)-one (447 mg, 1.89 mmol), phenylboronic acid (347 mg, 2.84 mmol), Pd(PPh3)4 (219 mg, 0.19 mmol), and K3PO4 (1.20 g, 5.67 mmol) in dioxane (20 mL) and H2O (2 mL) was stirred at 100°C for 15 hours under N2. The mixture was poured into H2O and extracted with siRNA. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel to obtain the desired product (454 mg, 86%). MS(ESI)m / e[M+1] + =278.

[0218] Step 6: 5-(1-hydroxyethyl)-2-methyl-3-phenylisoquinoline-1(2H)-one [ka] To a solution of 5-acetyl-2-methyl-3-phenylisoquinoline-1(2H)-one (454 mg, 1.64 mmol) in DCM (10 mL) and MeOH (10 mL), NaBH4 (93 mg, 2.46 mmol) was gradually added at 0°C. The resulting solution was stirred at room temperature for 1 hour. The mixture was diluted with H2O (10 mL) and extracted with DCM (30 mL x 2). The combined organic extract was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel to obtain the desired product (357 mg, 99%). MS(ESI)m / e[M+1] + =280.

[0219] Step 7: 5-(1-bromoethyl)-2-methyl-3-phenylisoquinoline-1(2H)-one [ka] To a solution of 5-(1-hydroxyethyl)-2-methyl-3-phenylisoquinoline-1(2H)-one (100 mg, 0.36 mmol) in DCM (5 mL), PBr3 (291 mg, 1.08 mmol) was added dropwise at 0°C. The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (20 mL) at 0°C, and the pH was adjusted to 8 with saturated NaHCO3 aqueous solution. The mixture was extracted with DCM (10 mL x 2). The combined organic extract was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the desired product (100 mg, 90%). MS(ESI)m / e[M+1] + =342.

[0220] Step 8: Methyl 2-((1-(2-methyl-1-oxo-3-phenyl-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate [ka] DIEA (100 mg, 0.78 mmol) was added to a solution of 5-(1-bromoethyl)-2-methyl-3-phenylisoquinoline-1(2H)-one (90 mg, 0.26 mmol) and methyl 2-aminobenzoate (48 mg, 0.32 mmol) in DMF (3 mL). The resulting solution was stirred at 90°C for 4 hours. After cooling to room temperature, the reaction product was diluted with water (30 mL) and extracted with  (30 mL x 2). The combined organic extract was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel to obtain the desired product (50 mg, 46%). MS(ESI)m / e[M+1] + =413.

[0221] Step 9: 2-((1-(2-methyl-1-oxo-3-phenyl-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Lithium hydroxide monohydrate (51 mg, 1.21 mmol) was added to a solution of methyl 2-((1-(2-methyl-1-oxo-3-phenyl-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate (50 mg, 0.12 mmol) in methanol (4 mL), H2O (2 mL), and THF (4 mL). The resulting solution was stirred at 50°C for 4 hours. The solution was concentrated under vacuum. The residue was redissolved in H2O and acidified to pH 5-6 with HCl (2 M in water). The mixture was filtered, and the filtration cake was purified by preparative HPLC to obtain the desired product (27 mg, 56%). 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.76(brs,1H),8.38(d,J=3.7 Hz,1H),8.15(d,J=7.8 Hz,1H),7.78(d,J=7.8 Hz,1H),7.64-7.56(m,3H),7.52-7.48(m,3H),7.41(t,J=7.6 Hz,1H),7.13(t,J=7.6 Hz,1H),6.84(s,1H),6.49(t,J=7.4 Hz,1H),6.30(d,J=8.5 Hz,1H),5.23(m,1H),3.31(s,3H),1.50(d,J=6.2 Hz, 3H).MS(ESI)m / e[M+1] + =399.

[0222] Example 21: 2-((1-(2-methyl-1-oxo-3-(phenylthinyl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Step 1: 5-(1-aminoethyl)-3-chloro-2-methylisoquinoline-1(2H)-one [ka] A mixture of 5-acetyl-3-chloro-2-methylisoquinoline-1(2H)-one (200 mg, 0.85 mmol), HCOOH (78.00 mg, 1.70 mmol), HCOONH4 (160 mg, 2.54 mmol), and Cp*Ir[N-[4-(trifluoromethyl)phenyl]-2-pyridinecarboxamidate]-Cl in MeOH (5 mL) was stirred at 60°C for 16 hours under an N2 atmosphere. The reaction mixture was concentrated under vacuum. The residue was purified by combiflash® to obtain the desired product (80 mg, 40%). MS(ESI)m / e[M+1] + =237.

[0223] Step 2: 5-(1-aminoethyl)-2-methyl-3-(phenylthinyl)isoquinoline-1(2H)-one [ka] A mixture of 5-(1-aminoethyl)-3-chloro-2-methylisoquinoline-1(2H)-one (80 mg, 0.34 mmol), ethynylbenzene (41 mg, 0.40 mmol), Pd(PPh3)2Cl2 (12 mg, 0.017 mmol), and CuI (6.4 mg, 0.034 mmol) in Et3N (1 mL) and DMF (1 mL) was stirred at 80°C for 16 hours under an N2 atmosphere. The reaction product was diluted with water and extracted with DCM (50 mL). The organic phase was concentrated under vacuum, and the residue was purified by preparative TLC to obtain the desired product (90 mg, 88%).

[0224] Step 3: 2-((1-(2-methyl-1-oxo-3-(phenylthinyl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] A mixture of 5-(1-aminoethyl)-2-methyl-3-(phenylthinyl)isoquinoline-1(2H)-one (90 mg, 0.30 mmol), 2-iodobenzoic acid (74 mg, 0.30 mmol), CuI (5.7 mg, 0.030 mmol), L-proline (6.9 mg, 0.060 mmol), and K2CO3 (82 mg, 0.60 mmol) in DMSO (2 mL) was stirred at 100°C for 16 hours under an N2 atmosphere. The reaction product was extracted using DCM (30 mL x 3). The combined organic phase was concentrated under vacuum, and the residue was purified by preparative HPLC to obtain the desired product (7.4 mg, 6%). 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.72(brs,1H),8.51(s,1H),8.13(d,J=6.4 Hz,1H),7.80(d,J=7.6 Hz,1H),7.73-7.60(m,3H),7.59-7.37(m,5H),7.12(s,1H),6.49(s,1H),6.28(d,J=8.0 Hz,1H),5.30(s,1H),3.72(s,3H),1.52(brs,3H).MS(ESI)m / e[M+1] + = 423.

[0225] Example 22: 2-((1-(2,7-dimethyl-3-(2-methyl-2H-indazole-7-yl)-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Step 1: 5-Acetyl-2,7-dimethyl-3-(2-methyl-2H-indazole-7-yl)isoquinoline-1(2H)-one [ka] A mixture of 5-acetyl-3-chloro-2,7-dimethylisoquinoline-1(2H)-one (100 mg, 4.00 mmol), 2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (155 mg, 6.00 mmol), Pd(PPh3)4 (23 mg, 0.20 mmol), and K3PO4 (254 mg, 12.00 mmol) in dioxane (5 mL) and H2O (0.5 mL) was stirred at 100°C for 12 hours under N2. The mixture was poured into H2O and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by CombiFlash® chromatography on silica gel to obtain the desired product (135 mg, 98%). MS(ESI)m / e[M+1] + =346.

[0226] Step 2: 5-(1-aminoethyl)-2,7-dimethyl-3-(2-methyl-2H-indazole-7-yl)isoquinoline-1(2H)-one [ka] To a solution of 5-acetyl-2,7-dimethyl-3-(2-methyl-2H-indazole-7-yl)isoquinoline-1(2H)-one (135 mg, 0.4 mmol) in ethanol (5 mL), ammonium acetate (154 mg, 2.00 mmol) and NaBH3CN (30 mg, 0.48 mmol) were added. The resulting solution was stirred at 90°C for 15 hours. The solution was concentrated under vacuum. The residue was purified by CombiFlash® chromatography on silica gel to obtain the desired product (78 mg, 56%). MS(ESI)m / e[M+1] + =347.

[0227] Step 3: 2-((1-(2,7-dimethyl-3-(2-methyl-2H-indazole-7-yl)-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] To a solution of 5-(1-aminoethyl)-2,7-dimethyl-3-(2-methyl-2H-indazole-7-yl)isoquinoline-1(2H)-one (78 mg, 0.22 mmol), 2-aminobenzoic acid (84 mg, 0.34 mmol), L-proline (4 mg, 0.02 mmol), and K2CO3 (82 mg, 0.60 mmol) in 2 mL of DMSO, CuI (6 mg, 0.02 mmol) was added. The resulting solution was stirred overnight at 100°C under N2. After cooling to room temperature, the solution was concentrated under vacuum, and the residue was dissolved in water. The pH was adjusted to 4-5, and the resulting mixture was filtered. The filtered cake was purified by preparative HPLC to obtain the desired product (21 mg, 20%). 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.73(brs,1H),8.47(s,1H),8.35(s,1H),8.02(s,1H),7.86(d,J=8.3 Hz,1H),7.78(d,J=7.7 Hz,1H),7.47(s,1H),7.39(d,J=6.4 Hz,1H),7.24-6.95(m,2H),6.91(s,1H),6.49(t,J=7.0 Hz,1H),6.31(d,J=8.1 Hz,1H),5.16(s,1H),4.15(s,3H),3.27(s,3H),2.37(s,3H),1.49(d,J=5.3 Hz, 3H).MS(ESI)m / e[M+1] + =467.

[0228] Example 23: 2-((1-(2,7-dimethyl-3-(4-(1-methyl-1H-pyrazole-4-yl)phenyl)-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Step 1: 5-Acetyl-2,7-dimethyl-3-(4-(1-methyl-1H-pyrazole-4-yl)phenyl)isoquinoline-1(2H)-one [ka] A mixture of 5-acetyl-3-chloro-2,7-dimethylisoquinoline-1(2H)-one (100 mg, 4.00 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole (170 mg, 6.00 mmol), Pd(PPh3)4 (23 mg, 0.20 mmol), and K3PO4 (254 mg, 12.00 mmol) in dioxane (5 mL) and H2O (0.5 mL) was stirred at 100°C for 12 hours under N2. The mixture was poured into H2O and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by CombiFlash® chromatography on silica gel to obtain the desired product (85 mg, 57%). MS(ESI)m / e[M+1] + =372

[0229] Step 2: 5-(1-aminoethyl)-2,7-dimethyl-3-(4-(1-methyl-1H-pyrazole-4-yl)phenyl)isoquinoline-1(2H)-one [ka] To a solution of 5-acetyl-2,7-dimethyl-3-(4-(1-methyl-1H-pyrazole-4-yl)phenyl)isoquinoline-1(2H)-one (85 mg, 0.2 mmol) in ethanol (4 mL), ammonium acetate (77 mg, 1.00 mmol) and NaCNBH3 (15 mg, 0.24 mmol) were added. The resulting solution was stirred at 90°C for 15 hours. The solution was concentrated under vacuum. The residue was purified by CombiFlash® chromatography on silica gel to obtain the desired product (38 mg, 45%). MS(ESI)m / e[M+1] + =373.

[0230] Step 3: 2-((1-(2,7-dimethyl-3-(4-(1-methyl-1H-pyrazole-4-yl)phenyl)-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] To a solution of 5-(1-aminoethyl)-2,7-dimethyl-3-(4-(1-methyl-1H-pyrazole-4-yl)phenyl)isoquinoline-1(2H)-one (38 mg, 0.10 mmol), 2-aminobenzoic acid (37 mg, 0.15 mmol), L-proline (2 mg, 0.01 mmol), and K2CO3 (41 mg, 0.30 mmol) in 2 mL of DMSO, CuI (3 mg, 0.01 mmol) was added. The resulting solution was stirred overnight at 100°C under N2. After cooling to room temperature, the solution was concentrated under vacuum, and the residue was dissolved in water. The pH was adjusted to 4-5, and the resulting mixture was filtered. The filtered cake was purified by preparative HPLC to obtain the desired product (10 mg, 20%). 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.75(brs,1H),8.39(s,1H),8.22(s,1H),8.03-7.89(m,2H),7.84-7.73 (m,1H),7.73-7.62(m,2H),7.61-7.51(m,2H),7.46(s,1H),7.15(t,J=7.2 Hz,1H),6.83(s,1H),6.50(t,J=6.9 Hz,1H),6.32(d,J=8.1 Hz,1H),5.19(s,1H),3.87(s,3H),3.34(s,3H),2.35(s,3H),1.50(d,J=4.5 Hz, 3H).MS(ESI)m / e[M+1] + =493.

[0231] Example 24: 2-((1-(3-benzamido-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Step 1: Methyl 2-((1-(3-benzamido-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)aminobenzoate [ka] To a solution of methyl 2-((1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate (60 mg, 0.16 mmol), benzamide (38 mg, 0.31 mmol), xantPhos (18 mg, 0.03 mmol), and Cs2CO3 (152 mg, 0.47 mmol) in 10 mL of dioxane, Pd2(dba)3.CHCl3 (16 mg, 0.02 mmol) was added. The resulting solution was stirred overnight at 130 °C under N2. After cooling to room temperature, the solution was concentrated under vacuum, and the residue was purified by CombiFlash® to obtain the desired product (60 mg, 82%). MS(ESI)m / e[M+1] + =470.

[0232] Step 2: 2-((1-(3-benzamido-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Lithium hydroxide monohydrate (54 mg, 1.28 mmol) was added to a solution of methyl 2-((1-(3-benzamido-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate (60 mg, 0.13 mmol) in methanol (4 mL), H2O (2 mL), and THF (4 mL). The resulting solution was stirred at 50°C for 6 hours. The solution was concentrated under vacuum. The residue was redissolved in H2O and acidified to pH 5-6 with HCl (2 M in water). The mixture was filtered, and the filtered cake was purified by preparative HPLC to obtain the desired product. MS(ESI)m / e[M+1] + = 456.

[0233] Example 25: 2-((1-(4-oxo-2-phenyl-4H-quinoridine-9-yl)ethyl)amino)benzoic acid [ka] Step 1: 2-(3-bromopyridine-2-yl)-1-phenylethane-1-one [ka] To a solution of 3-bromo-2-methylpyridine (5.0 g, 29.07 mmol) in THF (50 mL), LDA (2.0 M in THF, 31 mL, 61.05 mmol) was added dropwise at -65°C. The reaction mixture was stirred at -65°C for 0.5 hours, and then N-methoxy-N-methylbenzamide (5.3 g, 32.00 mmol in 20 mL of THF) was added dropwise at -65°C. The reaction mixture was heated to 0°C and stirred for 2 hours. The resulting mixture was quenched with aqueous NH4Cl solution (50 mL) and extracted with EA (50 mL x 3). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified using CombiFlash® silica gel to obtain the desired product (2.7 g, 34%). MS(ESI)m / e[M+1] + =276

[0234] Step 2: 9-Bromo-2-phenyl-4H-quinoridine-4-one [ka] To a solution of 2-(3-bromopyridine-2-yl)-1-phenylethane-1-one (2.3 g, 8.3 mmol) in toluene (30 mL), NaH (60%, 667 mg, 16.6 mmol) was added in batches, and the reaction mixture was stirred at 25°C for 1 hour. Then, ethyl 2-(diethoxyphosphoryl) acetate (3.7 g, 16.6 mmol) was added. The reaction mixture was stirred at 25°C for 1 hour, and then at 120°C for 15 hours. The resulting solution was quenched with NH4Cl aqueous solution (20 mL) and extracted with EA (30 mL x 3). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified using CombiFlash® silica gel to obtain the desired product (1.1 g, 44%). MS(ESI)m / e[M+1] + =300

[0235] Step 3: 9-acetyl-2-phenyl-4H-quinolidine-4-one [ka] A mixture of 9-bromo-2-phenyl-4H-quinoridine-4-one (1.1 g, 3.70 mmol), tributyl(1-ethoxyvinyl) stannan (1.6 g, 4.40 mmol), and Pd(PPh3)2Cl2 (260 mg, 0.37 mmol) in dioxane (30 mL) was stirred at 100 °C for 15 hours under N2. After cooling to room temperature, HCl (2 M in water, 5 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. The resulting solution was diluted with HCl and washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified using CombiFlash® silica gel to obtain the desired product (750 mg, 77%). MS(ESI)m / e[M+1] + =264

[0236] Step 4: 9-(1-aminoethyl)-2-phenyl-4H-quinoridine-4-one [ka] To a solution of 9-acetyl-2-phenyl-4H-quinoridine-4-one (500 mg, 1.90 mmol) in ethanol (15 mL), ammonium acetate (732 mg, 9.50 mmol) was added, followed by NaBH3CN (144 mg, 2.30 mmol). The resulting solution was stirred at 90°C for 15 hours. The reaction solution was concentrated under vacuum, and the residue was purified using CombiFlash® silica gel to obtain the desired product (310 mg, 62%). MS(ESI)m / e[M+1] + =265.

[0237] Step 5: 2-((1-(4-oxo-2-phenyl-4H-quinolidine-9-yl)ethyl)amino)benzoic acid [ka] To a solution of 9-(1-aminoethyl)-2-phenyl-4H-quinoridine-4-one (100 mg, 0.38 mmol), 2-aminobenzoic acid (112 mg, 0.46 mmol), L-proline (4 mg, 0.04 mmol), and K2CO3 (157 mg, 1.14 mmol) in 3 mL of DMSO, CuI (7 mg, 0.04 mmol) was added. The resulting solution was stirred overnight at 100°C under N2. After cooling to room temperature, the reaction solution was concentrated under vacuum. The residue was dissolved in water and the pH was adjusted to 4-5. The resulting mixture was filtered, and the solid was purified by preparative HPLC to obtain the desired product (18 mg, 12%). 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.82(s,1H),8.94(d,J=7.2 Hz,1H),8.55-8.29(m,1H),7.89(d,J=7.7 Hz,2H),7.82(d,J=7.9 Hz,1H),7.60-7.39(m,4H),7.32(s,1H),7.20(t,J=7.8 Hz,1H),7.12(t,J=7.1 Hz,1H),6.78(s,1H),6.55(t,J=7.5 Hz,1H),6.36(d,J=8.5 Hz,1H),5.54-5.17(m,1H),1.60(d,J=6.3 Hz, 3H).MS(ESI)m / e[M+1] + =385.

[0238] Example 26: 2-((1-(7-methyl-1-oxo-3-phenyl-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Step 1: 5-acetyl-3-chloro-7-methylisoquinoline-1(2H)-one [ka] To a solution of 5-bromo-3-chloro-7-methylisoquinoline-1(2H)-one (200 mg, 0.73 mmol) and tributyl(1-ethoxyvinyl) stannane (278 mg, 0.77 mmol) in dioxane (20 mL), bis(triphenylphosphine)palladium(II) chloride (51 mg, 0.07 mmol) was added under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 15 hours. After cooling to room temperature, the reaction product was treated with 1 M aqueous HCl (5 mL) and stirred for 30 minutes. The mixture was quenched with saturated aqueous KF (10 mL), stirred for 30 minutes, and filtered. The filtered cake was washed with 10% MeOH in DCM (20 ml x 3). The combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated to obtain a residue. This residue was then purified by silica gel column chromatography eluted with 50%-55% RINKAN in petroleum ether to obtain the product (140 mg, 81%). MS(ESI)m / e[M+1] + =236.

[0239] Step 2: 5-Acetyl-7-methyl-3-phenylisoquinoline-1(2H)-one [ka] A mixture of 5-acetyl-3-chloro-7-methylisoquinoline-1(2H)-one (140 mg, 0.59 mmol), phenylboronic acid (109 mg, 0.89 mmol), Pd(PPh3)4 (34 mg, 0.03 mmol), and K3PO4 (377 mg, 1.78 mmol) in dioxane (10 mL) and H2O (1 mL) was stirred at 100°C for 15 hours under N2. The mixture was poured into H2O and extracted with siRNA. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel to obtain the product (120 mg, 73%). MS(ESI)m / e[M+1] + =278.

[0240] Step 3: 5-(1-aminoethyl)-7-methyl-3-phenylisoquinoline-1(2H)-one [ka] To a solution of 5-acetyl-3-chloro-7-methylisoquinoline-1(2H)-one (100 mg, 0.26 mmol) and ammonium acetate (102 mg, 1.32 mmol) in 5 mL of ethanol, NaBH3CN (22 mg, 0.34 mmol) was added. The resulting solution was stirred overnight at 90°C. After cooling to room temperature, the solution was concentrated under vacuum, and the residue was purified by CombiFlash®, a silica gel eluted with 20%-30% MeOH in DCM, to obtain the desired product (80 mg, 80%). MS(ESI)m / e[M+1] + =279.

