TW202039483A - Pyrrolo[2,3-b]pyridines as hpk1 inhibitor and the use thereof - Google Patents

Abstract

Disclosed herein is a compound of Formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions comprising thereof. Also disclosed is a method of treating HPK1 related disorders or diseases by using the compound disclosed herein.

Description

Pyrrolo[2,3-b]pyridines as HPK1 inhibitors and their uses

This disclosure provides compounds and their compositions and methods of use. The compounds disclosed in the present invention can modulate (for example, inhibit) the activity of hematopoietic precursor cell kinase 1 (HPK1), and can treat various diseases including cancer.

HPK1 can regulate the different functions of a variety of immune cells, and studies have confirmed that it activates T cell receptors (TCR) [Liou J. et al., Immunity [Immunity], 2000. 12 (4): p.399-408], B Cell Receptor (BCR) [Liou J. et al., Immunity [Immunity], 2000. 12 (4): pages 399-408], transforming growth factor receptor (TGF-βR) [Wang, W. et al. , J Biol Chem [Journal of Biological Chemistry], 1997. 272 (36): p. 22771-5; Zhou, G. et al., J Biol Chem [Journal of Biological Chemistry], 1999. 274 (19): p. 13133-8 Page], or Gs coupled to PGE2 receptors (EP2 and EP4) [Ikegami, R. et al., J Immunol [Journal of Immunology], 2001. 166 (7): pages 4689-96], it induces the kinase of HPK1 active. The overexpression of HPK1 in a kinase-dependent manner inhibits the TCR-induced activation of AP-1-dependent gene transcription, indicating that HPK1 is required to inhibit the Erk MAPK pathway [Liou J. et al., Immunity [Immunity], 2000. 12 (4 ): pages 399-408], and it is believed that this blockade negatively regulates the inhibitory mechanism of TCR-induced IL-2 gene transcription [S. Sawasdikosol. et al., Immunol Res [Immuno Research], 2012. 54: 262 -265].

In vitro HPK1-/- T cells have a lower TCR activation threshold, can proliferate stably, and produce a larger amount of Th1 cytokine. HPK1-/- mice will have increasingly severe autoimmune symptoms [S. Sawasdikosol. et al., Immunol Res [Immuno Research], 2012. 54: 262-265]. For humans, the expression of HPK1 is decreased in peripheral blood mononuclear cells of patients with psoriatic arthritis or T cells of patients with systemic lupus erythematosus (SLE) [Batliwalla FM et al., Mol Med [Molecular Medicine], 2005. 11 (1-12): Pages 21-9], indicating that reducing HPK1 activity may help patients with autoimmune diseases. In addition, HPK1 can also regulate anti-tumor immunity through T cell-dependent mechanisms. In the Lewis lung cancer tumor model that produces PGE2, the tumor development of HPK1 knockout mice is slower than that of wild-type mice [US Patent Application No. 2007/0087988]. Compared with wild-type T cells, HPK1-deficient T cells can effectively control tumor growth and metastasis [Alzabin, S. et al., Cancer Immunol Immunother [Cancer Immunology and Immunotherapy], 2010. 59 (3): No. Pages 419-29]. Similarly, compared to wild-type BMDC, BMDC of HPK1 knockout mice can effectively enhance T cell response and eradicate Lewis lung cancer [Alzabin, S. et al., J Immunol [Journal of Immunology], 2009. 182 (10 ): Pages 6187-94]. In summary, HPK1 may be a good target for enhancing anti-tumor immunity.

As HPK1 modulators, WO 2016205942 discloses benzimidazole, WO 2018049152 A1 discloses pyrazolopyrimidine, WO 2018049191 A1 discloses pyrazolopyridone, and WO 2018049200 A1 and WO 2018049214 A1 disclose pyrazolopyridine.

Although WO 2008124849 discloses pyrrolo[2,3-b]pyridine as Abelson tyrosine kinase, Ron receptor tyrosine kinase, Met receptor tyrosine kinase, Fms-like tyrosine kinase-3, Aurora kinase, P21 activated kinase-4, or 3-phosphoinositide-dependent kinase-1, has not been reported as a pyrrolo[2,3-b]pyridine derivative as a HPK1 modulator.

The present invention discloses the pyrrolo[2,3-b]pyridine derivative of the chemical formula ( I ) and the method of use.

(I ) 或其藥學上可接受的鹽、或其立體異構物， 其中 R¹ 、R² 、R³ 各自係獨立之氫、鹵素、-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、環烷基、雜環基、芳基、雜芳基、側氧基、-CN、-NO₂ 、-OR^a 、-SO₂ R^a 、-COR^a 、-CO₂ R^a 、-CONR^a R^b 、-C(=NR^a )NR^b R^c 、-NR^a R^b 、-NR^a COR^b 、-NR^a CONR^b R^c 、-NR^a CO₂ R^b 、-NR^a SONR^b R^c 、-NR^a SO₂ NR^b R^c 、或-NR^a SO₂ R^b ，所述-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、環烷基、雜環基、芳基、或雜芳基皆視需要由鹵素、羥基、-C_1-8 烷氧基、環烷基、雜環基、芳基、或雜芳基取代； R^a 、R^b 、R^c 各自係獨立之氫、-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、環烷基、雜環基、芳基、或雜芳基； n係0或1； R⁴ 和R⁵ 在每次出現時，係獨立之鹵素、-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、環烷基、雜環基、芳基、雜芳基、側氧基、-CN、-NO₂ 、-OR^4a 、-SO₂ R^4a 、-SO₂ NR^4a R^4b 、-COR^4a 、-CO₂ R^4a 、-CONR^4a R^4b 、-C(=NR^4a )NR^4b R^4c 、-NR^4a R^4b 、-NR^4a COR^4b 、-NR^4a CONR^4b R^4c 、-NR^4a CO₂ R^4b 、-NR^4a SONR^4b R^4c 、-NR^4a SO₂ NR^4b R^4c 、或-NR^4a SO₂ R^4b ，所述-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、環烷基、雜環基、芳基、或雜芳基皆視需要由至少一個取代基R^4d 取代；或在苯基環的相鄰碳原子上時，R⁴ 和R⁵ 與其所附接的兩個居間碳原子（intervening carbon atom），共同形成包含0、1或2個雜原子作為一個或多個環成員的5員至8員環，該雜原子獨立選自氮、氧或視需要氧化之硫，所述環視需要由至少一個取代基R^4e 取代； R^4a 、R^4b 、R^4c 各自係獨立之氫、-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、環烷基、雜環基、芳基、或雜芳基，所述-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、環烷基、雜環基、芳基、或雜芳基皆視需要由至少一個取代基R^4e 取代；或（R^4a 和R^4b ）、（R^4b 和R^4c ）、或（R^4c 和R^4a ）與其所附接的一個或多個原子共同形成3員至12員環，所述環包含0、1或2個額外的雜原子作為一個或多個環成員，該雜原子獨立選自氮、氧或視需要氧化之硫，所述環視需要由至少一個取代基R^4e 取代； R^4d 和R^4e 各自係獨立之氫、鹵素、-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、環烷基、雜環基、芳基、雜芳基、側氧基、-CN、-NO₂ 、-OR^4f 、-SO₂ R^4f 、-SO₂ NR^4f R^4g 、-COR^4f 、-CO₂ R^4f 、-CONR^4f R^4g 、-C(=NR^4f )NR^4g R^4h 、-NR^4f R^4g 、-NR^4f COR^4g 、-NR^4f CONR^4g R^4h 、-NR^4f CO₂ R^4f 、-NR^4f SONR^4f R^4g 、-NR^4f SO₂ NR^4g R^4h 、或-NR^4f SO₂ R^4g ，所述-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、環烷基、雜環基、芳基、或雜芳基皆視需要由至少一個選自鹵素、-C_1-8 烷基、-OR⁴ⁱ 、-NR⁴ⁱ R^4j 、環烷基、雜環基、芳基、或雜芳基的取代基取代； R^4f 、R^4g 、R^4h 、R⁴ⁱ 、R^4j 各自係獨立之氫、-C_1-8 烷基、C_1-8 烷氧基-C_1-8 烷基-、-C_2-8 烯基、-C_2-8 炔基、環烷基、雜環基、芳基、或雜芳基； L¹ 係單鍵、伸烷基、環伸烷基、*¹ -O-伸烷基-**¹ 、*¹ -伸烷基-O-**¹ 、*¹ -NH-伸烷基-**¹ 、*¹ -伸烷基-NH-**¹ 、*¹ -NHC(O)-**¹ 、*¹ -C(O)NH-**¹ 、伸烯基、或伸炔基； 其中 *¹ 係指附接到Cy1的位置，並且 **¹ 係指附接到主鏈的位置； Cy1係各自視需要由R⁶ 取代的稠合雜環基、稠合雜芳基、稠合芳基、稠合環烷基、稠合環烯基、或稠合環炔基； m係0、1、2、3或4； R⁶ 在每次出現時，各自係獨立之鹵素、-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、環烷基、雜環基、芳基、雜芳基、側氧基、-CN、-NO₂ 、-OR^6a 、-SO₂ R^6a 、-SO₂ NR^6a R^6b 、-COR^6a 、-CO₂ R^6a 、-CONR^6a R^6b 、-C(=NR^6a )NR^6b R^6c 、-NR^6a R^6b 、-NR^6a COR^6b 、-NR^6a CONR^6b R^6c 、-NR^6a CO₂ R^6b 、-NR^6a SONR^6b R^6c 、-NR^6a SO₂ NR^6b R^6c 、或-NR^6a SO₂ R^6b ，所述-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、環烷基、雜環基、芳基、或雜芳基皆視需要由至少一個取代基R^6d 取代；或在m係2的情況下，兩個原始R⁶ 與其所附接的碳原子共同形成4員、5員、6員、7員或8員環，所述環包含0、1或2個雜原子作為一個或多個環成員，該雜原子獨立選自氮、氧或視需要氧化之硫，所述環視需要由至少一個取代基R^6e 取代； R^6a 、R^6b 、R^6c 各自係獨立之氫、-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、環烷基、雜環基、芳基、或雜芳基，所述-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、環烷基、雜環基、芳基、或雜芳基皆視需要由至少一個取代基R^6e 取代； R^6d 和R^6e 各自係獨立之氫、鹵素、-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、環烷基、雜環基、芳基、雜芳基、側氧基、-CN、-NO₂ 、-OR^6f 、-SO₂ R^6f 、-SO₂ NR^6f R^6g 、-COR^6f 、-CO₂ R^6f 、-CONR^6f R^6g 、-C(=NR^6f )NR^6g R^6h 、-NR^6f R^6g 、-NR^6f COR^6g 、-NR^6f CONR^6g R^6h 、-NR^6f CO₂ R^6f 、-NR^6f SONR^6f R^6g 、-NR^6f SO₂ NR^6g R^6h 、或-NR^6f SO₂ R^6g ，所述-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、環烷基、雜環基、芳基、或雜芳基皆視需要由至少一個選自鹵素、-C_1-8 烷基、-OR⁶ⁱ 、-NR⁶ⁱ R^6j 、環烷基、雜環基、芳基、或雜芳基的取代基取代； R^6f 、R^6g 、R^6h 、R⁶ⁱ 、R^6j 各自係獨立之氫、側氧基、-C_1-8 烷基、C_1-8 烷氧基-C_1-8 烷基-、-C_2-8 烯基、-C_2-8 炔基、環烷基、雜環基、芳基、或雜芳基。In the first aspect, the present invention discloses a compound of formula ( I )

( I ) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R ¹ , R ² , and R ³ are each independently hydrogen, halogen, -C _1-8 alkyl, -C _2-8 alkene Group, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, pendant oxy, -CN, -NO ₂ , -OR ^a , -SO ₂ R ^a , -COR ^a , -CO ₂ R ^a , -CONR ^a R ^b , -C(=NR ^a )NR ^b R ^c , -NR ^a R ^b , -NR ^a COR ^b , -NR ^a CONR ^b R ^c , -NR ^a CO ₂ R ^b , -NR ^a SONR ^b R ^c , -NR ^a SO ₂ NR ^b R ^c , or -NR ^a SO ₂ R ^b , the -C _1-8 alkyl group, -C _2-8 alkenyl group, -C _{2 -8alkynyl} , cycloalkyl, heterocyclyl, aryl, or heteroaryl are optionally composed of halogen, hydroxy, -C _1-8 alkoxy, cycloalkyl, heterocyclyl, aryl, or hetero Aryl substitution; R ^a , R ^b , and R ^c are each independently hydrogen, -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, Aryl or heteroaryl; n is 0 or 1; each time R ⁴ and R ⁵ appear, they are independent halogen, -C _1-8 alkyl, -C _2-8 alkenyl, -C _{2- 8} alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, ^{_{oxo, -CN, -NO 2, -OR 4a}} , -SO 2 R 4a, -SO 2 NR 4a R 4b, -COR ^4a , -CO ₂ R ^4a , -CONR ^4a R ^4b , -C(=NR ^4a )NR ^4b R ^4c , -NR ^4a R ^4b , -NR ^4a COR ^4b , -NR ^4a CONR ^4b R ^4c , -NR ^4a CO ₂ R ^4b , -NR ^4a SONR ^4b R ^4c , -NR ^4a SO ₂ NR ^4b R ^4c , or -NR ^4a SO ₂ R ^4b , the -C _1-8 alkyl group, -C _2-8 alkenyl group,- C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are optionally substituted with at least one substituent R ^4d ; or when on adjacent carbon atoms of the phenyl ring, R ⁴ and R ⁵ and its attached two intervening carbon atoms (intervening carbon atoms) together form a 5-membered to 8-membered ring containing 0, 1 or 2 heteroatoms as one or more ring members, and the heteroatoms are independently selected from Nitrogen, oxygen or optionally oxidized sulfur, the ring is optionally substituted by at least one substituent R ^4e ; R ^4a , R ^4b , and R ^4c are each independently hydrogen, -C _1-8 alkyl, -C _2-8 Alkenyl, -C _{2- 8} alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, The heterocyclic group, aryl group, or heteroaryl group are optionally substituted with at least one substituent R ^4e ; or (R ^4a and R ^4b ), (R ^4b and R ^4c ), or (R ^4c and R ^4a ) and their The attached one or more atoms together form a 3- to 12-membered ring containing 0, 1 or 2 additional heteroatoms as one or more ring members, which heteroatoms are independently selected from nitrogen, oxygen or Oxidized sulfur is required. The ring is optionally substituted by at least one substituent R ^4e ; R ^4d and R ^4e are each independently hydrogen, halogen, -C _1-8 alkyl, -C _2-8 alkenyl, -C _{2 -8alkynyl} , cycloalkyl, heterocyclyl, aryl, heteroaryl, pendant oxy, -CN, -NO ₂ , -OR ^4f , -SO ₂ R ^4f , -SO ₂ NR ^4f R ^4g ,- COR ^4f , -CO ₂ R ^4f , -CONR ^4f R ^4g , -C(=NR ^4f )NR ^4g R ^4h , -NR ^4f R ^4g , -NR ^4f COR ^4g , -NR ^4f CONR ^4g R ^4h , -NR ^4f CO ₂ R ^4f , -NR ^4f SONR ^4f R ^4g , -NR ^4f SO ₂ NR ^4g R ^4h , or -NR ^4f SO ₂ R ^4g , the -C _1-8 alkyl group, -C _2-8 alkenyl group, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are optionally selected from at least one halogen, -C _1-8 alkyl, -OR ⁴ⁱ , -NR ⁴ⁱ R ^4j , Cycloalkyl, heterocyclyl, aryl, or heteroaryl substituents; R ^4f , R ^4g , R ^4h , R ⁴ⁱ , R ^4j are each independently hydrogen, -C _1-8 alkyl, C _1-8 alkoxy-C _1-8 alkyl-, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; L ¹ series Single bond, alkylene, cycloalkylene, * ¹ -O-alkylene-** ¹ , * ¹ -alkylene-O-** ¹ , * ¹ -NH-alkylene-** ¹ , * ¹ -alkylene-NH-** ¹ , * ¹ -NHC(O)-** ¹ , * ¹ -C(O)NH-** ¹ , alkenylene, or alkynylene; where * ¹ refers to the position attached to Cy1, and ** ¹ refers to the position attached to the main chain; Cy1 is each optionally substituted with R ⁶ fused heterocyclic group, fused heteroaryl group, fused aryl group , Fused cycloalkyl, fused cycloalkenyl, or fused cycloalkynyl; m is 0, 1, 2, 3 or 4; each time R ⁶ occurs, each is an independent halogen, -C _{1- 8} alkyl, -C _2-8 ene Group, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, pendant oxy, -CN, -NO ₂ , -OR ^6a , -SO ₂ R ^6a , -SO ₂ NR ^6a R ^6b , -COR ^6a , -CO ₂ R ^6a , -CONR ^6a R ^6b , -C(=NR ^6a )NR ^6b R ^6c , -NR ^6a R ^6b , -NR ^6a COR ^6b , -NR ^6a CONR ^6b R ^6c , -NR ^6a CO ₂ R ^6b , -NR ^6a SONR ^6b R ^6c , -NR ^6a SO ₂ NR ^6b R ^6c , or -NR ^6a SO ₂ R ^6b , the -C _1-8 alkyl group, -C _{2 -8} alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are optionally substituted with at least one substituent R ^6d ; or in the case of m series 2, two The original R ⁶ and the carbon atom to which it is attached together form a 4-membered, 5-membered, 6-membered, 7-membered or 8-membered ring, which contains 0, 1 or 2 heteroatoms as one or more ring members, and The heteroatom is independently selected from nitrogen, oxygen or optionally oxidized sulfur, and the ring is optionally substituted by at least one substituent R ^6e ; R ^6a , R ^6b , and R ^6c are each independently hydrogen, -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are optionally substituted with at least one substituent R ^6e ; R ^6d and R ^6e are each independently hydrogen, halogen, -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, pendant oxy, -CN, -NO ₂ , -OR ^6f , -SO ₂ R ^6f , -SO ₂ NR ^6f R ^6g , -COR ^6f , -CO ₂ R ^6f , -CONR ^6f R ^6g , -C(=NR ^6f )NR ^6g R ^6h , -NR ^6f R ^6g , -NR ^6f COR ^6g , -NR ^6f CONR ^6g R ^6h , -NR ^6f CO ₂ R ^6f , -NR ^6f SONR ^6f R ^6g , -NR ^6f SO ₂ NR ^6g R ^6h , or -NR ^6f SO ₂ R ^6g , so The -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group are optionally selected from at least one halogen, Substituent substitution of -C _1-8 alkyl, -OR ⁶ⁱ , -NR ⁶ⁱ R ^6j , cycloalkyl, heterocyclyl, aryl, or heteroaryl; R ^6f , R ^6g , R ^6h , R ⁶ⁱ , and R ^6j are each independently hydrogen, pendant oxy group, -C _1-8 alkyl group, C _1-8 alkoxy group -C _1-8 alkyl group -, -C _2-8 alkene Group, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

In one embodiment, R ¹ , R ² , and R ³ are each hydrogen or -C _1-8 alkyl (preferably methyl).

In some embodiments, n is 0, and R ⁴ is -C _1-8 alkyl or -CONR ^4a R ^4b , wherein the -C _1-8 alkyl is optionally substituted with at least one substituent R ^4d , and R ^4a and R ^4b are as defined for formula (I).

In one embodiment, n is 0, and R ⁴ is -CONR ^4a R ^4b , wherein R ^4a and R ^4b are each independently hydrogen or -C _1-8 alkyl, preferably methyl or ethyl.

In one embodiment, n is 0, and R ⁴ is -CONR ^4a R ^4b , wherein R ^4a and R ^4b are each independently hydrogen or -C _1-8 alkyl, preferably methyl or ethyl, The -C _1-8 alkyl group is optionally substituted by a heterocyclic group (for example, the following heterocyclic group: for example, a monocyclic heterocyclic group, further a monocyclic 4- to 9-membered heterocyclic group).

In one embodiment, n is 0, and R ⁴ is -CONR ^4a R ^4b , wherein R ^4a and R ^4b and the nitrogen atom to which they are attached together form a 3- to 12-membered ring, the ring comprising 0, 1, or Two additional heteroatoms are used as one or more ring members, the heteroatoms are independently selected from nitrogen, oxygen or optionally oxidized sulfur, and the ring is optionally substituted by at least one substituent R ^4e . In a preferred embodiment, n is 0, and R ⁴ is -CONR ^4a R ^4b , wherein R ^4a and R ^4b and their attached nitrogen atoms together form 3 members, 4 members, 5 members, 6 members, A 7-membered or 8-membered monocyclic ring, the ring contains 0 or 1 additional heteroatoms as ring members, and the heteroatoms are independently selected from nitrogen, oxygen or optionally oxidized sulfur, and the ring optionally consists of at least one substituent R ^4e replaced. In a preferred embodiment, n is 0, and R ⁴ is -CONR ^4a R ^4b , wherein R ^4a and R ^4b and the nitrogen atom to which they are attached together form a 4-membered monocyclic ring (ie azetidine- 1-yl ring), the ring contains 0 additional heteroatoms, and the ring is optionally substituted by at least one substituent R ^4e . In these embodiments, R ^4e is as defined for formula (I). Preferably, R ^4e is halogen, -C _1-8 alkyl, -OR ^4f , or -NR ^4f R ^4g , wherein R ^4f and R ^4g are each independently hydrogen or -C _1-8 alkyl. The preferred one is methyl. More preferably, R ^4e is a hydroxyl group, a dimethylamino group or a methyl group.

In another preferred embodiment, n is 0, and R ⁴ is -CONR ^4a R ^4b , wherein R ^4a and R ^{4b together} with the nitrogen atom attached to it form a 7 to 12 membered spiro heterocyclic group, preferably Is a single spiro heterocyclic group, the ring contains 0 or 1 additional heteroatoms as ring members, the heteroatoms are independently selected from nitrogen, oxygen or optionally oxidized sulfur, the ring optionally consists of at least one substituent R ^4e replaced. More preferably, R ^4a and R ^{4b together} with the nitrogen atom to which they are attached form a 7 to 12 membered monospiro heterocyclic group, which is selected from 4 members/3 members, 4 members/4 members, 3 members/5 members, 4-member/5-member, 4-member/6-member, 5-member/5-member, or 5-member/6-member monospiro heterocyclic group, said heterocyclic group contains 0 or 1 additional heteroatom as a ring member, the hetero The atoms are independently selected from nitrogen, oxygen or optionally oxidized sulfur.

In one embodiment, n is 0, and R ⁴ is a -C _1-8 alkyl group optionally substituted with at least one substituent R ^4d , preferably methyl or ethyl. Preferably, each occurrence of R ^4d is halogen, cycloalkyl, heterocyclyl, aryl, heteroaryl, pendant oxy, or -OR ^4f , the cycloalkyl, heterocyclyl, The aryl and heteroaryl groups are optionally substituted with at least one substituent selected from halogen and -C _1-8 alkyl, wherein R ^4f is hydrogen or -C _1-8 alkyl. More preferably, each occurrence of R ^4d is a heterocyclic group (preferably a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered or 8-membered monocyclic ring containing a nitrogen atom as a ring member) Or -OR ^4f , wherein R ^4f is hydrogen, and wherein the heterocyclic group is optionally substituted by -C _1-8 alkyl (preferably methyl).

In one embodiment, n is 1, and when it is on the adjacent carbon atom of the phenyl ring, R ⁴ and R ⁵ and the two intervening carbon atoms to which they are attached together form a 5 containing 1 nitrogen atom as a ring member. A ring with a member, a 6-member, a 7-member, or an 8-membered ring is ^optionally substituted with at least one substituent R ^4e , wherein R ^4e is as defined for formula (I). In a preferred embodiment, n is 1, and when it is on the adjacent carbon atom of the phenyl ring, R ⁴ and R ⁵ and the two intervening carbon atoms attached to it together form a nitrogen atom as a ring A 5-membered or 6-membered ring of a member, the ring is optionally substituted with at least one substituent R ^4e , wherein R ^4e is a pendant oxy group or a -C _1-8 alkyl group (preferably a methyl group).

In one embodiment, L ¹ is a single bond.

In one embodiment, Cy1 is a bicyclic fused heterocyclic group, a bicyclic fused heteroaryl group, a bicyclic fused aryl group, a bicyclic fused cycloalkyl group, a bicyclic fused cycloalkenyl group, each optionally substituted by R ⁶ as needed. Or bicyclic fused cycloalkynyl.

In a preferred embodiment, Cy1 is a benzo-fused heterocyclic group, a benzo-fused heteroaryl group, a benzo-fused cycloalkyl group, and a benzo-fused cycloalkenyl group each optionally substituted by R ⁶ as needed. , Benzo-fused cycloalkynyl.

Preferably, the benzo-fused heterocyclic group is indoline, isoindolinyl, benzopiperanyl, dihydrothiazolopyrimidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl , Dihydrobenzofuranyl, dihydrobenzoxolyl, dihydrobenzimidazolyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, benzodioxolyl (benzodioxolyl), benzodioxolyl Benzodioxonyl (benzodioxonyl), chromanyl, chromenyl, octahydrochromenyl, dihydrobenzodioxynyl (dihydrobenzodioxynyl), dihydrobenzoxonyl ( dihydrobenzoxezinyl), dihydrobenzodioxepinyl (dihydrobenzodioxepinyl), dihydrothienodioxynyl (dihydrothienodioxynyl), dihydrobenzoxezinyl, tetrahydrobenzodioxepinyl , Dihydrobenzoazepine, tetrahydrobenzazepine, heterochroman, or chroman.

More preferably, the benzo-fused heterocyclic group is indoline, isoindolinyl, tetrahydroisoquinolinyl, dihydrobenzofuranyl, dihydrobenzimidazolyl, tetrahydrobenzo Oxynitrazine, tetrahydrobenzazepine, or heterochroman. In some examples, the tetrahydroisoquinolinyl group is such as 1,2,3,4-tetrahydroisoquinolinyl, such as 1,2,3,4-tetrahydroisoquinolin-6-yl, 1,2 ,3,4-Tetrahydroisoquinolin-7-yl; tetrahydrobenzoxazepine group such as 2,3,4,5-tetrahydrobenzoxazepine group, such as 2,3,4,5 -Tetrahydrobenzo[f][1,4]oxazepine-8-yl, or 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-yl; Tetrahydrobenzazepine is, for example, 2,3,4,5-tetrahydrobenzazepine, such as 2,3,4,5-tetrahydro-1H-benzo[c]aza-7-yl And 2,3,4,5-tetrahydro-1H-benzo[d]aza-7-yl; isoindolinyl group such as isoindolin-5-yl; isochroman group such as isochroman- 5-yl; dihydroisobenzofuranyl is, for example, 1,3-dihydroisobenzofuran-4-yl.

More preferably, the benzo-fused heteroaryl is benzisoxazolyl, benzodiazolyl, benzofuranyl, benzofuranyl, benzofuranyl, benzimidazolyl, benziso Thiazolyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzothiophenyl, benzotriazolyl, benzodiazolyl, benzoxazepine, indazolyl, indazole Dolyl, isobenzofuranyl, isoindolyl, isoquinolyl (or isoquinolyl), phthaloyl, pteridyl, purinyl, quinazolinyl, quinolyl (or quinolyl) ), or quinolinyl. In some examples, the indazole group is such as 1H-indazol-4-yl, 2H-indazol-4-yl, 1H-indazol-5-yl, 2H-indazol-5-yl, 1H-indazole -7-yl; benzodiazolyl system such as 1H-benzo[d]imidazol-4-yl, 1H-1,3-benzodiazol-5-yl or 1H-benzo[d]imidazole-5 -Group, 1H-benzo[d]imidazol-4-yl, 1H-benzo[d]imidazol-6-yl; benzoazolyl system such as benzo[d]azol-6-yl; benzo The diazole group is, for example, benzo[c][1,2,5] diazole-4-yl.

In some embodiments, Cy1 is a bicyclic fused heteroaryl group selected from the group consisting of fluoropyridyl, furopyrrolyl, imidazopyridyl, imidazopyridyl, imidazothiazolyl, indolinyl, naphthyridinyl , Pyrrolopyridyl, pyrazolopyridyl, pyrazolopyrimidinyl, pyrazolopyridyl, pyrazolotripyridyl, pyrrolopyridyl, pyrrolopyridyl, thiazolopyridyl, thiophene Pyridoxyl, thienopyrazolyl, thienopyridyl, thienopyrrolyl, thienothienyl, or triazolopyridyl. In some examples, the imidazopyridyl group is, for example, imidazo[1,2-a]pyridin-5-yl or imidazo[1,5-a]pyridin-5-yl.

In some embodiments, in the case of m series 2, two original R ⁶ and the carbon atoms to which they are attached together form a 5-membered or 6-membered spiro ring, the ring contains 0 or 1 heteroatom as a ring member, The heteroatom is independently selected from nitrogen, oxygen, or optionally oxidized sulfur. In a preferred embodiment, in the case of m series 2, two original R ⁶ and the carbon atom to which they are attached together form a 6-membered spiro ring, and the ring contains 0 or 1 nitrogen. In a preferred embodiment, in the case of m series 2, two original R ⁶ and their attached carbon atoms together form a 6-membered spiro ring, and the spiro ring contains 1 nitrogen atom, so that Cy1 is 3H -Spiro[benzofuran-2,4'-piperidin]-6-yl, 3H-spiro[benzofuran-2,4'-piperidin]-5-yl, 2H-spiro[benzofuran-3 ,4'-piperidine]-6-yl, or spiro[chroman-4,4'-piperidin]-7-yl.

In some embodiments, R ⁶ is optionally a cycloalkyl substituted with at least one R ^6d (for example, 1 or 2 R ^6d ), preferably a monocyclic C _3-8 cycloalkyl, more preferably A monocyclic C _3-6 cycloalkyl group is preferably cyclohexyl. In some preferred embodiments, R ^6d is -C _1-8 alkyl or -OR ^6f , wherein R ^6f is hydrogen.

In some embodiments, R ⁶ is a pendant oxy group, -OR ^6a , or -NR ^6a R ^6b , wherein R ^6a and R ^6b are each hydrogen, or -C _1-8 alkyl (preferably -C _{1 -3} alkyl, such as methyl).

In some embodiments, R ⁶ is a heterocyclic group optionally substituted with at least one substituent R ^6d . Preferably, the heterocyclic group is a 5-membered to 7-membered monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur, preferably 5-membered or 6-membered monocyclic Cyclic heterocyclyl. More preferably, the heterocyclic group is piperidine, piperidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropiperanyl, tetrahydropiperanyl, or pyrrolidine substituted by at least one substituent R ^6d as necessary base. Preferably, R ^6d is halogen, -C _1-8 alkyl (preferably -C _1-3 alkyl, such as methyl) or pendant oxy group. In some examples, R ⁶ is 4-methylpiperidin-1-yl, 1-methylpiperidin-4-yl, 1-methylpiperidin-3-yl, tetrahydrofuran-3-yl, tetrahydro- 2H-piperan-3-yl, tetrahydro-2H-piperan-4-yl, 1-methyl-1H-pyrazol-4-yl, 1-methylpyrrolidin-3-yl, or 5-side Oxypyrrolidin-3-yl.

In some embodiments, R ⁶ is a heteroaryl group optionally substituted with at least one substituent R ^6d . Preferably, the heteroaryl group is a 5-membered, 6-membered or 7-membered monocyclic heteroaryl group. More preferably, R ⁶ is a pyrazolyl substituted with a C _1-8 alkyl group. For example, R ⁶ is 1-methyl-1H-pyrazol-4-yl.

In some embodiments, R ⁶ is a -C _1-8 alkyl group optionally substituted with at least one substituent R ^6d . Preferably, R ⁶ is a -C _1-8 alkyl group optionally substituted with at least one substituent R ^6d , wherein R ^6d is halogen, heterocyclic, aryl, heteroaryl, -OR ^6f , -CONR ^6f R ^6g , or -NR ^6f R ^6g , the heterocyclic group, aryl group, or heteroaryl group is optionally selected from halogen, -C _1-8 alkyl, -OR ⁶ⁱ , or -NR ⁶ⁱ R ^6j Is substituted by at least one substituent of, wherein R ^6f , R ^6g , R ⁶ⁱ , and R ^6j are each independently hydrogen, or -C _1-8 alkyl (preferably -C _1-3 alkyl, such as methyl) . Preferably, the heterocyclic group as R ^6d is a 5-membered to 7-membered monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur, preferably 5-membered Or a 6-membered monocyclic heterocyclic group. More preferably, each of the heterocyclic groups is optionally substituted with -C _1-8 alkyl (preferably -C _1-3 alkyl, such as methyl) piperidinyl (for example, piperidine-4- Group), lino, pyrrolidinyl (for example, pyrrolidin-3-yl), piperidine (for example, piperidine-1-yl), tetrahydropiperanyl (for example, tetrahydro-2H-piperan- 4-yl), or tetrahydrofuran. Preferably, the heteroaryl group as R ^6d is a 5-membered, 6-membered or 7-membered monocyclic heteroaryl group containing 1 or 2 heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur, or 9-membered Or 10-membered bicyclic heteroaryl group. More preferably, each heteroaryl group is an imidazolyl group (for example, 1H-imidazole-2-) substituted with -C _1-8 alkyl group (preferably -C _1-3 alkyl group, such as methyl) as necessary. Group), pyrazole (for example, 1H-pyrazol-4-yl), pyridyl (for example, pyridin-3-yl, pyridin-4-yl), pyrimidinyl (for example, pyrimidin-5-yl) or indazole Group (for example, 1H-indazol-3-yl).

In some examples, R ⁶ is methyl, 2-hydroxyethyl, 3-(methylamino)-3-oxopropyl, difluoromethyl, (1-methylpiperidin-4-yl )Methyl, 1-(1-methylpiperidin-4-yl)ethyl, 2-(1H-imidazol-2-yl)ethyl, (1-methyl-1H-pyrazol-4-yl) Methyl, (1-methylpiperidin-3-yl)methyl, 2-(dimethylamino)ethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, (2-amine Pyrimidin-5-yl) methyl, 2-(1H-indazol-3-yl) ethyl, 2- linoethyl, 1-(3-fluorophenyl) ethyl, (5-oxo Pyrrolidin-3-yl)methyl, 2-(1-methylpiperidin-4-yl)ethyl, 2-(1-methylpiperidin-3-yl)ethyl, 2-(1-methyl Pyrrolidin-3-yl) ethyl, 2-(1-methylpyrrolidin-2-yl) ethyl, 2-(4-methylpiperidin-1-yl) ethyl, 2-(tetrahydro -2H-piperan-4-yl)ethyl, 2-(tetrahydrofuran-3-yl)ethyl, 2-(tetrahydrofuran-2-yl)ethyl, 2-phenethyl, 4-fluorophenethyl, 3-fluorophenethyl, 2-(3-fluorophenyl)propyl, 1-(3-fluorophenyl)prop-2-yl, 4-fluorobenzyl, or 3-fluorobenzyl.