[0241] Step 4: 2-((1-(7-methyl-1-oxo-3-phenyl-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzonitrile [ka] DIEA (148 mg, 1.15 mmol) was added to a solution of 5-(1-aminoethyl)-7-methyl-3-phenylisoquinoline-1(2H)-one (80 mg, 0.29 mmol) and 2-fluorobenzonitrile (52 mg, 0.43 mmol) in DMSO (3 mL). The resulting solution was stirred at 130 °C for 48 hours. The reaction mixture was quenched with water (10 mL) and extracted with RINKAN (10 mL x 2). The combined organic extract was washed with brine, dried over anhydrous sodium 2 SO4, filtered, and concentrated to obtain the desired product (30 mg, 27%). MS(ESI)m / e[M+1] + =380.

[0242] Step 5: 2-((1-(7-methyl-1-oxo-3-phenyl-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] To a solution of 2-((1-(7-methyl-1-oxo-3-phenyl-1,2-dihydroisoquinoline-5-yl)ethyl)aminobenzonitrile (30 mg, 0.08 mmol) in ethanol (4 mL), NaOH (6 M in water, 1 mL) was added. The resulting solution was stirred at 100 °C for 16 hours. The solution was concentrated under vacuum. The residue was redissolved in H2O and acidified to pH 5-6 with HCl (2 M in water). The mixture was filtered, and the filtration cake was purified by preparative HPLC to obtain the desired product (1 mg, 3%). 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.79(brs,1H),11.55(s,1H),8.53(s,1H),7.93(s,1H),7.86-7.74(m,3H),7.53-7.37(m,4H),7.21-7.05(m,2H),6.49(t,J=7.5 Hz,1H),6.37(d,J=8.5 Hz,1H),5.38-5.25(m,1H),2.34(s,3H),1.53(d,J=6.5 Hz,3H).MS(ESI)m / e[M+1] + =399.

[0243] Example 27: 2-((1-(2,7-dimethyl-1-oxo-3-(prop-1-in-1-yl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Step 1: Methyl 2-((1-(2,7-dimethyl-1-oxo-3-(prop-1-in-1-yl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate [ka] To a solution of methyl 2-((1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate (60 mg, 0.16 mmol) and propyne (1 M in THF, 0.30 mL, 0.31 mmol), Pd(PPh3)4 (9 mg, 0.01 mmol) and CuI (3 mg, 0.02 mmol) were added under N2. The resulting solution was stirred at 70°C for 15 hours. The mixture was poured into H2O and extracted with ethyl acetate. The combined organic extract was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography of silica gel eluted with 25%-30% ethyl acetate in petroleum ether to obtain the product (41 mg, 66%) as a yellow oil. MS(ESI)m / e[M+1] + =389.

[0244] Step 2: 2-((1-(3-(1-(3-cyanophenyl)-1H-pyrazole-4-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Lithium hydroxide monohydrate (23 mg, 0.55 mmol) was added to a solution of methyl 2-((1-(2,7-dimethyl-1-oxo-3-(prop-1-in-1-yl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate (43 mg, 0.11 mmol) in methanol (4 mL), H2O (2 mL), and THF (4 mL). The resulting solution was stirred at 50°C for 7 hours. The solution was concentrated under vacuum. The residue was redissolved in H2O and acidified to pH 5-6 with HCl (2 M in water). The mixture was filtered, and the filtration cake was purified by preparative HPLC to obtain the desired product (14 mg, 34%). 1H NMR(400 MHz,DMSO-d6).δ ppm 12.80(brs,1H),8.39(s,1H),7.91(s,1H),7.78(d,J=7.3 Hz,1H),7.44(s,1H),7.23(s,1H),7.15(t,J=7.5 Hz,1H),6.50(t,J=7.5 Hz,1H),6.27(d,J=8.5 Hz,1H),5.24-5.13(m,1H),3.60(s,3H),2.32(s,3H),2.17(s,3H),1.47(d,J=6.5 Hz,3H).MS(ESI)m / e[M+1] + =375.

[0245] Example 28: 2-((1-(3-(cyclohexylethynyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Step 1: Methyl 2-((1-(3-(cyclohexylethinyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate [ka] To a solution of methyl 2-((1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate (60 mg, 0.16 mmol) and ethynylcyclohexane (34 mg, 0.31 mmol) in DMF (4 mL) and TEA (2 mL), Pd(PPh3)4 (9 mg, 0.01 mmol) and CuI (3 mg, 0.02 mmol) were added under N2. The resulting solution was stirred at 70°C for 15 hours. The mixture was poured into H2O and extracted with ethyl acetate. The combined organic extract was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography of silica gel eluted with 20%-25% ethyl acetate in petroleum ether to obtain the product (55 mg, 75%) as a yellow oil. MS(ESI)m / e[M+1] + =457.

[0246] Step 2: 2-((1-(3-(cyclohexylethinyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Lithium hydroxide monohydrate (25 mg, 0.60 mmol) was added to a solution of methyl 2-((1-(3-(cyclohexylethynyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate (55 mg, 0.12 mmol) in methanol (4 mL), H2O (2 mL), and THF (4 mL). The resulting solution was stirred at 50°C for 7 hours. The solution was concentrated under vacuum. The residue was redissolved in H2O and acidified to pH 5-6 with HCl (2 M in water). The mixture was filtered, and the filtered cake was purified by preparative HPLC to obtain the desired product (21 mg, 40%). 1 H NMR(400 MHz,DMSO-d6).δ ppm 12.77(brs,1H),8.36(s,1H),7.91(s,1H),7.78(d,J=7.9 Hz,1H),7.44(s,1H),7.20(s,1H),7.15(t,J=7.5 Hz,1H),6.50(t,J=7.5 Hz,1H),6.27(d,J=8.5 Hz,1H),5.28-5.10(m,1H),3.61(s,3H),2.84-2.72(m,1H),2.32(s,3H),1.91-1.77 (m,2H),1.73-1.61(m,2H),1.60-1.43(m,6H),1.43-1.27(m,3H).MS(ESI)m / e[M+1] + =443.

[0247] Example 29: 2-((1-(3-(1-(3-cyanophenyl)-1H-pyrazole-4-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Step 1: Methyl 2-((1-(3-(1-(3-cyanophenyl)-1H-pyrazole-4-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate [ka] Pd(PPh3)4 (15 mg, 0.01 mmol) was added under N2 to a solution of methyl 2-((1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate (50 mg, 0.13 mmol), 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-yl)benzonitrile (77 mg, 0.26 mmol), and K3PO4 (83 mg, 0.39 mmol) in dioxane (8 mL) and H2O (1 mL). The resulting solution was stirred at 100°C for 15 hours. The mixture was poured into H2O and extracted with ethyl acetate. The combined organic extract was washed with brine (20 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography of silica gel eluted with 55%-60% Â in petroleum ether to obtain the product (62 mg, 93%). MS(ESI)m / e[M+1] + = 518.

[0248] Step 2: 2-((1-(3-(1-(3-cyanophenyl)-1H-pyrazole-4-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Lithium hydroxide monohydrate (25 mg, 0.60 mmol) was added to a solution of methyl 2-((1-(3-(1-(3-cyanophenyl)-1H-pyrazole-4-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate (62 mg, 0.12 mmol) in methanol (4 mL), H2O (2 mL), and THF (4 mL). The resulting solution was stirred at 45°C for 13 hours. The solution was concentrated under vacuum. The residue was redissolved in H2O and acidified to pH 5-6 with HCl (2 M in water). The mixture was filtered, and the filtered cake was purified by preparative HPLC to obtain the desired product (2 mg, 3%). 1 H NMR(400 MHz,DMSO-d6).δ ppm 9.05(s,1H),8.59(brs,1H),8.41(s,1H),8.33-8.27(m,,1H),8.25(s,1H),7.95(s,1H),7.88-7.70(m,3H),7.46(s,1H),7.12(t,J=7.5 Hz,1H),7.06(s,1H),6.48(t,J=7.4 Hz,1H),6.29(d,J=8.5 Hz,1H),5.27-5.15(m,1H),3.60(s,3H),2.34(s,3H),1.51(d,J=6.5 Hz,3H).MS(ESI)m / e[M+1] + =504.

[0249] Example 30: (R)-2-((1-(2,7-dimethyl-1-oxo-3-phenyl-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] (R)-2-((1-(2,7-dimethyl-1-oxo-3-phenyl-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid (30 mg) was obtained by chiral separation of racemic 2-((1-(2,7-dimethyl-1-oxo-3-phenyl-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid (30 mg) by SFC (column: DAIEL CHIRALCEL OD (250 mm × 30 mm, 10 μm); mobile phase: [CO2-MeOH (0.1% NH3H2O)]; B%: 32%, isocratic elution mode). Rt: 0.989 minutes. 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.75(s,1H),8.37(s,1H),8.00(s,1H),7.80(d,J=7.4 Hz,1H),7.62-7.45(m,6H),7.21-7.13(m,1H),6.83(s,1H),6.56-6.47(m,1H),6.34(d,J=8.1 Hz,1H),5.20(s,1H),3.33(s,3H),2.37(s,3H),1.51(d,J=3.7 Hz,7H).MS(ESI)m / e[M+1] + =413.

[0250] Example 31: (S)-2-((1-(2,7-dimethyl-1-oxo-3-phenyl-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] (S)-2-((1-(2,7-dimethyl-1-oxo-3-phenyl-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid (29.1 mg) was obtained by chiral separation of racemic 2-((1-(2,7-dimethyl-1-oxo-3-phenyl-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid (29.1 mg) by SFC (column: DAIEL CHIRALCEL OD (250 mm × 30 mm, 10 μm); mobile phase: [CO2-MeOH (0.1% NH3H2O)]; B%: 32%, isocratic elution mode). Rt: 1.502 minutes. 1H NMR(400 MHz,DMSO-d6)δ ppm 12.75(s,1H),8.37(s,1H),8.00(s,1H),7.80(d,J=7.4 Hz,1H),7.62-7.45(m,6H),7.21-7.13(m,1H),6.83(s,1H),6.56-6.47(m,1H),6.34(d,J=8.1 Hz,1H),5.20(s,1H),3.33(s,3H),2.37(s,3H),1.51(d,J=3.7 Hz,7H).MS(ESI)m / e[M+1] + =413.

[0251] Example 32: 2-((1-(3-(2-cyanophenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] The desired product (2.8 mg) was obtained by following the same procedure as in Example 10. 1 H NMR(400 MHz,DMSO-d6)δ ppm 8.46(s,1H),8.10-7.99(m,2H),7.92-7.70(m,4H),7.51(m,1H),7.11(m,2H),6.50(m,1H),6.32(m,1H),5.23(m,1H),3.27(d,J=2.4 Hz,3H),2.38(d,J=7.2 Hz,3H),1.55-1.44(m,3H).MS(ESI)m / e[M+1] + = 438.

[0252] Example 33: 3-((1-(3-(4-fluorophenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)picolinic acid [ka] Step 1: Methyl 3-((1-(3-(4-fluorophenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)picolinate [ka] A mixture of 5-(1-bromoethyl)-3-(4-fluorophenyl)-2,7-dimethylisoquinoline-1(2H)-one (60 mg, 0.16 mmol), methyl 3-aminopicolinate (37 mg, 0.24 mmol), and DIEA (62 mg, 0.48 mmol) in DMF (5 mL) was stirred at 90°C for 1 hour. The mixture was concentrated under vacuum. The residue was purified by preparative TLC to obtain the desired product (30 mg, 42%). MS(ESI)m / e[M+1] + =446.

[0253] Step 2: 3-((1-(3-(4-fluorophenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)picolinic acid [ka] To a solution of methyl 3-((1-(3-(4-fluorophenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)picolinate (30 mg, 0.07 mmol) in MeOH (1 mL) and THF (0.5 mL), 4N NaOH (0.2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was adjusted to pH=5 with 1N HCl and concentrated under vacuum. The residue was purified by preparative HPLC to obtain the desired product (6.0 mg, 21%). 1 H NMR(400 MHz,DMSO-d6)δ ppm 8.95-8.50(m,1H),7.99(s,1H),7.84-7.81(m,1H),7.67-7.64(m,2H),7.48(s,1H),7.39-7.34(m,2H),7.33-7.23(m,1H),6.88(d,J=7.2 Hz,1H),6.83(s,1H),5.35-5.20(m,1H),3.53(s,3H),2.36(s,3H),1.52(d,J=6.8 Hz,3H).MS(ESI)m / e[M+1] + = 432.

[0254] Example 34: (R)-2-((1-(3-(4-fluorophenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Chiral separation of racemic 2-((1-(3-(4-fluorophenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid (110 mg) by SFC (column: DAIEL CHIRALPAK OD (250 mm × 50 mm, 10 μm); mobile phase: [CO2-MeOH (0.1% NH3H2O)]; B%: 35%, isocratic elution mode) yields (R)-2-((1-(3-(4-fluorophenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid (43 mg). Rt: 4.033 minutes. 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.74 ppm(brs,1H),8.37(d,J=4.8 Hz,1H),7.99(s,1H),7.79(d,J=7.8 Hz,1H),7.68-7.62(m,2H),7.47(s,1H),7.36(t,J=7.8 Hz,2H),7.17(t,J=7.2 Hz,1H),6.83(s,1H),6.51(t,J=6.4 Hz,1H),6.33(d,J=8.4 Hz,1H),5.24-5.15(m,1H),3.32(s,3H),2.36(s,3H),1.50(d,J=4.8 Hz, 3H).MS(ESI)m / e[M+1] + =431.

[0255] Example 35: (S)-2-((1-(3-(4-fluorophenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] (S)-2-((1-(3-(4-fluorophenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid (18 mg) was obtained by chiral separation of racemic 2-((1-(3-(4-fluorophenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid (110 mg) by SFC (column: DAIEL CHIRALPAK OD (250 mm x 50 mm, 10 μm); mobile phase: [CO2-MeOH (0.1% NH3H2O)]; B%: 35%, isocratic elution mode). Rt: 3.630 minutes. 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.74(brs,1H),8.37(d,J=4.8 Hz,1H),7.99(s,1H),7.79(d,J=7.8 Hz,1H),7.68-7.62(m,2H),7.47(s,1H),7.36(t,J=7.8 Hz,2H),7.17(t,J=7.2 Hz,1H),6.83(s,1H),6.51(t,J=6.4 Hz,1H),6.33(d,J=8.4 Hz,1H),5.24-5.15(m,1H),3.32(s,3H),2.36(s,3H),1.50(d,J=4.8 Hz, 3H).MS(ESI)m / e[M+1] + =431.

[0256] Example 36: 2-((1-(2,7-dimethyl-1-oxo-3-(pyridine-2-yl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] The desired product (13 mg) was obtained by following the same procedure as in Example 10. 1H NMR(399 MHz,DMSO-d6)δ ppm 12.76(s,1H),8.74(d,J=4.1 Hz,1H),8.39(d,J=5.4 Hz,1H),8.08-7.96(m,2H),7.80(dd,J=13.2,4.9 Hz,2H),7.58-7.47(m,2H),7.18(t,J=7.1 Hz,1H),7.02(s,1H),6.52(m,1H),6.35(d,J=8.5 Hz,1H),5.44-5.07(m,1H),3.40(s,3H),2.39(s,3H),1.52(d,J=6.5 Hz,3H).MS(ESI)m / e[M+1] + =414.

[0257] Example 37: 2-((1-(2,7-dimethyl-1-oxo-3-(pyridine-3-yl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] The desired product (23.56 mg) was obtained by following the same procedure as in Example 10. 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.78(s,1H),8.82(d,J=1.6 Hz,1H),8.74-8.67(m,1H),8.46(s,1H),8.07(d,J=8.0 Hz,1H),8.00(s,1H),7.79(d,J=6.8 Hz,1H),7.57(m,1H),7.49(s,1H),7.15(t,J=7.2 Hz,1H),6.94(s,1H),6.50(m,1H),6.33(d,J=8.4 Hz,1H),5.24(m,1H),3.34(s,3H),2.37(s,3H),1.50(d,J=6.4 Hz, 3H).MS(ESI)m / e[M+1] + =414.

[0258] Example 38: 2-((1-(3-(5-fluoropyridine-3-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] The desired product (14.5 mg) was obtained by following the same procedure as in Example 10. 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.76(brs,1H),8.84-8.65(m,2H),8.42(s,1H),8.12(d,J=10.0 Hz,1H),8.00(s,1H),7.79(d,J=6.4 Hz,1H),7.49(s,1H),7.15(m,1H),7.01(s,1H),6.51(m,1H),6.33(d,J=8.8 Hz,1H),5.25(m,1H),3.36(s,3H),2.37(s,3H),1.50(d,J=6.8 Hz,3H).MS(ESI)m / e[M+1] + = 432.

[0259] Example 39: 2-((1-(2,7-dimethyl-3-(2-methyl-2H-pyrazolo[4,3-b]pyridine-5-yl)-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] The desired product (49.3 mg) was obtained by following the same procedure as in Example 10. 1 H NMR(400 MHz,DMSO-d6)δ ppm 8.77(s,2H),8.25(d,J=8.8 Hz,1H),8.01(s,1H),7.79(m,1H),7.63(d,J=8.8 Hz,1H),7.53(s,1H),7.18-6.95(m,2H),6.47(m,1H),6.29(d,J=8.4 Hz,1H),5.19(m,1H),4.27(s,3H),3.42(s,3H),2.38(s,3H),1.50(d,J=6.8 Hz,3H).MS(ESI)m / e[M+1] + = 468.

[0260] Example 40: (R)-2-((1-(2,7-dimethyl-3-(4-(1-methyl-1H-pyrazole-4-yl)phenyl)-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Chiral separation of racemic 2-((1-(2,7-dimethyl-3-(4-(1-methyl-1H-pyrazole-4-yl)phenyl)-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid (52 mg) by SFC (column name: CHIRALPAK AD-H 20×250 mm, 5 μm; cosolvent: 35% MeOH (0.1% DEA); temperature (°C): 35; flow rate (mL / min): 40 mL / min; back pressure: 100 bar) yields (R)-2-((1-(2,7-dimethyl-3-(4-(1-methyl-1H-pyrazole-4-yl)phenyl)-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid (52 mg). Rt: 6.45 minutes. 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.75(brs,1H),8.39(s,1H),8.22(s,1H),8.03-7.89(m,2H),7.84-7.73 (m,1H),7.73-7.62(m,2H),7.61-7.51(m,2H),7.46(s,1H),7.15(t,J=7.2 Hz,1H),6.83(s,1H),6.50(t,J=6.9 Hz,1H),6.32(d,J=8.1 Hz,1H),5.19(s,1H),3.87(s,3H),3.34(s,3H),2.35(s,3H),1.50(d,J=4.5 Hz, 3H).MS(ESI)m / e[M+1] + =493.

[0261] Example 41: (S)-2-((1-(2,7-dimethyl-3-(4-(1-methyl-1H-pyrazole-4-yl)phenyl)-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Chiral separation of racemic 2-((1-(2,7-dimethyl-3-(4-(1-methyl-1H-pyrazole-4-yl)phenyl)-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid (49.6 mg) by SFC (column name: CHIRALPAK AD-H 20×250 mm, 5 μm; cosolvent: 35% MeOH (0.1% DEA); temperature (°C): 35; flow rate (mL / min): 40 mL / min; back pressure: 100 bar). Rt: 10.05 minutes. 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.75(brs,1H),8.39(s,1H),8.22(s,1H),8.03-7.89(m,2H),7.84-7.73 (m,1H),7.73-7.62(m,2H),7.61-7.51(m,2H),7.46(s,1H),7.15(t,J=7.2 Hz,1H),6.83(s,1H),6.50(t,J=6.9 Hz,1H),6.32(d,J=8.1 Hz,1H),5.19(s,1H),3.87(s,3H),3.34(s,3H),2.35(s,3H),1.50(d,J=4.5 Hz, 3H).MS(ESI)m / e[M+1] + =493.

[0262] Example 42: 2-((1-(2,7-dimethyl-1-oxo-3-(phenylcarbamoyl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Step 1: Methyl 5-acetyl-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-3-carboxylate [ka] A mixture of 5-acetyl-3-chloro-2,7-dimethylisoquinoline-1(2H)-one (500 mg, 2.0 mmol), Pd(dppf)Cl2 (163 mg, 0.2 mmol), and TEA (606 mg, 6.0 mmol) in MeOH (15 mL) was stirred at 100 °C for 15 hours under a CO atmosphere (25 atm). The mixture was concentrated under vacuum. The residue was purified by CombiFlash® chromatography on silica gel (PE / EA = 1 / 1) to obtain the desired product (320 mg, 58%). MS(ESI)m / e[M+1] + =274.