部分係1,2,3,4-四氫異喹啉-7-基或1,2,3,4-四氫異喹啉-6-基，其皆視需要由如針對化學式 (I) 所定義的R⁶ 取代。較佳的是，R⁶ 係視需要由至少一個取代基R^6d 取代的-C_1-8 烷基，其中R^6d 係鹵素、雜環基、芳基、雜芳基、-OR^6f 、-CONR^6f R^6g 、或-NR^6f R^6g ，所述雜環基、芳基、或雜芳基皆視需要由選自鹵素、-C_1-8 烷基、-OR⁶ⁱ 、或-NR⁶ⁱ R^6j 的至少一個取代基取代，其中R^6f 、R^6g 、R⁶ⁱ 、R^6j 各自係獨立之氫、或-C_1-8 烷基（較佳的是-C_1-3 烷基，例如甲基）。In some embodiments,

Part of it is 1,2,3,4-tetrahydroisoquinolin-7-yl or 1,2,3,4-tetrahydroisoquinolin-6-yl, which are as required by the formula (I) The definition of R ^{6 is} substituted. Preferably, R ⁶ is a -C _1-8 alkyl group optionally substituted with at least one substituent R ^6d , wherein R ^6d is halogen, heterocyclic, aryl, heteroaryl, -OR ^6f , -CONR ^6f R ^6g , or -NR ^6f R ^6g , the heterocyclic group, aryl group, or heteroaryl group is optionally selected from halogen, -C _1-8 alkyl, -OR ⁶ⁱ , or -NR ⁶ⁱ R ^6j Is substituted by at least one substituent of, wherein R ^6f , R ^6g , R ⁶ⁱ , and R ^6j are each independently hydrogen, or -C _1-8 alkyl (preferably -C _1-3 alkyl, such as methyl) .

部分係1,2,3,4-四氫異喹啉-7-基或1,2,3,4-四氫異喹啉-6-基或異吲哚啉-5-基，其皆視需要由兩個-C_1-8 烷基（較佳的是-C_1-3 烷基，例如甲基）取代。In a preferred embodiment,

Part of it is 1,2,3,4-tetrahydroisoquinolin-7-yl or 1,2,3,4-tetrahydroisoquinolin-6-yl or isoindolin-5-yl, whichever depends on It needs to be substituted by two -C _1-8 alkyl groups (preferably -C _1-3 alkyl groups, such as methyl).

部分係1,2,3,4-四氫異喹啉-7-基或1,2,3,4-四氫異喹啉-6-基，其皆視需要由至少一個R⁶ 取代。較佳的是，每個R⁶ 係-C_1-8 烷基和/或-OR^6a ，R^6a 係氫、或-C_1-8 烷基（較佳的是-C_1-3 烷基，例如甲基）。In some embodiments,

Part of it is 1,2,3,4-tetrahydroisoquinolin-7-yl or 1,2,3,4-tetrahydroisoquinolin-6-yl, all of which are optionally substituted with at least one R ⁶ . Preferably, each R ⁶ is -C _1-8 alkyl and/or -OR ^6a , R ^6a is hydrogen, or -C _1-8 alkyl (preferably -C _1-3 alkyl, For example, methyl).

部分係1,2,3,4-四氫異喹啉-7-基或1,2,3,4-四氫異喹啉-6-基，其皆視需要由兩個R⁶ （m=2）取代。較佳的是，一個R⁶ 係-C_1-8 烷基，並且另一個R⁶ 係-C_1-8 烷基或-OR^6a ，R^6a 係獨立之氫、或-C_1-8 烷基（較佳的是-C_1-3 烷基，例如甲基）。In some embodiments,

Part of it is 1,2,3,4-tetrahydroisoquinolin-7-yl or 1,2,3,4-tetrahydroisoquinolin-6-yl, which are optionally composed of two R ⁶ (m= 2) Replace. Preferably, one R ⁶ is -C _1-8 alkyl, and the other R ⁶ is -C _1-8 alkyl or -OR ^6a , and R ^6a is independently hydrogen or -C _1-8 alkyl (Preferably -C _1-3 alkyl, such as methyl).

部分係1,2,3,4-四氫異喹啉-7-基、2-甲基-1,2,3,4-四氫異喹啉-7-基、1,2,3,4-四氫異喹啉-6-基、2-甲基-1,2,3,4-四氫異喹啉-6-基、2-(1-甲基哌啶-4-基)-1,2,3,4-四氫異喹啉-6-基、2-(2-羥基乙基)-1,2,3,4-四氫異喹啉-6-基、8-甲氧基-2-甲基-1,2,3,4-四氫異喹啉-1-酮、2-(1-甲基哌啶-4-基)-1,2,3,4-四氫異喹啉-6-基、2-(3-(甲基胺基)-3-側氧基丙基)-1,2,3,4-四氫異喹啉-7-基、2,8-二甲基-1-側氧基-1,2,3,4-四氫異喹啉-6-基、8-甲氧基-2-甲基-1,2,3,4-四氫異喹啉-6-基、2-[2-(1H-咪唑-2-基)乙基]-1,2,3,4-四氫異喹啉-7-基、8-甲氧基-2-甲基-3-側氧基-1,2,3,4-四氫異喹啉-6-基、8-甲氧基-2-甲基-4-側氧基-1,2,3,4-四氫異喹啉-6-基、5-甲氧基-2-甲基-1,2,3,4-四氫異喹啉-7-基、4-羥基-8-甲氧基-2-甲基-1,2,3,4-四氫異喹啉-6-基、2,5-二甲基-1,2,3,4-四氫異喹啉-7-基、2,8-二甲基-1,2,3,4-四氫異喹啉-6-基、4-羥基-2,8-二甲基-1,2,3,4-四氫異喹啉-6-基、4-胺基-2,8-二甲基-1,2,3,4-四氫異喹啉-6-基、2-((1-甲基哌啶-4-基)甲基)-1,2,3,4-四氫異喹啉-7-基、2-(1-甲基哌啶-4-基)-1,2,3,4-四氫異喹啉-7-基、2-(1-甲基哌啶-3-基)-1,2,3,4-四氫異喹啉-7-基、2-(四氫呋喃-3-基)-1,2,3,4-四氫異喹啉-7-基、2-(四氫-2H-哌喃-3-基)-1,2,3,4-四氫異喹啉-7-基、2-(四氫-2H-哌喃-4-基)-1,2,3,4-四氫異喹啉-7-基、2-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氫異喹啉-7-基、2-((1-甲基-1H-吡唑-4-基)甲基)-1,2,3,4-四氫異喹啉-7-基、2-((1-甲基哌啶-3-基)甲基)-1,2,3,4-四氫異喹啉-7-基、2-(2-(二甲基胺基)乙基)-1,2,3,4-四氫異喹啉-7-基、2-(4-氟苄基)-1,2,3,4-四氫異喹啉-7-基、2-(3-氟苄基)-1,2,3,4-四氫異喹啉-7-基、2-(吡啶-3-基甲基)-1,2,3,4-四氫異喹啉-7-基、2-(吡啶-4-基甲基)-1,2,3,4-四氫異喹啉-7-基、2-((2-胺基嘧啶-5-基)甲基)-1,2,3,4-四氫異喹啉-7-基、2-(1-甲基吡咯啶-3-基)-1,2,3,4-四氫異喹啉-7-基、2-(2-(1H-吲唑-3-基)乙基)-1,2,3,4-四氫異喹啉-7-基、2-(2-啉代乙基)-1,2,3,4-四氫異喹啉-7-基、2-(1-(3-氟苯基)乙基)-1,2,3,4-四氫異喹啉-7-基、2-((5-側氧基吡咯啶-3-基)甲基)-1,2,3,4-四氫異喹啉-7-基、2-(5-側氧基吡咯啶-3-基)-1,2,3,4-四氫異喹啉-7-基、2-(2-(1-甲基哌啶-4-基)乙基)-1,2,3,4-四氫異喹啉-7-基、2-(2-(1-甲基哌啶-3-基)乙基)-1,2,3,4-四氫異喹啉-7-基、2-(2-(1-甲基吡咯啶-3-基)乙基)-1,2,3,4-四氫異喹啉-7-基、2-(2-(1-甲基吡咯啶-2-基)乙基)-1,2,3,4-四氫異喹啉-7-基、2-(2-(4-甲基哌𠯤-1-基)乙基)-1,2,3,4-四氫異喹啉-7-基、2-(2-(四氫-2H-哌喃-4-基)乙基)-1,2,3,4-四氫異喹啉-7-基、2-(2-(四氫呋喃-3-基)乙基)-1,2,3,4-四氫異喹啉-7-基、2-(2-(四氫呋喃-2-基)乙基)-1,2,3,4-四氫異喹啉-7-基、2-苯乙基-1,2,3,4-四氫異喹啉-7-基、2-(4-氟苯乙基)-1,2,3,4-四氫異喹啉-7-基、2-(3-氟苯乙基)-1,2,3,4-四氫異喹啉-7-基、2-(2-(3-氟苯基)丙基)-1,2,3,4-四氫異喹啉-7-基、2-(1-(3-氟苯基)丙-2-基)-1,2,3,4-四氫異喹啉-7-基、2-((1r,4r)-4-羥基-4-甲基環己基)-1,2,3,4-四氫異喹啉-7-基、2-((1R,3R)-3-羥基環戊基)-1,2,3,4-四氫異喹啉-7-基、或2,7-二甲基異吲哚啉-5-基。In some instances,

Part of 1,2,3,4-tetrahydroisoquinolin-7-yl, 2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl, 1,2,3,4 -Tetrahydroisoquinolin-6-yl, 2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl, 2-(1-methylpiperidin-4-yl)-1 ,2,3,4-Tetrahydroisoquinolin-6-yl, 2-(2-hydroxyethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl, 8-methoxy -2-Methyl-1,2,3,4-tetrahydroisoquinolin-1-one, 2-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydroiso Quinolin-6-yl, 2-(3-(methylamino)-3-oxopropyl)-1,2,3,4-tetrahydroisoquinolin-7-yl, 2,8- Dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl, 8-methoxy-2-methyl-1,2,3,4-tetrahydroiso Quinolin-6-yl, 2-[2-(1H-imidazol-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl, 8-methoxy-2 -Methyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl, 8-methoxy-2-methyl-4-oxo-1,2,3 ,4-Tetrahydroisoquinolin-6-yl, 5-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl, 4-hydroxy-8-methoxy 2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl, 2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl , 2,8-Dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl, 4-hydroxy-2,8-dimethyl-1,2,3,4-tetrahydroiso Quinolin-6-yl, 4-amino-2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl, 2-((1-methylpiperidine-4 -Yl)methyl)-1,2,3,4-tetrahydroisoquinolin-7-yl, 2-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydro Isoquinolin-7-yl, 2-(1-methylpiperidin-3-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl, 2-(tetrahydrofuran-3-yl) -1,2,3,4-Tetrahydroisoquinolin-7-yl, 2-(tetrahydro-2H-piperan-3-yl)-1,2,3,4-tetrahydroisoquinolin-7 -Base, 2-(tetrahydro-2H-piperan-4-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl, 2-(1-methyl-1H-pyrazole- 4-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl, 2-((1-methyl-1H-pyrazol-4-yl)methyl)-1,2,3 ,4-Tetrahydroisoquinolin-7-yl, 2-((1-methylpiperidin-3-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-7-yl, 2-(2-(Dimethylamino)ethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl, 2-(4-fluorobenzyl)-1,2,3, 4-tetrahydroisoquinolin-7-yl, 2-(3-fluorobenzyl)-1,2,3,4-tetrahydroisoquinolin-7 -Yl, 2-(pyridin-3-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl, 2-(pyridin-4-ylmethyl)-1,2,3 ,4-Tetrahydroisoquinolin-7-yl, 2-((2-aminopyrimidin-5-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-7-yl, 2 -(1-Methylpyrrolidin-3-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl, 2-(2-(1H-indazol-3-yl)ethyl) -1,2,3,4-Tetrahydroisoquinolin-7-yl, 2-(2-linoethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl, 2- (1-(3-Fluorophenyl)ethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl, 2-((5-oxopyrrolidin-3-yl)methyl )-1,2,3,4-Tetrahydroisoquinolin-7-yl, 2-(5-oxopyrrolidin-3-yl)-1,2,3,4-tetrahydroisoquinoline- 7-yl, 2-(2-(1-methylpiperidin-4-yl)ethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl, 2-(2-(1 -Methylpiperidin-3-yl)ethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl, 2-(2-(1-methylpyrrolidin-3-yl)ethyl Yl)-1,2,3,4-tetrahydroisoquinolin-7-yl, 2-(2-(1-methylpyrrolidin-2-yl)ethyl)-1,2,3,4- Tetrahydroisoquinolin-7-yl, 2-(2-(4-methylpiperid-1-yl)ethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl, 2 -(2-(Tetrahydro-2H-piperan-4-yl)ethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl, 2-(2-(tetrahydrofuran-3-yl) )Ethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl, 2-(2-(tetrahydrofuran-2-yl)ethyl)-1,2,3,4-tetrahydroiso Quinolin-7-yl, 2-phenethyl-1,2,3,4-tetrahydroisoquinolin-7-yl, 2-(4-fluorophenethyl)-1,2,3,4- Tetrahydroisoquinolin-7-yl, 2-(3-fluorophenethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl, 2-(2-(3-fluorophenyl) )Propyl)-1,2,3,4-tetrahydroisoquinolin-7-yl, 2-(1-(3-fluorophenyl)propan-2-yl)-1,2,3,4- Tetrahydroisoquinolin-7-yl, 2-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-1,2,3,4-tetrahydroisoquinolin-7-yl, 2 -((1R,3R)-3-hydroxycyclopentyl)-1,2,3,4-tetrahydroisoquinolin-7-yl or 2,7-dimethylisoindolin-5-yl .

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  106 107 108   In one embodiment, the compound disclosed in the present invention, or a pharmaceutically acceptable salt or stereoisomer thereof, is selected from

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twenty one 22A 22B 23A

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In the second aspect, the pharmaceutical composition disclosed in the present invention includes the compound disclosed in the present invention, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

In the third aspect, the method disclosed in the present invention is a method for inhibiting the activity of HPK1, which method comprises administering to an individual the compound disclosed in the present invention, or a pharmaceutically acceptable salt thereof, including a compound of formula (I) or a specific compound exemplified by the present invention .

In a fourth aspect, the present invention discloses a method for treating a patient’s disease or disorder, which method comprises administering to the patient a therapeutically effective amount of the compound disclosed in the present invention, or a pharmaceutically acceptable salt thereof, as an HPK1 kinase inhibitor, wherein The compounds disclosed in the present invention include compounds of formula (I) or specific compounds exemplified in the present invention. In some embodiments, the disease or disorder is related to inhibition of HPK1 interaction. Preferably, the disease or disorder is cancer.

The following terms have designated meanings throughout the specification:

As used in the present invention, including the scope of the appended application, unless the context clearly dictates otherwise, the singular forms of words such as "一/个/种" (a/an) and "the" (the) include their corresponding The plural refers to things.

Unless the context clearly dictates otherwise, the term "or" means the term "and/or", and is used interchangeably with the term "and/or".

The term "alkyl" refers to a hydrocarbon group selected from the group comprising from 1 to 18 (e.g. from 1 to 12, further for example from 1 to 10, still further for example from 1 to 8, or from 1 to 6, or from 1 to 4) Straight and branched saturated hydrocarbon groups of carbon atoms. Examples of alkyl groups containing from 1 to 6 carbon atoms (ie C _1-6 alkyl) 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 secondary butyl (“s-Bu”), 1,1-dimethylethyl or tertiary 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, 3,3-dimethyl-2-butyl groups.

The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

The term "haloalkyl" refers to an alkyl group in which one or more hydrogens are replaced by one or more halogen atoms (eg fluorine, chlorine, bromine, iodine). Examples of haloalkyl include halo C _1-8 alkyl, halo C _1-6 alkyl, or halo C _1-4 alkyl, but are not limited to -CF ₃ , -CH ₂ Cl, -CH ₂ CF ₃ , -CCl ₂ , CF ₃ and so on.

The term "alkenyl" refers to a hydrocarbon group selected from linear and branched hydrocarbon groups containing at least one C=C double bond and from 2 to 18 (for example from 2 to 8, further for example from 2 to 6) carbon atoms group. Examples of alkenyl groups (such as C _2-6 alkenyl) include but are not limited to: vinyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl , But-1-enyl, but-2-enyl, but-3-enyl, butane-1,3-dienyl, 2-methylbut-1,3-dienyl, hex-1 -Alkenyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-1,3-dienyl groups.

The term "alkynyl" refers to a hydrocarbon group selected from linear and branched hydrocarbon groups containing at least one C≡C triple bond and from 2 to 18 (for example, from 2 to 8, further for example, 2 to 6) carbon atoms . Examples of alkynyl groups (such as C _2-6 alkynyl) include but are not limited to: ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butyne Group, 3-butynyl group.

The term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups containing monocyclic and polycyclic (eg bicyclic and tricyclic) groups (including fused, bridged or spiro cycloalkyl) .

For example, a cycloalkyl group may contain from 3 to 12, such as from 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4 carbon atoms. Even further for example, the cycloalkyl group may be selected from monocyclic groups containing from 3 to 12, such as from 3 to 10, further such as 3 to 8, 3 to 6 carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-ene Group, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclo Nonyl, cyclodecyl, cycloundecyl, cyclododecyl groups. In particular, examples of saturated monocyclic cycloalkyl groups (such as C _3-8 cycloalkyl) include but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl Group. In a preferred embodiment, the cycloalkyl group contains a monocyclic ring with 3 to 6 carbon atoms (abbreviated as C _3-6 cycloalkyl), including but not limited to: cyclopropyl, cyclobutyl, cyclopentyl , Cyclohexyl. Examples of bicyclic cycloalkyl groups include those having from 7 to 12 ring atoms and having a condensed bicyclic arrangement (selected from [4,4], [4,5], [5,5], [5,6] , [6,6] ring system), or those with a bridged bicyclic arrangement (selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane). Other examples of bicyclic cycloalkyl groups include those having a bicyclic arrangement (selected from [5,6] and [6,6] ring systems).

The term "spirocycloalkyl" refers to a ring structure containing carbon atoms and formed by at least two rings which share one atom. The term "7-membered to 12-membered spirocycloalkyl" refers to a ring structure containing 7 to 12 carbon atoms and formed by at least two rings that share one atom.

The term "fused cycloalkyl" refers to a bicyclic cycloalkyl group as defined in the present invention, which is saturated and formed by two or more rings sharing two adjacent atoms.

The term "bridged cycloalkyl" refers to a ring structure containing carbon atoms and formed by at least two rings that share two atoms that are not adjacent to each other. The term "7- to 10-membered bridged cycloalkyl" refers to a ring structure containing 7 to 12 carbon atoms and formed by at least two rings that share two atoms that are not adjacent to each other.

The term "cycloalkenyl" refers to a non-aromatic cycloalkyl group having a single ring or multiple rings, having at least one double bond (and preferably from 1 to 2 double bonds), and from 3 to 10 carbon atoms Group. In one embodiment, the cycloalkenyl group is cyclopentenyl or cyclohexenyl, preferably cyclohexenyl.

The term "fused cycloalkenyl" refers to a bicyclic cycloalkyl group as defined in the present invention, which contains at least one double bond and is formed by two or more rings sharing two adjacent atoms.

The term "cycloalkynyl" refers to a non-aromatic cycloalkyl group having a single ring or multiple rings, having at least one triple bond, and from 5 to 10 carbon atoms.

The term "fused cycloalkynyl" refers to a bicyclic cycloalkyl group as defined in the present invention, which contains at least one triple bond and is formed by two or more rings sharing two adjacent atoms.

和

，其中波浪線指示附接點。The term "benzo-fused cycloalkyl" refers to a bicyclic fused cycloalkyl in which a 4- to 8-membered monocyclic cycloalkyl ring is fused with a benzene ring. For example, benzo-fused cycloalkyl system

with

, Where the wavy line indicates the attachment point.

The term "benzo-fused cycloalkenyl" refers to a bicyclic fused cycloalkenyl group in which a 4- to 8-membered monocyclic cycloalkenyl ring is fused with a benzene ring.

The term "benzo-fused cycloalkynyl" refers to a bicyclic fused cycloalkynyl group in which a 4- to 8-membered monocyclic cycloalkynyl ring is fused with a benzene ring.

Examples of fused cycloalkyl, fused cycloalkenyl, or fused cycloalkynyl include, but are not limited to: 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 benzo 3 to 8 member cycloalkyl, benzo C _4-6 Cycloalkenyl, 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, etc. A preferred embodiment is a fused ring with 8 to 9 members, which refers to a ring structure containing 8 to 9 ring atoms in the above examples.

The term "aryl" used alone or in combination with other terms refers to a group selected from: 5-membered and 6-membered carbocyclic aromatic rings, such as phenyl; Bicyclic ring systems (for example, bicyclic ring systems with 7 to 12 members), in which at least one ring system is carbocyclic and aromatic, such as naphthyl and indenyl; and A tricyclic ring system (for example a 10-membered to 15-membered tricyclic ring system), in which at least one ring system is carbocyclic and aromatic, such as a stilbene group.

The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably in the complete disclosure of this invention. In some embodiments, the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (ie, C _5-10 aryl). Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to: phenyl, naphth-1-yl, naphth-2-yl, anthryl, phenanthryl and the like. In some embodiments, the aromatic hydrocarbon ring system is a naphthalene ring (naphth-1-yl or naphth-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring system is a phenyl ring.

Specifically, the term "bicyclic fused aryl" refers to a bicyclic aryl ring as defined in the present invention, and a typical bicyclic fused aryl is naphthalene.

The term "heteroaryl" refers to a group selected from: A 5-membered, 6-membered, or 7-membered aromatic monocyclic ring comprising at least one heteroatom selected from nitrogen (N), sulfur (S), oxygen (O) (for example, from 1 to 4, or in some embodiments From 1 to 3, in some embodiments from 1 to 2 heteroatoms), wherein the remaining ring atoms are carbon; 7-membered to 12-membered bicyclic ring, which contains at least one heteroatom selected from N, O, S (for example, from 1 to 4, or in some embodiments from 1 to 3, or in other embodiments 1 or 2 Heteroatoms), wherein the remaining ring atoms are carbon, and at least one of the ring systems is aromatic, and at least one heteroatom is present in the aromatic ring; and An 11-member to 14-member tricyclic ring, which contains at least one heteroatom selected from N, O, S (for example, from 1 to 4, or in some embodiments from 1 to 3, or in other embodiments 1 or 2 heteroatoms), wherein the remaining ring atoms are carbon, and at least one of the ring systems is aromatic, and at least one heteroatom is present in the aromatic ring.

When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl group does not exceed 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle does not exceed one. When a heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. The nitrogen atom in one or more rings of the heteroaryl group can be oxidized to form an N-oxide.

Specifically, the term "bicyclic fused heteroaryl" refers to a 7 to 12 member, preferably 7 to 10 member, more preferably 9 or 10 member fused bicyclic heterocyclic group as defined in the present invention. Aryl ring. Generally speaking, a bicyclic fused heteroaryl group is a 5-member/5-member, 5-member/6-member, 6-member/6-member, or 6-member/7-member bicyclic ring. The group can be attached to the rest of the molecule through any ring.

Representative examples of bicyclic fused heteroaryl groups include, but are not limited to, the following groups: benzisoxazolyl, benzodiazolyl, benzofuranyl, benzofuracryl, benzofuranyl, benzimidazole Group, benzoisothiazolyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzothiophenyl, benzotriazolyl, benzodiazolyl, benzoxazepine, Fluoropyridyl, furopyrrolyl, imidazopyridyl, imidazopyridyl, imidazothiazolyl, indazolyl, indolyl, indolyl, isobenzofuranyl, isoindolyl, isoquine Linyl (or isoquinolinyl), naphthyridinyl, phthalopyridyl, pterridinyl, purinyl, pyrazolopyridyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridinyl, Pyrazolotripyridyl, pyrrolopyridyl, pyrrolopyridyl, quinazolinyl, quinolinyl (or quinolinyl), quinazolinyl, thiazolopyridyl, thienopyridyl, thiophene Pyrazolyl, thienopyridyl, thienopyrrolyl, thienothienyl, or triazolopyridyl.

The term "benzo-fused heteroaryl" refers to a bicyclic fused heteroaryl group, in which a 5-member to 7-member (preferably 5-member or 6-member) monocyclic heteroaryl ring as defined in the present invention is combined with benzene Ring fused.

The terms "aromatic heterocycle" and "heteroaryl" are used interchangeably in the complete disclosure of this invention. In some embodiments, the monocyclic or bicyclic aromatic heterocyclic ring has 5, 6, 7, 8, 9 or 10 ring-forming members, wherein 1, 2, 3, or 4 heteroatom ring members are independently selected from nitrogen (N ), sulfur (S), oxygen (O), and the remaining ring members are carbon. In some embodiments, the monocyclic or bicyclic aromatic heterocyclic ring system includes a monocyclic or bicyclic ring having 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocyclic ring is a 5- to 6-membered heteroaryl ring, which is a monocyclic ring and has 1 independently selected from nitrogen (N), sulfur (S), and oxygen (O). Or 2 heteroatom ring members. In some embodiments, the monocyclic or bicyclic aromatic heterocyclic ring is an 8-membered to 10-membered heteroaryl ring, which is a bicyclic ring and has 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen.

Examples of heteroaryl groups, or monocyclic or bicyclic aromatic heterocycles include, but are not limited to: (numbering from the attachment position designated as priority 1) pyridyl (e.g., 2-pyridyl, 3-pyridyl, Or 4-pyridyl), cinolinyl, pyrimidinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridinyl, isoazolyl, azazolyl, Thiazolyl, isothiazolyl, thiadiazolyl (for example, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, or 1,3,4-thiadiazolyl), four Azolyl, thienyl (for example, thiophen-2-yl, thiophen-3-yl), trithiophene, benzothienyl, furan or furyl, benzofuranyl, benzimidazolyl, indolyl, Isoindolyl, oxadiazolyl (for example, 1,2,3- oxadiazolyl, 1,2,4- oxadiazolyl, or 1,3,4- oxadiazolyl), phthalazolyl , Pyridine, pyrrolyl, triazolyl (for example, 1,2,3-triazolyl, 1,2,4-triazolyl, or 1,3,4-triazolyl), Quinolinyl, isoquinolinyl, pyrazolyl, pyrrolopyridyl (for example, 1H-pyrrolo[2,3-b]pyridin-5-yl), pyrazolopyridyl (for example, 1H-pyrazole And [3,4-b]pyridin-5-yl), benzoxazol-6-yl (for example, benzo[d]azol-6-yl), pteridyl, 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-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl, 1-thia-3,4-diazolyl, furazanyl (For example, furazan-2-yl, furazan-3-yl), benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazepine, quinazolinyl, quinazolinyl , Naphthyridinyl, fluoropyridyl, benzothiazolyl (for example, benzo[d]thiazol-6-yl), indazolyl (for example, 1H-indazol-5-yl).

"Heterocyclyl", "heterocyclic" or "heterocyclic" are interchangeable and refer to a non-aromatic heterocyclic group (which contains one or more selected from nitrogen, oxygen, or optionally oxidized sulfur Heteroatoms are used as ring members, and the remaining ring members are carbon), including monocyclic, fused, bridged, and spiro rings, that is, containing monocyclic heterocyclic groups, bridged heterocyclic groups, spiro heterocyclic groups, Condensed heterocyclic group.

The term "optionally oxidized sulfur" used in the present invention refers to S, SO or SO ₂ .

The term "monocyclic heterocyclic group" refers to a heteroatom monocyclic group in which at least one ring member (for example, 1-3 heteroatoms, 1 or 2 heteroatoms) is selected from nitrogen, oxygen, or optionally oxidized sulfur group. The heterocyclic ring may be saturated or partially saturated.

Exemplary monocyclic 4- to 9-membered heterocyclyl groups include, but are not limited to: (numbered from the attachment position designated as priority 1) pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidine-3- Yl, imidazolidinone-2-yl, imidazolidinone-4-yl, pyrazolidine-2-yl, pyrazolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidine -3-yl, piperidin-4-yl, 2,5-piperidinyl, piperanyl, linyl, lino, lin-2-yl, lin-3-yl, oxirane, aziryl Cyclo-1-yl, aziridin-2-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, azetidin-4-yl, Azetidin-5-yl, thiiranyl, azetidine-1-yl, azetidine-2-yl, azetidine-3-yl, oxa Cyclobutanyl, thietanyl, 1,2-thiocyclobutane, 1,3-thiocyclobutane, dihydropyridyl, tetrahydropyridyl, thiolinyl, oxathia Cyclohexyl, piperidine, homopiperidinyl, homopiperidinyl, azepan-1-yl, azepan-2-yl, azepan-3-yl, nitrogen Heptan-4-yl, oxepanyl, thioepanyl, 1,4-oxepanyl, 1,4-dioxepanyl, 1,4- Oxazepanyl, 1,4-oxazepanyl, 1,4-dithiazepanyl, 1,4-thiazepanyl and 1,4 -Diazacycloheptanyl, 1,4-dithiazolyl, 1,4-azathiazolyl, oxazepine, diazacycloheptanyl, sulfazepine, dihydrothienyl, dihydro Piperanyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropiperanyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indoline Dolyl, 2H-piperanyl, 4H-piperanyl, 1,4-dioxolane, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithiopyranyl, two Thiopentyl, pyrazolidinyl, imidazolinyl, pyrimidinone, 1,1-di-side oxy-thiolinyl.

The term "spiroheterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group having rings connected by a common carbon atom (called a spiro atom), which contains one or more selected from nitrogen, oxygen or optionally The heteroatoms of oxidized sulfur serve as ring members, and the remaining ring members are carbon. One or more rings of a spiroheterocyclic group may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. Preferably, the spiro heterocyclic group has 6 to 14 members, more preferably 7 to 12 members. According to the number of spiro atoms in common, spiro heterocyclic groups are classified into single spiro heterocyclic groups, di-spiro heterocyclic groups, or polyspiro heterocyclic groups, preferably referring to single spiro heterocyclic groups or di-spiro heterocyclic groups. Basic, and better is 4 members/3 members, 4 members/4 members, 3 members/5 members, 4 members/5 members, 4 members/6 members, 5 members/5 members, or 5 members/6 members Spiro heterocyclyl. Representative examples of spiroheterocyclic groups include, but are not limited to, the following groups: 2,3-dihydrospiro[indene-1,2'-pyrrolidine] (e.g., 2,3-dihydrospiro[indene-1,2 '-Pyrrolidine]-1'-yl), 1,3-dihydrospiro[indene-2,2'-pyrrolidine] (for example, 1,3-dihydrospiro[indene-2,2'-pyrrolidine ]-1'-yl), azaspiro[2.4]heptane (for example, 5-azaspiro[2.4]heptane-5-yl), 2-oxa-6-azaspiro[3.3]heptane (For example, 2-oxa-6-azaspiro[3.3]heptane-6-yl), azaspiro[3.4]octane (for example, 6-azaspiro[3.4]octane-6-yl) , 2-oxa-6-azaspiro[3.4]octane (for example, 2-oxa-6-azaspiro[3.4]octane-6-yl), azaspiro[3.4]octane (for example , 6-azaspiro[3.4]octane-6-yl), azaspiro[3.4]octane (for example, 6-azaspiro[3.4]octane-6-yl), 1,7-diox Heterosspiro[4.5]decane, 2-oxa-7-aza-spiro[4.4]nonane (for example, 2-oxa-7-aza-spiro[4.4]non-7-yl), 7- Oxa-spiro[3.5]nonyl and 5-oxa-spiro[2.4]heptyl.

The term "fused heterocyclyl" refers to a 5-member to 20-member polycyclic heterocyclyl group (wherein each ring in the system shares adjacent pairs of atoms (carbon and carbon atoms, or carbon and nitrogen atoms) with another ring )), containing one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, and the remaining ring members are carbon. One or more rings of the fused heterocyclic group may contain one or more double bonds, but the fused heterocyclic group does not have a fully conjugated π electron system. Preferably, the fused heterocyclic group has 6 to 14 members, more preferably 7 to 12 members or 7 to 10 members. According to the number of constituent rings, condensed heterocyclic groups are divided into bicyclic, tricyclic, tetracyclic, and polycyclic condensed heterocyclic groups. The group can be attached to the rest of the molecule through any ring.

Specifically, the term "bicyclic fused heterocyclic group" refers to a 7 to 12 member, preferably 7 to 10 member, more preferably 9 or 10 member fused heterocyclic ring as defined in the present invention The group contains two condensed rings, and contains 1 to 4 heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members. Generally speaking, the bicyclic fused heterocyclic group is a 5-member/5-member, 5-member/6-member, 6-member/6-member, 6-member/7-member bicyclic fused heterocyclic group. Representative examples of (bicyclic) fused heterocycles include, but are not limited to, the following groups: octahydrocyclopenta[c]pyrrole, octahydropyrrolo[3,4-c]pyrrolyl, octahydroisoindolyl, iso Indolinyl, octahydro-benzo[b][1,4]di㗁𠯤, indolinyl, isoindolinyl, benzopiperanyl, dihydrothiazolopyrimidinyl, tetrahydroquine Linyl, tetrahydroisoquinolinyl (or tetrahydroisoquinolinyl), dihydrobenzofuranyl, dihydrobenzofuranyl, dihydrobenzimidazolyl, tetrahydrobenzothienyl, tetrahydro Benzofuranyl, benzodioxolyl, benzodioxonyl, chromanyl, chromenyl, octahydrochromenyl, dihydrobenzodioxolyl Dihydrobenzodioxynyl (dihydrobenzodioxynyl), dihydrobenzoxezinyl, dihydrobenzodioxepinyl, dihydrothienodioxynyl , Dihydrobenzoxazepine, tetrahydrobenzoxazepine, dihydrobenzoxazepine, tetrahydrobenzoazepine, isochromanyl, chromanyl, tetrahydropyrazolopyrimidinyl (For example, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl).

The term "benzo-fused heterocyclic group" refers to a bicyclic fused heterocyclic group, in which a monocyclic 4- to 9-membered heterocyclic group (preferably 5-membered or 6-membered) as defined in the present invention is fused with a benzene ring Together.

The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocycloalkyl group (wherein any two rings in the system share two atoms that are not directly connected), containing one or more selected from nitrogen, Oxygen or optionally oxidized sulfur heteroatoms are used as ring members, with the remaining ring members being carbon. One or more rings of the bridged heterocyclic group may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. Preferably, the bridged heterocyclic group has 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, bridged heterocyclic groups are classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic bridged heterocyclic groups, and more preferably Is a bicyclic or tricyclic bridged heterocyclic group. Representative examples of bridged heterocyclic groups include, but are not limited to, the following groups: 2-azabicyclo[2.2.1]heptyl, azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.2.2] Octyl and 2-azabicyclo[3.3.2]decyl.

The term "at least one substituent" disclosed in the present invention includes, for example, from 1 to 4, such as from 1 to 3, and further such as 1 or 2 substituents, provided that the valence theory is satisfied. For example, the "at least one substituent R ^6d "disclosed in the present invention includes from 1 to 4, such as from 1 to 3, and further such as 1 or 2 substituents, which are selected from the list of R ^6d disclosed in the present invention.

The compounds disclosed in the present invention may contain asymmetric centers, and therefore may exist as enantiomers. "Enantiomers" refer to two stereoisomers of a compound, which are non-superimposable mirror images of each other. When the compound disclosed in the present invention has two or more chiral centers, it may additionally exist as diastereomers. Spiegelmers and diastereomers belong to a broader category of stereoisomers and are intended to include all possible stereoisomers, such as substantially pure, resolved Spiegelmers, racemic mixtures thereof , And a mixture of diastereomers. It is intended to include all the stereoisomers of the compounds disclosed in the present invention and/or their pharmaceutically acceptable salts. Unless specifically stated otherwise, reference to one isomer applies to all possible isomers. If the composition of isomers is not specified, all possible isomers are included.

As used in the present invention, the term "substantially pure" means that the target stereoisomer contains no more than 35% by weight, such as no more than 30%, further such as no more than 25%, even further such as no more than 20% Any one or more other stereoisomers. In some embodiments, the term "substantially pure" means that the target stereoisomer contains no more than 10% by weight, such as no more than 5%, such as no more than 1% of any one or more other stereoisomers .

When the compound disclosed in the present invention contains olefin double bonds, unless otherwise specified, such double bonds are intended to include E and Z geometric isomers.

When the compound disclosed in the present invention contains a disubstituted cyclohexyl or cyclobutyl group, the substituents found on the cyclohexyl or cyclobutyl ring can be formed in cis and trans forms. The cis form means that both substituents are on the upper side of the 2 substituent positions on the carbon, and the trans form means that they are on the opposite side.

It may be advantageous to separate the reaction products from each other and/or from the starting materials. With general techniques in the art, the desired product of each step or a series of steps is separated and/or purified (hereinafter referred to as separation) to a desired uniformity. Generally speaking, this type of separation involves multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve many methods, including for example: reverse phase and normal phase; size exclusion; ion exchange; high, medium, and low pressure liquid chromatography methods and devices; small-scale analysis; simulated moving bed ("SMB") and preparation Type thin-layer or thick-layer chromatography, as well as small-scale thin-layer and flash chromatography techniques. Those familiar with the technology will apply the technology most likely to achieve the required separation.

"Diastereomers" refers to stereoisomers of compounds that have two or more chiral centers but are not mirror images of each other. Based on their physical and chemical differences, the diastereomer mixture can be divided into its individual diastereomers by methods familiar to those skilled in the art (for example, by chromatography and/or fractional crystallization). Spiegelmers can be separated by the following method: by reacting with a suitable optically active compound (for example, a chiral auxiliary, such as a chiral alcohol or Mosher's acid chlorid), the enantiomer mixture is converted It is a mixture of diastereomers, the diastereomers are separated, and the individual diastereomers are converted (for example, hydrolyzed) into the corresponding pure enantiomers. A chiral HPLC column can also be used to separate the enantiomers Things.

Single stereoisomers (for example, substantially pure enantiomers) can be obtained by resolving racemic mixtures using methods such as the use of optically active resolving agents to form diastereomers (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. [Stereochemistry of Organic Compounds] New York: John Wiley and Sons, Inc. [New York: John Wiley and Sons Publishing Company], 1994; Lochmuller, CH et al. "Chromatographic resolution of enantiomers: Selective review. [Chromatographic resolution of mirror image isomers: Selectivity review]" J. Chromatogr. [Journal of Chromatography], 113(3) (1975): pages 283-302). The racemic mixture of the chiral compound of the present invention can be separated and separated by all suitable methods. The method includes: (1) Forming an ionic diastereomer salt with the chiral compound and crystallization by step Or other methods; (2) form diastereomer compounds with chiral derivatization reagents, separate the diastereomers and convert them into pure stereoisomers; and (3) directly under chiral conditions, the separation is basically Pure or enriched stereoisomers. See: Wainer, Irving W. Edited Drug Stereochemistry: Analytical Methods and Pharmacology. [Pharmaceutical Stereochemistry: Analytical Methods and Pharmacology] New York: Marcel Dekker, Inc. [New York: Marcel Dekker], 1993.

The term "pharmaceutically acceptable salt" means that it is suitable for use in contact with human and lower animal tissues within the scope of reasonable medical judgment, without undue toxicity, irritation, allergic reactions, etc., and with reasonable benefits /Risk ratio commensurate with those salts. Pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds disclosed in the present invention, or prepared separately by reacting free base groups with suitable organic acids, or by reacting acid groups with suitable organic acids. The base reaction is prepared separately.

In addition, if the compound disclosed in the present invention is obtained as an acid addition salt, the free base can be obtained by alkalizing a solution of the acid salt. On the contrary, if the product is a free base, the conventional procedure for preparing acid addition salts from base compounds can be followed by dissolving the free base in a suitable organic solvent and treating the solution with an acid to produce addition salts (such as pharmaceuticals). Acceptable addition salt). Those familiar with the technology will recognize multiple synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts without undue experimentation.

As defined in the present invention, "the pharmaceutically acceptable salt thereof" includes at least one salt of the compound of formula (I), and the salt of the stereoisomer of the compound of formula (I), such as the salt of the enantiomer and/or The diastereomer salt.

The terms "administration (administering)" and "treatment" in the present invention mean exogenous when applied to animals, humans, experimental subjects, cells, tissues, organs or biological fluids Drugs, therapeutic reagents, diagnostic reagents or compositions come into contact with the animal, human body, subject, cell, tissue, organ or biological body fluid. Cell processing encompasses contacting reagents with cells, as well as contacting reagents with bodily fluids, where the bodily fluids contact the cells. The terms "administration" and "treatment" also mean treatment of cells in vitro and ex vivo, for example, by reagents, diagnostic reagents, binding compounds, or another type of cell. The term "subject" in the present invention includes all living things, preferably animals, more preferably mammals (for example, rats, mice, dogs, cats, rabbits), and most preferably humans.

The term "effective amount" or "therapeutically effective amount" refers to an active ingredient (such as a compound) that is sufficient to affect the treatment of a disease, disorder, or disorder when administered to a subject to treat a disease, or at least one clinical symptom or disorder of the disease, ) Content. The "therapeutically effective amount" may vary depending on the compound, disease, disorder, and/or symptoms of the disease or disorder, the severity of the disease, disorder, and/or the symptoms of the disease or disorder, the age of the subject to be treated, and/or The weight of the treated subjects varies. In any given case, the appropriate amount is obvious to those skilled in the art or can be determined by routine experimentation. In some embodiments, the "therapeutically effective amount" is at least one compound and/or at least one of its stereoisomers, and/or at least one of its pharmaceutically acceptable salts as defined in the present invention, which is effective The content of the disease or disorder in the treated subject. In the case of combination therapy, "therapeutically effective amount" refers to the total amount of the combined substance used to effectively treat the disease, disorder or condition.

The pharmaceutical composition containing the compound disclosed in the present invention can be administered to a subject in need by oral, inhalation, rectal, parenteral or topical administration. For oral administration, the pharmaceutical composition may be conventional solid formulations, such as lozenges, powders, granules, capsules, etc.; liquid formulations, such as water or oil suspensions; or other liquid formulations, such as syrups, solutions, suspensions, etc. ; For parenteral administration, the pharmaceutical composition can be a solution, an aqueous solution, an oil suspension concentrate, a lyophilized powder, and the like. Preferably, the formulation of the pharmaceutical composition is selected from the group consisting of lozenges, coated lozenges, capsules, suppositories, nasal sprays or injections, and more preferably lozenges or capsules. The pharmaceutical composition can be administered in a single dose with precise dosage. In addition, the pharmaceutical composition may further contain other active ingredients.

All formulations of the pharmaceutical composition disclosed in the present invention can be produced by conventional methods in the pharmaceutical field. For example, the active ingredient can be mixed with one or more excipients and then prepared into the desired formulation. "Pharmaceutically acceptable excipients" refer to conventional pharmaceutical carriers suitable for the desired pharmaceutical formulations, such as diluents, carriers (such as water, various organic solvents, etc.), fillers (such as starch, sucrose, etc.), Binders (such as cellulose derivatives, alginate, gelatin, and polyvinylpyrrolidone (PVP)); wetting agents, such as glycerin; disintegrating agents, such as agar, calcium carbonate, and sodium bicarbonate; absorption enhancers, such as Quaternary ammonium compounds; surfactants such as cetyl alcohol; absorption carriers such as kaolin and bentonite; lubricants such as talc, calcium stearate, magnesium stearate, polyethylene glycol and the like. In addition, the pharmaceutical composition also contains other pharmaceutically acceptable excipients, such as dispersants, stabilizers, thickeners, complexing agents, buffers, penetration enhancers, polymers, aromatic compounds, sweeteners and dyes. .

The term "disease" refers to any disease, discomfort, disease, symptom or indication, and can be interchanged with the term "disorder" or "condition".

Throughout this specification and the accompanying patent application, unless the context requires otherwise, the term "comprises" and variants such as "including" and "containing" are intended to specify the existence of subsequent features, but do not exclude one or more The presence or addition of other features. When used in the present invention, the term "comprising" can be replaced with the term "containing" or "including", or sometimes with "having".

Throughout the specification and the scope of the accompanying patent application, the term "C _nm "indicates a range including endpoints, where n and m are integers and indicate the number of carbons. Examples include C _1-8 , C _1-6 and the like.

Unless specifically defined elsewhere in the document of the present invention, all other technical and scientific terms used in the present invention have meanings that can be understood by those skilled in the art to which the present disclosure belongs. General Synthesis

The compounds (including their salts) disclosed in the present invention can be prepared using known organic synthesis techniques, and can be synthesized according to any one of many possible synthetic routes.

Those skilled in the field of organic synthesis can easily select a suitable solvent to carry out the reaction for preparing the compound disclosed in the present invention. A suitable solvent may not substantially react with the starting materials, intermediates, or products at the temperature at which the reaction is performed (for example, a temperature ranging from the boiling temperature of the solvent). A given reaction can be carried out in one solvent or a mixture of more than one solvent.

Those familiar with the technology can easily determine and select the appropriate protective group.

The reaction can be monitored according to any suitable method known in the art (for example, NMR, UV, HPLC, LC-MS, and TLC). Compounds can be purified by a variety of methods (including HPLC and normal phase silica gel chromatography).

The chiral analytical HPLC is used for the residence time analysis of different chiral examples, and the conditions are divided into the following methods according to the column, mobile phase and solvent ratio used. Scheme I

For example, the compound of formula (I) can be formed as shown in Scheme 1 . The compound (i) can be reacted with boric acid under a palladium-catalyzed reaction to give compound (ii), and this compound (ii) can be halogenated with N-iodosuccinamide to give compound (iii), Compound (iii) is used for the next coupling under transition metal to give compound (iv), and this compound (iv) is deprotected to give compound (v) (ie formula (I) ).

Scheme II

For example, the compound of formula (I) can be formed as shown in Scheme I. The compound (i) can be reacted with a halogenated analogue of the Cy1 fused ring under a palladium-catalyzed reaction to give compound (ii), which is halogenated with N-iodosuccinamide to give Compound (iii) is produced, and the compound (iii) is used for the next coupling under transition metal to give compound (iv), and the compound (iv) is deprotected to give compound (v) (ie, chemical formula (I) ).

Shorthand Eq. equivalent rt Room temperature THF Tetrahydrofuran NBS N-bromosuccinimide MeOH Methanol XPhos Pd G2 Chlorine (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl) Base)) Palladium(II) TFA Trifluoroacetate HCHO Formalin TLC Thin layer chromatography Pd(dppf)Cl ₂ [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride AcOK Potassium acetate EA Ethyl acetate Pd(OAc) ₂ Palladium acetate DBU 1,8-diazabicyclo[5.4.0]undec-7-ene Et ₃ N Triethylamine DMF N,N-Dimethylformamide HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate NIS N -iodosuccinimide DMSO Diabetes Bu Butyl NMR NMR DCM Dichloromethane TEA Triethylamine TFAA Trifluoroacetic anhydride BPD Bis(pinacol) diboron PE Petroleum ether Ts Toluenesulfonyl (4-toluenesulfonyl) Boc Tertiary butyloxycarbonyl DIPEA N,N -Diisopropylethylamine TBS Tertiary Butyl Dimethylsilyl TBAF Tetra-n-butylammonium fluoride TMS Trimethylsilyl MTBE Methyl tertiary butyl ether

Example A Example 1: N,N-dimethyl-4-(5-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrrolo[2,3-b]pyridine -3-yl)benzamide (compound 1)

Step 1-1: Tertiary butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (Compound 1-1)

Combine 7-bromo-1,2,3,4-tetrahydroisoquinoline (1 g, 4.72 mmol, 1 eq), di-tertiary butyl dicarbonate (1.23 g, 5.66 mmol, 1.2 eq) and Et ₃ N A solution of (1.36 mL, 9.44 mmol, 2 eq) in THF (30 mL) was stirred at rt for 5 hr. The reaction mixture was concentrated under reduced pressure. The crude product was applied to a silica gel column (using PE/EA (10/1)) to give the title compound (1.45 g, 98.6%) as a pale yellow oil.

Step 1-2: Tertiary butyl 7-(1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (compound 1-2)

Under nitrogen atmosphere, to tertiary butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.45 g, 4.65 mmol, 1 eq) and 5-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (1.14 g, 4.65 mmol, 1 eq) in Add K ₂ CO ₃ (1.6 g, 11.6 mmol, 2.5 eq) and Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (336 mg, 0.46 mmol, 0.1 eq) to a solution in 30 mL of bismuth and 8 mL of water. After stirring for 15 hr under a nitrogen atmosphere at 90°C, the reaction mixture was concentrated under reduced pressure. The crude product was applied to a silica gel column (with methylene chloride/methanol (50/1)) to give the title compound (1.6 g, 98%) as a pale yellow solid. LCMS (M+H) ⁺ = 349.9.

Step 1-3: Tertiary butyl 7-(3-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydroisoquinoline-2(1H)-methan Esters (compounds 1-3)

At rt, to tertiary butyl 7-(1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.6 g , 4.56 mmol, 1 eq) in THF (30 mL) was added N-iodosuccinimide (1.33 g, 5.92 mmol, 1.3 eq). After stirring for 2 hr, the reaction mixture was concentrated under reduced pressure. The crude product was applied to a silica gel column (with methylene chloride/methanol (50/1)) to give the title compound (2.17 g, 99%) as a pale yellow solid. LCMS (M+H) ⁺ = 475.7.

Step 1-4: Tertiary butyl 7-(1-(tertiary butoxycarbonyl)-3-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydro Isoquinoline-2(1H)-carboxylate (Compound 1-4)

The tertiary butyl 7-(3-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.17 g, 4.56 mmol, 1 eq), di-tertiary butyl dicarbonate (1.2 g, 5.47 mmol, 1.2 eq) and Et ₃ N (0.92 g, 9.12 mmol, 2 eq) in THF (20 mL) Stir at rt for 5 hr. The reaction mixture was concentrated under reduced pressure. The crude product was applied to a silica gel column (with methylene chloride/methanol (50/1)) to give the title compound (2.23 g, 85%) as a pale yellow solid. LCMS (M+H) ⁺ = 575.8.

Step 1-5: Tertiary butyl 7-(3-(4-(dimethylaminomethanyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3 ,4-Dihydroisoquinoline-2(1H)-carboxylate (Compound 1-5)

Under nitrogen atmosphere, to tertiary butyl 7-(1-(tertiary butoxycarbonyl)-3-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-di Hydroisoquinoline-2(1H)-carboxylate (280 mg, 0.48 mmol, 1 eq) and (4-(dimethylaminomethanyl)phenyl)boronic acid (97.5 mg, 0.58 mmol, 1.2 eq) ) Add K ₃ PO ₄ (213 mg, 0.96 mmol, 2 eq) and chlorine (2-dicyclohexylphosphino-2',4',6'-triisopropyl) to a solution of 30 mL di㗁𠮿 and 8 mL water Propyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (40 mg, 0.048 mmol, 0.1 eq). After stirring for 15 hr under a nitrogen atmosphere at 90°C, the reaction mixture was concentrated under reduced pressure. The crude product was applied to a silica gel column (with methylene chloride/methanol (20/1)) to give the title compound (100 mg, 42%) as a white solid. LCMS (M+H) ⁺ = 496.9.

Step 1-6: N,N-Dimethyl-4-(5-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrrolo[2,3-b]pyridine -3-yl)benzamide (compound 1-6)

To tertiary butyl 7-(3-(4-(dimethylaminomethanyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-di A solution of hydrogen isoquinoline-2(1H)-formate (100 mg, 0.15 mmol, 1 eq) in CH ₂ Cl ₂ (20 mL) was added TFA (2 mL). The resulting mixture was stirred at room temperature for 2 hr. The mixture was concentrated under reduced pressure, and the residue was purified by preparative TLC (dichloromethane/methanol=10/1) to give the title compound (50 mg, 62%). ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.13 (s, 1H), 9.32 (s, 1H), 8.58 (d, J = 1.9 Hz, 1H), 8.47 (d, J = 1.7 Hz, 1H), 8.03 (d, J = 2.6 Hz, 1H), 7.85 (d, J = 8.3 Hz, 2H), 7.76-7.65 (m, 2H), 7.50 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.0 Hz, 1H), 4.35 (s, 2H), 3.42 (t, J = 6.2 Hz, 2H), 3.06 (t, J = 6.1 Hz, 2H), 3.01 (s, 6H). LCMS (M+H) ⁺ = 396.9. HPLC: 254 nm, 97.9%.

Example 2 : N,N-dimethyl-4-(5-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrrolo[2,3- b]Pyridin-3-yl)benzamide (compound 2)

At rt, N,N-dimethyl-4-(5-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrrolo[2,3-b]pyridine- 3-yl) benzamide (100 mg, 0.25 mmol, 1 eq) in DCM (20 mL) was added 37% HCHO solution (126 mg, 1.26 mmol, 5 eq) and NaBH(OAc) ₃ (160 mg, 0.75 mmol, 3 eq). The mixture was stirred for 1 h. The reaction mixture was quenched with aqueous K ₂ CO ₃ (20 mL) and stirred for 5 hr, then extracted with DCM (3 x 30 mL). The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane/methanol = 10/1) to give the title compound (16 mg, 15.5%). ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.07 (s, 1H), 8.54 (d, J = 1.8 Hz, 1H), 8.44 (d, J = 1.9 Hz, 1H), 8.00 (s, 1H), 7.85 (d, J = 8.1 Hz, 2H), 7.59-7.41 (m, 4H), 7.22 (d, J = 7.8 Hz, 1H), 3.58 (s, 2H), 3.00 (s, 6H), 2.90-2.81 (m, 2H), 2.65-2.59 (m, 2H), 2.36 (s, 3H). LCMS (M+H) ⁺ = 410.9.

Example 3 : (3-Hydroxyazetidin-1-yl)(4-(5-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H- Pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanone (Compound 3)

Step 3-1: Tertiary butyl 7-(3-(4-(methoxycarbonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-di Hydroisoquinoline-2(1H)-carboxylate (Compound 3-1)

In the same manner as described in compound 1, step 1-5, from tertiary butyl 7-(1-(tertiary butoxycarbonyl)-3-iodo-1H-pyrrolo[2,3-b]pyridine- 5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate and (4-(methoxycarbonyl)phenyl)boronic acid prepared the title compound. 650 mg, 86%, white solid. LCMS (M+H) ⁺ = 483.9.

Step 3-2: Methyl 4-(5-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzene Ester (Compound 3-2)

In the same manner as described in compound 1, step 1-6, from tertiary butyl 7-(3-(4-(methoxycarbonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine -5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate and TFA to prepare the title compound. 500 mg, 96%, yellow solid. LCMS (M+H) ⁺ = 383.9.

Step 3-3: Methyl 4-(5-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrrolo[2,3-b]pyridine- 3-yl) benzoate (compound 3-3)

At rt, to methyl 4-(5-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid Add 37% HCHO solution (1.3 g, 13 mmol, 10 eq) and NaBH(OAc) ₃ (827 mg, 3.9 mmol, 3 eq) to a solution of ester (500 mg, 1.3 mmol, 1 eq) in DCM (20 mL) eq). The mixture was stirred for 1 h. The reaction mixture was quenched by aqueous K ₂ CO ₃ (20 mL) and stirred for 5 hr, then extracted with DCM (3 x 30 mL). The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was applied to a silica gel column (with dichloromethane/methanol (20/1)) to give the title compound (500 mg, 96.5%) as a yellow solid. LCMS (M+H) ⁺ = 397.9.

Step 3-4: 4-(5-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrrolo[2,3-b]pyridine-3- Yl)benzoic acid (compound 3-4)

Methyl 4-(5-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl) A solution of benzoate (500 mg, 1.26 mmol, 1 eq), NaOH (252 mg, 6.3 mmol, 5 eq) in THF (20 mL) and water (5 mL) was stirred at 50°C for 4 hr. The reaction mixture was concentrated under reduced pressure. The residue was acidified with HCl (4 M) to pH = 2 to 3, and the precipitate was collected by filtration to give the title compound (300 mg, 62%) as a yellow solid. LCMS (M+H) ⁺ = 383.9.

Step 3-5: (3-Hydroxyazetidin-1-yl)(4-(5-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)- 1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanone (Compound 3-5)

Under nitrogen, to 4-(5-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrrolo[2,3-b]pyridine-3- Base) benzoic acid (100 mg, 0.26 mmol, 1.0 eq) and azetidine-3-ol (38 mg, 0.52 mmol, 2.0 eq) in DMF (15 mL) were added HATU (148 mg, 0.39 mmol, 1.5 eq). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 X 20 mL). The combined organic layer was washed with brine (3×30 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane: MeOH = 6:1) to give the title compound (50 mg, 43.8%). ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.17 (s, 1H), 8.58 (d, J = 1.9 Hz, 1H), 8.48 (s, 1H), 8.06 (d, J = 2.6 Hz, 1H), 7.98-7.83 (m, 2H), 7.75-7.64 (m, 3H), 7.59 (s, 1H), 7.33 (d, J = 8.1 Hz, 1H), 5.80 (d, J = 5.8 Hz, 1H), 4.58 -4.48 (m, 2H), 4.34-4.21 (m, 2H), 4.15-4.05 (m, 1H), 3.88-3.73 (m 1H), 3.15-3.05 (s, 2H), 2.85-2.73 (m, 2H) ), 2.35 (s, 3H). LC-MS (M+H) ⁺ = 438.9.

Example 4 : (4-(5-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl )Phenyl)(2-oxa-6-azaspiro[3.3]heptane-6-yl)methanone (Compound 4)

In the same manner as described in compound 3, step 3-5, from 4-(5-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrrolo [2,3-b]pyridin-3-yl)benzoic acid and 2-oxa-6-azaspiro[3.3]heptane prepared the title compound. 10 mg, 8.26%. ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.13 (s, 1H), 8.55 (d, J = 1.9 Hz, 1H), 8.44 (d, J = 2.0 Hz, 1H), 8.05 (s, 1H), 7.88 (d, J = 8.3 Hz, 2H), 7.70 (d, J = 8.3 Hz, 2H), 7.53 (d, J = 8.1 Hz, 1H), 7.46 (s, 1H), 7.22 (d, J = 7.9 Hz, 1H), 4.75-4.65 (m, 4H), 4.55 (s, 2H), 4.23 (s, 2H), 3.58 (s, 2H), 2.87 (t, J = 5.6 Hz, 2H), 2.63 (t , J = 5.8 Hz, 2H), 2.37 (s, 3H) LCMS (M+H) ⁺ = 464.9. HPLC: 254 nm, 99.6%.

Example 5 : (3-(Dimethylamino)azetidin-1-yl)(4-(5-(2-methyl-1,2,3,4-tetrahydroisoquinoline-7 -Yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanone (compound 5)

In the same manner as described in compound 3, step 3-5, from 4-(5-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrrolo [2,3-b]pyridin-3-yl)benzoic acid and N,N-dimethylazetidine-3-amine to prepare the title compound. 5 mg, 6.86%. ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.12 (s, 1H), 8.55 (d, J = 1.9 Hz, 1H), 8.44 (d, J = 2.0 Hz, 1H), 8.05 (s, 1H), 7.88 (d, J = 8.1 Hz, 2H), 7.72 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 7.5 Hz, 1H), 7.46 (s, 1H), 7.22 (d, J = 7.8 Hz, 1H), 4.43-4.32 (m, 1H), 4.20-4.03 (m, 2H), 3.90-3.78 (m, 1H), 3.58 (s, 2H), 3.12-3.07 (m, 1H), 2.89- 2.84 (m, 2H), 2.66-2.61 (m, 2H), 2.37 (s, 3H), 2.10 (s, 6H). LCMS (M+H) ⁺ = 466.1.

Example 6 : N-(2-(Dimethylamino)ethyl)-N-methyl-4-(5-(2-methyl-1,2,3,4-tetrahydroisoquinoline-7 -Yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide (compound 6)

In the same manner as described in compound 3, step 3-5, from 4-(5-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrrolo [2,3-b]pyridin-3-yl)benzoic acid and N ₁ , N ₁ , N ₂ -trimethylethane-1,2-diamine to prepare the title compound. 35 mg, 20%. ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.08 (s, 1H), 8.55 (d, J = 1.9 Hz, 1H), 8.44 (d, J = 2.0 Hz, 1H), 8.01 (d, J = 2.6 Hz, 1H), 7.86 (d, J = 8.2 Hz, 2H), 7.54 (d, J = 7.9 Hz, 1H), 7.47 (d, J = 6.2 Hz, 3H), 7.23 (d, J = 7.9 Hz, 1H), 3.65 (s, 2H), 3.62-3.52 (m, 1H), 3.47-3.36 (m, 1H), 3.00 (s, 3H), 2.93-2.84 (m, 2H), 2.75-2.67 (m, 2H), 2.66-2.56 (m, 1H), 2.55-2.51 (m, 1H), 2.42 (s, 3H), 2.33 (s, 3H), 2.04 (s, 3H). LCMS (M+H) ⁺ = 467.9.

Example 7 : N,N-Dimethyl-4-(5-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrrolo[2,3-b]pyridine-3 -Yl)benzamide (compound 7)

Step 7-1: Tertiary butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (Compound 7-1)

In the same manner as described in compound 1, step 1-1, the title compound was prepared from 6-bromo-1,2,3,4-tetrahydroisoquinoline and Boc ₂ O (di-tertiary butyl dicarbonate). 1.45 g, 98.6%, pale yellow oil.

Step 7-2: Tertiary butyl 6-(1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (compound 7-2)

In the same manner as described in compound 1, step 1-2, from tertiary butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate and 5-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine was used to prepare the title compound. 1.2 g, 74%, pale yellow solid. LCMS (M+H) ⁺ = 349.9

Step 7-3: Tertiary butyl 6-(3-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydroisoquinoline-2(1H)-methan Ester (Compound 7-3)

In the same manner as described in compound 1, step 1-3, from tertiary butyl 6-(1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydroisoquinoline -2(1H)-formate and NIS to prepare the title compound. 1.3 g, 79.7%, pale yellow solid. LCMS (M+H) ⁺ = 475.7.

Step 7-4: Tertiary butyl 6-(1-(tertiary butoxycarbonyl)-3-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydro Isoquinoline-2(1H)-carboxylate (Compound 7-4)

In the same manner as described in compound 1, step 1-4, from tertiary butyl 6-(3-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-di perhydroisoquinoline -2 (1H) - carboxylate Boc ₂ O and the title compound was prepared. 1.4 g, 89.2%, pale yellow solid. LCMS (M+H) ⁺ = 575.8.

Step 7-5: Tertiary Butyl 6-(3-(4-(dimethylaminomethanyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3 ,4-Dihydroisoquinoline-2(1H)-carboxylate (Compound 7-5)

In the same manner as described in compound 1, step 1-5, from tertiary butyl 6-(1-(tertiary butoxycarbonyl)-3-iodo-1H-pyrrolo[2,3-b]pyridine- 5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate and 4-(dimethylaminomethanyl)phenyl)boronic acid prepared the title compound. 700 mg, 58.3%, white solid. LCMS (M+H) ⁺ = 496.9.

Step 7-6: N,N-Dimethyl-4-(5-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrrolo[2,3-b]pyridine -3-yl)benzamide (compound 7-6)

In the same manner as described in compound 1, step 1-6, from tertiary butyl 6-(3-(4-(dimethylaminomethanyl)phenyl)-1H-pyrrolo[2,3 -b]Pyridin-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate and TFA to prepare the title compound. 500 mg, 89.4%. ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.13 (s, 1H), 9.39 (s, 1H), 8.59 (d, J = 2.0 Hz, 1H), 8.48 (d, J = 1.7 Hz, 1H), 8.02 (d, J = 2.6 Hz, 1H), 7.86 (d, J = 8.2 Hz, 2H), 7.71-7.65 (m, 2H), 7.49 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.0 Hz, 1H), 4.30 (s, 2H), 3.40 (t, J = 6.2 Hz, 2H), 3.11 (t, J = 6.0 Hz, 2H), 3.01 (s, 6H). LCMS (M+H) ⁺ = 396.9.

Example 8 : N,N-dimethyl-4-(5-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrrolo[2,3- b]Pyridin-3-yl)benzamide (compound 8)

To N,N-dimethyl-4-(5-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl ) Benzamide (100 mg, 0.25 mmol, 1 eq) in DCM (20 mL) was added 37% HCHO solution (126 mg, 1.26 mmol, 5 eq) and NaBH(OAc) ₃ (160 mg, 0.75 mmol, 3 eq), the mixture was stirred at rt for 1 h. The reaction mixture was quenched with aqueous K ₂ CO ₃ (20 mL) and stirred for 5 hr, then extracted with DCM (3 x 30 mL). The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane/methanol=10/1) to give the title compound (16 mg, 15.5%). ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.08 (s, 1H), 8.54 (d, J = 1.9 Hz, 1H), 8.43 (d, J = 2.0 Hz, 1H), 8.00 (s, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.53-7.46 (m, 4H), 7.16 (d, J = 8.4 Hz, 1H), 3.53 (s, 2H), 3.00 (s, 6H), 2.92 (t , J = 5.7 Hz, 2H), 2.63 (t, J = 5.9 Hz, 2H), 2.36 (s, 3H). LCMS (M+H) ⁺ = 411.

Example 9 : (3-Hydroxyazetidin-1-yl)(4-(5-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H- Pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanone (Compound 9)

Step 9-1: 4-(5-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrrolo[2,3-b]pyridine-3- Yl)benzoic acid (compound 9-1)

The N,N-dimethyl-4-(5-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrrolo[2,3-b] A solution of pyridin-3-yl)benzamide (400 mg, 0.98 mmol, 1 eq), NaOH (195 mg, 4.88 mmol, 5 eq) in EtOH (10 mL) and water (10 mL) at 90° C stir overnight. The reaction mixture was concentrated under reduced pressure. The residue was acidified with HCl (4 M) to pH = 2 to 3, and the precipitate was collected by filtration to give the title compound (300 mg, 80%) as a yellow solid. LCMS (M+H) ⁺ = 383.9.

Step 9-2: (3-Hydroxyazetidin-1-yl)(4-(5-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)- 1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanone (Compound 9-2)

In the same manner as described in compound 3, step 3-5, from 4-(5-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrrolo [2,3-b]pyridin-3-yl)benzoic acid and azetidine-3-ol to prepare the title compound. 33 mg, 57.6%. ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.18 (s, 1H), 8.58 (d, J = 1.9 Hz, 1H), 8.53-8.45 (m, 1H), 8.13-8.04 (m, 1H), 7.98 -7.83 (m, 2H), 7.78-7.63 (m, 4H), 7.29 (d, J = 8.4 Hz, 1H), 5.80 (d, J = 5.5 Hz, 1H), 4.58-4.47 (m, 2H), 4.40-4.18 (m, 3H), 4.15-4.05 (m, 1H), 3.88-3.72 (m, 1H), 3.27-3.10 (m, 2H), 3.05-2.75 (m, 2H), 2.37 (s, 3H) ). LC-MS (M+H) ⁺ = 438.9.

Example 10 : (4-(5-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl )Phenyl)(2-oxa-6-azaspiro[3.3]heptane-6-yl)methanone (compound 10)

In the same manner as described in compound 3, step 3-5, from 4-(5-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrrolo [2,3-b]pyridin-3-yl)benzoic acid and 2-oxa-6-azaspiro[3.3]heptane prepared the title compound. 24 mg, 39.8%. ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.18 (s, 1H), 8.59 (d, J = 1.8 Hz, 1H), 8.48 (d, J = 1.7 Hz, 1H), 8.07 (d, J = 2.6 Hz, 1H), 7.89 (d, J = 8.3 Hz, 2H), 7.73-7.63 (m, 4H), 7.29 (d, J = 8.5 Hz, 1H), 4.75-4.65 (m, 4H), 4.55 (s , 2H), 4.36-4.16 (m, 4H), 3.31-3.25 (m, 2H), 3.22-3.12 (m, 2H), 2.83 (s, 3H). LCMS (M+H) ⁺ = 464.9.

Example 11 : (3-(Dimethylamino)azetidin-1-yl)(4-(5-(2-methyl-1,2,3,4-tetrahydroisoquinoline-6 -Yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanone (Compound 11)

In the same manner as described in compound 3, step 3-5, from 4-(5-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrrolo [2,3-b]pyridin-3-yl)benzoic acid and N,N-dimethylazetidine-3-amine to prepare the title compound. 17 mg, 14%. ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.16 (s, 1H), 8.58 (d, J = 2.1 Hz, 1H), 8.47 (d, J = 2.1 Hz, 1H), 8.07 (s, 1H), 7.94-7.84(m, 2H), 7.77 -7.68(m, 2H), 7.66-7.58 (m, 2H), 7.25 (d, J = 7.2 Hz, 1H), 4.45-4.32(m, 1H), 4.24- 3.95 (m, 4H), 3.93-3.81 (m, 1H), 3.23-2.96 (m, 5H), 2.77-2.62 (m, 3H), 2.13 (s, 6H). LCMS (M+H) ⁺ = 466.

Example 12 : N-(2-(dimethylamino)ethyl)-N-methyl-4-(5-(2-methyl-1,2,3,4-tetrahydroisoquinoline-6 -Yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide (compound 12)

In the same manner as described in compound 3, step 3-5, from 4-(5-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrrolo [2,3-b]pyridin-3-yl)benzoic acid and N1,N1,N2-trimethylethane-1,2-diamine to prepare the title compound. 17 mg, 14%. ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.08 (s, 1H), 8.55 (d, J = 2.1 Hz, 1H), 8.43 (d, J = 2.1 Hz, 1H), 8.00 (s, 1H), 7.88-7.83 (m, 2H), 7.54-7.49 (m, 2H), 7.47-7.45 (m, 1H), 7.45-7.43 m, 1H), 7.16 (d, J = 8.4 Hz, 1H), 3.53 (s , 2H), 3.35-3.30 (m, 2H), 2.99 (s, 3H), 2.95-2.89 (m, 2H), 2.65-2.60 (m, 2H), 2.52-2.49 (m, 2H), 2.36 (s , 3H), 2.22 (s, 3H), 2.01 (s, 3H). LCMS (M+H) ⁺ = 467.9.

Example 13 : N,N-dimethyl-4-(5-(2-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl) -1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide (compound 13)

To N,N-dimethyl-4-(5-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl ) Benzamide (200 mg, 0.5 mmol, 1 eq) in DCM (20 mL) was added 1-methylpiperidin-4-one (85 mg, 0.75 mmol, 1.5 eq) and NaBH (OAc ) ₃ (318 mg, 1.5 mmol, 3 eq), the mixture was stirred at rt for 2 days. The reaction mixture was extracted with DCM (3 x 30 mL). The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane/methanol=6/1) to give the title compound (18 mg, 7.3%). ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.09 (s, 1H), 8.55 (d, J = 1.8 Hz, 1H), 8.44 (s, 1H), 8.01 (d, J = 2.6 Hz, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.57-7.51 (m, 2H), 7.49 (d, J = 8.2 Hz, 2H), 7.20 (d, J = 7.8 Hz, 1H), 3.82 (s, 2H ), 3.01 (s, 6H), 2.97-2.78 (m, 6H), 2.74-2.63 (m,3H), 2.51 (s, 3H), 2.14-1.96 (m, 2H), 1.89-1.71 (m, 2H) ). LCMS (M+H) ⁺ = 494.