[0263] Step 2: 5-acetyl-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid [ka] A solution of methyl 5-acetyl-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-3-carboxylate (320 mg, 1.2 mmol) in methanol (5 mL) was mixed with NaOH (3 M, 1 mL). The resulting solution was stirred at 25°C for 2 hours. The solution was concentrated under vacuum. The residue was redissolved in H2O and acidified to pH 5-6 with HCl (2 M in water). The mixture was filtered, and the solid was collected to obtain the desired product (280 mg, crude). MS(ESI)m / e[M+1] + =260.

[0264] Step 3: 5-Acetyl-2,7-dimethyl-1-oxo-N-phenyl-1,2-dihydroisoquinoline-3-carboxamide [ka] A mixture of 5-acetyl-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid (280 mg, 1.1 mmol), aniline (113 mg, 1.2 mmol), HATU (627 mg, 1.6 mmol), and DIEA (426 mg, 3.3 mmol) in DMF (5 mL) was stirred at 25°C for 15 hours under N2. The mixture was concentrated under vacuum. The residue was purified by CombiFlash® chromatography on silica gel (PE / EA = 2 / 3) to obtain the desired product (230 mg, 62%). MS(ESI)m / e[M+1] + =335.

[0265] Step 4: 5-(1-aminoethyl)-2,7-dimethyl-1-oxo-N-phenyl-1,2-dihydroisoquinoline-3-carboxamide [ka] To a solution of 5-acetyl-2,7-dimethyl-1-oxo-N-phenyl-1,2-dihydroisoquinoline-3-carboxamide (230 mg, 0.7 mmol) in ethanol (10 mL), ammonium acetate (539 mg, 7 mmol) was added, followed by the addition of NaBH3CN (70 mg, 1.1 mmol). The resulting solution was stirred at 90°C for 15 hours. The solution was concentrated under vacuum. The residue was purified by CombiFlash® chromatography on silica gel (DCM / MeOH with 1% ammonium hydroxide) to obtain the desired product (130 mg, 55%). MS(ESI)m / e[M+1] + =336.

[0266] Step 5: 2-((1-(2,7-dimethyl-1-oxo-3-(phenylcarbamoyl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] To a solution of 5-(1-aminoethyl)-2,7-dimethyl-1-oxo-N-phenyl-1,2-dihydroisoquinoline-3-carboxamide (130 mg, 0.39 mmol), 2-aminobenzoic acid (69 mg, 0.50 mmol), L-proline (4 mg, 0.04 mmol), and K2CO3 (166 mg, 1.2 mmol) in 3 mL of DMSO, CuI (7 mg, 0.04 mmol) was added. The resulting solution was stirred overnight at 110°C under N2. After cooling to room temperature, the solution was concentrated under vacuum, and the residue was dissolved in water. The pH of the solution was adjusted to 4-5, and the solid was collected by filtration. The crude product was purified by preparative HPLC (mobile phase: water (10 mmol / L FA) and ACN (25% phase B, up to 80% in 8 minutes); detector: UV 254 nm) to obtain 2-((1-(2,7-dimethyl-1-oxo-3-(phenylcarbamoyl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid (19 mg, 11%). 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.78(brs,1H),10.87(s,1H),8.41(s,1H),7.99(s,1H),7.86-7.64(m,3H),7.56-7.05(m,6H),6.51(m,1H),6.31(d,J=8.4 Hz,1H),5.36-5.17(m,1H),3.52(s,3H),2.36(s,3H),1.53(d,J=6.1 Hz,3H).MS(ESI)m / e[M+1] + = 456.

[0267] Example 43: 2-((1-(2,7-dimethyl-1-oxo-3-(phenylthinyl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Step 1: Methyl 2-((1-(2,7-dimethyl-1-oxo-3-(phenylthinyl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate [ka] A mixture of methyl 2-((1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate (80 mg, 0.2 mmol), ethinylbenzene (31 mg, 0.3 mmol), and Pd(PPh3)2Cl2 (14 mg, 0.02 mmol) in TEA (1 mL) and DMF (2 mL) was stirred at 100°C for 15 hours under N2. The mixture was poured into H2O and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (PE / EA = 2:1) to obtain the desired product (50 mg, 55%). MS(ESI)m / e[M+1] + =451.

[0268] Step 2: 2-((1-(2,7-dimethyl-1-oxo-3-(phenylthinyl)-1,2-dihydroisoquinoline-5-yl)ethyl) Aminobenzoic acid [ka] To a solution of methyl 2-((1-(2,7-dimethyl-1-oxo-3-(phenylthinyl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate (25 mg, 0.06 mmol) in methanol (3 mL), NaOH (3 M, 1 mL) was added. The resulting solution was stirred at 50°C for 5 hours. The solution was concentrated under vacuum. The residue was redissolved in H2O and acidified to pH 5-6 with HCl (2 M in water). The mixture was filtered, the solid was collected, and purified by preparative HPLC (mobile phase, water (10 mmol / L FA) and ACN (25% phase B, up to 80% in 8 minutes); detector, UV 254 nm) to obtain the desired product (15 mg, 46%). 1H NMR(400 MHz,DMSO-d6)δ ppm 12.79(s,1H),8.42(s,1H),7.96(s,1H),7.83-7.73(m,1H),7.72-7.61(m,2H),7.56-7.41(m,5H),7.16(m,1H),6.51(m,1H),6.30(d,J=8.5 Hz,1H),5.33-5.17(m,1H),3.71(s,3H),2.35(s,3H),1.51(d,J=6.4 Hz,3H).MS(ESI)m / e[M+1] + = 437.

[0269] Example 44: (E)-2-((1-(2,7-dimethyl-1-oxo-3-styryl-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Step 1: Methyl(E)-2-((1-(2,7-dimethyl-1-oxo-3-styryl-1,2-dihydroisoquinoline-5-yl)ethyl)aminobenzoate [ka] To a solution of methyl 2-((1-(2,7-dimethyl-1-oxo-3-(phenylthinyl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate (25 mg, 0.06 mmol) in MeOH (3 mL), NaBH4 (7 mg, 0.18 mmol) was added. The resulting solution was stirred at 0-10°C for 1 hour. The mixture was quenched with water and concentrated under vacuum. The residue was purified by preparative TLC (PE / EA = 2:1) to obtain the desired product (20 mg, 74%). MS(ESI)m / e[M+1] + =453.

[0270] Step 2: (E)-2-((1-(2,7-dimethyl-1-oxo-3-styryl-1,2-dihydroisoquinoline-5-yl)ethyl)amino) benzoic acid [ka] A solution of methyl(E)-2-((1-(2,7-dimethyl-1-oxo-3-styryl-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate (20 mg, 0.04 mmol) in methanol (3 mL) was mixed with NaOH (3 M, 1 mL). The resulting solution was stirred at 50°C for 5 hours. The solution was concentrated under vacuum. The residue was redissolved in H2O and acidified to pH 5-6 with HCl (2 M in water). The mixture was filtered, the solid was collected and purified by preparative HPLC (mobile phase, water (10 mmol / L FA) and ACN (25% phase B, up to 80% in 8 minutes; detector, UV 254 nm) to obtain (E)-2-((1-(2,7-dimethyl-1-oxo-3-styryl-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid (10 mg, 57%). 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.76(brs,1H),8.27(s,1H),7.92(s,1H),7.78-7.72(m,1H),7.33(s,1H),7.30-7.13(m, 5H),7.12-7.04(m,1H),6.96-6.89(m,1H),6.71-6.58(m,2H),6.48(m,1H),5.96(d,J=8.5 Hz,1H),4.76-4.62(m,1H),3.56(s,3H),2.30(s,3H),1.16(t,J=5.2 Hz,3H).MS(ESI)m / e[M+1] + = 439.

[0271] Example 45: 2-((1-(3-(3,4-dihydronaphthalene-2-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] The desired product (13.6 mg) was obtained by following the same procedure as in Example 10. 1H NMR(399 MHz,DMSO-d6)δ ppm 12.76(brs,1H),8.40(s,1H),7.94(s,1H),7.79(dd,J=7.9,1.4 Hz,1H),7.45(s,1H),7.29-7.06(m,5H),6.87(s,1H),6.79(s,1H),6.50(m,1H),6.33(d,J=8.5 Hz,1H),5.23-5.09(m,1H),3.50(s,3H),2.93(t,J=8.0 Hz,2H),2.56(t,J=7.9 Hz,2H),2.34(s,3H),1.52(d,J=6.5 Hz, 3H).MS(ESI)m / e[M+1] + =465.3.MS(ESI)m / e[M+1] + = 465.

[0272] Example 46: 2-((1-(2,7-dimethyl-1-oxo-3-(1-phenyl-1,2,3,6-tetrahydropyridine-4-yl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] The desired product (10 mg) was obtained by following the same procedure as in Example 10. 1 H NMR(399 MHz,DMSO-d6)δ ppm 12.78(brs,1H),8.47(s,1H),7.92(s,1H),7.81-7.72(m,1H),7.44(s,1H),7.29-7.19(m,2H),7.14(t,J=7.5 Hz,1H),6.98(d,J=8.1 Hz,2H),6.82-6.68(m,2H),6.49(m,1H),6.29(d,J=8.4 Hz,1H),6.11(s,1H),5.15(s,1H),3.85(s,2H),3.49(t,J=5.4 Hz,2H),3.42(s,3H),2.54-2.50(m,2H),2.32(s,J=8.8 Hz,3H),1.50(d,J=6.5 Hz,3H).MS(ESI)m / e[M+1] + = 494.

[0273] Example 47: 5-((1-(2,7-dimethyl-1-oxo-3-phenyl-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzo[b]thiophene-6-carboxylic acid [ka] Step 1: Methyl 6-bromo-5-nitrobenzo[b]thiophene-2-carboxylate [ka] A mixture of 4-bromo-2-fluoro-5-nitrobenzaldehyde (1.0 g, 4.03 mmol), methyl 2-mercaptoacetate (427 mg, 4.03 mmol), and K2CO3 (1.1 g, 8.06 mmol) in DMF (10 mL) was stirred at 80°C for 2 hours. The mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography using silica gel to obtain the desired product (1.0 g, 79%). MS(ESI)m / e[M+1] + =316.

[0274] Step 2: 6-bromo-5-nitrobenzo[b]thiophene-2-carboxylic acid [ka] A mixture of methyl 6-bromo-5-nitrobenzo[b]thiophene-2-carboxylate (1.0 g, 3.17 mmol) and LiOH (762 mg, 31.74 mmol) in MeOH (3 mL), THF (3 mL), and H2O (3 mL) was stirred at room temperature for 5 hours. The mixture was adjusted to pH=5 with 1N HCl and concentrated under vacuum. The mixture was filtered, and the filter cake was washed with water to obtain the desired product (600 mg, 63%). MS(ESI)m / e[M+1] + =302.

[0275] Step 3: 6-bromo-5-nitrobenzo[b]thiophene [ka] A mixture of 6-bromo-5-nitrobenzo[b]thiophene-2-carboxylic acid (500 mg, 1.66 mmol) and LiCl (349 mg, 8.31 mmol) in DMSO (10 mL) was stirred at 190 °C for 2 hours. The mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to obtain the desired product (300 mg, 70%). MS(ESI)m / e[M+1] + =258.

[0276] Step 4: 6-bromobenzo[b]thiophene-5-amine [ka] A mixture of 6-bromo-5-nitrobenzo[b]thiophene (300 mg, 1.17 mmol) and Fe (654 mg, 11.67 mmol) in MeOH (5 mL) and saturated NH4Cl (aqueous solution, 5 mL) was stirred at 60°C for 30 minutes. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to obtain the desired product (220 mg, 83%). MS(ESI)m / e[M+1] + =228.

[0277] Step 5: Methyl 5-aminobenzo[b]thiophene-6-carboxylate [ka] A mixture of 6-bromobenzo[b]thiophene-5-amine (300 mg, 1.17 mmol), Pd(dppf)Cl2 (654 mg, 11.67 mmol), and TEA (654 mg, 11.67 mmol) in MeOH (10 mL) was stirred overnight at 120 °C under a CO2 atmosphere (20 atm). The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to obtain the desired product (100 mg, 55%). MS(ESI)m / e[M+1] + =208.

[0278] Step 6: Methyl 5-((1-(2,7-dimethyl-1-oxo-3-phenyl-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzo[b]thiophene-6-carboxylate [ka] A mixture of 5-(1-bromoethyl)-2,7-dimethyl-3-phenylisoquinoline-1(2H)-one (50 mg, 0.14 mmol), methyl 5-aminobenzo[b]thiophene-6-carboxylate (29 mg, 0.14 mmol), and DIEA (54 mg, 0.42 mmol) in DMF (2 mL) was stirred at 90°C for 1 hour. The mixture was concentrated under vacuum. The residue was purified by preparative TLC to obtain the desired product (30 mg, 44%). MS(ESI)m / e[M+1] + = 483.

[0279] Step 7: 5-((1-(2,7-dimethyl-1-oxo-3-phenyl-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzo[b]thiophene-6-carboxylic acid [ka] A mixture of methyl 5-((1-(2,7-dimethyl-1-oxo-3-phenyl-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzo[b]thiophene-6-carboxylate (30 mg, 0.06 mmol) in NaOH (1 mL, 4 N), MeOH (1 mL), and THF (1 mL) was stirred at 50°C for 3 hours. The mixture was adjusted to pH 5 with 1 N HCl and concentrated under vacuum. The residue was purified by preparative HPLC to obtain the desired product (6.99 mg, 24%). 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.94(brs,1H),8.44(s,1H),8.31(brs,1H),7.99(s,1H),7.75(d,J=8.0 Hz,1H),7.60-7.52(m,6H),7.06(d,J=5.4 Hz,1H),6.86(s,1H),6.72(s,1H),5.21-5.20(m,1H),3.33(s,3H),2.36(s,3H),1.54(d,J=8.0 Hz,3H).MS(ESI)m / e[M+1] + =469.

[0280] Example 48: 3-((1-(2,7-dimethyl-1-oxo-3-phenyl-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzo[b]thiophene-2-carboxylic acid [ka] Step 1: Methyl 3-((1-(2,7-dimethyl-1-oxo-3-phenyl-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzo[b]thiophene-2-carboxylate [ka] A solution of 5-(1-bromoethyl)-2,7-dimethyl-3-phenylisoquinoline-1(2H)-one (70 mg, 0.2 mmol), methyl 3-aminobenzo[b]thiophene-2-carboxylate (83 mg, 0.4 mmol), and TEA (101 mg, 1 mmol) in DMF (4 mL) was stirred at 90°C for 2 hours. The mixture was cooled to room temperature. The solvent was removed, and the crude residue was purified by preparative TLC to obtain the desired product (45 mg, 47%). MS(ESI)m / e[M+H] + = 483.

[0281] Step 2: 3-((1-(2,7-dimethyl-1-oxo-3-phenyl-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzo [b] Thiofen-2-carboxylic acid [ka] A solution of methyl 3-((1-(2,7-dimethyl-1-oxo-3-phenyl-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzo[b]thiophene-2-carboxylate (45 mg, 0.093 mmol) in NaOH (1N, 10 mL) and MeOH (10 mL) was stirred at 70°C for 4 hours. The solvent was removed, and the residue was redissolved in H2O (2 mL). A white solid was collected, and the solid was purified by preparative HPLC to obtain the desired product (21 mg, 48%). 1 H NMR(400 MHz,DMSO-d6)δ ppm 8.41-8.15(m,1H),7.91(s,1H),7.82(d,J=8.4 Hz,1H),7.76(s,1H),7.68(d,J=7.9 Hz,1H),7.51(s,5H),7.23(s,1H),7.10(m,1H),6.79(s,1H),5.74(s,1H),3.28(s,3H),2.37(s,3H),1.49(d,J=6.2 Hz,3H).MS(ESI)m / e[M+H] + =469.

[0282] Example 49: 2-((1-(2,7-dimethyl-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] The desired product (46 mg) was obtained by following the same procedure as in Example 10. 1 H NMR(399 MHz,DMSO-d6)δ ppm 12.75(brs,1H),8.74(s,1H),7.99(s,1H),7.93-7.72(m,5H),7.51(s,1H),7.08(s,1H),6.93(s,1H),6.50-6.40(m,1H),6.27(d,J=8.4 Hz,1H),5.18(s,1H),3.34(s,3H),2.37(s,3H),1.48(d,J=6.5 Hz,3H).MS(ESI)m / e[M+1] + =481.

[0283] Example 50: 2-((1-(2,7-dimethyl-1-oxo-3-(3-(trifluoromethyl)phenyl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] The desired product (42 mg) was obtained by following the same procedure as in Example 10. 1 H NMR(399 MHz,DMSO-d6)δ ppm 9.83(s,1H),8.06-7.94(m,2H),7.94-7.84(m,2H),7.81-7.72(m,2H),7.66-7.49(m,2H),6.96-6.83(m,2H),6.35(m,1H),6.12(d,J=8.1 Hz,1H),5.09(s,1H),3.31(s,3H),2.36(s,3H),1.44(d,J=6.5 Hz,3H).MS(ESI)m / e[M+1] + =481.

[0284] Example 51: 2-((1-(3-(4-(2-hydroxypropan-2-yl)phenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Step 1: Methyl 2-((1-(3-(4-(2-hydroxypropan-2-yl)phenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate [ka] A mixture of methyl 2-((1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate (50 mg, 0.13 mmol), (4-(2-hydroxypropan-2-yl)phenyl)boronic acid (46.8 mg, 0.26 mmol), Pd(dppf)Cl2 (9.5 mg, 0.013 mmol), and K3PO4 (55 mg, 0.26 mmol) in dioxane (8 mL) and H2O (2 mL) was stirred at 90°C for 5 hours under N2. The solvent was removed, and the residue was purified by silica gel flash column to obtain the desired crude product (100 mg, crude). MS(ESI)m / e[M+H] + = 485.

[0285] Step 2: 2-((1-(3-(4-(2-hydroxypropan-2-yl)phenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] A solution of methyl 2-((1-(3-(4-(2-hydroxypropane-2-yl)phenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate (100 mg, crude) in NaOH (1N, 5 mL) and MeOH (5 mL) was stirred at 60°C for 2 hours. The solvent was removed, the aqueous layer was acidified with HCl (2N), and extracted with EA. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain the desired product (48 mg, 78% in 2 steps). 1 H NMR(400 MHz,DMSO-d6)δ ppm 8.08(s,1H),7.90(d,J=7.9 Hz,1H),7.66(d,J=8.3 Hz,2H),7.58(s,1H),7.48(d,J=8.4 Hz,2H),7.11(dd,J=11.3,4.3 Hz,1H),6.90(s,1H),6.52(t,J=7.5 Hz,1H),6.29(d,J=8.5 Hz,1H),5.12(m,1H),3.45(s,3H),2.41(s,3H),1.61-1.56(m,9H).MS(ESI)m / e[MH] - =469.

[0286] Example 52: 2-((1-(2,7-dimethyl-1-oxo-3-(4-(prop-1-in-1-yl)phenyl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] The desired product (13.5 mg) was obtained by following the same procedure as in Example 10. 1H NMR(400 MHz,DMSO-d6)δ ppm 12.96(brs,1H),8.52(s,1H),7.98(s,1H),7.80(d,J=7.7 Hz,1H),7.61-7.44(m,5H),7.18-7.08(m,1H),6.84(s,1H),6.59-6.39(m,1H),6.31(d,J=8.4 Hz,1H),5.27-5.13(m,1H),3.32(s,3H),2.36(s,3H),2.08(s,3H),1.49(d,J=6.4 Hz,3H).MS(ESI)m / e[M+1] + =451.

[0287] Example 53: 2-((1-(3-(1a,6b-dihydro-1H-cyclopropa[b]benzofuran-5-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] The desired product (12.6 mg) was obtained by following the same procedure as in Example 10. 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.68(brs,1H),8.32-8.23(m,1H),7.88(s,1H),7.73(d,J=8.0 Hz,1H),7.51(s,1H),7.39(s,1H),7.20(d,J=8.0 Hz,1H),7.15-7.05(m,1H),6.88(d,J=8.0 Hz,1H),6.71(s,1H),6.44(t,J=7.2 Hz,1H),6.26(d,J=8.0 Hz,1H),5.18-5.05(m,1H),5.00-4.89(m,1H),3.22(s,3H),2.73-2.63(m,1H),2.47-2.38(m,1H),2.29(s,3H),1.43(d,J=6.8 Hz,3H),1.11-1.01(m,1H).MS(ESI)m / e[M+1] + =467.