Example 14 : 4-(5-(2-(2-hydroxyethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrrolo[2,3-b]pyridine -3-yl)-N,N-dimethylbenzamide (Compound 14)

Step 14-1: 2-(6-Bromo-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1-ol (Compound 14-1)

To 6-bromo-1,2,3,4-tetrahydroisoquinoline (1 g, 4.7 mmol, 1 eq) and 2-bromoethane-1-ol (0.88 g, 7 mmol, 1.5 eq) in 40 Add K ₂ CO ₃ (1.3 g, 9.4 mmol, 2 eq) to the solution in mL of CH ₃ CN. After stirring for 15 hr at 60°C under a nitrogen atmosphere, the reaction mixture was concentrated under reduced pressure to give the title compound (1.2 g, 100%) as a pale yellow solid. LCMS (M+H) ⁺ = 255.8.

Step 14-2: 2-(6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquine Lin-2(1H)-yl)ethane-1-ol (Compound 14-2)

In a 100-mL sealed tube purged and maintained with an inert nitrogen atmosphere, the 2-(6-bromo-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1-ol (1.2 g, 4.7 mmol, 1 eq), BPD (bis(pinacol) diboron) (1.55 g, 6.1 mmol, 1.30 eq), Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (206 mg, 0.28 mmol, 0.06 eq), a mixture of KOAc (1.38 g, 14 mmol, 3.00 eq) in two 㗁𠮿 (30 mL) was stirred overnight at 90°C in an oil bath. The solid was filtered off, and the residue was applied to a silica gel column (with DCM/MeOH (20/1)) to give the title compound (800 mg, 57%) as a white solid. LCMS (M+H) ⁺ = 303.9.

Step 14-3: 5-Bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine (Compound 14-3)

At rt, to a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (5 g, 25.4 mmol, 1 eq) in THF (80 mL) was added NIS (6.85 g, 30.4 mmol, 1.2 eq). After stirring for 2 hr at rt, the reaction mixture was concentrated under reduced pressure. The crude product was applied to a silica gel column (using PE/EA (15/1)) to give the title compound (8 g, 97%) as a pale yellow solid. LCMS (M+H) ⁺ = 322.6.

Step 14-4: Tertiary butyl 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (Compound 14-4)

Combine 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine (8 g, 24.7 mmol, 1 eq), Boc ₂ O (7.5 g, 34.6 mmol, 1.4 eq) and Et ₃ N ( A solution of 7.4 g, 74 mmol, 3 eq) in THF (80 mL) was stirred at rt overnight. The reaction mixture was concentrated under reduced pressure. The crude product was applied to a silica gel column (using PE/EA (20/1)) to give the title compound (10 g, 95%) as a pale yellow solid. LCMS (M+H) ⁺ = 422.6.

Step 14-5: 4-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylbenzamide (Compound 14-5)

Under nitrogen atmosphere, to tertiary butyl 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (2 g, 4.71 mmol, 1 eq) and (4- (Dimethylaminomethanyl)phenyl)boronic acid (0.91 g, 4.71 mmol, 1 eq) was added to a solution of 50 mL dimethan and 10 mL water with K ₂ CO ₃ (1.3 g, 9.4 mmol, 2 eq) and Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (345 mg, 0.47 mmol, 0.1 eq). After stirring at 90°C for 5 hr under a nitrogen atmosphere, the reaction mixture was concentrated under reduced pressure. The crude product was applied to a silica gel column (with DCM/MeOH (30/1)) to give the title compound (1.2 g, 74%) as a pale yellow solid. LCMS (M+H) ⁺ = 343.8.

Step 14-6: 4-(5-(2-(2-hydroxyethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrrolo[2,3-b ]Pyridin-3-yl)-N,N-dimethylbenzamide (Compound 14-6)

Under a nitrogen atmosphere, add 4-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylbenzamide (100 mg, 0.29 mmol, 1 eq) and 2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline- 2(1H)-yl)ethane-1-ol (264 mg, 0.876 mmol, 3 eq) was added to a solution of 20 mL of diethyl and 5 mL of water with K ₂ CO ₃ (80 mg, 0.58 mmol, 2 eq ) And Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (22 mg, 0.029 mmol, 0.1 eq). After stirring at 90°C for 15 hr under a nitrogen atmosphere, the reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative TLC (dichloromethane/methanol=10/1) to give the title compound (23 mg, 18%). ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.08 (s, 1H), 8.55 (d, J = 2.0 Hz, 1H), 8.44 (d, J = 2.0 Hz, 1H), 8.00 (s, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.54-7.46 (m, 4H), 7.16 (d, J = 7.8 Hz, 1H), 4.48 (t, J = 5.4 Hz, 1H), 3.65 (s, 2H ), 3.63-3.57 (m, 2H), 3.00 (s, 6H), 2.93-2.86 (m, 2H), 2.74 (t, J = 5.7 Hz, 2H), 2.58 (t, J = 6.2 Hz, 2H) . LCMS (M+H) ⁺ = 440.9.

Example 15 : N,N-dimethyl-4-(5-(5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-yl )-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide (compound 15)

Step 15-1: Methyl 4-bromo-2-(2-((tertiary butoxycarbonyl)amino)ethoxy)benzoate (Compound 15-1)

Methyl 4-bromo-2-hydroxybenzoate (1 g, 4.33 mmol, 1 eq), tertiary butyl (2-hydroxyethyl) carbamate (0.694 mg, 4.33 mmol, 1 eq) , DTBAD (di-tertiary butyl azodicarboxylate) (1.49 g, 6.5 mmol, 1.5 eq) and PPh ₃ (1.7 g, 6.5 mmol, 1.5 eq) in toluene (30 mL) in a mixture of 60 °C stir under nitrogen atmosphere for 3 hr. LCMS showed that SM has been completely exhausted. Most of the solvent was removed in vacuo, and the residue was purified by silica gel column (using PE/EA (10/1)) to give the title compound (1.5 g, 92%) as a yellow solid. LCMS (M+H) ⁺ = 373.8.

Step 15-2: Methyl 2-(2-aminoethoxy)-4-bromobenzoate (Compound 15-2)

To methyl 4-bromo-2-(2-((tertiary butoxycarbonyl)amino)ethoxy) benzoate (1.5 g, 4 mmol, 1 eq) in CH ₂ Cl ₂ (20 mL) Add TFA (2 mL) to the solution. The resulting mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue was dissolved in MTBE (methyl tertiary butyl ether) (30 mL). The organic phase was washed with 2N HCl solution (20 mL×3). The combined acid extracts were washed with MTBE (50 mL) and then treated with EA (20 mL). With vigorous stirring, the resulting mixture was basified using NaOH solution. The layers were separated, and the aqueous phase was further extracted with EA (4 X 50 mL). The combined organics were dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound (0.9 g, 82.5%) as a yellow oil. LCMS (M+H) ⁺ = 273.8.

Step 15-3: 8-bromo-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one (Compound 15-3)

A solution of methyl 2-(2-aminoethoxy)-4-bromobenzoate (0.9 g, 3.28 mmol, 1 eq) in toluene (20 mL) was stirred under reflux overnight. The mixture was concentrated under reduced pressure to give the title compound (0.63 g, 80%) as a yellow solid. LCMS (M+H) ⁺ = 243.8.

Step 15-4: N,N-Dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide (Compound 15-4)

In a 100-mL sealed tube purged and maintained with an inert nitrogen atmosphere, the 4-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethyl Benzamide (200 mg, 0.58 mmol, 1 eq), BPD (bis(pinacol) diboron) (221 mg, 0.87 mmol, 1.5 eq), Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (25 A mixture of mg, 0.035 mmol, 0.06 eq), KOAc (170 mg, 1.74 mmol, 3.00 eq) in diacetate (30 mL) was stirred at 90°C in an oil bath overnight. The solid was filtered off, and the residue was applied to a silica gel column (with DCM/MeOH (20/1)) to give the title compound (120 mg, 53%) as a pale yellow solid.

Step 15-5: N,N-Dimethyl-4-(5-(5-Pendoxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8 -Yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide (compound 15-5)

Under nitrogen atmosphere, to N,N-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide (180 mg, 0.46 mmol, 1 eq) and 8-bromo-3,4-dihydrobenzo[f][1 ,4]Oxazepine-5(2H)-one (111 mg, 0.46 mmol, 1 eq) in a solution of 20 mL of di㗁𠮿 and 5 mL of water add K ₂ CO ₃ (127 mg, 0.92 mmol, 2 eq) ) And Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (34 mg, 0.046 mmol, 0.1 eq). After stirring at 90°C for 15 hr under a nitrogen atmosphere, the reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative TLC (dichloromethane/methanol=10/1) to give the title compound (48 mg, 24.5%). ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.15 (s, 1H), 8.63 (d, J = 2.0 Hz, 1H), 8.54 (d, J = 1.9 Hz, 1H), 8.35 (s, 1H), 8.04 (d, J = 2.6 Hz, 1H), 7.93-7.86 (m, 3H), 7.58-7.55 (m, 1H), 7.49 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 1.6 Hz , 1H), 4.41-4.32 (m, 2H), 3.42-3.36 (m, 2H), 3.01 (s, 6H). LCMS (M+H) ⁺ = 426.9.

Example 16 : N,N-Dimethyl-4-(5-(4-methyl-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxynitrogen Phenol-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide (compound 16)

Step 16-1: 8-bromo-4-methyl-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one (compound 16-1)

At 0°C, add 8-bromo-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one (300 mg, 1.24 mmol, 1 eq) in DMF (10 Add NaH (99 mg, 2.48 mmol, 3 eq) to the solution in mL). The reaction was stirred at 0°C for 30 min, and MeI (528 mg, 3.72 mmol, 2 eq) was added at 0°C. The reaction was stirred at rt overnight. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 X 20 mL). The combined organic layer was washed with brine (30 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (0.2 g, 63%) as a yellow solid. LCMS (M+H) ⁺ = 255.8.

Step 16-2: N,N-Dimethyl-4-(5-(4-methyl-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4] Oxazepine-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide (compound 16-2)

In the same manner as described in compound 15, step 15-5, from N,N-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxide Cyclopentaborin-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide and 8-bromo-4-methyl-3,4-dihydrobenzo [f][1,4]oxazepine-5(2H)-one to prepare the title compound. 55 mg, 27.2%. ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.16 (s, 1H), 8.63 (d, J = 2.0 Hz, 1H), 8.54 (d, J = 2.0 Hz, 1H), 8.04 (s, 1H), 7.88 (d, J = 8.3 Hz, 2H), 7.77 (d, J = 8.1 Hz, 1H), 7.63-7.57 (m, 1H), 7.52-7.45 (m, 3H), 4.43 (t, J = 4.9 Hz , 2H), 3.61 (t, J = 5.0 Hz, 2H), 3.12 (s, 3H), 3.01 (s, 6H). 1LCMS (M+H) ⁺ = 440.9.

Example 17 : N,N-dimethyl-4-(5-(4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-yl) -1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide (compound 17)

Step 17-1: 8-Bromo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazin (Compound 17-1)

At 0°C, add 8-bromo-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one (500 mg, 2.07 mmol, 1 eq) in THF (8 Add BH ₃ .THF (1 M, 10.36 mL, 10.36 mmol, 5 eq) to the solution in mL). The reaction was stirred at 70°C overnight. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 X 20 mL). The combined organic layer was washed with brine (2×30 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (0.45 g, 95%) as a yellow solid. LCMS (M+H) ⁺ = 227.8.

Step 17-2: 8-bromo-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (Compound 17-2)

To a solution of 8-bromo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (500 mg, 2.2 mmol, 1 equivalent) in DCM (20 mL) was added 37 % HCHO solution (1.8 g, 22 mmol, 10 eq) and NaBH(OAc) ₃ (933 mg, 4.4 mmol, 2 eq), the mixture was stirred at rt for 1 h. The reaction mixture was quenched by aqueous K ₂ CO ₃ (20 mL) and stirred for 5 hr, then extracted with DCM (3 x 30 mL). The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column (dichloromethane/methanol=20/1) to give the title compound (0.35 g, 65.7%) as a yellow oil. LCMS (M+H) ⁺ = 241.8.

Step 17-3: N,N-Dimethyl-4-(5-(4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8- Yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide (compound 17-3)

In the same manner as described in compound 15, step 15-5, from N,N-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxide Cyclopentaborin-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide and 8-bromo-4-methyl-2,3,4,5- Tetrahydrobenzo[f][1,4]oxazin prepared the title compound. 50 mg, 15%. ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.16 (s, 1H), 8.61 (d, J = 2.0 Hz, 1H), 8.51 (d, J = 1.9 Hz, 1H), 8.03 (d, J = 2.6 Hz, 1H), 7.88 (d, J = 8.3 Hz, 2H), 7.62-7.57 (m, 1H), 7.53 (d, J = 1.5 Hz, 1H), 7.51-7.47 (m, 3H), 4.5-4.35 (m, 2H), 4.34-4.2 (m, 2H) 3.61-3.45 (m, 2H), 3.01 (s, 6H), 2.80 (s, 3H). LCMS (M+H) ⁺ = 426.9.

Example 18 : (3-Hydroxyazetidin-1-yl)(4-(5-(6-methoxy-4-methyl-2,3,4,5-tetrahydrobenzo[f] [1,4]Oxazepin-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanone (Compound 18)

Step 18-1: 1-(4-Bromobenzyl)azetidine-3-ol (Compound 18-1)

At room temperature, add DIEA (1286 mg, 9.949 mmol), HATU (2270 mg, 5.970 mmol), azetidine to a solution of 4-bromobenzoic acid (1000 mg, 4.975 mmol) in DMF (30 mL) Alkan-3-ol hydrochloride (545 mg, 4.975 mmol). The resulting mixture was stirred at room temperature for 16 h. When the reaction is complete, it is then quenched by adding water (40 mL). The resulting mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over Na ₂ SO ₄ and washed with brine. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography (eluted with EtOAc in hexane (0% to 100% gradient)) to give 1-(4-) as a pink solid Bromobenzyl) azetidine-3-ol (1.19 g, 92%). LCMS (M+H) ⁺ = 256.1.

Step 18-2: 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]azetidine -3-ol (Compound 18-2)

At room temperature under a nitrogen atmosphere, to a solution of 1-(4-bromobenzyl)azetidin-3-ol (500 mg, 1.952 mmol) in dichloromethane (15 mL), add BPD ( Bis(pinacol) diboron) (728 mg, 2928.555 mmol), Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (100 mg, 136.666 mmol), KOAc (563 mg, 5587.110 mmol). The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 16 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography (eluted with MeOH in EtOAc (0% to 10% gradient)) to give 1 as a yellow solid. -[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]azetidine-3-ol (570 mg, 96%). LCMS (M+H) ⁺ = 304.2.

Step 18-3: (4-(5-Bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)(3-hydroxyazetidine- 1-yl) ketone (compound 18-3)

At room temperature under nitrogen atmosphere, to 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]nitrogen Add 5-bromo-3-iodo-1-(4-methylbenzenesulfonyl)-1H to a solution of ethidium-3-ol (797 mg, 2.628 mmol) in diethyl (15 mL) -Pyrrolo[2,3-b]pyridine (1.04 g, 2.190 mmol), Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (215 mg, 0.263 mmol) and K ₂ CO ₃ (611 mg, 4.381 mmol) in Solution in H ₂ O (1 mL). The resulting mixture was stirred for 3 h at 80°C under nitrogen atmosphere. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography (eluted with MeOH in DCM (0% to 10% gradient)) to give a brownish-yellow solid 1-[4-[5-Bromo-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]benzyl]azetidine- 3-alcohol (871 mg, 75%). LCMS (M+H) ⁺ = 527.9.

Step 18-4: (3-Hydroxyazetidin-1-yl)(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxole Alkyl-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanone (Compound 18-4)

At room temperature under a nitrogen atmosphere, to 1-[4-[5-bromo-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]benzene Methyl]azetidine-3-ol (188 mg, 0.357 mmol) was added 4,4,5,5-tetramethyl-2-(4,4) to a solution of diazetidine (16 mL) ,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (109 mg, 0.429 mmol), Pd (dppf) Cl ₂ .CH ₂ Cl ₂ (29 mg, 0.036 mmol), KOAc (53.11 mg, 0.536 mmol). The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography (eluted with MeOH in DCM (0% to 50% gradient)) to give 1 as a black solid -[4-[1-(4-Methylbenzenesulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) -1H-pyrrolo[2,3-b]pyridin-3-yl]benzyl]azetidine-3-ol (628 mg, 61%). LCMS (M+H) ⁺ = 574.2.

Step 18-5: 4-Bromo-2,6-difluoro-N-(2-hydroxyethyl)-N-methylbenzamide (Compound 18-5)

To a solution of 4-bromo-2,6-difluorobenzoic acid (950 mg, 4.008 mmol) in DMF (20 mL) at room temperature, add 2-(methylamino)ethane-1-ol ( 100 mg, 1.323 mmol), HATU (1982 mg, 5.211 mmol) and DIEA (1295 mg, 10.021 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 16 h. When the reaction is complete, it is quenched by adding water (50 mL). The resulting mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over Na ₂ SO ₄ and washed with brine. The solvent was removed under reduced pressure, and the residue was subjected to reversed-phase flash chromatography (MeCN in water (with 10 mmol/L NH ₄ HCO ₃ ) (with a gradient of 1% to 95% in 40 min) Elution) Purification to give 4-bromo-2,6-difluoro-N-(2-hydroxyethyl)-N-methylbenzamide (1.08 g, 90%) as a yellow oil. LCMS (M+H) ⁺ = 295.9.

Step 18-6: 8-bromo-6-fluoro-4-methyl-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one (compound 18-6)

At room temperature under a nitrogen atmosphere, add 4-bromo-2,6-difluoro-N-(2-hydroxyethyl)-N-methylbenzamide (435 mg, 1.48 mmol) in DMF (10 mL Add NaH (39 mg, 1.63 mmol) to the solution in ). The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 15 h. When the reaction is complete, it is then quenched by adding ice water (30 mL). The resulting mixture was extracted with DCM (100 mL x 3). The organic phases were combined, dried over Na ₂ SO ₄ and washed with brine. The solvent was removed under reduced pressure, and the residue was purified by reverse-phase flash chromatography (eluted with MeCN in water (with a gradient of 1% to 95% in 40 min)) to give a yellow solid 8-Bromo-6-fluoro-4-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-5-one (432 mg, 53%). LCMS (M+H) ⁺ = 274.0.

Step 18-7: 8-Bromo-6-methoxy-4-methyl-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one (compound 18- 7)

At room temperature, add 8-bromo-6-fluoro-4-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-5-one (406 mg, 1.483 mmol) in Add sodium methoxide (1075 mg, 19.906 mmol) to the solution in MeOH (20 mL). The resulting mixture was stirred at 80°C for 16 h. After the reaction was completed, the pH of the reaction mixture was adjusted to about 7 with HCl (7 N) in methanol solution. The resulting mixture was concentrated under reduced pressure and diluted with THF (20 mL). The precipitated solid was filtered off, and the filtrate was concentrated under reduced pressure to give 8-bromo-6-methoxy-4-methyl-2,3,4,5-tetrahydro as a yellow syrup -1,4-Benzoxazin-5-one (358 mg, 84%). LCMS (M+H) ⁺ = 286.0.

Step 18-8: 8-Bromo-6-methoxy-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (Compound 18-8)

In a nitrogen atmosphere at room temperature, to 8-bromo-6-methoxy-4-methyl-2,3,4,5-tetrahydro-1,4-benzoxazin-5-one (55 mg, 0.192 mmol) in THF (2 mL), slowly add BH ₃ in THF (0.85 mL, 0.850 mmol, 1 M). The resulting mixture was stirred at 65 °C under nitrogen atmosphere for 3 h. When the reaction is complete, it is quenched by adding NaOH solution (0.5 mL, 2 M). The resulting mixture was concentrated under reduced pressure and azeotroped with toluene. The residue was purified by flash chromatography (eluted with EtOAc in hexane (0% to 15% gradient)) to give 8-bromo-6-methoxy-4-methyl as a pale yellow solid Base-2,3,4,5-tetrahydro-1,4-benzoxazepine (22 mg, 38%). LCMS (M+H) ⁺ = 272.1.

Step 18-9: (3-Hydroxyazetidin-1-yl)(4-(5-(6-methoxy-4-methyl-2,3,4,5-tetrahydrobenzo[ f][1,4]oxazepine-8-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanone (compound 18-9 )

At room temperature under nitrogen atmosphere, to 1-[4-[1-(4-methylbenzenesulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-bis Oxaloborolan-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]benzoyl]azetidine-3-ol (63 mg, 0.110 mmol) in Add 8-bromo-6-methoxy-4-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine (20 mg) to the solution in two 㗁𠮿 (8 mL) , 0.073 mmol), Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (6 mg, 0.007 mmol) and K ₂ CO ₃ (20.52 mg, 0.147 mmol) in H ₂ O (0.8 mL). The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 2 h. When the reaction was complete, the reaction mixture was then diluted with ethyl acetate (40 mL) and washed with brine (2 x 30 mL). The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (eluted with MeOH in water (with 10 mmol/L NH ₄ HCO ₃ ) (with a gradient of 0% to 95% in 40 min)) to produce a light 1-[4-[5-(6-Methoxy-4-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-8-yl) of brown slurry -1-(4-Methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]benzyl]azetidine-3-ol (18 mg, 39% ). LCMS (M+H) ⁺ = 639.4.

Step 18-10: (3-Hydroxyazetidin-1-yl)(4-(5-(6-methoxy-4-methyl-2,3,4,5-tetrahydrobenzo[ f][1,4]oxazepine-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanone (Compound 18-10)

To 1-[4-[5-(6-methoxy-4-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-8-yl)-1-( 4-Methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]benzoyl]azetidine-3-ol (18 mg, 0.028 mmol) in MeOH ( Add NaOH aqueous solution (0.1 mL, 0.200 mmol, 2 M) to the solution in 5 mL). The resulting mixture was stirred at 65°C for 1 h. When the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column, XBridge Shield RP18 OBD column, 150 x 30 mm, 5 um; mobile phase, acetonitrile in water (with 10 mmol/L NH ₄ HCO ₃ ), in 20% to 45% gradient in 10 minutes; detector, UV 254 nm. (3-Hydroxyazetidine-1-yl)(4-(5-(6-methoxy-4-methyl-2,3,4,5-tetrahydrobenzo[f][1 ,4]Oxazepin-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanone (2.5 mg, 18%). ¹ H NMR (400 MHz, DMSO- d6 , ppm) δ 12.16 (s, 1 H), 8.61 (s, 1 H), 8.48 (s, 1 H), 8.06 (s, 1 H), 7.90 (d, J = 8.0 Hz, 2 H), 7.71 (d, J = 8.0 Hz, 2 H), 7.07 (s, 1 H), 7.00 (s, 1 H), 5.78 (s, 1 H), 4.53 (s, 2 H), 4.29-4.25 (m, 1 H), 4.13-4.01 (m, 3 H), 3.90 (s, 3 H), 3.84-3.71 (m, 3 H), 2.91-2.85 (m, 2 H) ), 2.32 (s, 3 H). LC-MS (M+H) ⁺ = 485.3.

Example 19 : 4-[5-(2,8-Dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrrolo[2,3-b]pyridine-3 -Yl]-N,N-dimethylbenzamide (compound 19)

Step 19-1: 4-[5-Bromo-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-N,N-dimethyl Benzamide (Compound 19-1)

To a solution of [4-(dimethylaminomethanyl)phenyl]boronic acid (4.00 g, 20.724 mmol) in dichloromethane (90 mL) at room temperature under a nitrogen atmosphere, add 5-bromo- 3-iodo-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine (9.89 g, 20.724 mmol), Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (1693 mg, 2.072 mmol) and K ₂ CO ₃ (5.73 g, 41.449 mmol) in water (9 mL). The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 3 h. When the reaction is complete, it is then quenched by adding water (150 mL). The resulting mixture was extracted with ethyl acetate (300 mL x 3). The organic phases were combined, dried over Na ₂ SO ₄ and washed with brine. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography (eluted with MeOH in EtOAc (0% to 10% gradient)) to give 4-[5-bromo as a yellow solid -1-(4-Methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-N,N-dimethylbenzamide (7.00 g, 68%) . LCMS (M+H) ⁺ = 498.2.

Step 19-2: N,N-Dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1-Toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide (Compound 19-2)

At room temperature under nitrogen atmosphere, to 4-[5-bromo-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-N,N -Dimethylbenzamide (2.00 g, 4.009 mmol) was added to a solution of dimethan (15 mL) with BPD (bis(pinacol) diboron) (1.52 g, 5.986 mmol), KOAc (1.18) g, 12.026 mmol), Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (328 mg, 0.401 mmol). The resulting mixture was stirred at 100°C under nitrogen atmosphere for 3 h. When the reaction is complete, it is quenched by adding water (50 mL). The resulting mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over Na ₂ SO ₄ and washed with brine. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography (eluted with MeOH in DCM (0% to 65% gradient)) to give N,N-dimethyl as a brown solid -4-[1-(4-Methylbenzenesulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )-1H-pyrrolo[2,3-b]pyridin-3-yl]benzamide (2.04 g, 93%). LCMS (M+H) ⁺ = 546.2.

Step 19-3: Tertiary Butyl Neopentyloxy Carbamate (Compound 19-3)

At room temperature, to a solution of tert-butylhydroxycarbamate (15.0 g, 113 mmol) in acetonitrile (300 mL) was slowly added trimethylacetic anhydride (23.0 g, 124 mmol). The resulting mixture was stirred at 70°C for 16 h. When the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was diluted with DCM (300 mL), and the resulting solution was washed with saturated NaHCO ₃ solution (300 mL x 3). The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to give tertiary butyl neopentyloxy carbamate (26.4 g, 86%) as a white solid.

Step 19-4: O-Neopentyl Hydroxylamine (Compound 19-4)

At 0°C, to a solution of tertiary butyl neopentyloxycarbamate (26.4 g, 97 mmol) in dry diethyl ether (240 mL) was slowly added TFA (9.6 g, 99 mmol). The resulting mixture was stirred at room temperature for 1 h. When the reaction was complete, hexane (250 mL) was added, and the resulting mixture was stirred for 10 min. The precipitated solid was collected, rinsed with hexane, and dried in a vacuum oven overnight to produce O-neopentyl hydroxylamine (24.8 g, 91%) as a white solid. LCMS (M+H) ⁺ = 118.2.

Step 19-5: (4-Bromo-2-methylphenyl)carboxamido 2,2-dimethylpropionate (Compound 19-5)

At 0°C, to a solution of 4-bromo-2-methylbenzoic acid (4.85 g, 22.577 mmol) in THF (100 mL) was added T ₃ P(2,4,6- Tripropyl-1,3,5,2,4,6-trioxatriphosphine-2,4,6-trioxide) (20.71 g, 64.908 mmol). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 30 min, and then amino 2,2-dimethylpropionate (8.26 g, 70.552 mmol) and DIEA (15.61 g, 121.707 mmol) were added. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 h. When the reaction is complete, it is quenched by adding water (200 mL). The resulting mixture was extracted with ethyl acetate (300 mL x 3). The organic phases were combined, dried over Na ₂ SO ₄ and washed with brine. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography (eluted with EtOAc in hexane (0% to 50% gradient)) to give (4-bromo- 2-Methylphenyl)carboxamido 2,2-dimethylpropionate (5.53 g, 25%). LCMS (M+H) ⁺ = 313.9.

Step 19-6: 6-Bromo-8-methyl-1,2,3,4-tetrahydroisoquinolin-1-one (Compound 19-6)

At room temperature under a nitrogen atmosphere, to (4-bromo-2-methylphenyl) carboxamido 2,2-dimethylpropionate (738 mg, 2.348 mmol) in MeCN (20 mL) KOAc (456 mg, 4.648 mmol) and dichloro(pentamethylcyclopentadienyl) rhodium(III) dimer (68 mg, 0.111 mmol) were added to the solution. The resulting mixture was stirred at room temperature for 5 min and then cooled to -30°C and ethylene (2.8 g, 100 mmol) was added slowly. The resulting mixture was warmed to room temperature and stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography (eluted with MeOH in DCM (0% to 10% gradient)) to give a red oil 6-bromo-8-methyl-1,2,3,4-tetrahydroisoquinolin-1-one (294 mg, 52%). LCMS (M+H) ⁺ = 240.0.

Step 19-7: 6-Bromo-8-methyl-1,2,3,4-tetrahydroisoquinoline (Compound 19-7)

At room temperature, add 6-bromo-8-methyl-1,2,3,4-tetrahydroisoquinolin-1-one (245 mg, 1.019 mmol) in THF (10 mL) to a solution of BH ₃ .Me ₂ S in THF (4.8 mL, 48.000 mmol, 10 M). The resulting mixture was stirred at 70°C under a nitrogen atmosphere for 4 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (eluted with MeCN in water (with a gradient of 0% to 50% in 30 min)) to give 6-bromo-8-methyl as a red oil -1,2,3,4-tetrahydroisoquinoline (83 mg, 36%). LCMS (M+H) ⁺ = 226.0.

Step 19-8: 6-Bromo-2,8-dimethyl-1,2,3,4-tetrahydroisoquinoline (Compound 19-8)

At room temperature, add HOAc (30.00 μL) to a solution of 6-bromo-8-methyl-1,2,3,4-tetrahydroisoquinoline (39 mg, 0.175 mmol) in MeOH (10 mL) And formalin (0.1 mL, 13.357 mmol, 37%). With stirring, NaBH(AcO) ₃ (134 mg, 0.632 mmol) was added in portions to the resulting mixture at room temperature over a period of 30 min. At 65°C, the reaction mixture was stirred for another 1 h. When the reaction is complete, it is quenched by adding water (2 mL). The resulting mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over Na ₂ SO ₄ and washed with brine. The solvent was removed under reduced pressure to give 6-bromo-2,8-dimethyl-1,2,3,4-tetrahydroisoquinoline (19 mg, 45%) as a red solid. LCMS (M+H) ⁺ = 242.0.

Step 19-9: 4-[5-(2,8-Dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1-(4-methylbenzenesulfonyl) -1H-pyrrolo[2,3-b]pyridin-3-yl]-N,N-dimethylbenzamide (Compound 19-9)

At room temperature under a nitrogen atmosphere, add 6-bromo-2,8-dimethyl-1,2,3,4-tetrahydroisoquinoline (76 mg, 0.316 mmol) in dichloromethane (8 mL) Add N,N-dimethyl-4-[1-(4-methylbenzenesulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-bis Oxaloborolan-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]benzamide (207 mg, 0.338 mmol), Pd(dppf)Cl ₂ .CH ₂ A solution of Cl ₂ (38 mg, 0.047 mmol) and K ₂ CO ₃ (110 mg, 0.799 mmol) in H ₂ O (2 mL). The resulting mixture was stirred at 100°C under nitrogen atmosphere for 3 h. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography (eluted with MeOH in EtOAc (0% to 10% gradient)) to give a brown oil 4-[5-(2,8-Dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1-(4-methylbenzenesulfonyl)-1H-pyrrole And [2,3-b]pyridin-3-yl]-N,N-dimethylbenzamide (68 mg, 54%). LCMS (M+H) ⁺ = 579.4.

Step 19-10: 4-[5-(2,8-Dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrrolo[2,3-b]pyridine -3-yl]-N,N-dimethylbenzamide (Compound 19-10)

By a method similar to the final step of Example 18, from 4-[5-(2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1-(4 -Methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-N,N-dimethylbenzamide Preparation Example 19. ¹ H NMR (400 MHz, DMSO- d6 , ppm) δ 12.07 (s, 1 H), 8.54 (d, J = 2.0 Hz, 1 H), 8.43 (d, J = 2.0 Hz, 1 H), 8.00 ( d, J = 2.8 Hz, 1 H), 7.85 (d, J = 8.4 Hz, 2 H), 7.49 (d, J = 8.4 Hz, 2 H), 7.39 (s, 1 H), 7.35 (s, 1 H), 3.45 (s, 2 H), 3.00 (s, 6 H), 2.96-2.88 (m, 2 H), 2.65-2.58 (m, 2 H), 2.42 (s, 3 H), 2.25 (s , 3 H). LC-MS (M+H) ⁺ = 425.6.

Example 20 : 6-[3-[4-(3-hydroxyazetidine-1-carbonyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-8-methan Oxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-one (Compound 20)

Step 20-1: 4-Bromo-2-methoxy-N-(neopentoxy)benzamide (Compound 20-1)

Under a nitrogen atmosphere, to a solution of 4-bromo-2-methoxybenzoic acid (10.00 g, 43.29 mmol) in THF (150 mL) at 0°C, add T ₃ P(2,4,6- Tripropyl-1,3,5,2,4,6-trioxatriphosphine-2,4,6-trioxide) (27.55 g, 86.58 mmol). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 0.5 h. At room temperature, DIEA (17.07 g, 132.29 mmol) and amino 2,2-dimethylpropionate (12.00 g, 102.56 mmol) were added to the above mixture. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for another 16 h. When the reaction is complete, it is quenched by adding water (300 mL). The resulting mixture was extracted with ethyl acetate (500 mL x 3). The organic phases were combined, dried over Na ₂ SO ₄ and washed with brine. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography (eluted with EtOAc in hexane (0% to 10% gradient)) to give (4-bromo- 2-Methoxyphenyl)carboxamido 2,2-dimethylpropionate (9.83 g, 69%). LCMS (M+H) ⁺ = 330.2.

Step 20-2: 6-Bromo-8-methoxy-3,4-dihydroisoquinolin-1(2H)-one (Compound 20-2)

By a method similar to step 19-6 of Example 19, compound 20-2 was prepared from (4-bromo-2-methoxyphenyl)carboxamido 2,2-dimethylpropionate. LCMS (M+H) ⁺ = 256.1.

Step 20-3: 6-Bromo-8-methoxy-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (Compound 20-3)

At 0°C under nitrogen atmosphere, add 6-bromo-8-methoxy-1,2,3,4-tetrahydroisoquinolin-1-one (1.43 g, 5.576 mmol) in DMF (16 mL) Add NaH (600 mg, 25.002 mmol) to the solution in. The resulting mixture was stirred for 20 min and then MeI (2.28 g, 16.063 mmol) was slowly added at room temperature. The reaction mixture was stirred at room temperature under nitrogen atmosphere for 3 h. When the reaction is complete, it is then quenched by adding ice water (50 mL). The resulting mixture was extracted with ethyl acetate (250 mL x 3). The organic phases were combined, dried over Na ₂ SO ₄ and washed with brine. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography (eluted with MeOH in DCM (0% to 50% gradient)) to give 6-bromo-8- as a red solid. Methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-one (970 mg, 34%). LCMS (M+H) ⁺ = 270.1.

Step 20-4: 8-Methoxy-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 3,4-Dihydroisoquinoline-1(2H)-one (Compound 20-4)

Prepared from 6-bromo-8-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-one and BPD by a method similar to step 18-2 of Example 18 Compound 20-4. LCMS (M+H) ⁺ = 318.2.

Step 20-5: 6-[3-[4-(3-hydroxyazetidine-1-carbonyl)phenyl]-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2 ,3-b]pyridin-5-yl]-8-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-one (compound 20-5)

By a method similar to steps 18-9 of Example 18, from 1-[4-[5-bromo-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine -3-yl]benzyl)azetidine-3-ol and 8-methoxy-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinolin-1-one was used to prepare compound 20-5. LCMS (M+H) ⁺ = 637.2.