[0288] Example 54: 3-((1-(3-(4-fluorophenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)isonicotinic acid [ka] Step 1: Methyl 3-((1-(3-(4-fluorophenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)isonicotinate [ka] A mixture of 5-(1-bromoethyl)-3-(4-fluorophenyl)-2,7-dimethylisoquinoline-1(2H)-one (60 mg, 0.16 mmol), methyl 3-aminoisonicotinate (37 mg, 0.24 mmol), and DIEA (62 mg, 0.48 mmol) in DMF (5 mL) was stirred at 90°C for 1 hour. The mixture was concentrated under vacuum. The residue was purified by preparative TLC to obtain the desired product (20 mg, 29%). MS(ESI)m / e[M+1] + =446.

[0289] Step 2: 3-((1-(3-(4-fluorophenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)isonicotinic acid [ka] To a solution of methyl 3-((1-(3-(4-fluorophenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)isonicotinate (20 mg, 0.04 mmol) in MeOH (1 mL) and THF (0.5 mL), 4N NaOH (0.2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was adjusted to pH 5 with 1N HCl and concentrated under vacuum. The residue was purified by preparative HPLC to obtain the desired product (2.9 mg, 15%). 1H NMR(400 MHz,DMSO-d6)δ ppm 8.43-8.23(m,1H),8.00(s,1H),7.75-7.72(m,2H),7.68-7.65(m,2H),7.57(d,J=5.0 Hz,1H),7.51(s,1H),7.39-7.34(m,2H),6.87(s,1H),5.40-5.30(m,1H),3.56(s,3H),2.37(s,3H),1.51(d,J=8.0 Hz,3H).MS(ESI)m / e[M+1] + = 432.

[0290] Example 55: 2-((1-(3-(6-(2-hydroxypropan-2-yl)pyridine-3-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] The desired product (70 mg) was obtained by following the same procedure as in Example 10. 1 H NMR(400 MHz,DMSO-d6)δ ppm 8.77-8.67(m,1H),8.53(s,1H),8.10-8.01(m,1H),7.99(s,1H),7.84-7.74(m,2H),7.49(d,J=1.3 Hz,1H),7.19-7.09(m,1H),6.95(s,1H),6.49(m,1H),6.32(d,J=8.5 Hz,1H),5.43-5.30(m,1H),5.29-5.16(m,1H),3.35(s,3H),2.37(s,3H),1.50(m,9H).MS(ESI)m / e[M+1] + = 472.

[0291] Example 56: (R)-2-((1-(3-(6-(2-hydroxypropan-2-yl)pyridine-3-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Chiral separation of racemic 2-((1-(3-(6-(2-hydroxypropan-2-yl)pyridine-3-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid (68 mg) by SFC (column name: YMC Cellulose-C 20×250 mm, 5 μm; cosolvent: 38% MeOH; temperature (°C): 35; flow rate (mL / min): 40 mL / min; back pressure: 100 bar) yields (R)-2-((1-(3-(6-(2-hydroxypropan-2-yl)pyridine-3-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid (23.7 mg). Rt: 7.15 minutes. 1 H NMR(400 MHz,DMSO-d6)δ ppm 8.77-8.67(m,1H),8.53(s,1H),8.10-8.01(m,1H),7.99(s,1H),7.84-7.74(m,2H),7.49(d,J=1.3 Hz,1H),7.19-7.09(m,1H),6.95(s,1H),6.49(m,1H),6.32(d,J=8.5 Hz,1H),5.43-5.30(m,1H),5.29-5.16(m,1H),3.35(s,3H),2.37(s,3H),1.50(m,9H).MS(ESI)m / e[M+1] + = 472.

[0292] Example 57: (S)-2-((1-(3-(6-(2-hydroxypropan-2-yl)pyridine-3-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Chiral separation of racemic 2-((1-(3-(6-(2-hydroxypropan-2-yl)pyridine-3-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid (68 mg) by SFC (column name: YMC Cellulose-C 20×250 mm, 5 μm; cosolvent: 38% MeOH; temperature (°C): 35; flow rate (mL / min): 40 mL / min; back pressure: 100 bar) yields (S)-2-((1-(3-(6-(2-hydroxypropan-2-yl)pyridine-3-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid (21.4 mg). Rt: 5.12 min. 1 H NMR(400 MHz,DMSO-d6)δ ppm 8.77-8.67(m,1H),8.53(s,1H),8.10-8.01(m,1H),7.99(s,1H),7.84-7.74(m,2H),7.49(d,J=1.3 Hz,1H),7.19-7.09(m,1H),6.95(s,1H),6.49(m,1H),6.32(d,J=8.5 Hz,1H),5.43-5.30(m,1H),5.29-5.16(m,1H),3.35(s,3H),2.37(s,3H),1.50(m,9H).MS(ESI)m / e[M+1] + = 472.

[0293] Example 58: 2-((1-(3-(5-fluoro-6-methoxypyridine-3-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] The desired product (49 mg) was obtained by following the same procedure as in Example 10. 1H NMR(400 MHz,DMSO-d6)δ ppm 12.76(brs,1H),8.41(s,1H),8.25(d,J=1.7 Hz,1H),8.08(dd,J=11.2,1.7 Hz,1H),7.99(s,1H),7.86-7.73(m,1H),7.48(s,1H),7.21-7.10(m,1H),6.95(s,1H),6.55-6.45(m,1H),6.33(d,J=8.5 Hz,1H),5.28-5.18(m,1H),4.03(s,3H),3.37(s,3H),2.37(s,3H),1.50(d,J=6.5 Hz, 3H).MS(ESI)m / e[M+1] + = 462.

[0294] Example 59: (R)-2-((1-(3-(5-fluoro-6-methoxypyridine-3-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Chiral separation of racemic 2-((1-(3-(5-fluoro-6-methoxypyridine-3-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid (18.1 mg) by SFC (column name: YMC Cellulose-C 20×250 mm, 5 μm; cosolvent: 35% MeOH; temperature (°C): 35; flow rate (mL / min): 40 mL / min; back pressure: 100 bar) yields (R)-2-((1-(3-(5-fluoro-6-methoxypyridine-3-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid (18.1 mg). Rt: 7.55 minutes. 1H NMR(400 MHz,DMSO-d6)δ ppm 12.76(s,1H),8.41(s,1H),8.25(d,J=1.7 Hz,1H),8.08(dd,J=11.2,1.7 Hz,1H),7.99(s,1H),7.86-7.73(m,1H),7.48(s,1H),7.21-7.10(m,1H),6.95(s,1H),6.51(m,1H),6.33(d,J=8.5 Hz,1H),5.28-5.18(m,1H),4.03(s,3H),3.37(s,3H),2.37(s,3H),1.50(d,J=6.5 Hz,3H).MS(ESI)m / e[M+1] + = 462.

[0295] Example 60: (S)-2-((1-(3-(5-fluoro-6-methoxypyridine-3-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Chiral separation of racemic 2-((1-(3-(5-fluoro-6-methoxypyridine-3-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid (16.8 mg) by SFC (column name: YMC Cellulose-C 20×250 mm, 5 μm; cosolvent: 35% MeOH; temperature (°C): 35; flow rate (mL / min): 40 mL / min; back pressure: 100 bar) yields (S)-2-((1-(3-(5-fluoro-6-methoxypyridine-3-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid (16.8 mg). Rt: 5.73 minutes. 1H NMR(400 MHz,DMSO-d6)δ ppm 12.76(s,1H),8.41(s,1H),8.25(d,J=1.7 Hz,1H),8.08(dd,J=11.2,1.7 Hz,1H),7.99(s,1H),7.86-7.73(m,1H),7.48(s,1H),7.21-7.10(m,1H),6.95(s,1H),6.51(m,1H),6.33(d,J=8.5 Hz,1H),5.28-5.18(m,1H),4.03(s,3H),3.37(s,3H),2.37(s,3H),1.50(d,J=6.5 Hz,3H).MS(ESI)m / e[M+1] + = 462.

[0296] Example 61: 2-((1-(2,7-dimethyl-1-oxo-3-(pyrimidine-5-yl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] The desired product (35 mg) was obtained by following the same procedure as in Example 10. 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.70(brs,1H),9.32(s,1H),9.12(s,2H),8.47-8.34(m,1H),8.01(s,1H),7.79(dd,J=7.9,1.4 Hz,1H),7.53-7.47(m,1H),7.21-7.12(m,1H),7.08(s,1H),6.51(m,1H),6.34(d,J=8.5 Hz,1H),5.32-5.20(m,1H),3.39(s,3H),2.38(s,3H),1.50(d,J=6.5 Hz,3H).MS(ESI)m / e[M+1] + =415.

[0297] Example 62: 2-((1-(3-(4-(1-hydroxycyclopropyl)phenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] The desired product (15 mg) was obtained by following the same procedure as in Example 10. 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.81(brs,1H),8.44(s,1H),8.13-8.05(m,2H),8.00(s,1H),7.84-7.70(m,3H),7.50(s,1H),7.15(m,1H),6.89(s,1H),6.51(t,J=7.5 Hz,1H),6.33(d,J=8.4 Hz,1H),5.28-5.13(m,1H),3.33(s,3H),3.18-3.05(m,2H),2.37(s,3H),1.50(d,J=6.5 Hz,3H),1.12(t,J=7.1 Hz,2H).MS(ESI)m / e[M+1] + =469.

[0298] Example 63: 2-((1-(2-(cyanomethyl)-3-(4-fluorophenyl)-7-methyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Step 1: 2-(5-acetyl-3-chloro-7-methyl-1-oxoisoquinoline-2(1H)-yl)acetonitrile [ka] A solution of 5-acetyl-3-chloro-7-methylisoquinoline-1(2H)-one (350 mg, 1.49 mmol) and K2CO3 (616 mg, 4.46 mmol) in DMF (15 mL) was mixed with 2-bromoacetonitrile (267 mg, 2.23 mmol) at 0°C. The reaction mixture was stirred at room temperature for 1 hour. The mixture was poured into H2O and extracted with EA. The combined organic solution was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography to obtain the product (150 mg, 37%). MS(ESI)m / e[M+1] + =275.

[0299] Step 2: 2-(5-acetyl-3-(4-fluorophenyl)-7-methyl-1-oxoisoquinoline-2(1H)-yl)acetonitrile [ka] To a solution of 2-(5-acetyl-3-chloro-7-methyl-1-oxoisoquinoline-2(1H)-yl)acetonitrile (150 mg, 0.55 mmol), (4-fluorophenyl)boronic acid (115 mg, 0.82 mmol), and K3PO4 (350 mg, 1.65 mmol) in dioxane (10 mL) and H2O (1 mL), Pd(PPh3)4 (31 mg, 0.03 mmol) was added under N2. The resulting solution was stirred overnight at 100°C. The mixture was poured into H2O and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel to obtain the product (175 mg, 93%). MS(ESI)m / e[M+1] + =335.

[0300] Step 3: 2-(3-(4-fluorophenyl)-5-(1-hydroxyethyl)-7-methyl-1-oxoisoquinoline-2(1H)-yl)acetonitrile [ka] A solution of 2-(5-acetyl-3-(4-fluorophenyl)-7-methyl-1-oxoisoquinoline-2(1H)-yl)acetonitrile (100 mg, 0.30 mmol) in DCM (10 mL) and MeOH (10 mL) was treated little by little with NaBH4 (12 mg, 0.33 mmol) at 0°C. The resulting solution was stirred at room temperature for 1 hour. The mixture was diluted with H2O (10 mL) and extracted with DCM (20 mL x 2). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel to obtain the product (99 mg, 95%). MS(ESI)m / e[M+1] + =337.

[0301] Step 4: 2-((1-(2-(cyanomethyl)-3-(4-fluorophenyl)-7-methyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] A solution of 2-(3-(4-fluorophenyl)-5-(1-hydroxyethyl)-7-methyl-1-oxoisoquinoline-2(1H)-yl)acetonitrile (99 mg, 0.30 mmol), PPh3 (117 mg, 0.45 mmol), and 2H-benzo[d][1,3]oxazine-2,4(1H)-dione (63 mg, 0.39 mmol) was prepared in THF (10 mL) with the addition of DIAD (91 mg, 0.45 mmol) at 0°C. After stirring at 0°C for 1 hour, 1 mL of NaOH (1 M in water) was added to the mixture. The resulting solution was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was redissolved in H2O and acidified to pH 5-6 with HCl (2 M in water). The mixture was filtered, and the filtration cake was purified by preparative HPLC to obtain the desired product (17 mg, 13%). 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.78(brs,1H),8.47-8.28(m,1H),8.01(s,1H),7.80(dd,J=7.9,1.5 Hz,1H),7.72-7.59(m,2H),7.55(d,J=1.3 Hz,1H),7.50-7.40(m,2H),7.22-7.09(m,1H),6.97(s,1H),6.55-6.45(m,1H),6.33(d,J=8.5 Hz,1H),5.30-5.18(m,1H),4.79(s,2H),2.38(s,3H),1.50(d,J=6.5 Hz, 3H).MS(ESI)m / e[M+1] + = 456.

[0302] Example 64: (R)-2-((1-(2-(cyanomethyl)-3-(4-fluorophenyl)-7-methyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Chiral separation of racemic 2-((1-(2-(cyanomethyl)-3-(4-fluorophenyl)-7-methyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid (8.8 mg) by SFC (column name: YMC Cellulose-C 20×250 mm, 5 μm; cosolvent: 32% MeOH; temperature (°C): 35; flow rate (mL / min): 40 mL / min; back pressure: 100 bar) yields (R)-2-((1-(2-(cyanomethyl)-3-(4-fluorophenyl)-7-methyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid (8.8 mg). Rt: 7.23 minutes. 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.78(s,1H),8.47-8.28(m,1H),8.01(s,1H),7.80(dd,J=7.9,1.5 Hz,1H),7.72-7.59(m,2H),7.55(d,J=1.3 Hz,1H),7.44(m,2H),7.22-7.09(m,1H),6.97(s,1H),6.51(m,1H),6.33(d,J=8.5 Hz,1H),5.30-5.18(m,1H),4.79(s,2H),2.38(s,3H),1.50(d,J=6.5 Hz,3H).MS(ESI)m / e[M+1] + = 456.

[0303] Example 65: (S)-2-((1-(2-(cyanomethyl)-3-(4-fluorophenyl)-7-methyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Chiral separation of racemic 2-((1-(2-(cyanomethyl)-3-(4-fluorophenyl)-7-methyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid (8.1 mg) by SFC (column name: YMC Cellulose-C 20×250 mm, 5 μm; cosolvent: 32% MeOH; temperature (°C): 35; flow rate (mL / min): 40 mL / min; back pressure: 100 bar) yields (S)-2-((1-(2-(cyanomethyl)-3-(4-fluorophenyl)-7-methyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid (8.1 mg). Rt: 5.43 minutes. 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.78(s,1H),8.47-8.28(m,1H),8.01(s,1H),7.80(dd,J=7.9,1.5 Hz,1H),7.72-7.59(m,2H),7.55(d,J=1.3 Hz,1H),7.44(m,2H),7.22-7.09(m,1H),6.97(s,1H),6.51(m,1H),6.33(d,J=8.5 Hz,1H),5.30-5.18(m,1H),4.79(s,2H),2.38(s,3H),1.50(d,J=6.5 Hz,3H).MS(ESI)m / e[M+1] + = 456.

[0304] Example 66: 2-((1-(3-(2-(2-hydroxypropan-2-yl)pyrimidine-5-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Step 1: 2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-yl)propan-2-ol [ka] A solution of 2-(5-bromopyrimidine-2-yl)propan-2-ol (100 mg, 0.46 mmol), bis(pinacolate)diborone (129 mg, 0.51 mmol), and KOAc (135 mg, 1.38 mmol) in dioxane (30 mL) was mixed with Pd(dppf)Cl2·DCM (290 mg, 0.40 mmol) under N2 conditions. The resulting solution was stirred at 90°C for 12 hours. The solution was filtered and concentrated under vacuum. The residue was purified by flash chromatography of the eluted silica gel to obtain the product (95 mg, 78%). MS(ESI)m / e[M+1] + =265.

[0305] Step 2: Methyl 2-((1-(3-(2-(2-hydroxypropan-2-yl)pyrimidine-5-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate [ka] Pd(PPh3)4 (21 mg, 0.02 mmol) was added under N2 to a solution of methyl 2-((1-(3-(2-(2-hydroxypropan-2-yl)pyrimidine-5-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate (70 mg, 0.18 mmol), 2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-yl)propan-2-ol (95 mg, 0.36 mmol), and K3PO4 (116 mg, 0.55 mmol) in dioxane (8 mL) and H2O (1 mL). The resulting solution was stirred at 100°C for 15 hours. The mixture was poured into H2O and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography using silica gel to obtain the product (80 mg, 89%). MS(ESI)m / e[M+1] + = 487.

[0306] Step 3: 2-((1-(3-(2-(2-hydroxypropan-2-yl)pyrimidine-5-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] A solution of methyl 2-((1-(3-(2-(2-hydroxypropan-2-yl)pyrimidine-5-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate (80 mg, 0.16 mmol) in methanol (4 mL), H2O (2 mL), and THF (4 mL) was mixed with 1 N NaOH (0.5 mL). The resulting solution was stirred at 50 °C for 7 hours. The solution was concentrated under vacuum. The residue was redissolved in H2O and acidified to pH 5-6 with HCl (2 M in water). The mixture was filtered, and the filtered cake was purified by preparative HPLC to obtain the desired product (24 mg, 25%). 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.80(brs,1H),9.07(s,2H),8.51-8.36(m,1H),8.01(s,1H),7.84-7.75(m,1H) ,7.49(s,1H),7.22-7.11(m,1H),7.09(s,1H),6.55-6.45(m,1H),6.33(d,J=8.5 Hz,1H),5.34-5.25(m,1H),5.20(s,1H),3.39(s,3H),2.37(s,3H),1.56(s,6H),1.50(d,J=6.5 Hz,3H).MS(ESI)m / e[M+1] + = 473.

[0307] Example 67: (R)-2-((1-(3-(2-(2-hydroxypropan-2-yl)pyrimidine-5-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Chiral separation of racemic 2-((1-(3-(2-(2-hydroxypropan-2-yl)pyrimidine-5-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid (45 mg) by SFC (column name: YMC Cellulose-C 20×250 mm, 5 μm; cosolvent: 40% MeOH; temperature (°C): 35; flow rate (mL / min): 40 mL / min; back pressure: 100 bar) yields (R)-2-((1-(3-(2-(2-hydroxypropan-2-yl)pyrimidine-5-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid (20.3 mg). Rt: 9.62 minutes. 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.80(s,1H),9.07(s,2H),8.51-8.36(m,1H),8.01(s,1H),7.84-7.75(m,1 H),7.49(s,1H),7.22-7.11(m,1H),7.09(s,1H),6.51(m,1H),6.33(d,J=8.5 Hz,1H),5.34-5.25(m,1H),5.20(s,1H),3.39(s,3H),2.37(s,3H),1.56(s,6H),1.50(d,J=6.5 Hz,3H).MS(ESI)m / e[M+1] + = 473.

[0308] Example 68: (S)-2-((1-(3-(2-(2-hydroxypropan-2-yl)pyrimidine-5-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] (S)-2-((1-(3-(2-(2-hydroxypropan-2-yl)pyrimidine-5-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid (21.0 mg) was obtained by chiral separation of racemic 2-((1-(3-(2-(2-hydroxypropan-2-yl)pyrimidine-5-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid (21.0 mg) by SFC (column name: YMC Cellulose-C 20×250 mm, 5 μm; cosolvent: 40% MeOH; temperature (°C): 35; flow rate (mL / min): 40 mL / min; back pressure: 100 bar). Rt: 5.97 minutes. 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.80(s,1H),9.07(s,2H),8.51-8.36(m,1H),8.01(s,1H),7.84-7.75(m,1 H),7.49(s,1H),7.22-7.11(m,1H),7.09(s,1H),6.51(m,1H),6.33(d,J=8.5 Hz,1H),5.34-5.25(m,1H),5.20(s,1H),3.39(s,3H),2.37(s,3H),1.56(s,6H),1.50(d,J=6.5 Hz,3H).MS(ESI)m / e[M+1] + = 473.