Step 20-6: 6-[3-[4-(3-Hydroxyazetidine-1-carbonyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-8 -Methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-one (Compound 20-6)

By a method similar to the final step of Example 18, from 6-[3-[4-(3-hydroxyazetidine-1-carbonyl)phenyl]-1-(4-methylbenzenesulfonyl )-1H-pyrrolo[2,3-b]pyridin-5-yl]-8-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-one preparation example 20. ¹ H NMR (400 MHz, DMSO- d6 , ppm) δ 12.21 (d, J = 2.0 Hz, 1 H), 8.67 (d, J = 2.0 Hz, 1 H), 8.56 (d, J = 1.6 Hz, 1 H), 8.08 (d, J = 2.8 Hz, 1 H), 7.90 (d, J = 8.0 Hz, 2 H), 7.72 (d, J = 8.0 Hz, 2 H), 7.32-7.26 (m, 2 H ), 5.81-5.75 (m, 1 H), 4.55-4.51 (m, 2 H), 4.30-4.25 (m, 1 H), 4.13-4.08 (m, 1 H), 3.89 (s, 3 H), 3.84-3.80 (m, 1 H), 3.52-3.49 (m, 2 H), 3.02 (s, 3 H), 2.99-2.96 (m, 2 H). LC-MS (M+H) ⁺ = 483.2.

Example 21 : N,N-dimethyl-4-[5-[7-(4-methylpiperid-1-yl)-1H-indazol-4-yl]-1H-pyrrolo[2,3 -b]pyridin-3-yl]benzamide (compound 21)

Step 21-1: 1-(4-Bromo-3-methyl-2-nitrophenyl)-4-methylpiperidine (Compound 21-1)

At room temperature, to a solution of 1-bromo-4-fluoro-2-methyl-3-nitrobenzene (1000 mg, 4.273 mmol) in DMF (20 mL), add 1-methylpiperidine (642 mg , 6.410 mmol) and K ₂ CO ₃ (1772 mg, 12.819 mmol). The resulting mixture was stirred at 140°C under nitrogen atmosphere for 6 h. When the reaction was complete, it was quenched by adding water (40 mL). The resulting mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over Na ₂ SO ₄ and washed with brine. The solvent was removed under reduced pressure to give 1-(4-bromo-3-methyl-2-nitrophenyl)-4-methylpiperidine (709 mg, 53%) as a yellow solid. LCMS (M+H) ⁺ = 314.1.

Step 21-2: 3-Bromo-2-methyl-6-(4-methylpiperid-1-yl)aniline (Compound 21-2)

At room temperature, add Fe to a solution of 1-(4-bromo-3-methyl-2-nitrophenyl)-4-methylpiper (900 mg, 2.865 mmol) in MeOH (5 mL) Powder (560 mg, 10.026 mmol), HCOOH (2.00 mL) and THF (2.00 mL). The resulting mixture was stirred at 80°C for 2 h. After the reaction was completed, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with water (20 mL), and the pH of the mixture was adjusted to about 11 with NaOH solution (2 M). The resulting mixture was extracted with EtOAc (50 mL x 4). The organic phases were combined, dried over Na ₂ SO ₄ and washed with brine. The solvent was removed under reduced pressure to give 3-bromo-2-methyl-6-(4-methylpiperid-1-yl)aniline (638 mg, 78%) as a yellow oil. LCMS (M+H) ⁺ = 285.2.

Step 21-3: 4-Bromo-7-(4-methylpiper-1-yl)-1H-indazole (Compound 21-3)

At room temperature, to a solution of 3-bromo-2-methyl-6-(4-methylpiperid-1-yl)aniline (400 mg, 1.404 mmol) in EtOAc (15 mL) was added KOAc (165 mg, 1.685 mmol), Ac ₂ O (229 mg, 2.246 mmol) and 18-crown-6 (238 mg, 0.899 mmol). The resulting mixture was stirred at room temperature for 15 min, and then n-AmONO (n-pentyl nitrite) (361 mg, 3.089 mmol) was added at room temperature. The reaction mixture was stirred at 70°C for another 16 h. When the reaction was complete, it was quenched by adding saturated NaHCO ₃ solution (10 mL). The resulting mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over Na ₂ SO ₄ and washed with brine. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography (eluted with EtOAc in hexane (0% to 10% gradient)) to give 4-bromo-7 as a yellow solid -(4-Methylpiperidin-1-yl)-1H-indazole (124 mg, 30%). LCMS (M+H) ⁺ = 295.2.

Step 21-4: N,N-Dimethyl-4-[1-(4-methylbenzenesulfonyl)-5-[7-(4-methylpiperid-1-yl)-1H-indyl Azol-4-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl]benzamide (Compound 21-4)

By a method similar to steps 18-9 of Example 18, from N,N-dimethyl-4-[1-(4-methylbenzenesulfonyl)-5-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]benzamide and 4-bromo-7 -(4-Methylpiperid-1-yl)-1H-indazole to prepare compound 21-4. LCMS (M+H) ⁺ = 634.3.

Step 21-5: N,N-Dimethyl-4-[5-[7-(4-methylpiperid-1-yl)-1H-indazol-4-yl]-1H-pyrrolo[2 ,3-b]pyridin-3-yl]benzamide (compound 21-5)

By a method similar to the final step of Example 18, from N,N-dimethyl-4-[1-(4-methylbenzenesulfonyl)-5-[7-(4-methylpiper𠯤- 1-yl)-1H-indazol-4-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl]benzamide Preparation Example 21. ¹ H NMR (400 MHz, DMSO- d6 , ppm) δ 13.24 (s, 1 H), 12.14 (s, 1 H), 8.59 (s, 1 H), 8.47 (s, 1 H), 8.20 (s, 1 H), 8.05 (s, 1 H), 7.86 (d, J = 7.9 Hz, 2 H), 7.49 (d, J = 7.9 Hz, 2 H), 7.22 (d, J = 7.6 Hz, 1 H) , 6.90 (d, J = 7.6 Hz, 1 H), 3.17-3.12 (m, 4 H), 3.00 (s, 6 H), 2.64-2.58 (m, 4 H), 2.29 (s, 3 H). LC-MS (M+H) ⁺ = 480.2.

Example 22 : N,N-dimethyl-4-(5-(1-(1-methylpiperidin-4-yl)-1H-indazol-4-yl)-1H-pyrrolo[2,3 -b]pyridin-3-yl)benzamide (compound 22A) and N,N-dimethyl-4-(5-(2-(1-methylpiperidin-4-yl)-2H-indyl (Azol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide (Compound 22B)

Step 22-1: Tertiary butyl 4-(4-bromo-2H-indazol-2-yl)piperidine-1-carboxylate (Compound 22-1A) and tertiary butyl 4-(4-bromo -1H-indazol-1-yl)piperidine-1-carboxylate (Compound 22-1B)

To a solution of 4-bromo-1H-indazole (1.00 g, 5.075 mmol) in DMF (40 mL) at 0°C, add sodium hydride (414 mg, 10.15 mmol, 60%). The mixture was stirred at 0 °C for 15 min and then tertiary butyl 4-[(4-methylbenzenesulfonyl)oxy]piperidine-1-carboxylate (4.51 g, 12.688 mmol) was added. The resulting mixture was heated to 40°C and stirred for 16 h. When the reaction is complete, it is quenched by adding ice water (50 mL). The resulting mixture was extracted with DCM (100 mL x 3). The organic phases were combined, dried over Na ₂ SO ₄ and washed with brine. The solvent was removed under reduced pressure, and the residue was subjected to reversed-phase flash chromatography (MeCN in water with 10 mmol/L NH ₄ HCO ₃ ) (35% to 55% gradient in 30 min) Elution) purification to produce tertiary butyl 4-(4-bromo-2H-indazol-2-yl)piperidine-1-carboxylate and tertiary butyl 4-(4-bromo -1H-indazol-1-yl)piperidine-1-carboxylate (414 mg, 21% total yield). LCMS (M+H) ⁺ = 382.2.

Step 22-2: 4-Bromo-2-(1-methylpiperidin-4-yl)-2H-indazole (Compound 22-2A) and 4-bromo-1-(1-methylpiperidine-4 -Yl)-1H-indazole (Compound 22-2B)

At room temperature, add tertiary butyl 4-(4-bromo-2H-indazol-2-yl)piperidine-1-carboxylate and tertiary butyl 4-(4-bromo-1H-indazole- The 1-yl) piperidine-1-carboxylate mixture (400.00 mg, 1.052 mmol) in AcOH (15 mL) was added with formalin (0.15 mL, 2.00 mmol, 37%). The resulting mixture was stirred at 100°C for 16 h. When the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column, XBridge Shield RP18 OBD column, 150 x 30 mm, 5 um; mobile phase, acetonitrile in water (with 10 mmol/L NH ₄ HCO ₃ ), in 32% to 60% gradient within 7 minutes; detector, UV 254 nm. 4-bromo-1-(1-methylpiperidin-4-yl)-1H-indazole and 4-bromo-2-(1-methylpiperidin-4-yl)-2H- were obtained as white solids Indazole mixture (198 mg, total yield 65%). LCMS (M+H) ⁺ = 394.0.

Step 22-3: N,N-Dimethyl-4-(5-(2-(1-methylpiperidin-4-yl)-2H-indazol-4-yl)-1-toluenesulfonyl -1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide (compound 22-3A) and N,N-dimethyl-4-(5-(1-(1-methyl) Piperidin-4-yl)-1H-indazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide (Compound 22- 3B)

By a method similar to steps 18-9 of Example 18, from N,N-dimethyl-4-[1-(4-methylbenzenesulfonyl)-5-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]benzamide and 4-bromo-1 -(1-methylpiperidin-4-yl)-1H-indazole and 4-bromo-2-(1-methylpiperidin-4-yl)-2H-indazole mixture to prepare a compound 22-3 mixture. LCMS (M+H) ⁺ = 633.2.

Step 22-4: N,N-Dimethyl-4-(5-(1-(1-methylpiperidin-4-yl)-1H-indazol-4-yl)-1H-pyrrolo[2 ,3-b]pyridin-3-yl)benzamide (compound 22A) and N,N-dimethyl-4-(5-(2-(1-methylpiperidin-4-yl)-2H -Indazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide (Compound 22B)

By a method similar to the final step of Example 18, from N,N-dimethyl-4-(5-(2-(1-methylpiperidin-4-yl)-2H-indazol-4-yl )-1-Tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide and N,N-dimethyl-4-(5-(1-(1- (Methylpiperidin-4-yl)-1H-indazol-4-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide preparation example twenty two.

Example 22A : ¹ H NMR (400 MHz, DMSO- d6 , ppm) δ 12.22 (br s, 1 H), 8.62 (d, J = 1.6 Hz, 1 H), 8.53 (d, J = 2.0 Hz, 1 H ), 8.23 (s, 1 H), 8.08 (s, 1 H), 7.88-7.85 (m, 2 H), 7.76 (d, J = 8.5 Hz, 1 H), 7.53-7.47 (m, 3 H) , 7.36 (d, J = 7.0 Hz, 1 H), 4.66 (s, 1 H), 3.04-2.86 (m, 8 H), 2.33-2.12 (m, 7 H), 1.96-1.91 (m, 2 H ). LC-MS (M+H) ⁺ = 479.2.

Example 22B : ¹ H NMR (400 MHz, DMSO- d6 , ppm) δ 12.18 (s, 1 H), 8.64 (d, J = 2.0 Hz, 1H), 8.61 (s, 1 H), 8.52 (s, 1 H), 8.06 (d, J = 2.4 Hz, 1 H), 7.93-7.81 (m, 2 H), 7.64 (d, J = 8.6 Hz, 1 H), 7.52-7.45 (m, 2 H), 7.40 -7.32 (m, 1 H), 7.25 (d, J = 8.6 Hz, 1 H), 4.58-4.47 (m, 1H), 3.00 (s, 6 H), 2.94-2.87 (m, 2 H), 2.26 -2.13 (m, 5 H), 2.13-2.03 (m, 4 H). LC-MS (M+H) ⁺ = 479.2.

Example 23 : N,N-dimethyl-4-(5-(2-((1-methylpiperidin-4-yl)methyl)-2H-indazol-5-yl)-1H-pyrrolo [2,3-b]pyridin-3-yl)benzamide (compound 23A) and N,N-dimethyl-4-(5-(1-((1-methylpiperidin-4-yl) )Methyl)-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide (Compound 23B)

Step 23-1: 5-Bromo-2-((1-methylpiperidin-4-yl)methyl)-2H-indazole (Compound 23-1A) and 5-bromo-1-((1-methyl Piperidin-4-yl)methyl)-1H-indazole (Compound 23-1B)

At room temperature, to a solution of 5-bromo-1H-indazole (588 mg, 3.045 mmol) in MeCN (15 mL), add 4-(bromomethyl)-1-methylpiperidine hydrobromide ( 815 mg, 3.045 mmol), Cs ₂ CO ₃ (2.92 g, 9.135 mmol). The resulting solution was stirred at 80°C for 16 h. When the reaction was complete, the reaction mixture was then diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over Na ₂ SO ₄ and washed with brine. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography (eluted with EtOAc in hexane (0% to 20% gradient)) to give 5-bromo-1 as a white solid -((1-methylpiperidin-4-yl)methyl)-1H-indazole and 5-bromo-2-((1-methylpiperidin-4-yl)methyl)-2H-indazole (560 mg, 60% total yield) mixture. LCMS (M+H) ⁺ = 382.2.

Step 23-2: N,N-Dimethyl-4-(5-(2-((1-methylpiperidin-4-yl)methyl)-2H-indazol-5-yl)-1- Tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide (compound 23-2A) and N,N-dimethyl-4-(5-(1-( (1-methylpiperidin-4-yl)methyl)-1H-indazol-5-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl) Benzamide (Compound 23-2B)

By a method similar to steps 18-9 of Example 18, from N,N-dimethyl-4-[1-(4-methylbenzenesulfonyl)-5-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]benzamide and 5-bromo-1 -((1-methylpiperidin-4-yl)methyl)-1H-indazole and 5-bromo-2-((1-methylpiperidin-4-yl)methyl)-2H-indazole Mixture Preparation of compound 23-2 mixture. LCMS (M+H) ⁺ = 648.2.

Step 23-3: N,N-Dimethyl-4-(5-(2-((1-methylpiperidin-4-yl)methyl)-2H-indazol-5-yl)-1H- Pyrrolo[2,3-b]pyridin-3-yl)benzamide (compound 23A) and N,N-dimethyl-4-(5-(1-((1-methylpiperidine-4 -Yl)methyl)-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide (compound 23B)

By a method similar to the final step of Example 18, from N,N-dimethyl-4-(5-(2-((1-methylpiperidin-4-yl)methyl)-2H-indazole -5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide and N,N-dimethyl-4-(5-(1 -((1-Methylpiperidin-4-yl)methyl)-1H-indazol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3- Benzamide Preparation Example 23. Two isomer products were obtained by separation on SFC under the following conditions: column, CHIRALPAK IE, 2 x 25 cm, 5 μm. Mobile phase: hexane in EtOH (with 0.2% isopropylamine), 70% isocratic within 20 min; detector, UV 254 nm.

Example 23A : ¹ H NMR (400 MHz, DMSO- d6 , ppm) δ 12.08 (s, 1 H), 8.61 (s, 1 H), 8.50 (s, 1 H), 8.45 (s, 1 H), 8.07 -7.99 (m, 2 H), 7.88 (d, J = 7.9 Hz, 2 H), 7.75-7.66 (m, 2 H), 7.50 (d, J = 7.9 Hz, 2 H), 4.49-4.41 (m , 2 H), 3.03-2.99 (m, 7 H), 2.69-2.64 (m, 1 H), 2.45-2.39 (m, 1 H), 2.25 (s, 3 H), 2.18-2.12 (m, 1 H), 2.04-1.86 (m, 4 H), 1.41-1.37 (m, 1 H). LC-MS (M+H) ⁺ = 493.3. Retention time: 12.875 min.

Example 23B : ¹ H NMR (400 MHz, DMSO- d6 , ppm) δ 12.09 (s, 1 H), 8.62 (s, 1 H), 8.52 (s, 1 H), 8.13 (s, 2 H), 8.03 (s, 1 H), 7.89 (d, J = 8.1 Hz, 2 H), 7.86-7.75 (m, 2 H), 7.50 (d, J = 8.2 Hz, 2 H), 4.49-4.41 (m, 2 H), 3.26-3.24 (m, 1 H), 3.01 (s, 6 H), 2.70-2.61 (m, 1 H), 2.49-2.39 (m, 1 H), 2.26 (s, 3 H), 2.21 -2.12 (m, 1 H), 1.98-1.81 (m, 4 H), 1.45-1.32 (m, 1 H). LC-MS (M+H) ⁺ = 493.3. Retention time: 10.217 min.

Example 24 : N,N-dimethyl-4-[5-[1-(1-methylpiperidin-4-yl)-1H-1,3-benzodiazol-5-yl]-1H- Pyrrolo[2,3-b]pyridin-3-yl]benzamide (Compound 24)

Step 24-1: N-(4-Bromo-2-nitrophenyl)-1-methylpiperidin-4-amine (Compound 24-1)

At room temperature, to a solution of 4-bromo-1-fluoro-2-nitrobenzene (5.00 g, 22.83 mmol) in DMF (30 mL), add Cs ₂ CO ₃ (8.90 g, 27.33 mmol) and 1- Methylpiperidin-4-amine (3.1 g, 27.33 mmol). The resulting mixture was stirred at room temperature for 8 h. After the reaction was completed, the reaction mixture was diluted with EtOAc (400 mL). The resulting mixture was washed with saturated NH ₄ Cl and brine. The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure to give N-(4-bromo-2-nitrophenyl)-1-methylpiperidin-4-amine (7.5 g , Crude), the crude product was used in the next step without further purification. LCMS (M+H) ⁺ = 314.0.

Step 24-2: 4-Bromo-N1-(1-methylpiperidin-4-yl)benzene-1,2-diamine (Compound 24-2)

At room temperature, add Fe powder to a solution of N-(4-bromo-2-nitrophenyl)-1-methylpiperidin-4-amine (7.2 g, 22.92 mmol) in MeOH (50 mL) (3.5 g, 65.49 mmol), NH ₄ Cl (5.80 g, 108.33 mmol), and H ₂ O (50 mL). The resulting mixture was stirred at 80°C for 6 h. When the reaction was completed, the insoluble solid was filtered off, and the filtrate was concentrated to remove the organic solvent. The remaining mixture was then diluted with THF (500 mL) and filtered again to remove insoluble solids. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography (eluted with EtOAc in hexane (0% to 70% gradient)) to give 4-bromo- as a pale yellow solid. N1-(1-methylpiperidin-4-yl)benzene-1,2-diamine (3.58 g, 55%). LCMS (M+H) ⁺ = 286.0.

Step 24-3: 5-Bromo-1-(1-methylpiperidin-4-yl)-1H-1,3-benzodiazole (Compound 24-3)

To a solution of 4-bromo-N1-(1-methylpiperidin-4-yl)benzene-1,2-diamine (510 mg, 1.795 mmol) in MeCN (50 mL) at room temperature, add trimethyl Oxymethane (390 mg, 3.675 mmol). The resulting mixture was stirred at 80°C for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography (eluted with MeOH) to give 5-bromo-1-(1-methylpiperidine) as a brown solid -4-yl)-1H-1,3-benzodiazole (500 mg, 94%). LCMS (M+H) ⁺ = 296.1.

Step 24-4: N,N-Dimethyl-4-[1-(4-methylbenzenesulfonyl)-5-[1-(1-methylpiperidin-4-yl)-1H-1 ,3-Benzodiazol-5-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl]benzamide (Compound 24-4)

By a method similar to steps 18-9 of Example 18, from N,N-dimethyl-4-[1-(4-methylbenzenesulfonyl)-5-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]benzamide and 5-bromo-1 -(1-methylpiperidin-4-yl)-1H-1,3-benzodiazole to prepare compound 24-4. LCMS (M+H) ⁺ = 633.3.

Step 24-5: N,N-dimethyl-4-[5-[1-(1-methylpiperidin-4-yl)-1H-1,3-benzodiazol-5-yl]- 1H-Pyrrolo[2,3-b]pyridin-3-yl]benzamide (Compound 24-5)

By a method similar to the final step of Example 18, from N,N-dimethyl-4-[1-(4-methylbenzenesulfonyl)-5-[1-(1-methylpiperidine- 4-yl)-1H-1,3-benzodiazol-5-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl]benzamide Preparation Example 24. ¹ H NMR (400 MHz, DMSO- d6 , ppm) δ 12.08 (s, 1 H), 8.62 (d, J = 2.0 Hz, 1 H), 8.51 (d, J = 2.0 Hz, 1 H), 8.42 ( s, 1 H), 8.08-8.00 (m, 2 H), 7.93-7.86 (m, 2 H), 7.77 (d, J = 8.5 Hz, 1 H), 7.66 (d, J = 8.5 Hz, 1 H ), 7.54-7.47 (m, 2 H), 4.43-4.39 (m, 1 H), 3.01 (s, 6 H), 2.97-2.88 (m, 2 H), 2.26 (s, 3 H), 2.22- 2.07 (m, 4 H), 2.07-2.01 (m, 2 H). LC-MS (M+H) ⁺ = 479.5.

Example 25 : N,N-dimethyl-4-(5-(1-(1-(1-methylpiperidin-4-yl)ethyl)-1H-benzo[d]imidazol-5-yl )-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide (Compound 25)

Step 25-1: 4-Bromo-N-(1-(1-methylpiperidin-4-yl)ethyl)-2-nitroaniline (Compound 25-1)

By a method similar to step 24-1 of Example 24, compound 25-1 was prepared from 4-bromo-1-fluoro-2-nitrobenzene and 1-(1-methylpiperidin-4-yl)ethylamine . LCMS (M+H) ⁺ = 344.1.

Step 25-2: 4-Bromo-N1-(1-(1-methylpiperidin-4-yl)ethyl)benzene-1,2-diamine (Compound 25-2)

By a method similar to step 24-2 of Example 24, compound 25-2 was prepared from 4-bromo-N-(1-(1-methylpiperidin-4-yl)ethyl)-2-nitroaniline . LCMS (M+H) ⁺ = 312.1.

Step 25-3: 5-Bromo-1-(1-(1-methylpiperidin-4-yl)ethyl)-1H-benzo[d]imidazole (Compound 25-3)

By a method similar to step 24-3 of Example 24, from 4-bromo-N1-[1-(1-methylpiperidin-4-yl)ethyl]benzene-1,2-diamine and trimethoxy Methyl methane to prepare compound 25-3. LCMS (M+H) ⁺ = 322.1.

Step 25-4: N,N-Dimethyl-4-(5-(1-(1-(1-methylpiperidin-4-yl)ethyl)-1H-benzo[d]imidazole-5 -Yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide (Compound 25-4)

By a method similar to steps 18-9 of Example 18, from N,N-dimethyl-4-[1-(4-methylbenzenesulfonyl)-5-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]benzamide and 5-bromo-1 -(1-(1-Methylpiperidin-4-yl)ethyl)-1H-benzo[d]imidazole to prepare compound 25-4. LCMS (M+H) ⁺ = 661.3.

Step 25-5: N,N-Dimethyl-4-(5-(1-(1-(1-methylpiperidin-4-yl)ethyl)-1H-benzo[d]imidazole-5 -Yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide (compound 25-5)

By a method similar to the final step of Example 18, from N,N-dimethyl-4-(5-(1-(1-(1-methylpiperidin-4-yl)ethyl)-1H- Benzo[d]imidazol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide Preparation Example 25. ¹ H NMR (400 MHz, DMSO- d6 , ppm) δ 12.08 (s, 1 H), 8.62 (d, J = 2.0 Hz, 1 H), 8.52 (d, J = 2.0 Hz, 1 H), 8.37 ( s, 1 H), 8.05-8.00 (m, 2 H), 7.94-7.87 (m, 2 H), 7.77 (d, J = 8.4 Hz, 1 H), 7.64 (d, J = 8.4 Hz, 1 H ), 7.53-7.47 (m, 2 H), 4.48-4.36 (m, 1 H), 3.01 (s, 6 H), 2.86-2.78 (m, 1 H), 2.68-2.61 (m, 1 H), 2.10 (s, 3 H), 1.87-1.75 (m, 3 H), 1.71-1.61 (m, 1 H), 1.59 (d, J = 6.9 Hz, 3 H), 1.38-1.11 (m, 2 H) , 1.04-0.97 (m, 1 H). LC-MS (M+H) ⁺ = 507.3.

Example 26 : (1-Methylazetidin-3-yl)(4-(5-(2-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydro Isoquinolin-6-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanone (Compound 26)

Step 26-1: 6-Bromo-2-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydroisoquinoline (Compound 26-1)

At room temperature, add 1-methylpiperidin-4-one to a solution of 6-bromo-1,2,3,4-tetrahydroisoquinoline (422 mg, 1.890 mmol) in DCM (15 mL) (270 mg, 2.388 mmol) and NaBH(OAc) ₃ (633 mg, 2.985 mmol). Under a nitrogen atmosphere, the resulting mixture was stirred at room temperature for 2 h. When the reaction was completed, the reaction mixture was diluted with H ₂ O (50 mL), and the pH of the resulting mixture was adjusted to about 7 with saturated NaHCO ₃ solution. The mixture was extracted with DCM (100 mL x 3). The organic phases were combined, dried over Na ₂ SO ₄ and washed with brine. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography (eluted with EtOAc in DCM (0% to 18% gradient)) to give 6-bromo-2-(1-methyl Piperidin-4-yl)-1,2,3,4-tetrahydroisoquinoline (468 mg, 80%). LCMS (M+H) ⁺ = 309.1.

Step 26-2: 2-(1-Methylpiperidin-4-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2 -Yl)-1,2,3,4-tetrahydroisoquinoline (compound 26-2)

Prepared from 6-bromo-2-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydroisoquinoline and BPD by a method similar to step 18-2 of Example 18 Compound 26-2. LCMS (M+H) ⁺ = 357.3.

Step 26-3: 3-(4-Bromobenzyl)-1-methylazetidine (Compound 26-3)

Add AcOH (0.83 mL) to the solution of 3-(4-bromobenzyl)azetidine hydrochloride (1.90 g, 6.870 mmol) in MeOH (30 mL) under nitrogen atmosphere at room temperature And formalin (0.6 mL, 8.000 mmol, 37%). The resulting mixture was stirred at room temperature for 1 h. Then NaBH(OAc)3 (4.38 g, 20.664 mmol) was added, and the reaction mixture was stirred at room temperature under a nitrogen atmosphere for another 2 h. When the reaction is completed, the pH value of the reaction mixture is adjusted to about 7 with saturated NaHCO ₃ solution. The resulting mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over Na ₂ SO ₄ and washed with brine. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography (eluted with MeOH in DCM (0% to 10% gradient)) to give 3- (4-Bromobenzyl)-1-methylazetidine (1.68 g, 96%). LCMS (M+H) ⁺ = 254.0.

Step 26-4: (1-Methylazetidin-3-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane- 2-yl)phenyl)methanone (compound 26-4)

By a method similar to step 18-2 of Example 18, compound 26-4 was prepared from 3-(4-bromobenzyl)-1-methylazetidine and BPD. LCMS (M+H) ⁺ = 302.2.

Step 26-5: 3-[4-[5-Bromo-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]benzoyl]- 1-Methylazetidine (Compound 26-5)

By a method similar to steps 18-9 of Example 18, from 5-bromo-3-iodo-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine and 1 -Methyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]azetidine Compound 26-5. LCMS (M+H) ⁺ = 526.0. Step 26-6: 6-[3-[4-(1-Methylazetidine-3-carbonyl)phenyl]-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[ 2,3-b]pyridin-5-yl]-2-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydroisoquinoline (compound 26-6)

By a method similar to steps 18-9 of Example 18, from 2-(1-methylpiperidin-4-yl)-6-(4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline and 3-[4-[5-bromo-1-(4-methylbenzenesulfonyl) -1H-pyrrolo[2,3-b]pyridin-3-yl]benzoyl]-1-methylazetidine compound 26-6 was prepared. LCMS (M+H) ⁺ = 674.3. Step 26-7: (1-Methylazetidin-3-yl)(4-(5-(2-(1-methylpiperidin-4-yl)-1,2,3,4- Tetrahydroisoquinolin-6-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanone (Compound 26-7)

By a method similar to the final step of Example 18, from (1-methylazetidin-3-yl)(4-(5-(2-(1-methylpiperidin-4-yl)- 1,2,3,4-Tetrahydroisoquinolin-6-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanone 26. ¹ H NMR (400 MHz, DMSO- d6 , ppm) δ 12.21 (s, 1 H), 8.56 (d, J = 2.0 Hz, 1 H), 8.48 (d, J = 2.0 Hz, 1 H), 8.12 ( s, 1 H), 8.00-7.90 (m, 4 H), 7.55-7.48 (m, 2 H), 7.18 (d, J = 7.9 Hz, 1 H), 4.26-4.14 (m, 1 H), 3.74 (s, 2 H), 3.59 (t, J = 7.5 Hz, 2 H), 3.22 (t, J = 7.1 Hz, 2 H), 2.92-2.75 (m, 6 H), 2.41-2.31 (m, 1 H), 2.23-2.14 (m, 6 H), 1.95-1.85 (m, 2 H), 1.85-1.77 (m, 2 H), 1.62-1.48 (m, 2 H). LC-MS (M+H) ⁺ = 520.4.

Example 27 : N,N-dimethyl-4-(5-(1-(1-methylpiperidin-4-yl)-2-oxo-2,3-dihydro-1H-benzo[ d]imidazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide (compound 27)

Step 27-1: 5-Bromo-1-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazole-2(3H)-one (Compound 27-1)

At room temperature, add CDI to a solution of 4-bromo-N1-(1-methylpiperidin-4-yl)benzene-1,2-diamine (787 mg, 3.110 mmol) in MeCN (10 mL) (Carbodiimidazole) (941 mg, 5.808). The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over Na ₂ SO ₄ and washed with brine. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography (eluted with MeOH in DCM (0% to 10% gradient)) to give 5-bromo-1-bromo-1-as an off-white solid (1-Methylpiperidin-4-yl)-1H-benzo[d]imidazole-2(3H)-one (568 mg, 60.2%). LCMS (M+H) ⁺ = 309.1.

Step 27-2: 1-(1-Methylpiperidin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2 -Yl)-1H-benzo[d]imidazole-2(3H)-one (compound 27-2)

By a method similar to step 18-2 of Example 18, from 5-bromo-1-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazole-2(3H)-one and Compound 27-2 was prepared from BPD. LCMS (M+H) ⁺ = 358.2.

Step 27-3: N,N-Dimethyl-4-(5-(1-(1-methylpiperidin-4-yl)-2-oxo-2,3-dihydro-1H-benzene And [d]imidazol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide (compound 27-3)

By a method similar to steps 18-9 of Example 18, from 1-(1-methylpiperidin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl)-2,3-dihydro-1H-1,3-benzodiazol-2-one and 4-[5-bromo-1-(4-methyl Benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-N,N-dimethylbenzamide was used to prepare compound 27-3. LCMS (M+H) ⁺ = 629.2.

Step 27-4: N,N-Dimethyl-4-(5-(1-(1-methylpiperidin-4-yl)-2-oxo-2,3-dihydro-1H-benzene And [d]imidazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide (compound 27-4)

By a method similar to the final step of Example 18, from N,N-dimethyl-4-[1-(4-methylbenzenesulfonyl)-5-[1-(1-methylpiperidine- 4-yl)-2-side oxy-2,3-dihydro-1H-1,3-benzodiazol-5-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl ] Benzamide Preparation Example 27. ¹ H NMR (400 MHz, DMSO-d6, ppm) δ 12.07 (s, 1 H), 10.97 (s, 1 H), 8.52 (s, 1 H), 8.41 (s, 1 H), 8.01 (s, 1 H), 7.89-7.82 (m, 2 H), 7.53-7.46 (m, 2 H), 7.41-7.29 (m, 3 H), 4.23-4.00 (m, 1 H), 3.01 (s, 6 H) ), 2.96-2.89 (m, 2 H), 2.46-2.33 (m, 2 H), 2.24 (s, 3 H), 2.11-2.01 (m, 2 H), 1.71-1.63 (m, 2 H). LC-MS (M+H) ⁺ = 495.2.

Example 28 : N,N-dimethyl-4-(5-(1-(1-(1-methylpiperidin-4-yl)ethyl)-2-oxo-2,3-dihydro -1H-Benzo[d]imidazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide (Compound 28)

Step 28-1: 5-Bromo-1-(1-(1-methylpiperidin-4-yl)ethyl)-1H-benzo[d]imidazole-2(3H)-one (Compound 28-1 )

By a method similar to step 27-1 of Example 27, from 4-bromo-N1-(1-(1-methylpiperidin-4-yl)ethyl)benzene-1,2-diamine and CDI ( Carbonyl diimidazole) to prepare compound 28-1. LCMS (M+H) ⁺ = 338.1.

Step 28-2: N,N-Dimethyl-4-(5-(1-(1-(1-methylpiperidin-4-yl)ethyl)-2-oxo-2,3- Dihydro-1H-benzo[d]imidazol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide (compound 28-2 )

By a method similar to steps 18-9 of Example 18, from N,N-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxa Cyclopentaborin-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide and 5-bromo-1-(1-(1 -Methylpiperidin-4-yl)ethyl)-1H-benzo[d]imidazole-2(3H)-one to prepare compound 28-2. LCMS (M+H) ⁺ = 677.3.

Step 28-3: N,N-Dimethyl-4-(5-(1-(1-(1-methylpiperidin-4-yl)ethyl)-2-oxo-2,3- Dihydro-1H-benzo[d]imidazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide (Compound 28-3)

By the method similar to the final step of Example 18, from N,N-dimethyl-4-(5-(1-(1-(1-methylpiperidin-4-yl)ethyl)-2- Pendant oxy-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzene Formamide Preparation Example 28. ¹ H NMR (400 MHz, DMSO-d6, ppm) δ 12.08 (s, 1 H), 10.93 (s, 1 H), 8.52 (d, J = 2.0 Hz, 1 H), 8.42 (d, J = 2.0 Hz, 1 H), 8.02 (s, 1 H), 7.90-7.83 (m, 2 H), 7.52-7.46 (m, 2 H), 7.38-7.27 (m, 3 H), 4.17-4.07 (m, 1 H), 3.01 (s, 6 H), 2.86-2.79 (m, 1 H), 2.70-2.63 (m, 1 H), 2.12 (s, 3 H), 2.02-1.95 (m, 1 H), 1.92-1.81 (m, 1 H), 1.72-1.62 (m, 1 H), 1.46 (d, J = 7.0 Hz, 3 H), 1.35-1.02 (m, 4 H). LC-MS (M+H) ⁺ = 523.4.

Example 29 : (1-Methylazetidin-3-yl)(4-(5-(2-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydro Isoquinolin-6-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanol (Compound 29)

Step 29-1: (1-Methylazetidin-3-yl)(4-(5-(2-(1-methylpiperidin-4-yl)-1,2,3,4- Tetrahydroisoquinolin-6-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanol (Compound 29-1)

At room temperature, add 6-[3-[4-(1-methylazetidine-3-carbonyl)phenyl]-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[ 2,3-b]pyridin-5-yl]-2-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydroisoquinoline (118 mg, 0.176 mmol) in MeOH Add NaBH ₄ (19 mg, 0.502 mmol) to the solution in (5 mL). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. When the reaction was complete, it was quenched by adding saturated NH ₄ Cl solution (10 mL). The resulting mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over Na ₂ SO ₄ and washed with brine. The solvent was removed under reduced pressure to produce (1-methylazetidin-3-yl) ([4-[1-(4-methylbenzenesulfonyl)-5- [2-(1-Methylpiperidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-1H-pyrrolo[2,3-b]pyridine-3- Yl]phenyl])methanol (82 mg, 69%). LCMS (M+H) ⁺ = 676.4.