[0309] Example 69: 2-((1-(3-(4-fluorophenyl)-7-methyl-1-oxo-2-(tetrahydrofuran-3-yl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] The desired product (65 mg) was obtained by following the same procedure as in Example 63. 1H NMR(400 MHz,DMSO-d6)δ ppm 12.82(s,1H),8.53(s,1H),8.36-8.27(m,2H),8.22(s,1H),7.88(s,1H),7.81(dd,J=7.9,1.5 Hz,1H),7.60-7.50(m,1H),7.40-7.27(m,2H),7.21-7.08(m,1H),6.51(m,1H),6.39(d,J=8.5 Hz,1H),5.92-5.80(m,1H),5.66-5.48(m,1H),4.20-4.06(m,1H),4.01-3.91(m,2H), 3.90-3.77(m,1H),2.41(s,3H),2.40-2.32(m,1H),2.26-2.16(m,1H),1.59(d,J=6.5 Hz,3H).MS(ESI)m / e[M+1] + = 487.

[0310] Example 70: 2-((1-(2,7-dimethyl-3-(2-methyl-1-oxoisoindolin-5-yl)-1-oxo-1,2-dihydroisoquinolin-5-yl)ethyl)amino)benzoic acid [ka] The desired product (55 mg) was obtained by following the same procedure as in Example 10. 1 H NMR(400 MHz,DMSO-d6)δ ppm 8.90(s,1H),7.99(s,1H),7.84-7.74(m,3H),7.72-7.65(m,1H),7.55-7.46(m,1H),7.06(m,1H),6.88(s,1H),6.45(m,1H),6.26(d,J=8.4 Hz,1H),5.21-5.06(m,1H),4.67-4.41(m,2H),3.32(s,3H),3.09(s,J=17.2 Hz,3H),2.37(s,3H),1.49(d,J=6.6 Hz,3H).MS(ESI)m / e[M+1] + = 482.

[0311] Example 71: 2-((1-(3-(4-fluorophenyl)-7-methyl-1-oxo-2-(thiazole-2-yl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Step 1: 5-Acetyl-3-(4-fluorophenyl)-7-methylisoquinoline-1(2H)-one [ka] To a solution of 5-acetyl-3-chloro-7-methylisoquinoline-1(2H)-one (737 mg, 3.13 mmol), (4-fluorophenyl)boronic acid (657 mg, 4.69 mmol), and K3PO4 (2.00 g, 9.38 mmol) in dioxane (20 mL) and H2O (3 mL), Pd(PPh3)4 (180 mg, 0.16 mmol) was added under N2. The resulting solution was stirred overnight at 100°C. The mixture was poured into H2O and extracted with siRNA. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel flash chromatography to obtain the product (370 mg, 93%). MS(ESI)m / e[M+1] + =296.

[0312] Step 2: 5-Acetyl-3-(4-fluorophenyl)-7-methyl-2-(thiazole-2-yl)isoquinoline-1(2H)-one [ka] To a solution of 5-acetyl-3-(4-fluorophenyl)-7-methylisoquinoline-1(2H)-one (180 mg, 0.61 mmol), 2-bromothiazole (200 mg, 1.22 mmol), and K2CO3 (253 mg, 1.83 mmol) in DMAc (10 mL), CuI (12 mg, 0.06 mmol) and 4,7-dimethoxy-1,10-phenanthroline (29 mg, 0.12 mmol) were added under N2 conditions. The resulting solution was irradiated by mw at 150 °C for 3 hours. After cooling to room temperature, it was concentrated under vacuum. The residue was purified by flash chromatography on silica gel to obtain the isomer (105 mg, 46%). MS(ESI)m / e[M+1] + =379.

[0313] Step 3: 3-(4-fluorophenyl)-5-(1-hydroxyethyl)-7-methyl-2-(thiazole-2-yl)isoquinoline-1(2H)-one [ka] A solution of 5-acetyl-3-(4-fluorophenyl)-7-methyl-2-(thiazole-2-yl)isoquinoline-1(2H)-one (105 mg, 0.26 mmol) in DCM (10 mL) and MeOH (10 mL) was treated little by little with NaBH4 (20 mg, 0.53 mmol) at 0°C. The resulting solution was stirred at room temperature for 1 hour. The mixture was diluted with H2O (10 mL) and extracted with DCM (20 mL x 2). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica flash chromatography to obtain the product (35 mg, 33%). MS(ESI)m / e[M+1] + =381.

[0314] Step 4: 5-(1-bromoethyl)-3-(4-fluorophenyl)-7-methyl-2-(thiazole-2-yl)isoquinoline-1(2H)-one [ka] To a solution of 3-(4-fluorophenyl)-5-(1-hydroxyethyl)-7-methyl-2-(thiazole-2-yl)isoquinoline-1(2H)-one (35 mg, 0.09 mmol) in DCM (5 mL), PBr3 (75 mg, 0.27 mmol) was added dropwise at 0°C. The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (5 mL) at 0°C, and the pH was adjusted to 8 with saturated NaHCO3 aqueous solution. The mixture was extracted with DCM (10 mL x 2). The combined organic extract was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the desired product (30 mg, 78%). MS(ESI)m / e[M+1] + =443.

[0315] Step 5: Methyl 2-((1-(3-(4-fluorophenyl)-7-methyl-1-oxo-2-(thiazole-2-yl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate [ka] DIEA (44 mg, 0.34 mmol) was added to a solution of 5-(1-bromoethyl)-3-(4-fluorophenyl)-7-methyl-2-(thiazole-2-yl)isoquinoline-1(2H)-one (30 mg, 0.07 mmol) and methyl 2-aminobenzoate (30 mg, 0.20 mmol) in DMF (3 mL). The resulting solution was stirred at 90°C for 4 hours. After cooling to room temperature, the reaction mixture was diluted with water (30 mL) and extracted with  (30 mL × 2). The combined organic extract was washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column to obtain the desired product (20 mg, 57%). MS(ESI)m / e[M+1] + = 514.

[0316] Step 6: 2-((1-(3-(4-fluorophenyl)-7-methyl-1-oxo-2-(thiazole-2-yl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Lithium hydroxide monohydrate (16 mg, 0.39 mmol) was added to a solution of methyl 2-((1-(3-(4-fluorophenyl)-7-methyl-1-oxo-2-(thiazole-2-yl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate (20 mg, 0.04 mmol) in methanol (4 mL), H2O (2 mL), and THF (4 mL). The resulting solution was stirred at 50°C for 4 hours. The solution was concentrated under vacuum. The residue was redissolved in H2O and acidified to pH 5-6 with HCl (2 M in water). The mixture was filtered, and the filtered cake was purified by preparative HPLC to obtain the desired product (6 mg, 32%). 1 H NMR(400 MHz,DMSO-d6)δ ppm 8.55-8.30(m,1H),7.99(s,1H),7.86-7.72(m,2H),7.69-7.61(m,1H),7.61-7.55(m,1H),7.48(s,1H),7.45-7.32(m,2H),7.26-7. 05(m,3H),6.84(s,1H),6.59-6.47(m,1H),6.43-6.28(m,1H),5.38-5.12(m,1H),2.38(s,3H),1.63-1.45(m,3H).MS(ESI)m / e[M+1] + = 500.

[0317] Example 72: 2-((1-(3-(6-(4-hydroxy-4-methylpiperidine-1-yl)pyridine-3-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Step 1: Methyl 2-((1-(3-(6-fluoropyridine-3-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate [ka] A mixture of methyl 2-((1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate (150 mg, 0.39 mmol), 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (131 mg, 0.59 mmol), Pd(PPh3)4 (45 mg, 0.04 mmol), and K3PO4 (248 mg, 1.17 mmol) in dioxane and H2O(4:1)(10 mL) was stirred at 100°C for 1 hour. The mixture was concentrated under vacuum. The residue was purified by flash chromatography on silica gel to obtain the desired product (120 mg, 69%). MS(ESI)m / e[M+1] + =446.

[0318] Step 2: Methyl 2-((1-(3-(6-(4-hydroxy-4-methylpiperidine-1-yl)pyridine-3-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate [ka] A mixture of methyl 2-((1-(3-(6-fluoropyridine-3-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate (30 mg, 0.07 mmol), 4-methylpiperidine-4-ol (16 mg, 0.13 mmol), and Cs2CO3 (66 mg, 0.20 mmol) in DMSO (3 mL) was stirred at 120 °C for 1 hour. The mixture was concentrated under vacuum. The residue was purified by preparative TLC to obtain the desired product (20 mg, 55%). MS(ESI)m / e[M+1] + = 541.

[0319] Step 3: 2-((1-(3-(6-(4-hydroxy-4-methylpiperidine-1-yl)pyridine-3-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] A solution of methyl 2-((1-(3-(6-(4-hydroxy-4-methylpiperidine-1-yl)pyridine-3-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate (20 mg, 0.04 mmol) in MeOH (1 mL) and THF (0.5 mL) was mixed with 4 N NaOH (0.2 mL). The reaction mixture was stirred at 50 °C for 16 hours. The mixture was adjusted to pH 5 with 1 N HCl and concentrated under vacuum. The residue was purified by preparative HPLC to obtain the desired product (10.3 mg, 53%). 1 H NMR(400 MHz,DMSO-d6)δ ppm 8.65(brs,1H),8.29(s,1H),7.97(s,1H),7.81(d,J=8.0 Hz,1H),7.73(d,J=8.0 Hz,1H),7.48(s,1H),7.14-7.10(m,1H),6.94(d,J=8.9 Hz,1H),6.84(s,1H),6.51-6.47(m,1H),6.30(d,J=8.5 Hz,1H),5.25-5.10(m,1H),4.39(brs,1H),3.96-3.92(m,2H),3.43(s,3H),3.2 3-3.05(m,2H),2.36(s,3H),1.61-1.34(m,7H),1.17(s,3H).MS(ESI)m / e[M+1] + = 527.

[0320] Example 73: 2-((1-(3-(4-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Step 1: 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydro-2H-pyran-4-ol [ka] A mixture of 4-(4-bromophenyl)tetrahydro-2H-pyran-4-ol (300 mg, 1.2 mmol), bis(pinacolate)diborone (366 mg, 1.4 mmol), Pd(dppf)Cl2 (82 mg, 0.1 mmol), and potassium acetate (352 mg, 3.6 mmol) in dioxane (10 mL) was stirred at 90°C for 12 hours under N2. The mixture was poured into H2O and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by CombiFlash® chromatography on silica gel to obtain the desired product (310 mg, 85%). MS(ESI)m / e[M+1] + =305.

[0321] Step 2: Methyl 2-((1-(3-(4-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate [ka] A mixture of methyl 2-((1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate (80 mg, 0.2 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydro-2H-pyran-4-ol (92 mg, 0.3 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol), and K3PO4 (127 mg, 0.6 mmol) in dioxane (5 mL) and H2O (0.5 mL) was stirred at 110°C for 15 hours under N2. The mixture was poured into H2O and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative TLC to obtain the desired product (45 mg, 43%). MS(ESI)m / e[M+1] + = 527.

[0322] Step 3: 2-((1-(3-(4-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] A solution of methyl 2-((1-(3-(4-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate (45 mg, 0.09 mmol) in methanol (3 mL) was mixed with NaOH (3 M, 1 mL). The resulting solution was stirred at 60 °C for 5 hours. The solution was concentrated under vacuum. The residue was redissolved in H2O and acidified to pH 5-6 with HCl (2 M in water). The mixture was filtered, the solid was collected, and purified by preparative HPLC to obtain the desired product (21 mg, 46%). 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.79(brs,1H),8.44(s,1H),7.99(s,1H),7.84-7.76(m,1H),7.69-7.51( m,4H),7.47(s,1H),7.15(m,1H),6.83(s,1H),6.50(m,1H),6.32(d,J=8.5 Hz,1H),5.28-5.10(m,2H),3.89-3.65(m,4H),3.33(s,3H),2.36(s,3H),2.11-1.95(m,2H),1.65-1.53(m,2H),1.50(d,J=6.5 Hz, 3H).MS(ESI)m / e[M+1] + = 513.

[0323] Example 74: 2-((1-(3-(4-(4-methoxytetrahydro-2H-pyran-4-yl)phenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Step 1: 4-(4-bromophenyl)-4-methoxytetrahydro-2H-pyran [ka] To a solution of 4-(4-bromophenyl)tetrahydro-2H-pyran-4-ol (668 mg, 2.6 mmol) in DMF (10 mL), NaH (60% w / w in mineral oil, 125 mg, 3.1 mmol) was added at 0-10°C. After stirring at 0-10°C for 1 hour, CH3I (443 mg, 3.1 mmol in DMF) was added dropwise for 5 minutes. The resulting solution was stirred under N2 at 25°C for 12 hours. The mixture was poured into H2O and extracted with siRNA. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by CombiFlash® chromatography on silica gel to obtain the desired product (636 mg, 90%). MS(ESI)m / e[M+1] + =271.

[0324] Step 2: 2-(4-(4-methoxytetrahydro-2H-pyran-4-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] A mixture of 4-(4-bromophenyl)-4-methoxytetrahydro-2H-pyran (636 mg, 2.3 mmol), bis(pinacolate)diborone (894 mg, 3.5 mmol), Pd(dppf)Cl2 (163 mg, 0.2 mmol), and potassium acetate (460 mg, 4.6 mmol) in dioxane (10 mL) was stirred at 90°C for 12 hours under N2. The mixture was poured into H2O and extracted with RINKAN. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by CombiFlash® chromatography to obtain the desired product (650 mg, 88%). MS(ESI)m / e[M+1] + =319.

[0325] Step 3: Methyl 2-((1-(3-(4-(4-methoxytetrahydro-2H-pyran-4-yl)phenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate [ka] A mixture of methyl 2-((1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate (80 mg, 0.2 mmol), 2-(4-(4-methoxytetrahydro-2H-pyran-4-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (96 mg, 0.3 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol), and K3PO4 (127 mg, 0.6 mmol) in dioxane (5 mL) and H2O (0.5 mL) was stirred at 110°C for 15 hours under N2. The mixture was poured into H2O and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (PE / EA=2:1) ​​to obtain the desired product (52 mg, 48%). MS(ESI)m / e[M+1] + = 541.

[0326] Step 4: 2-((1-(3-(4-(4-methoxytetrahydro-2H-pyran-4-yl)phenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] A solution of methyl 2-((1-(3-(4-(4-methoxytetrahydro-2H-pyran-4-yl)phenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate (52 mg, 0.1 mmol) in methanol (3 mL) was mixed with NaOH (3 M, 1 mL). The resulting solution was stirred at 60 °C for 5 hours. The solution was concentrated under vacuum. The residue was redissolved in H2O and acidified to pH 5-6 with HCl (2 M in water). The solid was collected by filtration and purified by preparative HPLC (mobile phase, water (10 mmol / L FA) and ACN (25% phase B, up to 80% in 8 minutes); detector, UV 254 nm) to obtain the desired product (28 mg, 53%). 1 H NMR(400 MHz,DMSO-d6)δ ppm 8.44-8.31(m,1H),7.99(s,1H),7.84-7.76(m,1H),7.64-7.50(m,4H),7.47(d,J=1.3 Hz,1H),7.21-7.10(m,1H),6.85(s,1H),6.55-6.45(m,1H),6.33(d,J=8.4 Hz,1H),5.29-5.13(m,1H),3.79-3.67(m,4H),3.35(s,3H),2.95(s,3H),2.36(s,3H),2.01-1.90(m,4H),1.50(d,J=6.5 Hz, 3H).MS(ESI)m / e[M+1] + = 527.

[0327] Example 75: 2-((1-(2,7-dimethyl-3-(2-methyl-3-oxoisoindolin-5-yl)-1-oxo-1,2-dihydroisoquinolin-5-yl)ethyl)amino)benzoic acid [ka] The desired product (11.9 mg) was obtained by following the same procedure as in Example 10. 1H NMR(400 MHz,DMSO-d6)δ ppm 12.77(brs,1H),8.46-8.31(m,1H),8.00(s,1H),7.88-7.69(m,4H),7.51 -7.44(m,1H),7.20-7.12(m,1H),6.87(s,1H),6.51(m,1H),6.33(d,J=8.5 Hz,1H),5.31-5.12(m,1H),4.55(s,2H),3.31(s,3H),3.11(s,3H),2.37(s,3H),1.50(d,J=6.5 Hz,3H).MS(ESI)m / e[M+1] + = 482.

[0328] Example 76: 2-((1-(2,7-dimethyl-1-oxo-3-(1-phenyl-2,5-dihydro-1H-pyrrole-3-yl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Step 1: tert-butyl3-(5-(1-((2-(methoxycarbonyl)phenyl)amino)ethyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-3-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate [ka] A mixture of dioxane and methyl 2-((1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate (50.00 mg, 0.13 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (46.00 mg, 0.156 mmol), Pd(PPh3)4 (15.00 mg, 0.013 mmol), and K3PO4 (82.8 mg, 0.39 mmol) in H2O (5:1) (1 mL) was stirred at 90°C for 16 hours. The mixture was concentrated under vacuum. The residue was purified by preparative TLC to obtain the desired product (56 mg, 83.2%).

[0329] Step 2: Methyl 2-((1-(3-(2,5-dihydro-1H-pyrrole-3-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate [ka] To a solution of tert-butyl 3-(5-(1-((2-(methoxycarbonyl)phenyl)amino)ethyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-3-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (56 mg, 0.108 mmol) in DCM (2 mL), TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated and neutralized with saturated NaHCO3 aqueous solution. It was then extracted with DCM and dried over Na2SO4. The organic layer was filtered and concentrated to obtain the desired product (50 mg, crude).

[0330] Step 3: Methyl 2-((1-(2,7-dimethyl-1-oxo-3-(1-phenyl-2,5-dihydro-1H-pyrrole-3-yl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate [ka] Under nitrogen balloon conditions, a mixture of methyl 2-((1-(3-(2,5-dihydro-1H-pyrrole-3-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate (30 mg, 0.07 mmol), bromobenzene (13.5 mg, 0.086 mmol), XantPhos (8.1 mg, 0.014 mmol), Pd2(dba)3 (6.4 mg, 0.007 mmol), and cesium carbonate (68.4 mg, 0.21 mmol) in dioxane (2 mL) was stirred at 100°C for 2 hours. The reaction mixture was diluted with water and extracted with DCM (50 mL x 2). The organic phase was concentrated under vacuum, and the crude product was purified by preparative TLC (PE / EA=3 / 1) to obtain a mixture of methyl 2-((1-(2,7-dimethyl-1-oxo-3-(1-phenyl-2,5-dihydro-1H-pyrrole-3-yl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate and methyl 2-((1-(2,7-dimethyl-1-oxo-3-(1-phenyl-1H-pyrrole-3-yl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate as the product (35 mg, yield 98%).

[0331] Step 4: 2-((1-(2,7-dimethyl-1-oxo-3-(1-phenyl-2,5-dihydro-1H-pyrrole-3-yl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] A solution of the mixed material (35 mg, 0.07 mmol) in MeOH (1 mL) and THF (1 mL) was mixed with 4N NaOH (0.5 mL). The reaction mixture was stirred at 50°C for 1 hour. The mixture was adjusted to pH 5 with 1N HCl and concentrated under vacuum. The residue was purified by preparative HPLC to obtain the desired product, 2-((1-(2,7-dimethyl-1-oxo-3-(1-phenyl-2,5-dihydro-1H-pyrrole-3-yl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid (1.33 mg, yield 4%). 1H NMR(400 MHz,DMSO-d6)δ ppm 12.75(brs,1H),8.54(s,1H),7.96(s,1H),7.81(d,J=7.2 Hz,1H),7.50(s,1H),7.25-7.15(m,3H),7.01(s,1H),6.70-6.57(m,3H),6.55-6.45(m,2H),6.34(d,J=8.0 Hz,1H),5.30-5.20(m,1H),4.44(s,2H),4.30(s,2H),3.57(s,3H),2.36(s,3H),1.52(d,J=6.4 Hz,3H).MS(ESI)m / e[M+1] + =480.

[0332] Example 77: 2-((1-(2,7-dimethyl-1-oxo-3-(1-phenyl-1H-pyrrole-3-yl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] The desired product (19.71 mg) was obtained as a byproduct in the synthesis of Example 76. 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.69(brs,1H),8.37(d,J=6.0 Hz,1H),7.96(s,1H),7.85-7.76(m,2H),7.69(d,J=8.0 Hz,2H),7.60-7.50(m,3H),7.45(s,1H),7.31(t,J=7.6 Hz,1H),7.23-7.15(m,1H),6.94(s,1H),6.70-6.60(m,1H),6.55-6.45(m,1H),6.37(d,J=8.8 Hz,1H),5.34-5.07(m,1H),3.61(s,3H),2.35(s,3H),1.54(d,J=6.4 Hz,3H).MS(ESI)m / e[M+1] + = 478.

[0333] Example 78: 2-((1-(2,7-dimethyl-3-(6-(morpholinomethyl)pyridine-3-yl)-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] The desired product (18 mg) was obtained by following the same procedure as in Example 10. 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.77(brs,1H),8.73(d,J=1.6 Hz,1H),8.45(s,1H),8.08-7.96(m,2H),7.80(d,J=6.8 Hz,1H),7.60(d,J=8.4 Hz,1H),7.49(s,1H),7.20-7.10(m,1H),6.94(s,1H),6.55-6.45(m,1H),6.33(d,J=8.8 Hz,1H),5.30-5.20(m,1H),3.68(s,2H),3.65-3.57(m,4H),3.34-3.23(m,3H),2.50-2.40(m,4H),2.37(s,3H),1.50(d,J=6.4 Hz,3H).MS(ESI)m / e[M+1] + = 513.

[0334] Example 79: 2-((1-(3-(4-(dimethylphosphoryl)phenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] The desired product (49.24 mg) was obtained by following the same procedure as in Example 10. 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.74(brs,1H),8.38(d,J=4.7 Hz,1H),8.00(s,1H),7.92(dd,J=11.0,8.1 Hz,2H),7.80(d,J=6.5 Hz,1H),7.78-7.72(m,2H),7.49(s,1H),7.17(m,1H),6.89(s,1H),6.52(m,1H),6.34(d,J=8.5 Hz,1H),5.33-5.14(m,1H),3.34(s,3H),2.38(s,3H),1.71(d,J=13.4 Hz,6H),1.51(d,J=6.5 Hz, 3H).MS(ESI)m / e[M+1] +=489.MS(ESI)m / e[M+H] + =489.

[0335] Example 80: 2-((1-(2,7-dimethyl-3-((1-methyl-1H-pyrazole-4-yl)ethynyl)-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] The desired product (10 mg) was obtained by following the same procedure as in Example 43. 1 H NMR(400 MHz,DMSO-d6)δ ppm 8.66(s,1H),8.27-8.15(m,1H),7.93(s,1H),7.85-7.75(m,2H),7.47(s,1H),7.35(s,1H),7.10(m,1H),6.47(m,1H),6.25(d,J=8.3 Hz,1H),5.26-5.13(m,1H),3.87(s,3H),3.66(s,3H),2.33(s,3H),1.48(d,J=6.4 Hz,3H).MS(ESI)m / e[M+1] + =441.

[0336] Example 81: 6-Chloro-3-((1-(2-ethyl-3-(4-fluorophenyl)-7-methyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)picolinic acid [ka] Step 1: 5-Bromo-3-chloro-2-ethyl-7-methylisoquinoline-1(2H)-one [ka] A solution of 5-bromo-3-chloro-7-methylisoquinoline-1(2H)-one (300 mg, 1.10 mmol) and K2CO3 (455 mg, 3.30 mmol) in DMF (10 mL) was mixed with C2H5I (257 mg, 1.65 mmol) at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The mixture was poured into H2O and extracted with EA. The combined organic solution was washed with brine. The mixture was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography to obtain the product (210 mg, 63%). MS(ESI)m / e[M+1] + =300.

[0337] Step 2: 5-Acetyl-3-chloro-2-ethyl-7-methylisoquinoline-1(2H)-one [ka] To a solution of 5-bromo-3-chloro-2-ethyl-7-methylisoquinoline-1(2H)-one (210 mg, 0.70 mmol) and tributyl(1-ethoxyvinyl) stannan (250 mg, 0.70 mmol) in dioxane (20 mL), bis(triphenylphosphine)palladium(II) chloride (49 mg, 0.07 mmol) was added under a nitrogen atmosphere. The resulting mixture was stirred at 90°C for 15 hours. After cooling to room temperature, the reaction product was treated with 1 M aqueous HCl (5 mL) and stirred for 30 minutes. The mixture was quenched with saturated aqueous KF (20 mL), stirred for 30 minutes, and filtered. The filtered cake was washed with 10% MeOH in DCM (20 ml x 3). The combined extract was dried over anhydrous Na2SO4, filtered, and concentrated to obtain a residue, which was purified by silica gel column chromatography to obtain the product (138 mg, 75%). MS(ESI)m / e[M+1] + =264.

[0338] Step 3: 5-Acetyl-2-ethyl-3-(4-fluorophenyl)-7-methylisoquinoline-1(2H)-one [ka] A mixture of 5-acetyl-3-chloro-2-ethyl-7-methylisoquinoline-1(2H)-one (84 mg, 0.32 mmol), (4-fluorophenyl)boronic acid (67 mg, 0.48 mmol), Pd(PPh3)4 (37 mg, 0.03 mmol), and K3PO4 (204 mg, 0.96 mmol) in dioxane (8 mL) and H2O (1 mL) was stirred at 100°C for 12 hours under N2. The mixture was poured into H2O and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel to obtain the product (65 mg, 63%). MS(ESI)m / e[M+1] + =324.

[0339] Step 4: 5-(1-aminoethyl)-2-ethyl-3-(4-fluorophenyl)-7-methylisoquinoline-1(2H)-one [ka] To a solution of 5-acetyl-2-ethyl-3-(4-fluorophenyl)-7-methylisoquinoline-1(2H)-one (65 mg, 0.20 mmol) and ammonium acetate (154 mg, 2.00 mmol) in 5 mL of ethanol, NaBH3CN (15 mg, 0.24 mmol) was added. The resulting solution was stirred overnight at 90°C. After cooling to room temperature, the solution was concentrated under vacuum, and the residue was purified using CombiFlash® silica gel to obtain the desired product (38 mg, 59%). MS(ESI)m / e[M+1] + =325.

[0340] Step 5: tert-butyl 6-chloro-3-((1-(2-ethyl-3-(4-fluorophenyl)-7-methyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)picolinate [ka] DIEA (67 mg, 0.52 mmol) was added to a solution of 5-(1-aminoethyl)-2-ethyl-3-(4-fluorophenyl)-7-methylisoquinoline-1(2H)-one (38 mg, 0.12 mmol) and tert-butyl 6-chloro-3-fluoropicolinate (60 mg, 0.24 mmol) in DMF (3 mL). The resulting solution was stirred at 100 °C for 15 hours. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous sodium 2 SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography of the eluted silica gel to obtain the desired product (21 mg, 34%). MS(ESI)m / e[M+1] + = 536.

[0341] Step 6: 6-Chloro-3-((1-(2-ethyl-3-(4-fluorophenyl)-7-methyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)picolinic acid [ka] To a solution of tert-butyl 6-chloro-3-((1-(2-ethyl-3-(4-fluorophenyl)-7-methyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)picolinate (21 mg, 0.04 mmol) in 3 mL of DCM, TFA (1 mL) was added. The resulting solution was stirred at room temperature for 4 hours. The solution was concentrated under vacuum. The residue was purified by preparative HPLC to obtain the desired product (1.2 mg, 2%). 1 H NMR(400 MHz,DMSO-d6)δ ppm 13.09(s,1H),8.43-8.26(m,1H),8.00(s,1H),7.70-7.59(m,2H),7.45(s,1H),7.42-7.27(m,2H), 6.93-6.84(m,1H),6.75(s,1H),5.31-5.18(m,1H),3.98-3.78(m,2H),2.37(s,3H),1.50(d,J=6.3 Hz,3H),1.04(t,J=6.8 Hz,3H).MS(ESI)m / e[M+1] + =480.

[0342] Example 82: 2,7-dimethyl-5-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)-3-phenylisoquinoline-1(2H)-one [ka] DIEA (100 mg, 0.75 mmol) was added to a solution of 5-(1-bromoethyl)-2,7-dimethyl-3-phenylisoquinoline-1(2H)-one (90 mg, 0.25 mmol) and 2-(methylsulfonyl)aniline (86 mg, 0.51 mmol) in DMA (3 mL). The resulting solution was stirred overnight at 110 °C. After cooling to room temperature, the reaction product was diluted with water and extracted with Â. The combined organic extract was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC to obtain 2,7-dimethyl-5-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)-3-phenylisoquinoline-1(2H)-one (27 mg, 56%). 1 H NMR(400 MHz,DMSO-d6)δ ppm 8.01(s,1H),7.65-7.48(m,7H),7.35-7.25(m,1H),6.83(s,1H),6.75-6.65(m,1H),6.59(d,J=5.5 Hz,1H),6.46(d,J=8.4 Hz,1H),5.28-5.17(m,1H),3.33(s,3H),3.22(s,3H),2.38(s,3H),1.52(d,J=6.5 Hz,3H).MS(ESI)m / e[M+1] + =447.

[0343] Example 83: 3-((1-(2,7-dimethyl-1-oxo-3-phenyl-1,2-dihydroisoquinoline-5-yl)ethyl)amino)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid [ka] Step 1: 3-Nitro-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid [ka] To a solution of 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid (1 g, 6.57 mmol) in concentrated H2SO4 (10 mL), HNO3 (2 mL, 60%) was added dropwise at 0°C. The mixture was stirred overnight at room temperature. The mixture was poured onto ice. The solid was collected by filter, washed with water, and dried under high vacuum to obtain the desired product (1.0 g, 79%). MS(ESI)m / e[M+H] + =198.

[0344] Step 2: Methyl 3-nitro-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate [ka] A solution of 3-nitro-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid (1 g, 5.1 mmol) in MeOH (15 mL) and HCl / dioxane (4N, 2 mL) was stirred under reflux for 2 hours. The solvent was removed, and NaHCO3 (aqueous solution) was added to the crude residue. The aqueous layer was extracted with EA. The organic layer was dried and concentrated to obtain the desired product as a white solid (870 mg, 81%). MS(ESI)m / e[M+H] + =212.

[0345] Step 3: Methyl 3-amino-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate [ka] A solution of methyl 3-nitro-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate (870 mg, 4.12 mmol) and Pd / C (150 mg, 5% / wt%) in MeOH (50 mL) was stirred at room temperature under H2 (1 atm) for 5 hours. The mixture was filtered, and the filtrate was concentrated to obtain the desired product (550 mg, 74%). MS(ESI)m / e[M+H] + = 182.

[0346] Step 4: Methyl 3-((1-(2,7-dimethyl-1-oxo-3-phenyl-1,2-dihydroisoquinoline-5-yl)ethyl)amino)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate [ka] A solution of 5-(1-bromoethyl)-2,7-dimethyl-3-phenylisoquinoline-1(2H)-one (60 mg, 0.17 mmol), methyl 3-amino-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate (60.2 mg, 0.34 mmol), and DIEA (65.8 mg, 0.51 mmol) in DMF (5 mL) was stirred at 100 °C for 2 hours. The mixture was cooled to room temperature. The solvent was removed, and the crude residue was purified by preparative TLC to obtain the desired product (50 mg, 64%). MS(ESI)m / e[M+H] + =457.

[0347] Step 5: 3-((1-(2,7-dimethyl-1-oxo-3-phenyl-1,2-dihydroisoquinoline-5-yl)ethyl)amino)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid [ka] A solution of methyl 3-((1-(2,7-dimethyl-1-oxo-3-phenyl-1,2-dihydroisoquinoline-5-yl)ethyl)amino)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate (50 mg, 0.11 mmol) in NaOH (1N) (4 mL) and MeOH (4 mL) was stirred at 70°C for 3 hours. The solvent was removed, the aqueous layer was acidified with HCl (3N), and extracted with EA. The organic layer was dried and concentrated. The crude product was purified by preparative HPLC to obtain the desired product (26 mg, 53%). 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.42(brs,1H),7.97(s,1H),7.62-7.45(m,6H),6.67(s,1H),5.42(s,1H),4.94(d,J=6.5 Hz,1H),4.02-3.73(m,2H),3.31(s,3H),2.79-2.61(m,1H),2.38(s,3H),2.29(dd,J=12.9,6.3 Hz,1H),2.25-2.13(m,1H),2.01-1.88(m,1H),1.40(d,J=6.6 Hz,3H).MS(ESI)m / e[M+H] + =443.

[0348] Example 84: 2-((1-(2,7-dimethyl-1-oxo-3-(4-(pyrrolidine-1-yl)phenyl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] The desired product (16.8 mg) was obtained by following the same procedure as in Example 10. 1H NMR(400 MHz,DMSO-d6)δ ppm 8.38(s,1H),7.95(s,1H),7.82-7.76(m,1H),7.45(s,1H),7.34(d,J=8.5 Hz,2H),7.16(m,1H),6.71(s,1H),6.62(d,J=8.6 Hz,2H),6.51(m,1H),6.33(d,J=8.5 Hz,1H),5.21-5.06(m,1H),3.36(s,3H),3.31-3.18(m,4H),2.35(s,3H),2.01-1.91(m,4H),1.51(d,J=6.5 Hz,3H).MS(ESI)m / e[M+1] + = 482.

[0349] Example 85: 2-((1-(3-(2-hydroxypyrimidine-5-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] The desired product (32.66 mg) was obtained by following the same procedure as in Example 10. 1 H NMR(400 MHz,DMSO-d6)δ ppm 13.08-11.97(m,2H),8.67-8.31(m,3H),7.96(s,1H),7.79(d,J=8.0 Hz,1H),7.45(s,1H),7.14(m,1H),7.01(s,1H),6.50(m,1H),6.30(d,J=8.4 Hz,1H),5.28-5.19(m,1H),3.43(s,3H),2.35(s,3H),1.50(d,J=6.8 Hz,3H).MS(ESI)m / e[M+1] + =431

[0350] Example 86: 2-((1-(2,7-dimethyl-1-oxo-3-(6-(trifluoromethyl)pyridine-3-yl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] The desired product (33.3 mg) was obtained by following the same procedure as in Example 10. 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.75(s,1H),9.05(s,1H),8.50-8.32(m,2H),8.09(d,J=8.0 Hz,1H),8.01(s,1H),7.81-7.78(m,1H),7.50(s,1H),7.16(m,1H),7.08(s,1H),6.51(m,1H),6.33(d,J=8.0 Hz,1H),5.35-5.14(m,1H),3.36(s,3H),2.38(s,3H),1.50(d,J=6.8 Hz,3H).MS(ESI)m / e[M+1] + =482

[0351] Example 87: 2-((1-(3-(1-(((3S,5S)-adamantan-1-yl)methyl)-5-methyl-1H-pyrazole-4-yl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] The desired product (30 mg) was obtained by following the same procedure as in Example 10. 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.69(s,1H),8.30(d,J=6.0 Hz,1H),7.97(s,1H),7.79(dd,J=8.0,1.6 Hz,1H),7.65(s,1H),7.49(s,1H),7.18(m,1H),6.70(s,1H),6.51(m,1H),6.42(d,J=8.8 Hz,1H),5.26-5.16(m,1H),3.77(s,2H),3.36(s,3H),2.37(s,3H),2.19(s,3H),1.96(s,3H),1.67(m,3H),1.54(m,12H).MS(ESI)m / e[M+1] + = 565.

[0352] Example 88: 2-((1-(2,7-dimethyl-3-((1-methyl-1H-pyrazole-3-yl)ethynyl)-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Step 1: 1-methyl-3-((trimethylsilyl)ethynyl)-1H-pyrazole [ka] To a solution of 3-iodo-1-methyl-1H-pyrazole (1.00 g, 4.80 mmol) and ethinyltrimethylsilane (1.40 g, 14.42 mmol) in DMF (10 mL) and TEA (5 mL), Pd(PPh3)4 (278 mg, 0.24 mmol) and CuI (91 mg, 0.48 mmol) were added under N2. The resulting solution was stirred at 70°C for 15 hours. The mixture was poured into H2O and extracted with siRNA. The combined organic extract was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel flash chromatography to obtain the product (750 mg, 88%). MS(ESI)m / e[M+1] + =179.

[0353] Step 2: 3-Ethinyl-1-methyl-1H-pyrazole [ka] A solution of 1-methyl-3-((trimethylsilyl)ethynyl)-1H-pyrazole (750 mg, 4.19 mmol) in THF (20 mL) and H2O (4 mL) was mixed with KOH (235 mg, 4.19 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was poured into H2O and extracted with EA. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was used directly without further purification in the next step (350 mg, 79%). MS(ESI)m / e[M+1] + =107.

[0354] Step 3: Methyl 2-((1-(2,7-dimethyl-3-((1-methyl-1H-pyrazole-3-yl)ethynyl)-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate [ka] To a solution of methyl 2-((1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate (120 mg, 0.31 mmol) and 3-ethynyl-1-methyl-1H-pyrazole (67 mg, 0.62 mmol) in DMF (5 mL) and TEA (3 mL), Pd(PPh3)4 (18 mg, 0.02 mmol) and CuI (6 mg, 0.03 mmol) were added under N2. The resulting solution was stirred at 70°C for 15 hours. The mixture was poured into H2O and extracted with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel flash chromatography to obtain the product (100 mg, 70%). MS(ESI)m / e[M+1] + =455.

[0355] Step 4: Methyl 2-((1-(2,7-dimethyl-3-((1-methyl-1H-pyrazole-3-yl)ethynyl)-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate [ka] A solution of methyl 2-((1-(2,7-dimethyl-3-((1-methyl-1H-pyrazole-3-yl)ethynyl)-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate (100 mg, 0.22 mmol) in methanol (4 mL), H2O (2 mL), and THF (4 mL) was mixed with 1 N NaOH (0.5 mL). The resulting solution was stirred at 50 °C for 7 hours. The solution was concentrated under vacuum. The residue was redissolved in H2O and acidified to pH 5-6 with HCl (2 M in water). The mixture was filtered, and the filtered cake was purified by preparative HPLC to obtain the desired product (24 mg, 25%). 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.79(s,1H),8.49-8.29(m,1H),7.96(s,1H),7.84(m,1H),7.83-7.75(m,1H),7.53-7.42(m,2H),7.24-7.12(m,1H),6.65(d,J=2.2 Hz,1H),6.52(m,1H),6.31(d,J=8.5 Hz,1H),5.35-5.16(m,1H),3.88(s,3H),3.70(s,3H),2.35(s,3H),1.50(d,J=6.5 Hz,3H).MS(ESI)m / e[M+1] + =441.

[0356] Example 89: 2-((1-(3-((1-hydroxycyclopentyl)ethynyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] The desired product (18 mg) was obtained by following the same procedure as in Example 88. 1H NMR(400 MHz,DMSO-d6)δ ppm 12.79(s,1H),8.45-8.28(m,1H),7.94(s,1H),7.80(d,J=7.8 Hz,1H),7.47(s,1H),7.25(s,1H),7.22-7.09(m,1H),6.52(m,1H),6.29(d,J=8.5 Hz,1H),5.58(s,1H),5.30-5.13(m,1H),3.62(s,3H),2.35(s,3H),1.99-1.87(m,4H),1.84-1.63(m,4H),1.49(d,J=6.4 Hz,3H).MS(ESI)m / e[M+1] + =445.

[0357] Example 90: 2-((1-(3-(2-carbamoylphenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] The desired product (9.86 mg) was obtained by following the same procedure as in Example 10. 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.71(s,1H),8.39(s,1H),7.97(s,1H),7.88(d,J=7.2 Hz,1H),7.82-7.76(m,1H),7.70-7.49(m,4H),7.45-7.35(m,2H),7.25-7.15(m,1H),6. 75-6.65(m,1H),6.55-6.45(m,1H),6.30-6.20(m,1H),5.10-5.00(m,1H),3.23(d,J=7.2 Hz,3H),2.35(d,J=5.2 Hz,3H),1.48(d,J=6.4 Hz, 3H).MS(ESI)m / e[M+1] + = 456.

[0358] Example 91: 2-((1-(2,7-dimethyl-3-(1-methyl-1H-pyrazole-4-yl)-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] The desired product (11.5 mg) was obtained by following the same procedure as in Example 10. 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.79(brs,1H),8.39(s,1H),8.14(s,1H),7.94(s,1H),7.83-7.76(m,1H),7.65-7.50 (m,1H),7.44(s,1H),7.20-7.11(m,1H),6.88(s,1H),6.55-6.45(m,1H),6.33(d,J=8.5 Hz,1H),5.25-5.12(m,1H),3.91(s,3H),3.53(s,3H),2.34(s,3H),1.51(d,J=6.6 Hz,3H).MS(ESI)m / e[M+1] + =417.

[0359] Example 92: 2-((1-(2,7-dimethyl-1-oxo-3-phenyl-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzo[b]thiophene-3-carboxylic acid [ka] Step 1: Ethyl 2-((1-(2,7-dimethyl-1-oxo-3-phenyl-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzo[b]thiophene-3-carboxylate [ka] A solution of 5-(1-bromoethyl)-2,7-dimethyl-3-phenylisoquinoline-1(2H)-one (120 mg, 0.34 mmol), ethyl 2-aminobenzo[b]thiophene-3-carboxylate (150.1 mg, 0.68 mmol), and TEA (172 mg, 1.7 mmol) in DMF (5 mL) was stirred at 80°C for 2 hours. The mixture was cooled to room temperature. The solvent was removed, and the crude residue was purified by preparative TLC to obtain the desired product (40 mg, 24%). MS(ESI)m / e[M+H] + =497.