Step 29-2: (1-Methylazetidin-3-yl)(4-(5-(2-(1-methylpiperidin-4-yl)-1,2,3,4- Tetrahydroisoquinolin-6-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanol (Compound 29-2)

By a method similar to the final step of Example 18, from (1-methylazetidin-3-yl) ([4-[1-(4-methylbenzenesulfonyl)-5-[2 -(1-Methylpiperidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl] Phenyl]) Methanol Preparation Example 29. ¹ H NMR (400 MHz, DMSO- d6 , ppm) δ 11.96 (s, 1 H), 8.52 (s, 1 H), 8.37 (s, 1 H), 7.87 (s, 1 H), 7.71 (d, J = 7.9 Hz, 2 H), 7.52-7.44 (m, 2 H), 7.37 (d, J = 7.9 Hz, 2 H), 7.16 (d, J = 7.9 Hz, 1 H), 5.34 (br s, 1 H), 4.62 (d, J = 8.2 Hz, 1 H), 3.73 (s, 2 H), 3.29-3.23 (m, 1 H), 3.13-3.03 (m, 2 H), 2.94-2.67 (m , 7 H), 2.65-2.53 (m, 1 H), 2.40-2.30 (m, 1 H), 2.21 (s, 3 H), 2.15 (s, 3 H), 1.95-1.74 (m, 4 H) , 1.62-1.44 (m, 2 H). LC-MS (M+H) ⁺ = 522.4.

Example 30 : 2-Methyl-6-(5-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrrolo[2,3-b]pyridine -3-yl)-3,4-dihydroisoquinolin-1(2H)-one (Compound 30)

Step 30-1: 2-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3, 4-Tetrahydroisoquinoline (Compound 30-1)

By a method similar to step 18-2 of Example 18, compound 30-1 was prepared from 6-bromo-2-methyl-1,2,3,4-tetrahydroisoquinoline and BPD. LCMS (M+H) ⁺ = 423.3.

Step 30-2: 2-Methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-ylboronic acid (Compound 30-2)

By a method similar to step 18-2 of Example 18, compound 30-2 was prepared from 6-bromo-2-methyl-3,4-dihydroisoquinolin-1(2H)-one and BPD. LCMS (M+H) ⁺ = 274.2.

Step 30-3: 6-[5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl]-2-methyl-1,2,3,4-tetrahydroisoquinoline-1 -Ketone (Compound 30-3)

At room temperature, add (2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)boronic acid (879 mg, 4.390 mmol) in two 㗁𠮿 (12 mL ) In the solution, add [2-(2-aminophenyl)phenyl](chloro)palladium; dicyclohexyl({2-[2,4,6-tris(prop-2-yl)phenyl] Phenyl}) phosphine (311 mg, 0.439 mmol), 3-bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine (965 mg, 4.390 mmol), K ₃ PO ₄ (1825 mg, 8.780 mmol), H ₂ O (3 mL). The resulting solution was stirred at 100°C for 16 h. When the reaction is complete, the solid is filtered off. The solvent was concentrated under reduced pressure, and the residue was purified by flash chromatography (eluted with MeOH in DCM (0% to 20% gradient)) to give 6-[5-chloro as a yellow solid -1H-pyrrolo[2,3-b]pyridin-3-yl]-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-one (500 mg, 36%). LCMS (M+H) ⁺ = 312.1.

Step 30-4: 2-Methyl-6-(5-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrrolo[2,3-b ]Pyridin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one (Compound 30-4)

To 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydro Add 6-[5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl]-2- to a solution of isoquinoline (104 mg, 0.531 mmol) in bis-㗁𠮿 (4 mL) Methyl-1,2,3,4-tetrahydroisoquinolin-1-one (139.01 mg, 0.446 mmol), Pd(Cy ₃ ) ₂ Cl ₂ (42 mg, 0.064 mmol), K ₂ CO ₃ (143 mg, 1.062 mmol) and H ₂ O (1 mL). The resulting mixture was irradiated with microwave radiation at 120°C for 1 h. When the reaction is complete, the solid is filtered off. The solvent was concentrated under reduced pressure, and the residue was purified by preparative HPLC under the following conditions: column, XBridge Shield RP18 OBD column, 150 x 30 mm, 5 um; mobile phase, acetonitrile in water (with 10 mmol /L NH ₄ HCO ₃ ), 27% to 50% gradient within 7 min; detector, UV 254 nm. Obtain 2-methyl-6-[5-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrrolo[2,3-b]pyridine-3 -Yl]-1,2,3,4-tetrahydroisoquinolin-1-one (27 mg, 12%). ¹ H NMR (400 MHz, DMSO-d6, ppm) δ 12.12 (s, 1 H), 8.55 (d, J = 2.0 Hz, 1 H), 8.47 (d, J = 2.0 Hz, 1 H), 8.04 ( d, J = 2.8 Hz, 1 H), 7.93 (d, J = 8.1 Hz, 1 H), 7.78 (d, J = 8.1 Hz, 1 H), 7.70 (s, 1 H), 7.56-7.41 (m , 2 H), 7.17 (d, J = 7.8 Hz, 1 H), 3.63-3.52 (m, 4 H), 3.13-3.01 (m, 5 H), 2.93 (t, J = 5.8 Hz, 2 H) , 2.64 (t, J = 5.9 Hz, 2 H), 2.38 (s, 3 H). LC-MS (M+H) ⁺ = 423.3.

Example 31 : 6,6'-(1H-indole-3,5-diyl)bis(2-methyl-2,3,4,5-tetrahydrobenzo[c]azepin-1-one) (Compound 31)

Step 31-1: N-[(1E)-6-bromo-1,2,3,4-tetrahydronaphthalene-1-ylidene]hydroxyamine (Compound 31-1)

At room temperature, to a solution of 6-bromo-1,2,3,4-tetralin-1-one (1000 mg, 4.44 mmol) in EtOH (100 mL) was added NH ₂ OH.HCl (370 mg , 5.278 mmol) and NaOAc (729 mg, 8.797 mmol). The resulting mixture was stirred at 75°C for 2 h. After the reaction was completed, the solid in the reaction mixture was collected by filtration and rinsed with water (10 mL x 3). The resulting solid was dried under vacuum to produce N-[(1E)-6-bromo-1,2,3,4-tetrahydronaphthalene-1-ylidene]hydroxyamine (855 mg, 80%) as a white solid ). LCMS (M+H) ⁺ = 242.2.

Step 31-2: 7-Bromo-2,3,4,5-tetrahydrobenzo[c]azepine-1-one (Compound 31-2)

At room temperature, add N-[(1E)-6-bromo-1,2,3,4-tetrahydronaphthalene-1-ylidene]hydroxylamine (855 mg, 3.561 mmol) to SOCl ₂ (6 mL, 81.883 mmol). The resulting mixture was stirred at 50°C for 4 h. When the reaction is complete, it is quenched by adding water (20 mL). The resulting mixture was extracted with ethyl acetate (60 mL x 3). The organic phases were combined, dried over Na ₂ SO ₄ and washed with brine. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography (eluted with EtOAc in hexane (0% to 50% gradient)) to give 7-bromo-2 as a green solid ,3,4,5-Tetrahydro-1H-2-benzazepine-1-one (581 mg, 68%). LCMS (M+H) ⁺ = 240.0.

Step 31-3: 7-Bromo-2-methyl-2,3,4,5-tetrahydrobenzo[c]azaxi-1-one (Compound 31-3)

By a method similar to step 20-3 of Example 20, compound 31-3 was prepared from 7-bromo-2,3,4,5-tetrahydrobenzo[c]azaxi-1-one and MeI. LCMS (M+H) ⁺ = 254.1.

Step 31-4: 2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4, 5-Tetrahydrobenzo[c]azepine-1-one (Compound 31-4)

By a method similar to step 18-2 of Example 18, compound 31 was prepared from 7-bromo-2-methyl-2,3,4,5-tetrahydrobenzo[c]azaquin-1-one and BPD -4. LCMS (M+H) ⁺ = 302.2.

Step 31-5: 6,6'-(1-toluenesulfonyl-1H-indole-3,5-diyl)bis(2-methyl-2,3,4,5-tetrahydrobenzo[ c]Azepine-1-one) (Compound 31-5)

By a method similar to steps 18-9 of Example 18, from 2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2 -Yl)-2,3,4,5-tetrahydro-1H-2-benzoazepine-1-one and 5-bromo-3-iodo-1-(4-methylbenzenesulfonyl)-1H -Pyrrolo[2,3-b]pyridine to prepare compound 31-5. LCMS (M+H) ⁺ = 619.4.

Step 31-6: 6,6'-(1H-indole-3,5-diyl)bis(2-methyl-2,3,4,5-tetrahydrobenzo[c]azepine-1- Ketone) (Compound 31-6)

By a method similar to the final step of Example 18, from 6,6'-(1-toluenesulfonyl-1H-indole-3,5-diyl)bis(2-methyl-2,3,4 ,5-Tetrahydrobenzo[c]azaxi-1-one) Preparation Example 31. ¹ H NMR (400 MHz, DMSO- d6 , ppm) δ 12.14 (s, 1 H), 8.63 (d, J = 1.6 Hz, 1 H), 8.54 (s, 1 H), 8.02 (s, 1 H) , 7.82-7.72 (m, 2 H), 7.71-7.64 (m, 2 H), 7.63-7.54 (m, 2 H), 3.27-3.19 (m, 4 H), 3.12-3.06 (m, 6 H) , 2.86-2.76 (m, 4 H), 2.09-2.01 (m, 4 H). LC-MS (M+H) ⁺ = 465.3. Example 32: N,N-Dimethyl-4-(5-(2-(3-(methylamino)-3-oxopropyl)-1,2,3,4-tetrahydroisoquine Lin-7-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide (Compound 32)

Step 32-1: 3-(7-Bromo-3,4-dihydroisoquinolin-2(1H)-yl)-N-methylpropanamide (Compound 32-1)

At room temperature, add 7-bromo-1,2,3,4-tetrahydroisoquine to a solution of 3-chloro-N-methylpropanamide (121 mg, 0.993 mmol) in MeCN (10 mL) Morpholine (200 mg, 0.945 mmol) and TEA (193 mg, 1.914 mmol). The resulting mixture was stirred for 15 h at 85°C under a nitrogen atmosphere. When the reaction was complete, the reaction mixture was then diluted with water (20 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over Na ₂ SO ₄ and washed with brine. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography (eluted with MeOH in DCM (0% to 10% gradient)) to give 3-(7) as a colorless oil -Bromo-1,2,3,4-tetrahydroisoquinolin-2-yl)-N-methylpropanamide (174 mg, 62%). LCMS (M+H) ⁺ = 297.1.

Step 32-2: N-methyl-3-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4 -Dihydroisoquinoline-2(1H)-yl)propanamide (Compound 32-2)

Prepared from 3-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-N-methylpropanamide and BPD by a method similar to step 18-2 of Example 18 Compound 32-2. LCMS (M+H) ⁺ = 345.2.

Step 32-3: N,N-Dimethyl-4-(5-(2-(3-(methylamino)-3-oxopropyl)-1,2,3,4-tetrahydro Isoquinolin-7-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide (Compound 32-3)

By a method similar to steps 18-9 of Example 18, from N-methyl-3-(7-(4,4,5,5-tetramethyl-1,3,2-dioxolone Alkyl-2-yl)-3,4-dihydroisoquinoline-2(1H)-yl)propionamide and 4-(5-bromo-1-toluenesulfonyl-1H-pyrrolo[2,3 -b]pyridin-3-yl)-N,N-dimethylbenzamide compound 32-3 was prepared. LCMS (M+H) ⁺ = 636.3.

Step 32-4: N,N-Dimethyl-4-(5-(2-(3-(methylamino)-3-oxopropyl)-1,2,3,4-tetrahydro Isoquinolin-7-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide (Compound 32-4)

By a method similar to steps 18-10 of Example 18, N,N-dimethyl-4-(5-(2-(3-(methylamino)-3-oxopropyl)- 1,2,3,4-Tetrahydroisoquinolin-7-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide Preparation Example 32 . ¹ H NMR (400 MHz, DMSO- d6 , ppm) δ 12.08 (s, 1 H), 8.55 (d, J = 2.0 Hz, 1 H), 8.44 (d, J = 1.6 Hz, 1 H), 8.01 ( d, J = 2.4 Hz, 1 H), 7.89-7.82 (m, 3 H), 7.58-7.38 (m, 4 H), 7.22 (d, J = 7.9 Hz, 1 H), 3.67 (s, 2 H ), 3.01 (s, 6 H), 2.88-2.81 (m, 2 H), 2.77-2.67 (m, 4 H), 2.58 (d, J = 4.6 Hz, 3 H), 2.35 (t, J = 7.2 Hz, 2 H). LC-MS (M+H) ⁺ = 482.4.

Example 33 : 4-(5-(2,8-Dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrrolo[2,3 -b]pyridin-3-yl)-N,N-dimethylbenzamide (compound 33)

Step 33-1: 6-Bromo-2,8-dimethyl-3,4-dihydroisoquinolin-1(2H)-one (Compound 33-1)

By a method similar to Step 20-3 of Example 20, compound 33-1 was prepared from 6-bromo-8-methyl-3,4-dihydroisoquinolin-1(2H)-one and MeI. LCMS (M+H) ⁺ = 254.0.

Step 33-2: 4-(5-(2,8-Dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-1-toluenesulfonyl -1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylbenzamide (Compound 33-2)

By a method similar to steps 18-9 of Example 18, from N,N-dimethyl-4-[1-(4-methylbenzenesulfonyl)-5-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]benzamide and 6-bromo-2 ,8-Dimethyl-1,2,3,4-tetrahydronaphthalene-1-one to prepare compound 33-2. LCMS (M+H) ⁺ = 593.3.

Step 33-3: 4-(5-(2,8-Dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrrolo[2 ,3-b]pyridin-3-yl)-N,N-dimethylbenzamide (Compound 33-3)

By a method similar to the final step of Example 18, from 4-[5-(2,8-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl )-1-(4-Methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-N,N-dimethylbenzamide Preparation Example 33. ¹ H NMR (400 MHz, DMSO- d6 , ppm) δ 12.15 (s, 1 H), 8.63 (d, J = 2.0 Hz, 1 H), 8.53 (d, J = 2.0 Hz, 1 H), 8.03 ( d, J = 2.0 Hz, 1 H), 7.87 (d, J = 8.2 Hz, 2 H), 7.57 (s, 2 H), 7.51 (d, J = 8.2 Hz, 2 H), 3.53 (t, J = 6.4 Hz, 2 H), 3.08-2.99 (m, 11 H), 2.69 (s, 3 H). LC-MS (M+H) ⁺ = 439.2.

Example 34 : [4-[5-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl ]Phenyl](1-methylazetidin-3-yl)methanol (Compound 34)

Step 34-1: (4-(5-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1-tosyl-1H-pyrrolo[2, 3-b]pyridin-3-yl)phenyl)(1-methylazetidin-3-yl)methanone (Compound 34-1)

By a method similar to steps 18-9 of Example 18, from 3-[4-[5-bromo-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine -3-yl]benzyl)-1-methylazetidine and 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxane Penboran-2-yl)-1,2,3,4-tetrahydroisoquinoline was used to prepare compound 34-1. LCMS (M+H) ⁺ = 591.2.

Step 34-2: (4-(5-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1-tosyl-1H-pyrrolo[2, 3-b]pyridin-3-yl)phenyl)(1-methylazetidin-3-yl)methanol (compound 34-2)

By a method similar to step 29-1 of Example 29, from 2-methyl-6-[3-[4-(1-methylazetidine-3-carbonyl)phenyl]-1-( 4-Methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-1,2,3,4-tetrahydroisoquinoline was used to prepare compound 34-2. LCMS (M+H) ⁺ = 593.3.

Step 34-3: [4-[5-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrrolo[2,3-b]pyridine-3 -Yl]phenyl](1-methylazetidin-3-yl)methanol (Compound 34-3)

By a method similar to the final step of Example 18, from [4-[5-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1-(4-methyl Benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl](1-methylazetidin-3-yl)methanol Preparation Example 34. ¹ H NMR (400 MHz, DMSO- d6 , ppm) δ 11.96 (s, 1 H), 8.53 (d, J = 2.0 Hz, 1 H), 8.37 (d, J = 2.0 Hz, 1 H), 7.87 ( s, 1 H), 7.72 (d, J = 8.0 Hz, 2 H), 7.53-7.47 (m, 2 H), 7.38 (d, J = 8.0 Hz, 2 H), 7.16 (d, J = 8.1 Hz , 1 H), 5.33 (br s, 1 H), 4.63 (d, J = 8.2 Hz, 1 H), 3.53 (s, 2 H), 3.15-3.05 (m, 2 H), 2.96-2.85 (m , 3 H), 2.66-2.54 (m, 3 H), 2.40-2.29 (m, 4 H), 2.22 (s, 3 H). LC-MS (M+H) ⁺ = 439.1.

Example 35 : 4-[5-(6-Methoxy-4-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-8-yl)-1H-pyrrolo [2,3-b]pyridin-3-yl]-N,N-dimethylbenzamide (compound 35)

Step 35-1: 4-(5-(6-Methoxy-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-yl) -1-Tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylbenzamide (Compound 35-1)

By a method similar to steps 18-9 of Example 18, from N,N-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxa Cyclopentaborin-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide and 8-bromo-6-methoxy-4 -Methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine to prepare compound 35-1. LCMS (M+H) ⁺ = 611.3.

Step 35-2: 4-[5-(6-Methoxy-4-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-8-yl)-1H- Pyrrolo[2,3-b]pyridin-3-yl]-N,N-dimethylbenzamide (Compound 35-2)

At room temperature, add 4-[5-(6-methoxy-4-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-8-yl)-1- (4-Methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-N,N-dimethylbenzamide (24 mg, 0.040 mmol) in DMF ( Add 2-sulfanyl acetic acid (73 mg, 0.801 mmol) and LiOH.H ₂ O (67 mg, 1.603 mmol) to the solution in 2 mL). The resulting mixture was stirred at 60°C for 1 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC under the following conditions: column, XBridge Shield RP18 OBD column, 150 x 30 mm, 5 um; mobile phase, in water Acetonitrile (with 10 mmol/L NH ₄ HCO ₃ ), 30% to 50% gradient in 7 min; detector, UV 254 nm. 4-[5-(6-Methoxy-4-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-8-yl)-1H- was obtained as an off-white solid Pyrrolo[2,3-b]pyridin-3-yl]-N,N-dimethylbenzamide (14 mg, 76%). ¹ H NMR (400 MHz, DMSO- d6 , ppm) δ 12.12 (s, 1 H), 8.60 (d, J = 2.0 Hz, 1 H), 8.47 (d, J = 2.0 Hz, 1 H), 8.02 ( d, J = 2.4 Hz, 1 H), 7.87 (d, J = 8.3 Hz, 2 H), 7.50 (d, J = 8.3 Hz, 2 H), 7.07 (s, 1 H), 6.99 (s, 1 H), 4.08-4.02 (m, 2 H), 3.90 (s, 3 H), 3.75 (s, 2 H), 3.01 (s, 6 H), 2.91-2.84 (m, 2 H), 2.31 (s , 3 H). LC-MS (M+H) ⁺ = 457.4.

Example 36 : 4-(5-(8-Methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrrolo[2,3-b] (Pyridin-3-yl)-N,N-dimethylbenzamide (Compound 36)

Step 36-1: 6-Bromo-8-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (Compound 36-1)

By a method similar to Step 19-7 of Example 19, compound 36- was prepared from 6-bromo-8-methoxy-2-methyl-3,4-dihydroisoquinolin-1(2H)-one 1. LCMS (M+H) ⁺ = 256.0.

Step 36-2: 4-(5-(8-Methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1-toluenesulfonyl-1H- Pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylbenzamide (Compound 36-2)

By a method similar to steps 18-9 of Example 18, from N,N-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxa Cyclopentaborin-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide and 6-bromo-8-methoxy-2 -Methyl-1,2,3,4-tetrahydroisoquinoline to prepare compound 36-2. LCMS (M+H) ⁺ = 595.3.

Step 36-3: 4-(5-(8-Methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrrolo[2,3- b]Pyridin-3-yl)-N,N-dimethylbenzamide (Compound 36-3)

By a method similar to the final step of Example 18, from 4-(5-(8-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1 -Tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylbenzamide Preparation Example 36. ¹ H NMR (400 MHz, DMSO- d6 , ppm) δ 12.09 (s, 1 H), 8.58 (s, 1 H), 8.45 (s, 1 H), 8.00 (s, 1 H), 7.86 (d, J = 7.9 Hz, 2 H), 7.49 (d, J = 7.9 Hz, 2 H), 7.10 (s, 2 H), 3.89 (s, 3 H), 3.44 (s, 2 H), 3.01 (s, 6 H), 2.92-2.86 (m, 2 H), 2.64-2.57 (m, 2 H), 2.39 (s, 3 H). LC-MS (M+H) ⁺ = 441.4.

Example 37 : 4-(5-[2-[2-(1H-imidazol-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl]-1H-pyrrolo [2,3-b]Pyridin-3-yl)-N,N-dimethylbenzamide (Compound 37)

Step 37-1: Tertiary Butyl 2-(2-chloroethyl)-1H-imidazole-1-carboxylate (Compound 37-1)

At room temperature, add DIEA (257 mg, 1.995 mmol) and Boc ₂ to a solution of 2-(2-chloroethyl)-1H-imidazole hydrochloride (159 mg, 0.950 mmol) in DMF (4 mL) O (228 mg, 1.045 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 16 h. When the reaction is complete, the reaction is then quenched by adding water (10 mL). The resulting solution was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over Na ₂ SO ₄ and washed with brine. The solvent was concentrated under reduced pressure to give tertiary butyl 2-(2-chloroethyl)-1H-imidazole-1-carboxylate (199 mg, crude) as an off-white solid. LCMS (M+H) ⁺ = 231.1.

Step 37-2: Tertiary butyl 2-(2-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-1H-imidazole-1-carboxylate ( Compound 37-2)

At room temperature, to a solution of tertiary butyl 2-(2-chloroethyl)-1H-imidazole-1-carboxylate (199 mg, crude) in MeCN (10 mL), add 7-bromo- 1,2,3,4-Tetrahydroisoquinoline (131 mg, 0.618 mmol), TEA (124 mg, 1.220 mmol). The resulting mixture was stirred for 15 h at 80°C under a nitrogen atmosphere. When the reaction was completed, the resulting mixture was concentrated under reduced pressure to produce tertiary butyl 2-[2-(7-bromo-1,2,3,4-tetrahydroisoquinoline- as a yellow oil 2-yl)ethyl]-1H-imidazole-1-carboxylate (260 mg, crude). LCMS (M+H) ⁺ = 406.1.

Step 37-3: 2-(2-(1H-imidazol-2-yl)ethyl)-7-bromo-1,2,3,4-tetrahydroisoquinoline (Compound 37-3)

At room temperature, add tertiary butyl 2-[2-(7-bromo-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]-1H-imidazole-1-carboxylate (260 mg, crude) Add HCl in MeOH (1 mL, 4.00 mmol, 4 M) to a solution in MeOH (4 mL). The resulting mixture was stirred at room temperature for 5 h. When the reaction was completed, the resulting mixture was concentrated under reduced pressure. The resulting residue was diluted with water (15 mL) and adjusted to pH 9 with saturated Na ₂ CO ₃ . The resulting mixture was extracted with EtOAc (30 mL x 3). The organic phases were combined, dried over Na ₂ SO ₄ and washed with brine. The solvent was concentrated under reduced pressure, and the residue was applied to a C18 gel column and subjected to flash chromatography (MeCN in water (with 10 mmol/L NH ₄ HCO ₃ ), 0% to 0% within 30 min 60% gradient elution) to produce 7-bromo-2-[2-(1H-imidazol-2-yl)ethyl]-1,2,3,4-tetrahydroisoquine as a yellow oil Morinoline (162 mg, 43% for 3 steps). LCMS (M+H) ⁺ = 306.0.

Step 37-4: 4-(5-(2-(2-(1H-imidazol-2-yl)ethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-1- Tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylbenzamide (Compound 37-4)

By a method similar to steps 18-9 of Example 18, from N,N-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxa Cyclopentaborin-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide and 2-(2-(1H-imidazole-2) -Yl)ethyl)-7-bromo-1,2,3,4-tetrahydroisoquinoline to prepare compound 37-4. LCMS (M+H) ⁺ = 645.3.

Step 37-5: 4-(5-[2-[2-(1H-imidazol-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl]-1H- Pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylbenzamide (compound 37-5)

By a method similar to the final step of Example 18, from 4-(5-(2-(2-(1H-imidazol-2-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline -7-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylbenzamide Preparation Example 37. ¹ H NMR (400 MHz, DMSO-d6) δ 12.10 (s, 1 H), 8.56 (s, 1 H), 8.45 (s, 1 H), 8.02 (s, 1 H), 7.90-7.82 (m, 2 H), 7.60-7.50 (m, 4 H), 7.27-7.19 (m, 1 H), 7.06-6.94 (m, 2 H), 3.78 (s, 2 H), 3.10-2.80 (m, 15 H) ). LC-MS (M+H) ⁺ = 491.3.

Example 38 : 4-(5-(2,7-Dimethylisoindolin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethyl Benzamide

Step 38-1: 5-Bromo-7-methyl-2,3-dihydroisoindol-1-one

At room temperature, to a solution of methyl 4-bromo-2,6-dimethylbenzoate (5.42 g, 22.3 mmol) in CCl ₄ (80 mL), add NBS (3.99 g, 22.4 mmol) and peroxide Oxybenzoic acid (2.85 g, 11.1 mmol). The mixture was stirred at 90°C for 12 h and then cooled to room temperature. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel flash chromatography (eluted with EtOAc (0% to 10%) in hexane) to give crude methyl 4-bromo- 2-(Bromomethyl)-6-methylbenzoate. The residue was redissolved in MeOH (15 mL), and add ^{_{NH 3. H 2 O (10}} mL). The mixture was stirred at room temperature for 15 h and then concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with EtOAc (0% to 40%) in hexane) to give the title compound (1.70 g, 34%). LC-MS (M+H) ⁺ = 226.0.

Step 38-2: 6-Bromo-4-methyl-2,3-dihydro-1H-isoindole

The title compound (125 mg, 10%) was prepared from 5-bromo-7-methyl-2,3-dihydroisoindol-1-one in a similar manner as in Example 19, step 19-7. LC-MS (M+H) ⁺ = 212.0.

Step 38-3: N,N-Dimethyl-4-(5-(7-methylisoindolin-5-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b ]Pyridin-3-yl)benzamide

In a similar manner as in Example 19, Steps 19-9, from N,N-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxa Cyclopentaborin-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide and 6-bromo-4-methyl-2, The title compound (115 mg, 41%) was prepared from 3-dihydro-1H-isoindole. LC-MS (M+H) ⁺ = 551.2.

Step 38-4: 4-(5-(2,7-Dimethylisoindolin-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3- Yl)-N,N-dimethylbenzamide

In a similar manner as in Example 2, from N,N-dimethyl-4-(5-(7-methylisoindolin-5-yl)-1-toluenesulfonyl-1H-pyrrolo[ The title compound (65 mg, 54%) was prepared by 2,3-b]pyridin-3-yl)benzamide. LC-MS (M+H) ⁺ = 565.4.

Step 38-5: 4-(5-(2,7-Dimethylisoindolin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N- Dimethylbenzamide

In a similar manner as in Example 18 and Steps 18-10, from 4-(5-(2,7-dimethylisoindolin-5-yl)-1-toluenesulfonyl-1H-pyrrolo[ 2,3-b]pyridin-3-yl)-N,N-dimethylbenzamide Preparation Example 38 (16 mg, 42%). ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.07 (s, 1 H), 8.54 (s, 1 H), 8.43 (s, 1 H), 8.00 (d, J = 2.6 Hz, 1 H), 7.86 (d, J = 7.9 Hz, 2 H), 7.50 (d, J = 7.8 Hz, 2 H), 7.46-7.38 (m, 2 H), 3.92 (s, 2 H), 3.85 (s, 2 H) , 3.01 (s, 6 H), 2.54 (s, 3 H), 2.30 (s, 3 H). LC-MS (M+H) ⁺ = 411.3.

Example 39 : N,N-dimethyl-4-(5-(1'-methyl-2H-spiro[benzofuran-3,4'-piperidin]-6-yl)-1H-pyrrolo[ 2,3-b)pyridin-3-yl)benzamide

Step 39-1: Tertiary Butyl 4-(4-Bromo-2-fluorophenyl)-4-cyanopiperidine-1-carboxylate

Under a nitrogen atmosphere at room temperature, after 15 min, to a solution of 2-(4-bromo-2-fluorophenyl)acetonitrile (9.50 g, 44.4 mmol) in DMSO (250 mL) was added NaH (60 %, 9.20 g, 230 mmol). The mixture was stirred at 70°C for 20 min, and then tertiary butyl N,N-bis(2-chloroethyl)carbamate (15.2 g, 62.6 mmol) was added in portions over 30 min. The mixture was stirred at 70°C for another 3 h. The reaction mixture was cooled to room temperature and quenched by adding ice water (500 mL). The resulting mixture was sequentially extracted with ethyl acetate (700 mL x 3). The organic phases were combined, washed with brine (300 mL), dried over Na ₂ SO ₄ and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel flash chromatography (eluted with MeOH (0% to 10%) in DCM) to give the title compound (6.10 g, 36%) . LC-MS (M+H) ⁺ = 383.2.

Step 39-2: 4-(4-Bromo-2-fluorophenyl)piperidine-4-carboxylic acid

At room temperature, add tertiary butyl 4-(4-bromo-2-fluorophenyl)-4-cyanopiperidine-1-carboxylate (9.09 g, 23.7 mmol) in AcOH (200 mL) Add aqueous HCl (1 M, 30 mL, 30 mmol) dropwise to the solution. The resulting mixture was stirred at 70°C under nitrogen atmosphere for 5 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with ethyl acetate (150 mL). ₃ The pH of the mixture carefully adjusted to 7 with saturated NaHCO. The mixture was sequentially extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with brine (100 mL), dried over Na ₂ SO ₄ and filtered. The solvent was evaporated under reduced pressure to give the title compound (6.70 g, 94%). LC-MS (M+H) ⁺ = 302.1.

Step 39-3: (4-(4-Bromo-2-fluorophenyl)piperidin-4-yl)methanol

The title compound (700 mg, 92%) was prepared from 4-(4-bromo-2-fluorophenyl)piperidine-4-carboxylic acid in a similar manner as in Example 18, step 18-8. LC-MS (M+H) ⁺ = 288.1.

Step 39-4: (4-(4-Bromo-2-fluorophenyl)-1-methylpiperidin-4-yl)methanol

The title compound (290 mg, 90%) was prepared from (4-(4-bromo-2-fluorophenyl)piperidin-4-yl)methanol in a similar manner as in Example 19, Steps 19-8. LC-MS (M+H) ⁺ = 302.0.

Step 39-5: 6-Bromo-1'-methyl-2H-spiro[benzofuran-3,4'-piperidine]

At room temperature, add to a solution of (4-(4-bromo-2-fluorophenyl)-1-methylpiperidin-4-yl)methanol (190 mg, 0.631 mmol) in THF (12 mL) t-BuOK (160 mg, 1.42 mmol). The mixture was stirred at 100°C under nitrogen atmosphere for 0.5 h. The reaction mixture was cooled to room temperature and then quenched with water (20 mL). The mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with brine (50 mL), dried over Na ₂ SO ₄ and filtered. The solvent was evaporated under reduced pressure to give the title compound (55 mg, 31%). LC-MS (M+H) ⁺ = 283.1.

Step 39-6: N,N-Dimethyl-4-(5-(1'-methyl-2H-spiro[benzofuran-3,4'-piperidin]-6-yl)-1-toluene Sulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide

In a similar manner as in Example 19, Steps 19-9, from N,N-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxa Cyclopentaborin-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide and 6-bromo-1'-methyl-2H -Spiro[benzofuran-3,4'-piperidine] prepared the title compound (40 mg, 31%). LC-MS (M+H) ⁺ = 621.3.

Step 39-7: N,N-Dimethyl-4-(5-(1'-methyl-2H-spiro[benzofuran-3,4'-piperidin]-6-yl)-1H-pyrrole And [2,3-b]pyridin-3-yl)benzamide

In a similar manner as in Example 18, steps 18-10, from N,N-dimethyl-4-(5-(1'-methyl-2H-spiro[benzofuran-3,4'-piperidine ]-6-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide Preparation Example 39 (14 mg, 16%). ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.08 (s, 1 H), 8.53 (s, 1 H), 8.43 (s, 1 H), 8.01 (s, 1 H), 7.87 (d, J = 8.1 Hz, 2 H), 7.48 (d, J = 8.0 Hz, 2 H), 7.32 (d, J = 7.6 Hz, 1 H), 7.24 (d, J = 7.7 Hz, 1 H), 7.18 (s, 1 H), 4.43 (s, 2 H), 3.01 (s, 6 H), 2.80-2.73 (m, 2 H), 2.22 (s, 3 H), 2.04-1.87 (m, 4 H), 1.71- 1.63 (m, 2 H). LC-MS (M+H) ⁺ = 467.3.

Example 40 : 4-(5-(2,5-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrrolo[2,3-b]pyridine-3 -Yl)-N,N-dimethylbenzamide

Step 40-1: 2-(4-Bromo-2-methylphenyl)ethylamine hydrochloride

At 0 ° C, was added NiCl solution of 2- (4-bromo-2-methylphenyl) acetonitrile (30.0 g, 0.143 mol) in MeOH (200 mL) was ^{_{2. 6H 2 O (3.39 g}} , 0.0143 mol), Boc ₂ O (62.3 g, 0.286 mol). Then NaBH ₄ (64.8 g, 1.71 mol) was added in batches within 15 min. The resulting mixture was stirred at room temperature for 5 h. The reaction mixture was quenched with ice water. The resulting solution was extracted with ethyl acetate (1000 mL x 3). The organic phases were combined, washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. At room temperature, to the residue was added HCl (7 N, 50 mL, 0.350 mol) in MeOH, and the solution was stirred at room temperature for 16 h. The solvent was concentrated under reduced pressure to give the title compound (35.0 g, crude). LC-MS (M+H) ⁺ = 214.0.

Step 40-2: N-[2-(4-Bromo-2-methylphenyl)ethyl]-2,2,2-trifluoroacetamide

Add 2-(4-bromo-2-methylphenyl)ethylamine hydrochloride (350 mg, crude) in DCM (15 mL) at 0°C under nitrogen atmosphere with stirring. Add TEA (345 mg, 3.42 mmol) and TFAA (356 mg, 1.70 mmol). After 15 h, the reaction was then quenched by adding water (20 mL). The resulting solution was extracted with DCM (35 mL x 3). The organic phases were combined, washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the title compound (271 mg, 61% for 2 steps). LC-MS (M+H) ⁺ = 310.0.

Step 40-3: 1-(7-Bromo-5-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoroethanone

At room temperature, with stirring, add N-[2-(4-bromo-2-methylphenyl)ethyl]-2,2,2-trifluoroacetamide (271 mg, 0.874 mmol) in AcOH ( Add H ₂ SO ₄ (2 mL) and paraformaldehyde (176 mg, 1.95 mmol) to the solution in 3 mL). After 16 h, the reaction was then diluted by adding water (30 mL). The resulting solution was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by C18 column chromatography (eluted with MeCN (40% to 70%) in water) to give the title compound (100 mg, 36%). LC-MS (M+H) ⁺ = 322.2.