[0360] Step 2: 2-((1-(2,7-dimethyl-1-oxo-3-phenyl-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzo[b]thiophene-3-carboxylic acid [ka] A solution of ethyl 2-((1-(2,7-dimethyl-1-oxo-3-phenyl-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzo[b]thiophene-3-carboxylate (40 mg, 0.081 mmol) in NaOH (1N, 5 mL) and MeOH (5 mL) was stirred at 70°C for 4 hours. After removing the MeOH, the aqueous layer was purified by preparative HPLC to obtain the desired product (6.89 mg, 18%). 1 H NMR(400 MHz,DMSO-d6)δ ppm 10.32(s,1H),8.40(s,1H),7.98(s,1H),7.68-7.55(m,3H),7.54-7.46(m,3H),7.39(d,J=7.9 Hz,1H),7.10-7.00(m,1H),6.90-6.70(m,1H),6.77(s,1H),5.04(s,1H),3.33(s,3H),2.38(s,3H),1.53(d,J=6.4 Hz,3H).MS(ESI)m / e[M+H] + =469.

[0361] Example 93: 5-(1-(benzo[b]thiophen-3-ylamino)ethyl)-2,7-dimethyl-3-phenylisoquinoline-1(2H)-one [ka] The decarboxylation byproduct 5-(1-(benzo[b]thiophen-3-ylamino)ethyl)-2,7-dimethyl-3-phenylisoquinoline-1(2H)-one (19.62 mg) was obtained during the purification of 2-((1-(2,7-dimethyl-1-oxo-3-phenyl-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzo[b]thiophen-3-carboxylic acid (Example 92). 1H NMR(400 MHz,DMSO-d6)δ ppm 7.98(s,1H),7.83(s,1H),7.63(d,J=7.1 Hz,1H),7.54(s,1H),7.43(s,2H),7.38(s,3H),7.22(d,J=8.2 Hz,2H),6.74(s,1H),6.32(s,1H),5.44(s,1H),4.91(s,1H),2.22(s,3H),1.40(d,J=6.6 Hz,3H).MS(ESI)m / e[M+H] + = 425.

[0362] Example 94: 2-((1-(2,7-dimethyl-1-oxo-3-((1-phenyl-1H-pyrazole-4-yl)ethynyl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Step 1: 4-iodo-1-phenyl-1H-pyrazole [ka] Cu(OAc)2 (2.8g, 15mmol) was added to a solution of 4-iodo-1H-pyrazole (3g, 15mmol), phenylboronic acid (3.7g, 30mmol), and pyridine (5.9g, 75mmol) in DCM (10mL). The resulting solution was stirred at 25°C for 36 hours. The mixture was diluted with DCM and washed with H2O and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by CombiFlash® chromatography on silica gel to obtain the desired product (2.8g, 69%). MS(ESI)m / e[M+1] + =271.

[0363] Step 2: 1-Phenyl-4-((trimethylsilyl)ethynyl)-1H-pyrazole [ka] A mixture of 4-iodo-1-phenyl-1H-pyrazole (2.8 g, 10.3 mmol), ethinyltrimethylsilane (1.5 g, 15.5 mmol), and Pd(PPh2)Cl2 (702 mg, 1.0 mmol) in TEA (5 mL) and DMF (20 mL) was stirred under N2 at 80°C for 15 hours. The mixture was poured into H2O and extracted with SiO2. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by CombiFlash® chromatography on silica gel to obtain the desired product (2.3 g, 92%). MS(ESI)m / e[M+1] + =241.

[0364] Step 3: 4-Ethynyl-1-phenyl-1H-pyrazole [ka] To a solution of 1-phenyl-4-((trimethylsilyl)ethynyl)-1H-pyrazole (2.3 g, 9.5 mmol) in MeOH (30 mL), K2CO3 (2.6 g, 19 mmol) was added. The resulting mixture was stirred at 25°C for 15 hours. The mixture was concentrated under vacuum, diluted with ELISA, and washed with H2O and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by CombiFlash® chromatography on silica gel to obtain the desired product (1.1 g, 69%). MS(ESI)m / e[M+1] + =169.

[0365] Step 4: Methyl 2-((1-(2,7-dimethyl-1-oxo-3-((1-phenyl-1H-pyrazole-4-yl)ethynyl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate [ka] A mixture of methyl 2-((1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate (50 mg, 0.13 mmol), 4-ethynyl-1-phenyl-1H-pyrazole (50 mg, 0.3 mmol), and Pd(PPh2)Cl2 (8 mg, 0.01 mmol) in TEA (1 mL) and DMF (2 mL) was stirred at 100°C for 15 hours under N2. The mixture was poured into H2O and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative TLC to obtain the desired product (30 mg, 45%). MS(ESI)m / e[M+1] + = 517.

[0366] Step 5: 2-((1-(2,7-dimethyl-1-oxo-3-((1-phenyl-1H-pyrazole-4-yl)ethynyl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] A solution of methyl 2-((1-(2,7-dimethyl-1-oxo-3-((1-phenyl-1H-pyrazole-4-yl)ethynyl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoate (30 mg, 0.06 mmol) in methanol (3 mL) was mixed with NaOH (3 M, 1 mL). The resulting solution was stirred at 50 °C for 5 hours. The solution was concentrated under vacuum. The residue was redissolved in H2O and acidified to pH 5-6 with HCl (2 M in water). The mixture was filtered, the solid was collected, and purified by preparative HPLC to obtain the desired product (19 mg, 63%). 1H NMR(400 MHz,DMSO-d6)δ ppm 9.06(s,1H),8.55(s,1H),8.14(s,1H),7.96(s,1H),7.91-7.84(m,2H),7.83-7.76(m,1 H),7.59-7.47(m,3H),7.45-7.32(m,2H),7.21-7.09(m,1H),6.51(m,1H),6.30(d,J=8.5 Hz,1H),5.30-5.14(m,1H),3.71(s,3H),2.35(s,3H),1.51(d,J=6.5 Hz,3H).MS(ESI)m / e[M+1] + = 503.

[0367] Example 95: 2-((1-(3-(4-fluorophenyl)-7-methyl-2-(oxetan-3-yl)-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] The desired product (29 mg) was obtained by following the same procedure as in Example 63. 1 H NMR(400 MHz,DMSO-d6)δ ppm 8.72(s,1H),8.29-8.19(m,3H),7.96(s,1H),7.86-7.77(m,1H),7.58(s,1 H),7.39-7.26(m,2H),7.17-7.05(m,1H),6.55-6.45(m,1H),6.37(d,J=8.5 Hz,1H),5.95-5.84(m,1H),5.63-5.51(m,1H),5.07(t,J=6.9 Hz,2H),4.82-4.71(m,2H),2.43(s,3H),1.58(d,J=6.5 Hz,3H).MS(ESI)m / e[M+1] + = 473.

[0368] Example 96: 2-((1-(3-(4-fluorophenyl)-7-methyl-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] The desired product (55 mg) was obtained by following the same procedure as in Example 63. 1 H NMR(400 MHz,DMSO-d6)δ ppm 12.76(s,1H),8.54-8.41(m,1H),8.33-8.24(m,2H),8.19(s,1H),7.91(s,1H),7.81(dd,J=7.9,1.5 Hz,1H),7.59-7.49(m,1H),7.39-7.27(m,2H),7.21-7.10(m,1H),6.51(m,1H),6.40(d,J=8.5 Hz,1H),5.67-5.51(m,2H),4.01-3.89(m,2H),3.72-3.57(m,2H),2.42(s,3H),2.22-2.10(m,2H),1.91-1.75(m,2H),1.59(d,J=6.5 Hz,3H).MS(ESI)m / e[M+1] + =501.

[0369] Example 97: 4-((1-(3-(4-fluorophenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)nicotinic acid [ka] Step 1: Methyl 4-((1-(3-(4-fluorophenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)nicotinate [ka] A mixture of 5-(1-bromoethyl)-3-(4-fluorophenyl)-2,7-dimethylisoquinoline-1(2H)-one (40 mg, 0.11 mmol), methyl 4-aminonicotinate (24 mg, 0.16 mmol), and DIEA (41 mg, 0.32 mmol) in DMF (4 mL) was stirred at 90°C for 2 hours. The mixture was concentrated under vacuum. The residue was purified by preparative TLC to obtain the desired product (30 mg, 63%). MS(ESI)m / e[M+1] + =446.

[0370] Step 2: 4-((1-(3-(4-fluorophenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)nicotinic acid [ka] To a solution of methyl 4-((1-(3-(4-fluorophenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)nicotinate (20 mg, 0.04 mmol) in MeOH (1 mL) and THF (0.5 mL), 4N NaOH (0.2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was adjusted to pH 5 with 1N HCl and concentrated under vacuum. The residue was purified by preparative HPLC to obtain the desired product (6.88 mg, 35%). 1 H NMR(400 MHz,DMSO-d6)δ ppm 10.53-10.51(m,1H),8.64(s,1H),8.44(d,J=8.0 Hz,1H),8.14(s,1H),8.09(d,J=5.4 Hz,1H),7.74(s,1H),7.56-7.52(m,2H),7.36-7.32(m,2H),6.79(d,J=8.0 Hz,1H),6.61(s,1H),6.38(d,J=8.0 Hz,1H),3.27(s,3H),2.51(s,3H),1.86(d,J=6.7 Hz,3H).MS(ESI)m / e[M+1] + = 432.

[0371] Example 98: (R)-2-((1-(3-(4-(2-hydroxypropan-2-yl)phenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] Step 1: (S)-3-chloro-5-(1-hydroxyethyl)-2,7-dimethylisoquinoline-1(2H)-one [ka] A 100 mL screw-cap Schlenk bottle containing a magnetic stirring rod, filled with N2 and dried, was packed with Cu(OAc)2 (36 mg, 0.2 mmol) and S-DTBM-SEGPHOS (259 mg, 0.22 mol). Anhydrous THF (20 mL) was added, and the mixture was stirred for 30 minutes. PhSiH3 (648 mg, 6 mmol) was added to the resulting solution, and the solution was stirred for another 30 minutes. After cooling to -25°C, a solution of 5-acetyl-3-chloro-2,7-dimethylisoquinoline-1(2H)-one (1 g, 4 mmol) in 20 mL of THF was added. After stirring for 2 hours, a saturated NH4F solution in methanol was added, and the mixture was stirred for 10 minutes. Then, saturated NH4Cl (aqueous solution) was added. The resulting mixture was extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was subjected to silica gel column chromatography to obtain the product (820 mg, 96:4 er), which was then recrystallized in an organic solvent to obtain the desired product (650 mg, 65%, 99:1 er). MS(ESI)m / e[M+1] + =252.

[0372] Step 2: (R)-1-(1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)-2H-benzo[d][1,3]oxazine-2,4(1H)-dione [ka] To a solution of (S)-3-chloro-5-(1-hydroxyethyl)-2,7-dimethylisoquinoline-1(2H)-one (150 mg, 0.60 mmol), PPh3 (237 mg, 0.90 mmol), and 2H-benzo[d][1,3]oxazine-2,4(1H)-dione (147 mg, 0.90 mmol) in THF (1 mL), DIAD (180 mg, 0.90 mmol) was added at 0°C. The mixture was stirred at room temperature for 2 hours. The reaction product was quenched by adding H2O and extracted with EA. The combined organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue (150 mg, crude) was used directly in the next step without further purification. MS(ESI)m / e[M+1] + =367.

[0373] Step 3: (R)-2-((1-(3-(4-(2-hydroxypropan-2-yl)phenyl)-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)amino)benzoic acid [ka] A mixture of (R)-1-(1-(3-chloro-2,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-5-yl)ethyl)-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (150 mg crude, 0.4 mmol), (4-(2-hydroxypropan-2-yl)phenyl)boronic acid (140 mg, 0.8 mmol), Pd(PPh3)4 (46 mg, 0.04 mmol), and K3PO4 (169 mg, 0.8 mmol) in dioxane (24 mL) and H2O (6 mL) was stirred at 90°C for 5 hours under N2. The solvent was removed, and the residue was purified by preparative HPLC followed by chiral SFC to obtain the desired product (73 mg, 26% yield in 2 steps, 99.6:0.4 er). 1H NMR(400 MHz, DMSO-d6)δ ppm 12.80(brs,1H),8.41(s,1H),7.99(s,1H),7.81(dd,J=7.9,1.5 Hz,1H),7.62(d,J=8.3 Hz,2H),7.56-7.45(m,3H),7.25-7.08(m,1H),6.83(s,1H),6.58-6.46(m,1H),6.33(d,J=8.5 Hz,1H),5.25-5.16(s,1H),5.15(brs,1H),3.34(s,3H),2.37(s,3H),1.56-1.41(m,9H).MS(ESI)m / e[M+Na] + =493.

[0374] Biochemistry アッセイ PI3Kα(p110 / p85) kinase ADP-Glo ​​assay. Specific compounds disclosed herein were tested for inhibition of PI3Kα(p110 / p85) kinase (wild-type, "WT") in an assay based on the ADP-Glo® kinase assay method. The assay was performed in a 384-well white plate in a reaction mixture containing PI3Kα(p110 / p85) kinase, 25 μM ATP, 5.35 μg / mL PI(4,5)P2:PS lipid kinase substrate, and 0–100 μM of the compound in a buffer containing 50 mM HEPES pH 7.5, 50 mM NaCl, 3 mM MgCl2, 0.0025% BSA, and 2 mM DTT. The reaction was initiated by incubating PI3Kα(p110 / p85) kinase with the lipid kinase substrate and the compound at room temperature for 30 minutes, followed by the addition of ATP. After reacting at room temperature for 120 minutes, the kinase reaction was terminated by adding the ADP-Glo® reagent, and residual ATP was depleted according to the manufacturer's (Promega Corporation) instructions. After incubation at room temperature for 1 hour, the kinase detection reagent (prepared by reconstituting the lyophilized kinase detection substrate using the kit's kinase detection buffer) was added to convert ADP to ATP, allowing the newly synthesized ATP to be measured using a luciferase / luciferin reaction. After incubation at room temperature for 0.5 hours, the chemiluminescence signal was recorded using a PHERAstar FSX plate reader (BMG Labtech). The chemiluminescence generated in this assay correlates with the amount of ADP generated in the kinase assay, indicating kinase activity. Inhibition of PI3Kα(p110 / p85) kinase activity resulted in a decrease in the chemiluminescence signal. IC50 of each compound 50 This was derived by fitting the data to the four-parameter logistic equation using Dotmatics.

[0375] PI3Kα(p110[H1047R] / p85) kinase ADP-Glo ​​assay. Specific compounds disclosed herein were tested for inhibition of PI3Kα(p110[H1047R] / p85) kinase in an assay based on the ADP-Glo® kinase assay method. The assay was performed in a 384-well white plate in a reaction mixture containing 0–100 μM of the compound in a buffer containing PI3Kα(p110[H1047R] / p85) kinase, 25 μM ATP, 5.35 μg / mL PI(4,5)P2:PS lipid kinase substrate, and 50 mM HEPES pH 7.5, 50 mM NaCl, 3 mM MgCl2, 0.0025% BSA, and 2 mM DTT. PI3Kα(p110[H1047R] / p85) kinase was incubated with a lipid kinase substrate and the compound at room temperature for 30 minutes, and the reaction was initiated by adding ATP. After reacting at room temperature for 120 minutes, the kinase reaction was terminated by adding ADP-Glo® reagent, and the remaining ATP was depleted according to the manufacturer's (Promega Corporation) instructions. After incubation at room temperature for 1 hour, the kinase detection reagent (prepared by reconstituting the lyophilized kinase detection substrate using the kinase detection buffer in the kit) was added to convert ADP to ATP, allowing the newly synthesized ATP to be measured using a luciferase / luciferin reaction. After incubation at room temperature for 0.5 hours, the chemiluminescence signal was recorded using a PHERAstar FSX plate reader (BMG Labtech). The chemiluminescence generated in this assay correlates with the amount of ADP generated in the kinase assay, indicating kinase activity. Inhibition of PI3Kα(p110[H1047R] / p85) kinase activity resulted in a decrease in the chemiluminescence signal. IC50 of each compound 50 This was derived by fitting the data to the four-parameter logistic equation using Dotmatics. [Table 1-1] [Table 1-2] [Table 1-3]

[0376] Cell assay Cell culture maintenance. The T-47D (ATCC, HTB-133) cell line was obtained from the American Type Culture Collection. Cells were maintained in RPMI 1640 medium (Gibco, reference no. 22400105) supplemented with 10% fetal bovine serum (Gibco, reference no. 10091148). The cultures were maintained in a humidified incubator at 37°C under 5% CO2 / 95% air.

[0377] The SK-BR-3 (ATCC, HTB-30) cell line was obtained from the American Type Culture Collection. The cells were maintained in McCoy's 5A medium (Gibco, reference no. 16600108) supplemented with 10% fetal bovine serum. The cultures were maintained in a humidified incubator at 37°C under 5% CO2 / 95% air.

[0378] Phospho-AKT Inhibition Assay. The HTRF Phospho-AKT (Ser473) Detection Kit (Cisbio, reference no. 64AKSPEH) was used in the phosphor-AKT inhibition assay. For compound screening, PI3Kα H1047R mutant cell line T-47D and WT cell line SK-BR-3 cells were placed in 96-well plates (Costar, reference no. 3599) with 95 μL of assay medium (MEM medium (Gibco, reference no. 12561-056), 1 × NEAA (Gibco, reference no. 11140-050), 1 mM sodium pyruvate (Gibco, reference no. 11360-070), and 1 μg / ml human insulin (Topscience, reference no. T8221)) at a rate of 3 × 10⁶ cells per well. 4Cells were seeded overnight at a density of 100 cells. The compound, dissolved in a 10 mM stock solution in DMSO, was serially diluted 1:3 in DMSO to produce an 11-point dilution series, which was plated using an INTEGRA ASSIST PLUS pipetting robot. Then, 20-fold intermediate compound dilution plates were prepared in RPMI1640 medium (starting compound concentration 200 μM in 2% DMSO). 5 μL of the serially diluted intermediate compound was added to the cell plate in 0.1% DMSO to final concentrations ranging from 10 μM to 0.1 nM. Maximum signal was established using 0.1% DMSO alone, and GDC0077 was used as the reference compound for minimum signal at a final concentration of 10 μM. After 1 hour of processing, the medium was removed and 50 μL of replenished lysis buffer (1x) was immediately added. The cells were incubated at room temperature for at least 30 minutes under shaking. 16 μL of cell lysates were transferred from a 96-well cell culture plate to a 384-white detection plate (PerkinElmer, Optiplate 384, 6007299). 4 μL of pre-mixed antibody solution was added to the detection buffer. The plates were incubated in darkness at room temperature for 4 hours. The plates were read using a PHERAstar FSX microplate reader (BMG LABTECH, Inc.) with standard HTRF settings.

[0379] Relative IC 50 The values ​​were determined using emission units by calculating the inhibition percentage relative to the plate-bound "MIN" (GDC0077 reference control) and "MAX" (DMSO) controls. The data were analyzed using a four-parameter nonlinear logistic equation (four-parameter logistic concentration-response curve): Y = bottom + [(top - bottom) / 1 + (X / IC). 50 ) Inclination] In the formula, Y = inhibition percentage, X = concentration of the inhibitor, bottom = minimum value of y obtained by curve fitting, top = maximum value of y obtained by curve fitting, and slope = IC 50 This is the gradient of the curve.

[0380] Selectivity=IC 50 (PI3Kα WT) / IC 50 (PI3Kα H1047R) [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4]

[0381] Cell proliferation assay. PI3Kα H1047R mutant cell line T-47D cells and WT cell line SK-BR-3 cells were cultured in 95 μL of culture medium in a 96-well plate (Xinyou Biotechnology, 062096), with 3 × 10⁶ cells per well. 3 Cells were seeded overnight at a density of 1000 cells. The compound, dissolved in a 10 mM stock solution in DMSO, was serially diluted 1:3 in DMSO to produce a 9-point dilution series, which was plated using an INTEGRA ASSIST Plus pipetting robot. Then, 20-fold intermediate compound dilution plates were prepared in RPMI1640 medium (starting compound concentration 200 μM in 2% DMSO). 5 μL of the serially diluted intermediate compound was added to the cell plate in 0.1% DMSO to a final concentration ranging from 10 μM to 1 nM. Maximum signal was established using 0.1% DMSO alone, and minimum signal was established using a medium without cells. After 3 days of treatment, the plates and their contents were equilibrated at room temperature for approximately 30 minutes. 30 μL of CellTiter-Glo® reagent (Promega, reference no. G7571) was added to each well. The contents were then mixed in a plate shaker for 5 minutes to induce cell lysis. The plates were incubated at room temperature for 10 minutes to stabilize the luminescence signal. The plates were read using a PHERAstar FSX microplate reader with standard luminescence settings.

[0382] Relative IC 50The values ​​were determined using luminescence units by calculating the inhibition percentage relative to the in-plate "MIN" (culture medium only) and "MAX" (0.1% DMSO) controls. The data were analyzed using a four-parameter nonlinear logistic equation (four-parameter logistic concentration-response curve): Y = bottom + [(top - bottom) / 1 + (X / IC). 50 ) Inclination] In the formula, Y = inhibition percentage, X = concentration of the inhibitor, bottom = minimum value of y obtained by curve fitting, top = maximum value of y obtained by curve fitting, and slope = IC 50 This is the gradient of the curve.

[0383] Selectivity=IC 50 (PI3Kα WT) / IC 50 (PI3Kα H1047R) [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4]

[0384] Mouse pharmacokinetic (PK) methods. Male CD-1 mice (n=3 / study) were used to investigate the pharmacokinetics (cassette and discrete) of PI3Kα inhibitors. For PK investigations, five test compounds (cassette, discrete, 2 mg / kg for each compound, formulation: 10%EtOH / 30%PEG-400 / 60%phosal 50 PG) or a mixture of a single test compound (discrete) were designed at doses of 1 mg / kg (iv formulation: 20%DMA + 20%(30%solutol HS-15) + 60% physiological saline) or 5 mg / kg (po formulation: 0.5%MC). In the oral administration group, mice were fasted overnight, given free access to water, and fed 4 hours after administration. In the intravenous injection group, mice had free access to food and water. At post-administration time points (cassette oral administration group: 0.25 hours, 1 hour, 4 hours, 8 hours; separate oral administration group: 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours; intravenous administration group: 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours), mice were anesthetized with isoflurane, and blood samples were collected from orbital hemorrhages into 1.5 mL EDTA.K2 coated tubes. Plasma was then obtained by centrifugation at 5600 rpm for 7 minutes at 4°C. Samples were analyzed using LC-MS / MS. A non-compartment model (Phoenix Winnolin software 8.3) was used for pharmacokinetic parameter calculations.

[0385] Where any prior art publication is referenced herein, it should be understood that such reference does not constitute an endorsement that the publication forms part of the common general knowledge in the art in any country.

[0386] All publications, patents, patent applications, and disclosures of published patent applications referenced herein by identifying reference are incorporated herein in their entirety by reference.

[0387] Although the aforementioned invention has been described in some detail with illustrations and examples for the purpose of clarifying understanding, it will be obvious to those skilled in the art that certain minor changes and modifications will be made. Therefore, the description and examples should not be construed as limiting the scope of the invention.

Claims

1. Compound of formula (IV), 【Chemistry 295】 or its stereoisomers, tautomers, or pharmaceutically acceptable salts, During the ceremony, R １ However, hydrogen, deuterium, -C １－６ Alkyl, deuterated - C １－６ Alkyl, heterocyclyl, heteroaryl, or aryl, and the -C １－６ Alkyl, deuterated - C １－６ Alkyl, heterocyclyl, heteroaryl, or aryl each independently and optionally has at least one substituent R １１ａ It has been replaced with, Each R １１ａ is independently hydrogen, halogen, oxo, -C １－６ alkyl, -C ２－６ alkenyl, -C ２－６ alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -CN, -NO ２ , -OR １ａ , -COR １ａ , -CO ２ R １ａ , -CONR １ａ R １ｂ , -SO ２ R １ａ , -NR １ａ R １ｂ , -NR １ａ COR １ｂ , -NR １ａ CONR １ｂ R １ｃ , or -NR １ａ CO ２ R １ｂ , and said -C １－６ alkyl, -C ２－６ alkenyl, -C ２－６ alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl is each independently optionally substituted with at least one substituent R １ｄ , R １ａ , R １ｂ , and R １ｃ Each of them independently produces hydrogen, -C １－６ Alkyl, -C ２－６ Alkenyl, -C ２－６ Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl, and the -C １－６ Alkyl, -C ２－６ Alkenyl, -C ２－６ Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl each independently and optionally has at least one substituent R １ｄ It has been replaced with, Each R １ｄ These independently produce hydrogen, halogen, oxo, -CN, and -NO. ２ , -C １－６ Alkyl, -C ２－６ Alkenyl, -C ２－６ Alkinyl, -C １－６ Haloalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -OC １－６ Alkyl, -COC １－６ Alkyl, or -CO ２ C １－６ It is alkyl, R ３ However, hydrogen, halogen, -C １－６ Alkyl, -OC １－６ Alkyl, -CN, or -NO ２ And the above-C １－６ Alkyl or -OC １－６ Alkyl can be optionally hydrogen, halogen, or -C. １－６ Alkyl, -CN, and -NO ２ It is substituted with at least one substituent selected from the following: R ４Ａ and R ４Ｂ However, they may be the same or different, and each can be independently hydrogen, deuterium, halogen, and -C. １－６ Alkyl or deuterated C １－６ Alkyl, and the aforementioned -C １－６ Alkyl or deuterated C １－６ Each alkyl group can be independently and optionally selected as a halogen or -C. １－６ Alkyl, -C １－６ Haloalkyl, -CN, -NO ２ , -OC １－６ Alkyl, -COC １－６ Alkyl and -CO ２ C １－６ It is substituted with at least one substituent selected from alkyl groups. R ４Ｃ However, hydrogen, halogen, -C １－６ Alkyl or deuterated C １－６ Alkyl, and the aforementioned -C １－６ Alkyl or deuterated C １－６ Alkyl can be optionally hydrogen, halogen, or -C. １－６ Alkyl, -C １－６ Haloalkyl, -C ２－６ Alkenyl, -C ２－６ Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -CN, -NO ２ , -OC １－６ Alkyl, -COC １－６ Alkyl and -CO ２ C １－６ It is substituted with at least one substituent selected from alkyl groups. R ５ is hydrogen, halogen, -C １－６ alkyl, -OC １－６ alkyl, -CN, or -NO ２ wherein the -C １－６ alkyl or -OC １－６ alkyl is optionally substituted with at least one substituent selected from hydrogen, halogen, -C １－６ alkyl, -CN, and -NO ２ ; R ６ is hydrogen, halogen, -C １－６ alkyl, -OC １－６ alkyl, -CN, or -NO ２ wherein the -C １－６ alkyl or -OC １－６ alkyl is each independently optionally substituted with at least one substituent selected from hydrogen, deuterium, halogen, -C １－６ alkyl, -CN, and -NO ２ ; R ７ However, hydrogen, halogen, -C １－６ Alkyl, -OC １－６ Alkyl, -CN, or -NO ２ And the above-C １－６ Alkyl or -OC １－６ Alkyl can be optionally hydrogen, halogen, or -C. １－６ Alkyl, -CN, and -NO ２ It is substituted with at least one substituent selected from the following: -L ２Ａ - is a covalent bond, *-N(R ２１ａ )C(O)-**,**-N(R ２１ａ )C(O)-*,*-(CR ２２ａ R ２３ａ ) ｍ -C(R ２２ａ ) = C(R ２３ａ ) - (CR ２２ａ R ２３ａ ) ｎ -**,or 【Chemistry 296】 And, * indicates the position where it is bonded to isoquinoline-1(2H)-one. **But, R ２Ａ It refers to the position where it is connected. m and n are independently 0, 1, 2, or 3. R ２１ａ However, hydrogen or -C １－６ Alkyl, and the aforementioned -C １－６ The alkyl group optionally has at least one substituent R ２１１ｂ It has been replaced with, Each R ２１１ｂ These are independently hydrogen or halogen, R ２２ａ and R ２３ａ Each of these independently produces hydrogen, halogen, or -C １－６ Alkyl, and the aforementioned -C １－６ Each alkyl group independently and optionally has at least one substituent R ２２３ａ It has been replaced with, Each R ２２３ａ These are independently hydrogen or halogen, R ２Ａ However, -C １－６ Alkyl, 3-15 membered cycloalkyl, unsaturated 3-15 membered heterocyclyl containing at least one carbon-carbon double bond, 5-12 membered aryl, or 5-15 membered heteroaryl, and the -C １－６ Each of alkyl, 3-15 membered cycloalkyl, unsaturated 3-15 membered heterocyclyl containing at least one carbon-carbon double bond, 5-12 membered aryl, or 5-15 membered heteroaryl is optionally associated with at least one R Ｙ１ It has been replaced with, Each R Ｙ１ These independently produce hydrogen, halogen, oxo, and -C. １－６ Alkyl, -C ２－６ Alkenyl, -C ２－６ Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, -O-heterocyclyl, -CO-heterocyclyl, aryl, heteroaryl, -P(O)(C) １－６ Alkyl) ２ , -OH, -CN, -OC １－６ Alkyl, -SC １－６ Alkyl, or -NO ２ And the above-C １－６ Alkyl, -C ２－６ Alkenyl, -C ２－６ Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -OC １－６ Alkyl, or -SC １－６ Each alkyl group may independently and optionally have at least one substituent R Ｙ１ａ It has been replaced with, Each R Ｙ１ａ These independently produce hydrogen, halogen, and -C. １－６ Alkyl, -NHC １－６ Alkyl, -C ２－６ Alkenyl, -C ２－６ Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -OH, -CN, -CONH ２ , -COCH ３ , -OC １－６ Alkyl, or -NO ２ The compound of formula (IV) above, or its stereoisomer, tautomer, or pharmaceutically acceptable salt.

2. L ２Ａ The compound according to claim 1, wherein the bond is covalent, -NHC(O)-**, **-NHC(O)-*, *-CH=CH-**, or *-C≡C-**.

3. L ２Ａ The compound according to claim 1 or 2, wherein the bond is covalent.

4. R ２Ａ However, methyl, 【Chemistry 297】 Selected from, n Ｚ Each of these is independently selected from 0, 1, 2, or 3. The compound according to any one of claims 1 to 3, wherein n1 is independently selected from 0, 1, 2, or 3.

5. R ２Ａ but, 【Chemistry 298】 And, X is C(R Ｙ１２ ) or N, R Ｙ１１ , R Ｙ１２ , R Ｙ１３ , R Ｙ１４ , and R Ｙ１５ Each of these independently produces hydrogen, halogen, and -C. １－６ Alkyl, -C ２－６ Alkenyl, -C ２－６ Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, -O-heterocyclyl, -CO-heterocyclyl, aryl, heteroaryl, -P(O)(C) １－６ Alkyl) ２ , -OH, -CN, -OC １－６ Alkyl, -SC １－６ Alkyl, or -NO ２ And the above-C １－６ Alkyl, -C ２－６ Alkenyl, -C ２－６ Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -OC １－６ Alkyl, or -SC １－６ Each alkyl group may independently and optionally have at least one substituent R Ｙ１ａ It is replaced with, or (R Ｙ１１ and R Ｙ１２ ), (R Ｙ１２ and R Ｙ１３ ), (R Ｙ１３ and R Ｙ１４ ), or (R Ｙ１４ and R Ｙ１５ ) along with the atoms to which they are bonded, C ３－１０ Cycloalkyl, C ３－１０ A 4-12 membered heterocyclyl ring, a 6-12 membered aryl ring, or a 4-12 membered heteroaryl ring containing one, two, or three heteroatoms independently selected from cycloalkenyl, nitrogen, oxygen, and optionally oxidized sulfur, and optionally having at least one substituent R Ｙ１ａ It has been replaced with, Each R Ｙ１ａ These independently produce hydrogen, halogen, and -C. １－６ Alkyl, -NHC １－６ Alkyl, -C ２－６ Alkenyl, -C ２－６ Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -OH, -CN, -CONH ２ , -COCH ３ , -OC １－６ Alkyl, or -NO ２ The compound according to any one of claims 1 to 3.

6. R Ｙ１１ and R Ｙ１５ The compound according to claim 5, wherein the compound is hydrogen.

7. R Ｙ１２ , R Ｙ１３ , and R Ｙ１４ The compound according to claim 5 or 6, wherein one, two, or three of them are hydrogen.

8. R Ｙ１２ and R Ｙ１４ However, it is hydrogen, R Ｙ１３ However, halogen, -C １－６ Alkyl, -C ２－６ Alkenyl, -C ２－６ Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, -O-heterocyclyl, -CO-heterocyclyl, aryl, heteroaryl, -P(O)(C) １－６ Alkyl) ２ , -OH, -CN, -OC １－６ Alkyl, -SC １－６ Alkyl, or -NO ２ And the above-C １－６ Alkyl, -C ２－６ Alkenyl, -C ２－６ Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -OC １－６ Alkyl, or -SC １－６ Each alkyl group may independently and optionally have at least one substituent R Ｙ１ａ The compound according to claim 7, which is substituted with

9. R Ｙ１２ , R Ｙ１３ , and R Ｙ１４ However, hydrogen, halogen, -C １－６ Alkyl, -P(O)(C １－６ Alkyl) ２ , -OH, -CN, -OC １－６ Alkyl, -SC １－６ Alkyl, or -NO ２ A compound according to claim 7, selected from the above.

10. (R Ｙ１２ and R Ｙ１３ ) together with the atoms to which they are bonded, form a 4- to 12-membered heterocyclyl ring containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur, or a 4- to 12-membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur, and optionally at least one substituent R Ｙ１ａ The compound according to claim 7, which is substituted with

11. R ２Ａ but, 【Chemistry 299】 The compound according to claim 5.

12. R Ｙ１１ , R Ｙ１２ , R Ｙ１３ , R Ｙ１４ , and R Ｙ１５ Each of these independently produces hydrogen, halogen, and -C. １－６ Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OH, -CN, -OC １－６ Alkyl, -SC １－６ Alkyl, or -NO ２ And the above-C １－６ Alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl each independently and optionally have at least one substituent R Ｙ１ａ It is replaced with, or (R Ｙ１１ and R Ｙ１２ ), (R Ｙ１２ and R Ｙ１３ ), (R Ｙ１３ and R Ｙ１４ ), or (R Ｙ１４ and R Ｙ１５ ) together with the atoms to which they are bonded, form a 5-6 membered heterocyclyl ring, a 6-12 membered aryl ring, or a 5-6 membered heteroaryl ring containing one, two, or three heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur, and optionally, at least one substituent R Ｙ１ａ It has been replaced with, Each R Ｙ１ａ These independently produce hydrogen, -CN, halogen, and -C. １－６ Alkyl, -OC １－６ The compound according to claim 11, wherein it is alkyl or -OH.

13. R Ｙ１１ , R Ｙ１２ , R Ｙ１３ , R Ｙ１４ , and R Ｙ１５ Each of these independently comprises hydrogen, F, -CN, pyrazolyl, and -C. １－６ Alkyl, cyclopropanyl, piperidinyl, or tetrahydropyranyl, wherein the pyrazolyl, -C １－６ Alkyl, cyclopropanyl, piperidinyl, or tetrahydropyranyl each independently and optionally with at least one substituent R Ｙ１ａ It has been replaced with, Each R Ｙ１ａ These independently produce hydrogen, -CN, F, and -C. １－６ Alkyl, -OC １－６ The compound according to claim 11, wherein it is alkyl or -OH.

14. R ２Ａ but, [Chemical 300] The compound according to claim 11.

15. R ２Ａ but, 【Chemical 301】 The compound according to claim 5.

16. R Ｙ１１ , R Ｙ１３ , R Ｙ１４ , and R Ｙ１５ Each of these independently comprises hydrogen, F, -CN, pyrazolyl, and -C. １－６ Alkyl, cyclopropanyl, piperidinyl, or tetrahydropyranyl, wherein the pyrazolyl, -C １－６ Alkyl, cyclopropanyl, piperidinyl, or tetrahydropyranyl each independently and optionally with at least one substituent R Ｙ１ａ It has been replaced with, Each R Ｙ１ａ These independently produce hydrogen, -CN, F, and -C. １－６ Alkyl, -OC １－６ The compound according to claim 15, wherein it is alkyl or -OH.

17. R ２Ａ but, 【Chemical 302】 The compound according to claim 15.

18. R ２Ａ However, methyl, 【Chemical 303】 【Chemical 304】 【Chemical 305】 A compound selected from any one of claims 1 to 3.

19. R ４Ａ and R ４Ｂ However, they are different, and each is independent of hydrogen, deuterium, halogen, and -C. １－６ Alkyl or deuterated C １－６ It is alkyl, carbon atom R ４Ａ and R ４Ｂ The compound according to any one of claims 1 to 18, wherein the atoms bond to form an S or R configuration.

20. R ４Ａ However, it is hydrogen or deuterium, R ４Ｂ However, methyl or -CD ３ The compound according to any one of claims 1 to 19.

21. R ４Ａ However, it is hydrogen, R ４Ｂ The compound according to claim 20, wherein the compound is methyl.

22. Carbon atoms R ４Ａ and R ４Ｂ The compound according to any one of claims 1 to 21, wherein the atoms bond to form an S configuration.

23. Carbon atoms R ４Ａ and R ４Ｂ The compound according to any one of claims 1 to 21, wherein the atoms bond to form an R configuration.

24. The compound is the compound according to any one of claims 1 to 20, having formula (IV-1). 【Chemical 306】 or its tautomers or pharmaceutically acceptable salts.

25. R ４Ｃ The compound according to any one of claims 1 to 24, wherein the compound is hydrogen.

26. R １ However, -C １－６ Alkyl, deuterated - C １－６ Alkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, thietan 1,1-dioxydyl, pyrazolyl, isoxazolyl, oxazolyl, or thiazolyl, and the -C １－６ Alkyl or deuterated C １－６ Each alkyl group is optionally substituted with at least one substituent selected from -CN, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, thietanyl 1,1-dioxydyl, pyrazolyl, isoxazolyl, oxazolyl, and thiazolyl, and each of the oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, thietanyl 1,1-dioxydyl, pyrazolyl, isoxazolyl, oxazolyl, or thiazolyl groups is optionally substituted with -C １－６ The compound according to any one of claims 1 to 25, which is substituted with at least one substituent selected from alkyl groups.

27. R １ is hydrogen, methyl, -CH ２ CN, -CH ２ OCH ３ , -CH ２ CH ３ , -CH ２ CH ３ CN, -CH ２ SO ２ CH ３ , -COCH ３ , -CH ２ OH, -CH ２ CH ２ OCH ３ , 【Chemical 307】 The compound according to any one of claims 1 to 25.

28. R １ The compound according to any one of claims 1 to 27, wherein the compound is methyl.

29. R １ However, -CD ３ The compound according to any one of claims 1 to 27.

30. R ３ The compound according to any one of claims 1 to 29, wherein the compound is hydrogen.

31. R ５ The compound according to any one of claims 1 to 30, wherein the compound is hydrogen.

32. R ６ However, hydrogen, F, methyl, -CD ３ , -CF ３ ,-CHF ２ , or -CH ２ A compound according to any one of claims 1 to 31, wherein F.

33. R ６ The compound according to claim 32, wherein the compound is methyl.

34. R ６ However, -CD ３ The compound according to claim 32.

35. R ７ The compound according to any one of claims 1 to 34, wherein the compound is hydrogen.

36. A compound selected from the following: 【Chemical 308】 【Chemical 309】 【Chemical 310】 【Chemical 311】 【Chemical 312】 【Chemistry 313】 【Chemical 314】 【Chemical Industry 315】 【Chemical 316】 【Chemical 317】 【Chemical 318】 or a pharmaceutically acceptable salt thereof.

37. A compound selected from the following: 【Chemical 319】 【Chem.320】 or a pharmaceutically acceptable salt thereof.

38. A pharmaceutical composition comprising a compound according to any one of claims 1 to 37, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

39. A method for treating a disorder or disease in which the subject needs to be treated, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 37, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition according to claim 38.

40. The method according to claim 39, wherein the subject has PI3Kα containing at least one of the following mutations: H1047R, E542K, and E545K.

41. The method according to claim 39 or 40, wherein the disorder or disease is an inflammatory disorder, an autoimmune disease, or cancer.

42. The method according to claim 41, wherein the disorder or disease is cancer.

43. The method according to claim 39 or 40, wherein the disorder or disease is selected from the group consisting of endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, prostate cancer, cervical cancer, glioblastoma, pancreatic cancer, bladder cancer, CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, spinal cord / skeletal abnormalities / scoliosis), and PROS syndrome (PIK3CA-associated overgrowth syndrome).

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