Step 40-4: 7-Bromo-5-methyl-1,2,3,4-tetrahydroisoquinoline

At room temperature, with stirring, to 1-(7-bromo-5-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoroethanone (100 mg, 0.270 mmol) K ₂ CO ₃ (147 mg, 1.06 mmol) was added to a solution of EtOH (5 mL) and water (1 mL). The resulting mixture was warmed to 80°C. After 2 h, the reaction was cooled and diluted with water (10 mL). The resulting mixture was extracted with DCM (30 mL x 3). The organic phases were combined, washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the title compound (49 mg, 81%). LC-MS (M+H) ⁺ = 226.1.

Step 40-5: 7-bromo-2,5-dimethyl-1,2,3,4-tetrahydroisoquinoline

In a nitrogen atmosphere at room temperature, add 7-bromo-5-methyl-1,2,3,4-tetrahydroisoquinoline (100 mg, 0.398 mmol) and formalin (40%, 45 mg, 0.597 mmol) ) Add NaBH ₃ CN (39 mg, 0.60 mmol) to the stirring solution in MeOH (5 mL) in batches. After 3 h, the resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with DCM/MeOH (10:1)) to give the title compound (102 mg, 99% ). LC-MS (M+H) ⁺ = 240.0.

Step 40-6: 4-(5-(2,5-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrrolo[2,3-b]pyridine -3-yl)-N,N-dimethylbenzamide

In a similar manner as in Example 19, Steps 19-9, from N,N-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxa Cyclopentaborin-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide and 7-bromo-2,5-dimethyl-3,4-dihydro -1H-Isoquinoline Preparation Example 40 (165 mg, 24%). ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.06 (s, 1 H), 8.56-8.52 (m, 1 H), 8.44-8.41 (m, 1 H), 8.02-7.98 (m, 1 H), 7.88-7.83 (m, 2 H), 7.53-7.47 (m, 2 H), 7.41 (s, 1H), 7.29 (s, 1H), 3.56 (s, 2 H), 3.01 (s, 6 H), 2.81-2.60 (m, 4 H), 2.36 (s, 3 H), 2.28 (s, 3 H). LC-MS (M+H) ⁺ = 425.4.

Example 41 : N,N-dimethyl-4-(5-(5-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrrolo[2,3- b)Pyridin-3-yl)benzamide

Step 41-1: N,N-Dimethyl-4-(5-(5-methyl-2-(2,2,2-trifluoroacetinyl)-1,2,3,4-tetrahydro Isoquinolin-7-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide

In a similar manner to Example 19, Steps 19-9, from N,N-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxa Cyclopentaborin-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide and 1-(7-bromo-5-methyl-3,4-dihydro The title compound (85 mg, 72%) was prepared by -1H-isoquinolin-2-yl)-2,2,2-trifluoroethanone. ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.09 (s, 1 H), 8.59 (s, 1 H), 8.47 (s, 1 H), 8.02 (s, 1 H), 7.90-7.83 (m, 2 H), 7.60-7.42 (m, 4 H), 4.90-4.85 (m, 2 H), 3.95-3.87 (m, 2 H), 3.01 (s, 6 H), 2.91-2.80 (m, 2 H) ), 2.32 (s, 3 H). LC-MS (M+H) ⁺ = 507.5.

Step 41-2: N,N-Dimethyl-4-(5-(5-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrrolo[2, 3-b)pyridin-3-yl)benzamide

In a similar manner as in Example 40, Step 40-4, from N,N-dimethyl-4-(5-(5-methyl-2-(2,2,2-trifluoroacetanyl)- 1,2,3,4-Tetrahydroisoquinolin-7-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide Preparation Example 41 (11 mg, 34%) , And then purified by preparative HPLC. ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.07 (s, 1 H), 8.54 (s, 1 H), 8.42 (s, 1 H), 8.00 (s, 1 H), 7.85 (d, J = 8.0 Hz, 2 H), 7.50 (d, J = 7.9 Hz, 2 H), 7.40 (s, 1 H), 7.26 (s, 1 H), 3.93 (s, 2 H), 3.07-2.94 (m, 9 H), 2.62-2.55 (m, 2 H), 2.27 (s, 3 H). LC-MS (M+H) ⁺ = 411.6.

Example 42 : N,N-dimethyl-4-(5-(5-methyl-2-(2-linoethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl )-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide

Step 42-1: N,N-Dimethyl-4-(5-(5-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1-toluenesulfonyl- 1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide

In a similar manner to Example 19, Steps 19-9, from N,N-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxa Cyclopentaborin-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide and 7-bromo-5-methyl-1, The title compound (180 mg, 84%) was prepared by 2,3,4-tetrahydroisoquinoline. LC-MS (M+H) ⁺ = 565.2.

Step 42-2: N,N-Dimethyl-4-(5-(5-methyl-2-(2-linoethyl)-1,2,3,4-tetrahydroisoquinoline-7 -Yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide

In a similar manner to Example 32, step 32-1, from N,N-dimethyl-4-(5-(5-methyl-1,2,3,4-tetrahydroisoquinoline-7- Yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide and 4-(2-bromoethyl)line to prepare the title compound (130 mg, 71 %). LC-MS (M+H) ⁺ = 678.3.

Step 42-3: N,N-Dimethyl-4-(5-(5-methyl-2-(2-linoethyl)-1,2,3,4-tetrahydroisoquinoline-7 -Yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide

In a similar manner as in Example 18, Steps 18-10, from N,N-dimethyl-4-(5-(5-methyl-2-(2-linoethyl)-1,2,3 ,4-Tetrahydroisoquinolin-7-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide Preparation Example 42 (24 mg, 26 %). ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.07 (s, 1 H), 8.54 (s, 1 H), 8.42 (s, 1 H), 8.00 (s, 1 H), 7.88-7.82 (m, 2 H), 7.50 (s, 2 H), 7.43-7.38 (m, 1 H), 7.28 (s, 1 H), 3.65 (s, 2 H), 3.60-3.53 (m, 4 H), 3.01 ( s, 6 H), 2.79-2.65 (m, 4 H), 2.64-2.57 (m, 2 H), 2.56-2.51 (m, 2 H), 2.46-2.39 (m, 4 H), 2.26 (s, 3 H). LC-MS (M+H) ⁺ = 524.4.

Example 43 : 4-(5-(2,5-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrrolo[2,3-b]pyridine-3 -Yl)-N,N,2-trimethylbenzamide

Step 43-1: 4-Bromo-N,N,2-trimethylbenzamide

A mixture of 4-bromo-2-methylbenzoic acid (25.0 g, 116 mmol) in SOCl ₂ (200 mL) was stirred at 60 °C for 3 h. The solvent was removed in vacuo. The residue was redissolved in dry DCM (200 mL). Add dimethylamine hydrochloride (14.0 g, 174.4 mmol) and TEA (80 mL, 581 mmol) at 0°C. The mixture was stirred at room temperature for 2 h. Water (200 mL) was added, and the mixture was extracted with DCM (200 mL x 3). The combined organic layer was washed with brine (150 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the title compound (28.0 g, 99%). LC-MS (M+H) ⁺ =242.0, 244.0.

Step 43-2: N,N,2-Trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl Amide

Under nitrogen, the 4-bromo-N,N,2-trimethylbenzamide (28.0 g, 115 mmol), BPD (44.0 g, 174 mmol), Pd(dppf)Cl ₂ (5.1 g, 6.94 mmol) and AcOK (22.7 g, 231 mmol) are added to the two 㗁𠮿 (400 mL). The reaction mixture was heated to reflux overnight and then cooled to room temperature. EtOAc (400 mL) was added, and the mixture was washed with brine (300 mL x 2). The aqueous layer was extracted with EtOAc (400 mL). The combined organic layer was dried over Na ₂ SO ₄ and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with EtOAc/PE (15% to 70%)) to give the title compound (26.0 g, 73%). LC-MS (M+H) ⁺ =290.1.

Step 43-3: 5-Bromo-3-iodo-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine

At room temperature under a nitrogen atmosphere, to a solution of 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine (10.0 g, 29.4 mmol) in THF (150 mL) was added NaH (60 %, 1.53 g, 38.3 mmol). After 30 min, TsCl (6.20 g, 30.9 mmol) was added in batches at 0°C. The resulting mixture was stirred at room temperature for 2 h, and then quenched with ice water (100 mL). The resulting mixture was extracted with EtOAc (500 mL x 2). The combined organic layer was washed with water (300 mL), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure to give the title compound (5.0 g, 35%). LC-MS (M+H) ⁺ = 477.1.

Step 43-4: 4-(5-Bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N,2-trimethylbenzamide

In a similar manner as in Example 18, step 18-3, from N,N,2-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxane Penboran-2-yl) benzamide and 5-bromo-3-iodo-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine to prepare the title compound ( 1.93 g, 51%). LC-MS (M+H) ⁺ = 512.2.

Step 43-5: N,N,2-trimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )-1-Tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide

In a similar manner as in Example 18, step 18-4, from 4-(5-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N ,2-Trimethylbenzamide prepared the title compound (7.0 g, 88%). LC-MS (M+H) ⁺ = 560.5.

Step 43-6: 4-(5-(2,5-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1-tosyl-1H-pyrrolo[ 2,3-b)pyridin-3-yl)-N,N,2-trimethylbenzamide

In a similar manner as in Example 18, Step 18-9, from N,N,2-trimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-di Oxaloborolan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide and 7-bromo-2,5-di The title compound (889 mg, 65%) was prepared by methyl-3,4-dihydro-1H-isoquinoline. LC-MS (M+H) ⁺ = 593.3.

Step 43-7: 4-(5-(2,5-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrrolo[2,3-b]pyridine -3-yl)-N,N,2-trimethylbenzamide

In a similar manner as in Example 18, Step 18-10, from 4-(5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1- Tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N,2-trimethylbenzamide Preparation Example 43 (143 mg, 24%). ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.01 (s, 1 H), 8.55-8.50 (m, 1 H), 8.41-8.36 (m, 1 H), 7.95-7.90 (m, 1 H), 7.67-7.61 (m, 2 H), 7.40 (s, 1 H), 7.32-7.11 (m, 2 H), 3.56 (s, 2 H), 3.03 (s, 3 H), 2.83 (s, 3 H) ), 2.78-2.59 (m, 4 H), 2.36 (s, 3 H), 2.30-2.24 (m, 6 H). LC-MS (M+H) ⁺ = 439.5.

Instance 44A/44B

4-(5-(2-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-5-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylbenzamide and 4-(5-(2-((1s,4s)-4-hydroxy- 4-methylcyclohexyl)-5-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)- N,N-Dimethylbenzamide

Step 44-1: 4-(7-Bromo-5-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-1-methylcyclohexane-1-ol

In a similar manner as in Example 26, step 26-1, from 7-bromo-5-methyl-1,2,3,4-tetrahydroisoquinoline and 4-hydroxy-4-methylcyclohexane- The title compound (355 mg, 84%) was prepared from 1-ketone. LC-MS (M+H) ⁺ = 338.1.

Step 44-2: 4-(5-(2-(4-hydroxy-4-methylcyclohexyl)-5-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)- 1-Toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylbenzamide

In a similar manner as in Example 18, Steps 18-9, from N,N-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxa Cyclopentaborin-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide and 4-(7-bromo-5-methyl) -3,4-Dihydro-1H-isoquinolin-2-yl)-1-methylcyclohexane-1-ol prepared the title compound (300 mg, 71%). LC-MS (M+H) ⁺ = 677.6.

Step 44-3: 4-(5-(2-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-5-methyl-1,2,3,4-tetrahydroisoquinoline -7-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylbenzamide and 4-(5-(2-((1s,4s) -4-Hydroxy-4-methylcyclohexyl)-5-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrrolo[2,3-b]pyridine- 3-yl)-N,N-dimethylbenzamide

In a similar manner as in Example 18, Steps 18-10, from 4-(5-(2-(4-hydroxy-4-methylcyclohexyl)-5-methyl-1,2,3,4-tetra (Hydroisoquinolin-7-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylbenzamide Preparation Example 44A/ 44B. The two stereoisomers were separated by preparative HPLC.

Example 44A : (24 mg, 9%) ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.05 (s, 1 H), 8.54 (s, 1 H), 8.42 (s, 1 H), 7.99 (s, 1 H), 7.88-7.82 (m, 2 H), 7.53-7.46 (m, 2 H), 7.39 (s, 1 H), 7.30 (s, 1 H), 4.00 (s, 1 H), 3.78 ( s, 2 H), 3.01 (s, 6 H), 2.87-2.80 (m, 2 H), 2.72-2.64 (m, 2 H), 2.43-2.39 (m, 1 H), 2.26 (s, 3 H) ), 1.79-1.66 (m, 2 H), 1.66-1.53 (m, 4 H), 1.37-1.26 (m, 2 H), 1.11 (s, 3 H). LC-MS (M+H) ⁺ = 523.6.

Example 44B : (24 mg, 9%) ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.05 (s, 1 H), 8.53 (s, 1 H), 8.42 (s, 1 H), 7.99 (s, 1 H), 7.88-7.81 (m, 2 H), 7.53-7.46 (m, 2 H), 7.39 (s, 1 H), 7.30 (s, 1 H), 4.22 (s, 1 H), 3.75 ( s, 2 H), 3.01 (s, 6 H), 2.84-2.77 (m, 2 H), 2.71-2.64 (m, 2 H), 2.46-2.34 (m, 1 H), 2.26 (s, 3 H) ), 1.78 (d, J = 12.3 Hz, 2 H), 1.65-1.58 (m, 2 H), 1.56-1.44 (m, 2 H), 1.44-1.35 (m, 2 H), 1.13 (s, 3 H). LC-MS (M+H) ⁺ = 523.6.

Example 45 : N,N-dimethyl-4-(5-(5-methyl-2-(tetrahydro-2H-piperan-3-yl)-1,2,3,4-tetrahydroisoquine (Lin-7-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide

Step 45-1: N,N-Dimethyl-4-(5-(5-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1-toluenesulfonyl- 1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide

In a similar manner as in Example 18, Steps 18-9, from N,N-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxa Cyclopentaborin-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide and 7-bromo-5-methyl-1, The title compound (180 mg, 84%) was prepared by 2,3,4-tetrahydroisoquinoline. LC-MS (M+H) ⁺ = 565.2.

Step 45-2: N,N-Dimethyl-4-(5-(5-methyl-2-(tetrahydro-2H-piperan-3-yl)-1,2,3,4-tetrahydro Isoquinolin-7-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide

In a similar manner to Example 26, step 26-1, from N,N-dimethyl-4-(5-(5-methyl-1,2,3,4-tetrahydroisoquinoline-7- (Yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide and pyridine-3-one to prepare the title compound (42 mg, 59%). LC-MS (M+H) ⁺ = 649.4.

Step 45-3: N,N-Dimethyl-4-(5-(5-methyl-2-(tetrahydro-2H-piperan-3-yl)-1,2,3,4-tetrahydro Isoquinolin-7-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide

In a similar manner as in Example 18, Step 18-10, from N,N-dimethyl-4-(5-(5-methyl-2-(tetrahydro-2H-piperan-3-yl)- 1,2,3,4-Tetrahydroisoquinolin-7-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide Preparation Example 45 (11 mg, 39%). ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.06 (s, 1 H), 8.54 (s, 1 H), 8.42 (s, 1 H), 8.00 (s, 1 H), 7.89-7.82 (m, 2 H), 7.54-7.47 (m, 2 H), 7.40 (s, 1 H), 7.29 (s, 1 H), 4.03-3.94 (m, 1 H), 3.84-3.71 (m, 3 H), 3.32-3.21 (m, 3 H), 3.01 (s, 6 H), 2.93-2.77 (m, 2 H), 2.70-2.63 (m, 2 H), 2.26 (s, 3 H), 2.05-2.01 ( m, 1 H), 1.74-1.63 (m, 1 H), 1.56-1.47 (m, 2 H). LC-MS (M+H) ⁺ = 495.4.

Example 46 : N,N-dimethyl-4-(5-(5-methyl-2-(tetrahydro-2H-piperan-4-yl)-1,2,3,4-tetrahydroisoquine (Lin-7-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide

Step 46-1: 7-Bromo-5-methyl-2-(tetrahydrofuran-3-yl)-1,2,3,4-tetrahydroisoquinoline

In a similar manner as in Example 26, step 26-1, the title compound was prepared from 7-bromo-5-methyl-1,2,3,4-tetrahydroisoquinoline and tetrahydropiperan-4-one ( 75 mg, 32%). LC-MS (M+H) ⁺ = 296.1.

Step 46-2: N,N-Dimethyl-4-(5-(5-methyl-2-(tetrahydro-2H-piperan-4-yl)-1,2,3,4-tetrahydro Isoquinolin-7-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide

In a similar manner as in Example 18, Steps 18-9, from N,N-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxa Cyclopentaborin-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide and 7-bromo-5-methyl-2- (Tetrahydrofuran-3-yl)-1,2,3,4-tetrahydroisoquinoline prepared the title compound (140 mg, 57%). LC-MS (M+H) ⁺ = 649.4.

Step 46-3: N,N-Dimethyl-4-(5-(5-methyl-2-(tetrahydro-2H-piperan-4-yl)-1,2,3,4-tetrahydro Isoquinolin-7-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide

In a similar manner as in Example 18, Step 18-10, from N,N-dimethyl-4-(5-(5-methyl-2-(tetrahydro-2H-piperan-4-yl)- 1,2,3,4-Tetrahydroisoquinolin-7-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide Preparation Example 46 (11 mg, 10%). ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.07 (s, 1 H), 8.54 (s, 1 H), 8.43 (s, 1 H), 8.00 (s, 1 H), 7.88-7.81 (m, 2 H), 7.50 (d, J = 7.8 Hz, 2 H), 7.44-7.26 (m, 2 H), 3.96-3.88 (m, 2 H), 3.78 (s, 2 H), 3.36-3.15 (m , 2 H), 3.00 (s, 6 H), 2.85-2.81 (m, 2H), 2.74-2.57 (m, 3 H), 2.26 (s, 3 H), 1.83-1.76 (m, 2 H), 1.56-1.48 (m, 2 H). LC-MS (M+H) ⁺ = 495.5.

Example 47 : 4-(5-(5-Methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrrolo[2,3-b] (Pyridin-3-yl)-N,N-dimethylbenzamide

Step 47-1: N-(3-bromo-5-methoxybenzyl)-2,2-dimethoxyethylamine

At room temperature, to a solution of 2,2-dimethoxyethylamine (1.09 g, 10.4 mmol) in toluene (15 mL) was added 3-bromo-5-methoxybenzaldehyde (2.04 g, 9.50 mmol) ). The resulting mixture was stirred at 120°C under a nitrogen atmosphere for 15 h, and then cooled to room temperature. The reaction mixture was concentrated under reduced pressure and then redissolved in MeOH (15 mL). The mixture was cooled in an ice bath and NaBH ₄ (4.18 mg, 110 mmol) was added to it in portions within 10 min. The resulting mixture was warmed to room temperature. After 5 h, the reaction was quenched with ice water (20 mL). The resulting mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over Na ₂ SO ₄ and washed with brine. The solvent was concentrated under reduced pressure to give the title compound (2.80 g, crude). LC-MS (M+H) ⁺ = 304.4.

Step 47-2: 7-Bromo-5-methoxy-1,2,3,4-tetrahydroisoquinolin-4-ol

A mixture of N-(3-bromo-5-methoxybenzyl)-2,2-dimethoxyethylamine (2.80 g, from step 47-1) in HCl (6 M, 6.0 mL) in Stir at 40°C for 16 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC to provide the title compound (108 mg, 5% over 2 steps). LC-MS (M+H) ⁺ = 258.1.

Step 47-3: 7-Bromo-5-methoxy-1,2,3,4-tetrahydroisoquinoline

Add 7-bromo-5-methoxy-1,2,3,4-tetrahydroisoquinolin-4-ol (100 mg, 0.38 mmol) and triethylsilane (1.00 mL, 8.6 mmol) TFA (0.50 mL, 4.4 mmol) was added dropwise to the stirring mixture in DCM (5 mL). The resulting mixture was stirred at 40°C for 48 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was partitioned between EtOAc (30 mL) and saturated NaHCO ₃ (30 mL). The combined organic layer was separated, dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by C18 chromatography (eluted with MeCN (45% to 70%) in 0.05% aqueous NH ₄ HCO ₃ solution) to give the title compound (75 mg, 81%). ¹ H NMR (400 MHz, DMSO- d6 ) δ 6.92 (d, J = 1.9 Hz, 1 H), 6.84 (d, J = 1.9 Hz, 1 H), 3.82-3.74 (m, 5 H), 2.90 ( t, J = 6.0 Hz, 2 H), 2.77 (s, 1 H), 2.43 (t, J = 6.0 Hz, 2 H). LC-MS (M+H) ⁺ = 242.1.

Step 47-4: 4-(5-(5-Methoxy-1,2,3,4-tetrahydroisoquinolin-7-yl)-1-tosyl-1H-pyrrolo[2, 3-b)pyridin-3-yl)-N,N-dimethylbenzamide

In a similar manner as in Example 18, step 18-9, from 7-bromo-5-methoxy-1,2,3,4-tetrahydroisoquinoline and N,N-dimethyl-4-( 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3- b]Pyridin-3-yl)benzamide The title compound (100 mg, 55%) was prepared. LC-MS (M+H) ⁺ = 581.4.

Step 47-5: 4-(5-(5-Methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1-tosyl-1H- Pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylbenzamide

In a similar manner as in Example 19 and Step 19-8, from 4-(5-(5-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yl)-1-toluenesulfonate The title compound (97 mg, 97%) was prepared from acyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylbenzamide. LC-MS (M+H) ⁺ = 595.5.

Step 47-6: 4-(5-(5-Methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrrolo[2,3- b)Pyridin-3-yl)-N,N-dimethylbenzamide

In a similar manner as in Example 18, Steps 18-10, from 4-(5-(5-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -1-Tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylbenzamide Preparation Example 47 (25 mg, 34%). ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.08 (s, 1 H), 8.60-8.55 (m, 1 H), 8.45 (s, 1 H), 8.02-7.98 (m, 1 H), 7.85 ( d, J = 7.9 Hz, 2H), 7.49 (d, J = 7.9 Hz, 2H), 7.10 (s, 1 H), 7.04 (s, 1 H), 3.89 (s, 3 H), 3.53 (s, 2 H), 3.01 (s, 6 H), 2.73-2.64 (m, 2 H), 2.64-2.56 (m, 2 H), 2.35 (s, 3 H). LC-MS (M+H) ⁺ = 441.4.

Example 48 : 4-(5-(2-(2-(Dimethylamino)ethyl)-5-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H -Pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylbenzamide

Step 48-1: 4-(5-(2-(2-(Dimethylamino)ethyl)-5-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -1-Tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylbenzamide

In a similar manner to Example 26, step 26-1, from N,N-dimethyl-4-(5-(5-methyl-1,2,3,4-tetrahydroisoquinoline-7- Yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide and 2-(dimethylamino)acetaldehyde to prepare the title compound (38 mg, 34%). LC-MS (M+H) ⁺ = 636.5.

Step 48-2: 4-(5-(2-(2-(Dimethylamino)ethyl)-5-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylbenzamide

In a similar manner as in Example 18, Steps 18-10, from 4-(5-(2-(2-(dimethylamino)ethyl)-5-methyl-1,2,3,4- Tetrahydroisoquinolin-7-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylbenzamide Preparation Example 48 (2 mg, 6%). ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.05 (s, 1 H), 8.54 (s, 1 H), 8.42 (s, 1 H), 7.99 (s, 1 H), 7.88-7.82 (m, 2 H), 7.53-7.47 (m, 2 H), 7.41 (s, 1 H), 7.29 (s, 1 H), 3.66 (s, 2 H), 3.04-2.99 (m, 7 H), 2.78- 2.68 (m, 5 H), 2.63-2.55 (m, 2 H), 2.27 (s, 3 H), 2.20 (s, 6 H). LC-MS (M+H) ⁺ = 482.3.

Example 49 : 4-(5-(8-Methoxy-2-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H -Pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylbenzamide

Step 49-1: Tertiary butyl (neopentoxy) carbamate

To a stirred solution of pivalic anhydride (17.0 g, 86.7 mmol) in CHCl ₃ (300 mL) at 0°C, add tertiary butyl N-hydroxycarbamate (10.0 g, 71.3 mmol) dropwise . The reaction mixture was heated to 70°C for 16 h. The mixture was cooled to room temperature and concentrated under vacuum. The residue was partitioned between EtOAc (500 mL) and water (500 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to provide the title compound (7.2 g, 46%).

Step 49-2: O-Neopentyl Hydroxylamine

At room temperature, slowly add TFA (9.6 g, 99 mmol) to a solution of tertiary butyl (neopentoxy) carbamate (26.4 g, 97 mmol) in anhydrous diethyl ether (240 mL) . The resulting mixture was stirred for 1 h, and then hexane (250 mL) was added. The resulting mixture was stirred rapidly for 10 min. The precipitate was collected by filtration, rinsed with hexane (20 mL x 3), and dried in a vacuum oven overnight to give the title compound (24.8 g, 91%). LC-MS (M+H) ⁺ = 118.2.

Step 49-3: 4-Bromo-2-methoxy-N-(neopentoxy)benzamide

Under a nitrogen atmosphere at 0°C, to a solution of 4-bromo-2-methoxybenzoic acid (10.0 g, 43.3 mmol) in THF (150 mL) was added T ₃ P (27.6 g, 86.6 mmol). The resulting mixture was stirred at room temperature for 0.5 h. Then DIPEA (17.1 g, 132 mmol) and O-neopentyl hydroxylamine (12.0 g, 103 mmol) were added in portions at room temperature. The reaction mixture was stirred for another 16 h. The reaction was quenched by adding water (300 mL) and then extracted with ethyl acetate (500 mL x 3). The organic phases were combined, dried over Na ₂ SO ₄ and washed with brine. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with EtOAc/hexane (0:1 to 1:10)) to give the title compound (9.83 g, 69% ). LC-MS (M+H) ⁺ = 330.2.

Step 49-4: 6-Bromo-8-methoxy-3,4-dihydroisoquinolin-1(2H)-one

At room temperature under a nitrogen atmosphere, add 4-bromo-2-methoxy-N-(neopentyloxy)benzamide (10.0 g, 29.8 mmol) and KOAc (6.67 g, 64.6 mmol) in MeCN Add dichloro(pentamethylcyclopentadienyl) rhodium(III) dimer (968 mg, 1.489 mmol) to the stirring solution in (200 mL). At -30°C, ethylene was bubbled through the mixture for 1 h. The resulting mixture was stirred for another 16 h at room temperature under an ethylene atmosphere of 3 bar. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with DCM/MeOH (10:1)) to give the title compound (2.3 g, 28%). LC-MS (M+H) ⁺ = 256.1.

Step 49-5: 6-Bromo-8-methoxy-1,2,3,4-tetrahydroisoquinoline; trifluoroacetic acid

Add 6-bromo-8-methoxy-3,4-dihydroisoquinolin-1(2H)-one (400 mg, 1.56 mmol) in THF (20.0 mL) at 70°C under nitrogen atmosphere Add BH ₃ -Me ₂ S (8.00 mL, 84.3 mmol) to the stirring solution. The resulting mixture was stirred at 70°C for 12 h and then cooled to room temperature. The reaction was quenched with ice water. To the above mixture was added NaOH (5 M, 30 mL). The resulting mixture was stirred for another 30 min at 70°C and then cooled to room temperature. The resulting mixture was extracted with EtOAc (20 mL x 3). The combined organic layer was washed with brine (60 mL), and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 chromatography (eluted with acetonitrile/water (containing 0.05% TFA) (0:1 to 3:7)) to give the title compound (240 mg, 43%). LC-MS (M+H) ⁺ = 242.0.

Step 49-6: 6-Bromo-8-methoxy-2-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydroisoquinoline

In a similar manner as in Example 26, step 26-1, from 6-bromo-8-methoxy-1,2,3,4-tetrahydroisoquinoline; trifluoroacetic acid and 1-methylpiperidine- The title compound (111 mg, 64%) was prepared with 4-ketone. LC-MS (M+H) ⁺ = 341.1.

Step 49-7: 4-(5-(8-Methoxy-2-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl) -1-Tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylbenzamide

In a similar manner as in Example 18, Steps 18-9, from N,N-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxa Cyclopentaborin-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide and 6-bromo-8-methoxy-2 -(1-Methylpiperidin-4-yl)-1,2,3,4-tetrahydroisoquinoline to prepare the title compound (100 mg, 44%). LC-MS (M+H) ⁺ = 678.4.

Step 49-8: 4-(5-(8-Methoxy-2-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl) -1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylbenzamide

In a similar manner as in Example 18, Step 18-10, from 4-(5-(8-methoxy-2-(1-methylpiperidin-4-yl)-1,2,3,4- Tetrahydroisoquinolin-6-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylbenzamide Preparation Example 49 (22 mg, 29%). ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.08 (s, 1 H), 8.58 (s, 1 H), 8.44 (s, 1 H), 8.00 (s, 1 H), 7.89-7.82 (m, 2 H), 7.53-7.46 (m, 2 H), 7.12-7.06 (m, 2 H), 3.89 (s, 3 H), 3.62 (s, 2 H), 3.01 (s, 6 H), 2.87- 2.81 (m, 4 H), 2.77-2.70 (m, 2 H), 2.41-2.36 (m, 1 H), 2.18 (s, 3 H), 1.98-1.87 (m, 2 H), 1.85-1.77 ( m, 2 H), 1.61-1.48 (m, 2 H). LC-MS (M+H) ⁺ = 524.3.

Example 50A/50B : (S)-4-(5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrrolo[2,3 -b)Pyridin-3-yl)-N-methyl-N-((tetrahydrofuran-3-yl)methyl)benzamide and (R)-4-(5-(2,5-dimethyl -1,2,3,4-Tetrahydroisoquinolin-7-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methyl-N-((tetrahydrofuran-3 -(Yl)methyl)benzamide

Step 50-1: 4-Bromo-N-(oxolane-3-ylmethyl)benzamide

Under a nitrogen atmosphere at room temperature, to a solution of 4-bromobenzoic acid (700.00 mg, 3.48 mmol) and 1-(oxolane-3-yl)methylamine (387 mg, 3.830 mmol) in DMF, HATU ( 1986 mg, 5.22 mmol) and DIPEA (1350 mg, 10.4 mmol), and the mixture was stirred overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with DCM/EtOAc (5:1)) to give the title compound (900 mg, 91%). LCMS (M+H) ⁺ = 284.1.

Step 50-2: 4-Bromo-N-methyl-N-(oxolane-3-ylmethyl)benzamide

In a similar manner as in Example 51, step 51-2, the title compound (2.30 g, 70%) was prepared from 4-bromo-N-(oxolane-3-ylmethyl)benzamide. LCMS (M+H)+=298.2.

Step 50-3: N-methyl-N-((tetrahydrofuran-3-yl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxol Boran-2-yl)benzamide

In a similar manner as in Example 51, step 51-5, the title compound (crude) was prepared from 4-bromo-N-methyl-N-(oxolane-3-ylmethyl)benzamide. LCMS (M+H) ⁺ =346.1.

Step 50-4: 4-(5-Bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methyl-N-((tetrahydrofuran-3- (Yl)methyl)benzamide

In a similar manner as in Example 18, step 18-3, from N-methyl-N-((tetrahydrofuran-3-yl)methyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-Dioxaborolan-2-yl)benzamide and 5-bromo-3-iodo-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2, 3-b] Pyridine to prepare the title compound (2.80 g, 50% in 2 steps). LCMS (M+H) ⁺ =568.1.

Step 50-5: N-methyl-N-((tetrahydrofuran-3-yl)methyl)-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxide Cyclopentaborin-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide

In a similar manner as in Example 18, step 18-4, from 4-(5-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methyl -N-((tetrahydrofuran-3-yl)methyl)benzamide and BPD (1.50 g, 57%) prepared the title compound (1.50 g, 57%). LC-MS (M+H) ⁺ = 616.2.

Step 50-6: 4-(5-(2,5-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1-tosyl-1H-pyrrolo[ 2,3-b)pyridin-3-yl)-N-methyl-N-((tetrahydrofuran-3-yl)methyl)benzamide

In a similar manner as in Example 18, step 18-9, from N-methyl-N-((tetrahydrofuran-3-yl)methyl)-4-(5-(4,4,5,5-tetramethyl) Yl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide and 7-Bromo-2,5-dimethyl-1,2,3,4-tetrahydroisoquinoline (223 mg, 91%) prepared the title compound (223 mg, 91%). LC-MS (M+H) ⁺ = 649.5.

Step 50-7: (S)-4-(5-(2,5-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrrolo[2,3 -b)pyridin-3-yl)-N-methyl-N-((tetrahydrofuran-3-yl)methyl)benzamide and (R)-4-(5-(2,5-dimethyl -1,2,3,4-Tetrahydroisoquinolin-7-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methyl-N-((tetrahydrofuran-3 -(Yl)methyl)benzamide

In a similar manner as in Example 18, steps 18-10, from 4-(5-(2-(4-hydroxy-4-methylcyclohexyl)-5-methyl-1,2,3,4-tetra Hydroisoquinolin-7-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylbenzamide Preparation Example 50A/ 50B. The two stereoisomers were separated by chiral HPLC. Analytical chiral HPLC conditions: Repaired IC (0.46*10 cm; 5 μm); 0.14% isopropylamine + 33% DCM + 15% MeOH isocratic in 52% hexane; flow rate: 1.0 mL/min.

Example 50A ( R- isomer): (33 mg, 22%) ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.06 (s, 1 H), 8.57-8.52 (m, 1 H), 8.45-8.40 (m, 1 H), 8.02-7.98 (m, 1 H), 7.89-7.82 (m, 2 H), 7.52-7.38 (m, 3 H), 7.29 (s, 1 H), 3.84-3.61 (m , 3 H), 3.61-3.37 (m, 5 H), 3.00 (s, 3 H), 2.76-2.62 (m, 5 H), 2.36 (s, 3 H), 2.27 (s, 3 H), 2.10 -1.95 (m, 1 H), 1.64-1.30 (m, 1 H). LC-MS (M+H) ⁺ = 495.4. Chiral HPLC: tR=6.46 min.

Example 50B ( S- isomer): (26 mg, 17%) ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.06 (s, 1 H), 8.57-8.52 (m, 1 H), 8.45-8.40 (m, 1 H), 8.02-7.98 (m, 1 H), 7.89-7.82 (m, 2 H), 7.54-7.38 (m, 3 H), 7.31-7.26 (m, 1 H), 3.86-3.58 (m, 3 H), 3.60-3.37 (m, 5 H), 3.00 (s, 3 H), 2.78-2.55 (m, 5 H), 2.36 (s, 3 H), 2.27 (s, 3 H) , 1.99-1.95 (m, 1 H), 1.64-1.60 (m, 1 H). LC-MS (M+H) ⁺ = 495.5. Chiral HPLC: tR=7.69 min.

Example 51 : (S)-N-(2-hydroxypropyl)-4-(5-(8-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-6- Yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methylbenzamide

Step 51-1: 4-Bromo-N-[(2S)-2-hydroxypropyl]benzamide

To a solution of 4-bromobenzoic acid (11.80 g, 55.8 mmol) in DMF (120 mL) was added DIPEA (10.50 g, 104 mmol), HATU (22.40 g, 58.9 mmol) and (2S)-1-aminopropyl -2-ol (4.00 g, 53.3 mmol). The resulting mixture was stirred at room temperature for 6 h. The reaction was quenched by adding water. The resulting mixture was extracted with EtOAc (600 mL x 3). The combined organic layer was washed with brine (100 mL), and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE/EtOAc (30:70)) to give the title compound (12.0 g, 88%). LC-MS (M+H) ⁺ = 258.1

Step 51-2: 4-Bromo-N-[(2S)-2-[(tertiarybutyldimethylsilyl)oxy]propyl]benzamide

At 0°C, add 4-bromo-N-[(2S)-2-hydroxypropyl]benzamide (12.0 g, 46.7 mmol) and TBSCl (15.0 g, 59.0 mmol) in DCM (150 mL) Et ₃ N (15.0 g, 1.49 mmol) was added dropwise to the stirred mixture. The resulting mixture was stirred at room temperature for 15 h. The reaction was quenched by adding water. The resulting mixture was extracted with DCM (500 mL x 3). The combined organic layer was washed with brine (100 mL), and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to provide the title compound (19.0 g, crude). The crude product was used directly in step 51-3 without further purification. LC-MS (M+H) ⁺ = 372.2.

Step 51-3: 4-Bromo-N-[(2S)-2-[(tertiarybutyldimethylsilyl)oxy]propyl]-N-methylbenzamide

Under a nitrogen atmosphere at 0°C, add 4-bromo-N-[(2S)-2-[(tertiary butyldimethylsilyl)oxy]propyl]benzamide (19.0 g, from 2 steps, crude) NaH (5.10 g, 60%, 127 mmol) was added portionwise to a stirred solution in DMF (120 mL). The resulting mixture was stirred for 30 min, and then CH ₃ I (9.50 g, 63.6 mmol) was added dropwise at 0°C. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 3 h. The reaction was quenched with ice water at 0°C. The resulting mixture was extracted with EtOAc (700 mL x 3). The combined organic layer was washed with brine (150 mL), and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to give the title compound (18.0 g, crude). The crude product was used directly in step 4 without further purification. LC-MS (M+H) ⁺ = 386.3.

Step 51-4: 4-Bromo-N-[(2S)-2-hydroxypropyl]-N-methylbenzamide

To 4-bromo-N-[(2S)-2-[(tertiarybutyldimethylsilyl)oxy]propyl]-N-methylbenzamide (18.0 g, from step 51-3 Add TBAF (1.0 M in THF, 70 mL, 70 mmol) to a solution of crude product in THF (200 mL). The resulting mixture was stirred at room temperature for 15 h. The reaction mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography (eluted with EtOAc) to give the title compound (8.3 g, 65% over 3 steps). LC-MS (M+H) ⁺ = 272.0.

Step 51-5: N-[(2S)-2-hydroxypropyl]-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxolone Boran-2-yl)benzamide

To 4-bromo-N-[(2S)-2-hydroxypropyl]-N-methylbenzamide (8.3 g, 30.5 mmol) and BPD (12.0 g, 44.9 mmol) in two (200 mL) ) was added ^{_{Pd (dppf) Cl 2. DCM}} (2.60 g, 3.02 mmol) and KOAc (9.30 g, 90.0 mmol) . The reaction mixture was stirred at 100°C under a nitrogen atmosphere for 3 h. The mixture was cooled to room temperature and then filtered. Rinse the filter cake with two 㗁𠮿 (10 mL x 3). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with EtOAc) to give the title compound (7.8 g, 80%). LC-MS (M+H) ⁺ = 320.2.

Step 51-6: (S)-4-(5-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(2-hydroxypropyl) -N-Methylbenzamide

In a similar manner as in Example 18, step 18-3, from N-[(2S)-2-hydroxypropyl]-N-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-Dioxaborolan-2-yl)benzamide and 5-bromo-3-iodo-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2, 3-b] Pyridine to prepare the title compound (3.8 g, 55%). LC-MS (M+H) ⁺ = 542.2.

Step 51-7: (S)-N-(2-hydroxypropyl)-N-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxide Cyclopentaborin-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide

In a similar manner as in Example 18, step 18-4, from (S)-4-(5-bromo-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl) -N-(2-hydroxypropyl)-N-methylbenzamide prepared the title compound (5.8 g, 77%). LC-MS (M+H) ⁺ = 590.2.

Step 51-8: (S)-N-(2-hydroxypropyl)-4-(5-(8-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline- 6-yl)-1-toluene-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methylbenzamide

In a similar manner as in Example 18, steps 18-9, from (S)-N-(2-hydroxypropyl)-N-methyl-4-(5-(4,4,5,5-tetramethyl Yl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide and The title compound (43 mg, 54%) was prepared by 6-bromo-8-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline. LC-MS (M+H) ⁺ = 639.3.

Step 51-9: (S)-N-(2-hydroxypropyl)-4-(5-(8-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline- 6-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methylbenzamide

In a similar manner as in Example 18, steps 18-10, from (S)-N-(2-hydroxypropyl)-4-(5-(8-methoxy-2-methyl-1,2, 3,4-Tetrahydroisoquinolin-6-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methylbenzamide preparation example 51 (12 mg, 42%). ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.07 (s, 1 H), 8.60-8.55 (m, 1 H), 8.47-8.43 (m, 1 H), 8.02-7.98 (m, 1 H), 7.88-7.82 (m, 2 H), 7.53-7.47 (m, 2 H), 7.11 (s, 2 H), 4.89-4.80 (m, 1 H), 4.05-3.85 (m, 4 H), 3.38- 3.15 (m, 4 H), 3.04 (s, 3 H), 2.93-2.86 (m, 2 H), 2.63-2.56 (m, 2 H), 2.39 (s, 3 H), 1.18-0.89 (m, 3 H). LC-MS (M+H) ⁺ = 485.3.

Example 52 : 4-(5-(5-isopropyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrrolo[2,3-b] (Pyridin-3-yl)-N,N-dimethylbenzamide

Step 52-1: (E)-2-Bromo-4-chloro-1-(2-nitrovinyl)benzene

Under a nitrogen atmosphere at 90°C, mix 2-bromo-4-chlorobenzaldehyde (1.14 g, 4.9 mmol), nitromethane (0.80 mL, 14.2 mmol) and NH ₄ OAc (920 mg, 11.3 mmol) in AcOH The mixture in (13.00 mL, 95%) was stirred for 2 h. The mixture was cooled to room temperature and concentrated under reduced pressure, then redissolved in DCM (30 mL). The solution was washed with water (20 mL x 2), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was triturated with MeOH to give the title compound (703 mg, 55%). LC-MS (M+H) ⁺ = 262.0.

Step 52-2: 2-(2-Bromo-4-chlorophenyl)ethane-1-amine

Under a nitrogen atmosphere at room temperature, to a stirred solution of LiBH ₄ (2 M in THF, 10.9 mL, 21.8 mmol) in THF (20 mL) was added TMSCl (4.95 g, 43.3 mmol) dropwise. The mixture was stirred at 40°C for 30 min, and then N _{2 was} bubbled for 15 min. (E)-2-bromo-4-chloro-1-(2-nitrovinyl)benzene (1.90 g, 7.25 mmol) in THF (25 mL) was added dropwise to the mixture at room temperature over 5 min . The mixture was stirred at 75°C for another 2 h, and then cooled to 0°C. The reaction was quenched with MeOH at 0°C. The mixture was concentrated under reduced pressure. To the residue was added 20% aqueous KOH (20 mL). The mixture was extracted with EtOAc (25 mL x 2). The combined organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give the title compound (1.13 g, 67%). LC-MS (M+H) ⁺ = 234.0.

Step 52-3: N-(2-Bromo-4-chlorophenethyl)-2,2,2-trifluoroacetamide

In a similar manner as in Example 40, step 40-2, the title compound (1.70 g, 91%) was prepared from 2-(2-bromo-4-chlorophenyl)ethylamine. LC-MS (M+H) ⁺ = 330.0.

Step 52-4: 1-(5-Bromo-7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethane-1-one

In a similar manner as in Example 40, step 40-3, the title compound (650 mg, 38%) was prepared from N-(2-bromo-4-chlorophenethyl)-2,2,2-trifluoroacetamide ). LC-MS (M+H) ⁺ = 342.0.

Step 52-5: 5-Bromo-7-chloro-1,2,3,4-tetrahydroisoquinoline

In a similar manner as in Example 40, step 40-4, from 1-(5-bromo-7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- The title compound (420 mg, 94%) was prepared from trifluoroethane-1-one. LC-MS (M+H) ⁺ = 246.1.

Step 52-6: 5-Bromo-7-chloro-2-methyl-1,2,3,4-tetrahydroisoquinoline

The title compound (388 mg, 96%) was prepared from 5-bromo-7-chloro-1,2,3,4-tetrahydroisoquinoline in a similar manner as in Example 40, step 40-5. LC-MS (M+H) ⁺ = 260.0.

Step 52-7: 7-Chloro-2-methyl-5-(prop-1-en-2-yl)-1,2,3,4-tetrahydroisoquinoline

In a similar manner as in Example 19, step 19-9, from 5-bromo-7-chloro-2-methyl-1,2,3,4-tetrahydroisoquinoline and 4,4,5,5- Tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxolane prepared the title compound (256 mg, 77%). LC-MS (M+H) ⁺ = 222.1.

Step 52-8: 7-Chloro-5-isopropyl-2-methyl-1,2,3,4-tetrahydroisoquinoline

Under a nitrogen atmosphere at room temperature, add 7-chloro-2-methyl-5-(prop-1-en-2-yl)-3,4-dihydro-1H-isoquinoline (256 mg, 1.154 mmol ) A solution in DCM (10 mL) was added Rh(PPh ₃ ) ₃ Cl (62 mg, 0.067 mmol). The reaction flask was evacuated and flushed with hydrogen. The reaction mixture was then stirred under a hydrogen balloon at room temperature for 16 h. The solid was filtered off and the solution was concentrated under reduced pressure. The residue was purified by a C18 column and by flash chromatography (eluted with MeCN (50% to 70%) in 10 mM NH ₄ HCO ₃ ) to give the title compound (114 mg, 44%) ). LC-MS (M+H) ⁺ = 224.2.

Step 52-9: 5-isopropyl-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 3,4-Dihydro-1H-isoquinoline

To a solution of 7-chloro-5-isopropyl-2-methyl-3,4-dihydro-1H-isoquinoline (105 mg, 0.470 mmol) in dichloromethane (6 mL) at room temperature Add BPD (181 mg, 0.711 mmol), dichlorobis(tricyclohexylphosphine)palladium(II) (31 mg, 0.042 mmol) and KOAc (152 mg, 1.55 mmol). The mixture was stirred under a nitrogen atmosphere at 100°C for 4 h. The mixture was cooled to room temperature, and then diluted with water (30 mL). The mixture was sequentially extracted with DCM (50 mL x 3). The combined organic layer was washed with brine (50 mL), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure to give the title compound (190 mg, crude). The crude product was used directly in step 52-10 without further purification. LC-MS (M+H) ⁺ = 316.2.

Step 52-10: 4-(5-(5-isopropyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1-tosyl-1H- Pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylbenzamide

In a similar manner as in Example 19, Step 19-9, from 5-isopropyl-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxa Cyclopentaborin-2-yl)-1,2,3,4-tetrahydroisoquinoline and 4-[5-bromo-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2 ,3-b]pyridin-3-yl]-N,N-dimethylbenzamide prepared the title compound (142 mg, 50% in 2 steps). LC-MS (M+H) ⁺ = 607.4.

Step 52-11: 4-(5-(5-isopropyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrrolo[2,3- b)Pyridin-3-yl)-N,N-dimethylbenzamide

In a similar manner as in Example 18, Steps 18-10, from 4-(5-(5-isopropyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -1-Tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylbenzamide Preparation Example 52 (34 mg, 32%). ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.08 (s, 1 H), 8.54 (s, 1 H), 8.40 (s, 1 H), 8.00 (s, 1 H), 7.85 (d, J = 7.9 Hz, 2 H), 7.50 (d, J = 7.9 Hz, 2 H), 7.42 (s, 1 H), 7.26 (s, 1 H), 3.58 (s, 2 H), 3.20-3.08 (m, 1 H), 3.01 (s, 6 H), 2.88-2.81 (m, 2 H), 2.69-2.61 (m, 2 H), 2.36 (s, 3 H), 1.28-1.22 (m, 6 H). LC-MS (M+H) ⁺ = 453.4.

Example 53 : (R)-N-(2-hydroxypropyl)-4-(5-(8-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-6- Yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methylbenzamide

Step 53-1: 4-Bromo-N-[(2R)-2-hydroxypropyl]benzamide

The title compound (4.63 g, 67%) was prepared from 4-bromobenzoic acid and (2R)-1-aminopropan-2-ol in a similar manner as in Example 51, step 51-1. LC-MS (M+H) ⁺ = 258.1.

Step 53-2: 4-Bromo-N-[(2R)-2-[(tertiarybutyldimethylsilyl)oxy]propyl]benzamide

In a similar manner as in Example 51, step 51-2, the title compound (12.14 g, 60%) was prepared from 4-bromo-N-[(2R)-2-hydroxypropyl]benzamide and TBSCl. LC-MS (M+H) ⁺ = 372.3.

Step 53-3: 4-Bromo-N-[(2R)-2-[(tertiarybutyldimethylsilyl)oxy]propyl]-N-methylbenzamide

In a similar manner as in Example 51, step 51-3, from 4-bromo-N-[(2R)-2-[(tertiary butyldimethylsilyl)oxy]propyl]benzamide The title compound (9.79 g, 53%) was prepared with MeI. LC-MS (M+H) ⁺ = 386.1.

Step 53-4: 4-Bromo-N-[(2R)-2-hydroxypropyl]-N-methylbenzamide

In a similar manner as in Example 51, step 51-4, from 4-bromo-N-[(2R)-2-[(tertiarybutyldimethylsilyl)oxy]propyl]-N-methyl The title compound (5.48 g, 70%) was prepared by phenylbenzamide. LC-MS (M+H) ⁺ = 272.0.

Step 53-5: (R)-N-(2-hydroxypropyl)-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxol Boran-2-yl)benzamide

In a similar manner to that in Example 51, step 51-5, the title compound (3.75 g, 3) was prepared from 4-bromo-N-[(2R)-2-hydroxypropyl]-N-methylbenzamide and BPD 47%). LC-MS (M+H) ⁺ = 320.1.

Step 53-6: (R)-4-(5-Bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(2-hydroxypropyl) -N-Methylbenzamide

In a similar manner as in Example 18, step 18-3, from (R)-N-(2-hydroxypropyl)-N-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzamide and 5-bromo-3-iodo-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2, 3-b] Pyridine prepared the title compound (353 mg, 39%). LC-MS (M+H) ⁺ = 542.2.

Step 53-7: (R)-N-(2-hydroxypropyl)-N-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxide Cyclopentaborin-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide

In a similar manner as in Example 18, step 18-4, from (R)-4-(5-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl) -N-(2-hydroxypropyl)-N-methylbenzamide prepared the title compound (365 mg, 62%). LC-MS (M+H) ⁺ = 590.3.

Step 53-8: (R)-N-(2-hydroxypropyl)-4-(5-(8-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline- 6-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methylbenzamide

In a similar manner as in Example 18, Steps 18-9, from (R)-N-(2-hydroxypropyl)-N-methyl-4-(5-(4,4,5,5-tetramethyl Yl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide and The title compound (42 mg, 53%) was prepared from 6-bromo-8-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline. LC-MS (M+H) ⁺ = 639.4.

Step 53-9: (R)-N-(2-hydroxypropyl)-4-(5-(8-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline- 6-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methylbenzamide

In a similar manner as in Example 18, steps 18-10, from (R)-N-(2-hydroxypropyl)-4-(5-(8-methoxy-2-methyl-1,2, 3,4-Tetrahydroisoquinolin-6-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methylbenzamide preparation example 53 (12 mg, 41%). ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.08 (s, 1 H), 8.58 (s, 1 H), 8.46 (s, 1 H), 8.00 (s, 1 H), 7.88-7.82 (m, 2 H), 7.53-7.47 (m, 2 H), 7.11 (s, 2 H), 4.92-4.78 (m, 1 H), 4.05-3.82 (m, 4 H), 3.38-3.28 (m, 4 H) ), 3.03 (s, 3 H), 2.93-2.86 (m, 2 H), 2.63-2.56 (m, 2 H), 2.39 (s, 3 H), 1.17-0.89 (m, 3 H). LC-MS (M+H) ⁺ = 485.4.

Example 54A/54B : (S)-4-(5-(8-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrrolo[ 2,3-b)pyridin-3-yl)-N-methyl-N-((tetrahydrofuran-3-yl)methyl)benzamide and (R)-4-(5-(8-methoxy 2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methyl-N -((Tetrahydrofuran-3-yl)methyl)benzamide

Step 54-1: 4-(5-(8-Methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl)-1-tosyl-1H-pyrrolo[2, 3-b)pyridin-3-yl)-N-methyl-N-((tetrahydrofuran-3-yl)methyl)benzamide

In a similar manner as in Example 18, step 18-9, from N-methyl-N-((tetrahydrofuran-3-yl)methyl)-4-(5-(4,4,5,5-tetramethyl) Yl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide and The title compound (64 mg, 24%) was prepared from 6-bromo-8-methoxy-1,2,3,4-tetrahydroisoquinoline. LC-MS (M+H) ⁺ = 651.3.

Step 54-2: 4-(5-(8-Methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1-toluenesulfonyl-1H- Pyrrolo[2,3-b]pyridin-3-yl)-N-methyl-N-((tetrahydrofuran-3-yl)methyl)benzamide

In a similar manner as in Example 26 and Step 26-1, from 4-(5-(8-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl)-1-toluenesulfonate Preparation of the title compound (32 mg, with acyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methyl-N-((tetrahydrofuran-3-yl)methyl)benzamide 52%). LC-MS (M+H) ⁺ = 665.3.

Step 54-3: (S)-4-(5-(8-Methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrrolo[ 2,3-b)pyridin-3-yl)-N-methyl-N-((tetrahydrofuran-3-yl)methyl)benzamide and (R)-4-(5-(8-methoxy 2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methyl-N -((Tetrahydrofuran-3-yl)methyl)benzamide

In a similar manner as in Example 18, Steps 18-10, from 4-(5-(8-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl) -1-Tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methyl-N-((tetrahydrofuran-3-yl)methyl)benzamide preparation example 54A/54B. The two stereoisomers were separated by chiral HPLC. Analytical chiral HPLC conditions: Repaired IC (0.46*10 cm; 5 μm); 0.14% isopropylamine + 33% DCM + 15% MeOH isocratic in 52% hexane; flow rate: 1.0 mL/min.

Example 54A ( S- isomer): (6 mg, 8%) ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.08 (s, 1 H), 8.59 (s, 1 H), 8.45 (s, 1 H), 8.01 (s, 1 H), 7.89-7.83 (m, 2 H), 7.50-7.44 (m, 2 H), 7.13-7.08 (m, 2 H), 3.90 (s, 3 H), 3.82 -3.59 (m, 3 H), 3.51-3.38 (m, 5 H), 3.00 (s, 3 H), 2.93-2.86 (m, 2 H), 2.63-2.56 (m, 3 H), 2.39 (s , 3 H), 2.10-1.90 (m, 1 H), 1.75-1.50 (m, 1 H). LC-MS (M+H) ⁺ = 511.5. Chiral HPLC: tR=8.44 min.

Example 54B ( R- isomer): (9 mg, 12%) 1H NMR (400 MHz, DMSO-d6) δ 12.08 (s, 1 H), 8.59 (s, 1 H), 8.45 (s, 1 H) ), 8.01 (s, 1 H), 7.90-7.83 (m, 2 H), 7.50-7.44 (m, 2 H), 7.11 (s, 2 H), 3.90 (s, 3 H), 3.83-3.38 ( m, 8 H), 3.00 (s, 3 H), 2.94-2.87 (m, 2 H), 2.66-2.61 (m, 3 H), 2.41 (s, 3 H), 2.00-1.95 (m, 1 H) ), 1.69-1.55 (m, 1 H). LC-MS (M+H) ⁺ = 511.5. Chiral HPLC: tR=7.00 min.

Example 55 : (S)-N-(2-hydroxypropyl)-4-(5-(5-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-7- Yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methylbenzamide

Step 55-1: (S)-N-(2-hydroxypropyl)-4-(5-(5-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yl)- 1-Toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methylbenzamide

In a similar manner as in Example 18, Step 18-9, from (S)-N-(2-hydroxypropyl)-N-methyl-4-(5-(4,4,5,5-tetramethyl Yl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide and The title compound (57 mg, 74%) was prepared by 7-bromo-5-methoxy-1,2,3,4-tetrahydroisoquinoline. LC-MS (M+H) ⁺ = 625.3.

Step 55-2: (S)-N-(2-hydroxypropyl)-4-(5-(5-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline- 7-yl)-1-toluene-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methylbenzamide

In a similar manner as in Example 26, step 26-1, from (S)-N-(2-hydroxypropyl)-4-(5-(5-methoxy-1,2,3,4-tetra Hydroisoquinolin-7-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methylbenzamide prepared the title compound (47 mg, 76%). LC-MS (M+H) ⁺ = 639.4.

Step 55-3: (S)-N-(2-hydroxypropyl)-4-(5-(5-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline- 7-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methylbenzamide

In a similar manner as in Example 18, steps 18-10, from (S)-N-(2-hydroxypropyl)-4-(5-(5-methoxy-2-methyl-1,2, 3,4-Tetrahydroisoquinolin-7-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methylbenzamide preparation example 55 (15 mg, 38%). ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.09 (s, 1 H), 8.59 (s, 1 H), 8.46 (s, 1 H), 8.01 (s, 1 H), 7.89-7.82 (m, 2 H), 7.53-7.47 (m, 2 H), 7.11 (s, 1 H), 7.05 (s, 1 H), 4.95-4.80 (m, 1 H), 4.03-3.83 (m, 4 H), 3.54 (s, 2 H), 3.34-3.12 (m, 2 H), 3.04 (s, 3 H), 2.73-2.65 (m, 2 H), 2.64-2.57 (m, 2 H), 2.36 (s, 3 H), 1.15-0.89 (m, 3 H). LC-MS (M+H) ⁺ = 485.5.

Example 56 : 8-Methoxy-2-methyl-6-(3-(4-(5-methyl-1H-1,2,3-triazol-1-yl)phenyl)-1H-pyrrole And [2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinoline

Step 56-1: 1-(4-Bromophenyl)-5-methyl-1H-1,2,3-triazole

To a solution of 1-azido-4-bromobenzene (1.25 g, 6.38 mmol) in MeCN (20 mL) at room temperature, add 1,1,3,3-tetramethylguanidine (2.20 g, 19.1 mmol) mmol) and dimethyl 2-oxopropyl phosphonate (1.16 g, 7.02 mmol). The mixture was stirred for 16 h at 80°C under nitrogen atmosphere. The mixture was cooled to room temperature and quenched with water (50 mL). The mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with brine, dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography (eluted with EtOAc (0% to 50%) in hexane) to give the title compound (0.84 g, 55%) . LC-MS (M+H) ⁺ = 238.0.

Step 56-2: 5-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)- 1H-1,2,3-triazole

In a similar manner as in Example 18, step 18-2, the title compound (135 mg, 48) was prepared from 1-(4-bromophenyl)-5-methyl-1H-1,2,3-triazole and BPD %). LC-MS (M+H) ⁺ = 286.3.

Step 56-3: 5-Bromo-3-(4-(5-methyl-1H-1,2,3-triazol-1-yl)phenyl)-1-tosyl-1H-pyrrolo [2,3-b]pyridine

In a similar manner as in Example 18, step 18-3, from 5-bromo-3-iodo-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine and 5 -Methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-1,2, The title compound (268 mg, 53%) was prepared by 3-triazole. LC-MS (M+H) ⁺ = 508.1.

Step 56-4: 3-(4-(5-Methyl-1H-1,2,3-triazol-1-yl)phenyl)-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine

In a similar manner as in Example 18, step 18-4, from 5-bromo-3-(4-(5-methyl-1H-1,2,3-triazol-1-yl)phenyl)-1 -Tosyl-1H-pyrrolo[2,3-b]pyridine and BPD to prepare the title compound (150 mg, 99%). LC-MS (M+H) ⁺ = 556.2.

Step 56-5: 8-Methoxy-2-methyl-6-(3-(4-(5-methyl-1H-1,2,3-triazol-1-yl)phenyl)-1 -Tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinoline

In a similar manner as in Example 18, step 18-9, from 6-bromo-8-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline and 3-(4-( 5-methyl-1H-1,2,3-triazol-1-yl)phenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxol Boran-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine prepared the title compound (80 mg, 37%). LC-MS (M+H) ⁺ = 605.3.

Step 56-6: 8-Methoxy-2-methyl-6-(3-(4-(5-methyl-1H-1,2,3-triazol-1-yl)phenyl)-1H -Pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinoline

In a similar manner to Example 18, Step 10, from 8-methoxy-2-methyl-6-(3-(4-(5-methyl-1H-1,2,3-triazole-1 -Yl)phenyl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinoline Preparation Example 56 (9 mg, 11%). ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.16 (s, 1 H), 8.61 (s, 1 H), 8.50 (s, 1 H), 8.11-8.00 (m, 3H), 7.74-7.65 (m , 3 H), 7.12 (s, 2 H), 3.90 (s, 3 H), 3.42 (s, 2 H), 2.93-2.85 (m, 2 H), 2.62-2.53 (m, 2 H), 2.41 -2.36 (m, 6 H). LC-MS (M+H) ⁺ = 451.3.

Example 57 : (R)-N-(2-hydroxypropyl)-4-(5-(5-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-7- Yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methylbenzamide

Step 57-1: (R)-N-(2-hydroxypropyl)-4-(5-(5-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yl)- 1-Toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methylbenzamide

In a similar manner as in Example 18, Steps 18-9, from (R)-N-(2-hydroxypropyl)-N-methyl-4-(5-(4,4,5,5-tetramethyl Yl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide and The title compound (37 mg, 36%) was prepared by 7-bromo-5-methoxy-1,2,3,4-tetrahydroisoquinoline. LC-MS (M+H) ⁺ = 625.4.

Step 57-2: (R)-N-(2-hydroxypropyl)-4-(5-(5-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline- 7-yl)-1-toluene-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methylbenzamide

In a similar manner as in Example 26, step 26-1, from (R)-N-(2-hydroxypropyl)-4-(5-(5-methoxy-1,2,3,4-tetra Hydroisoquinolin-7-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methylbenzamide and formalin to prepare the title compound ( 37 mg, 90%). LC-MS (M+H) ⁺ = 639.4.

Step 57-3: (R)-N-(2-hydroxypropyl)-4-(5-(5-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline- 7-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methylbenzamide

In a similar manner as in Example 18, steps 18-10, from (R)-N-(2-hydroxypropyl)-4-(5-(5-methoxy-2-methyl-1,2, 3,4-Tetrahydroisoquinolin-7-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methylbenzamide preparation example 57 (6 mg, 19%). ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.07 (s, 1 H), 8.58 (s, 1 H), 8.45 (s, 1 H), 8.00 (s, 1 H), 7.85 (d, J = 7.8 Hz, 2 H), 7.50 (d, J = 7.9 Hz, 2 H), 7.11 (s, 1 H), 7.05 (s, 1 H), 4.91-4.78 (m, 1 H), 4.03-3.94 ( m, 1 H), 3.90 (s, 3 H), 3.55 (s, 2 H), 3.50-3.46 (m, 1 H), 3.21-3.17 (m, 1 H), 3.03 (s, 3 H), 2.71-2.65 (m, 2 H), 2.65-2.59 (m, 2 H), 2.36 (s, 3 H), 1.17-0.90 (m, 3 H). LC-MS (M+H) ⁺ = 485.4.

Example 58 : 4-(5-(2-(2-(Cyclopropanecarboxamido)ethyl)-5-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)- 1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylbenzamide

Step 58-1: Tertiary butyl 2-(7-(3-(4-(dimethylaminomethanyl)phenyl)-1-toluenesulfonyl-1H-pyrrolo[2,3- b)Pyridin-5-yl)-5-methyl-3,4-dihydroisoquinoline-2(1H)-yl)ethyl carbamate

In a similar manner to Example 26, step 26-1, from N,N-dimethyl-4-(5-(5-methyl-1,2,3,4-tetrahydroisoquinoline-7- Yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide and tertiary butyl 2-oxoethyl carbamate preparation title Compound (165 mg, 49%). LC-MS (M+H) ⁺ = 708.4.

Step 58-2: 4-(5-(2-(2-Aminoethyl)-5-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1-toluenesulfonate Aceto-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylbenzamide

In a similar manner as in Example 1, Steps 1-6, from tertiary butyl 2-(7-(3-(4-(dimethylaminomethanyl)phenyl)-1-toluenesulfonyl -1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethyl carbamate Preparation title Compound (136 mg, 96%). LC-MS (M+H) ⁺ = 608.3.

Step 58-3: 4-(5-(2-(2-(Cyclopropanecarboxamido)ethyl)-5-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl )-1-Tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylbenzamide

In a similar manner as in Example 3 and Step 3-5, from 4-(5-(2-(2-aminoethyl)-5-methyl-1,2,3,4-tetrahydroisoquinoline -7-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylbenzamide and cyclopropanecarboxylic acid to prepare the title compound ( 88 mg, 55%). LC-MS (MH) ⁺ = 676.6.

Step 58-4: 4-(5-(2-(2-(Cyclopropanecarboxamido)ethyl)-5-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl )-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylbenzamide

In a similar manner as in Example 18, steps 18-10, from 4-(5-(2-(2-(cyclopropanecarboxamido)ethyl)-5-methyl-1,2,3,4 -Tetrahydroisoquinolin-7-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylbenzamide preparation example 58 (21 mg, 31%). ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.06 (s, 1 H), 8.55 (s, 1 H), 8.43 (s, 1 H), 8.07-7.98 (m, 2 H), 7.85 (d, J = 8.0 Hz, 2 H), 7.50 (d, J = 8.0 Hz, 2 H), 7.42 (s, 1 H), 7.31 (s, 1 H), 3.68 (s, 2 H), 3.33-3.27 ( m, 2 H), 3.02 (s, 6 H), 2.79-2.70 (m, 4 H), 2.59-2.51 (m, 2 H), 2.28 (s, 3 H), 1.62-1.51 (m, 1 H ), 0.71-0.58 (m, 4 H). LC-MS (M+H) ⁺ = 522.3.

Example 59 : 4-(5-(2,5-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrrolo[2,3-b]pyridine-3 -Yl)-N-(2-(dimethylamino)ethyl)-N-methylbenzamide

Step 59-1: 4-(5-(2,5-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrrolo[2,3-b]pyridine -3-yl)benzoic acid

The 4-(5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl )-N,N-Dimethylbenzamide (1.8 g, 4.2 mmol) and NaOH (0.85 g, 21 mmol) in EtOH (50 mL) and water (20 mL) were stirred overnight at 90°C . The reaction mixture was cooled to room temperature and ethanol was evaporated under reduced pressure. Acidify the pH of the remaining solution to 2 to 3 with aqueous HCl (4 M). The precipitate was collected by filtration to give the title compound (1.5 g, 90%). LC-MS (M+H) ⁺ = 398.0.

Step 59-2: 4-(5-(2,5-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrrolo[2,3-b]pyridine -3-yl)-N-(2-(dimethylamino)ethyl)-N-methylbenzamide

The 4-(5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl ) Benzoic acid (300 mg, 0.76 mmol), N1,N1,N2-trimethylethane-1,2-diamine (154 mg, 1.51 mmol), HATU (433 mg, 1.14 mmol) and TEA (0.33 mL , 2.28 mmol) dissolved in DMF (10 mL). The mixture was stirred at room temperature overnight, then diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with brine (30 mL x 3), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM/MeOH=5:1) to give Example 59 (6 mg, 2%). ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.06 (s, 1H), 8.54 (s, 1H), 8.41 (s, 1H), 8.00 (s, 1H), 7.88-7.82 (m, 2H), 7.48 -7.43 (m, 2H), 7.41 (s, 1H), 7.28 (s, 1H), 3.60-3.52 (m, 3H), 3.42-3.36 (m, 1H), 2.99 (s, 3H), 2.76-2.70 (m, 2H), 2.69-2.62 (m, 2H), 2.52-2.50 (m, 2H), 2.36 (s, 3H), 2.27 (s, 3H), 2.22 (s, 3H), 2.02 (s, 3H) ). LC-MS (M+H) ⁺ = 481.9.

Example 60 : (R)-4-(5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrrolo[2,3-b ]Pyridin-3-yl)-N-(2-hydroxypropyl)-N-methylbenzamide

In a similar manner to Example 59, step 2, from 4-(5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrrolo [2,3-b]pyridin-3-yl)benzoic acid and (R)-1-(methylamino)propan-2-ol Preparation Example 60 (40 mg, 9%). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.48 (s, 1H), 8.46 (s, 1H), 7.87-7.78 (m, 3H), 7.61-7.52 (m, 2H), 7.46 (s, 1H) , 7.31 (s, 1H), 4.23-3.98 (m, 3H), 3.73-3.40 (m, 2H), 3.24-3.19 (m, 2H), 3.16 (s, 3H), 3.04-2.95 (m, 2H) , 2.77 (s, 3H), 2.36 (s, 3H), 1.31-1.01 (m, 3H). LC-MS (M+H) ⁺ = 469.0.

Example 61 : N,N-dimethyl-4-(5-(2,4,4,5-tetramethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H- Pyrrolo[2,3-b]pyridin-3-yl)benzamide

Step 61-1: 2-(4-Bromo-2-methylphenyl)-2-methylpropionitrile

Under N ₂ at 0°C, to a solution of 2-(4-bromo-2-methylphenyl)acetonitrile (3.45 g, 164 mmol) in DMF (50 mL) was added KO t- Bu (4.42 g , 39.4 mmol). After 10 minutes, MeI (5.35 g, 37.2 mmol) was added dropwise at 0°C. After 45 minutes, water (150 mL) was added, and the mixture was extracted with MTBE (60 mL x 2). The combined organic layer was washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with EtOAc (5% to 10%) in PE) to give the title compound (2.0 g, 51%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.38 (s, 1H), 7.36-7.30 (m, 1H), 7.20-7.14 (m, 1H), 2.62 (s, 3H), 1.77 (s, 6H).

Step 61-2: 2-(4-Bromo-2-methylphenyl)-2-methylprop-1-amine

To a solution of 2-(4-bromo-2-methylphenyl)-2-methylpropionitrile (2.0 g, 8.4 mmol) in THF (10 mL) at 0°C under nitrogen, add THF BH ₃ (1.0 M, 25.2 mL, 25.2 mmol). The reaction mixture was stirred at 70°C overnight and then cooled to 0°C. MeOH (25 mL) was added dropwise at 0°C, followed by 6 N HCl solution (25 mL). The mixture was heated to 75°C for 2 h, and then cooled to room temperature. Saturated NaHCO ₃ (150 mL) was added, and the mixture was extracted with EtOAc (50 mL x 2). The combined organic layer was washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (2.1 g, 100%). LC-MS (M+H) ⁺ = 241.9, 243.9.

Step 61-3: N-(2-(4-Bromo-2-methylphenyl)-2-methylpropyl)-2,2,2-trifluoroacetamide

At 0°C, add 2-(4-bromo-2-methylphenyl)-2-methylpropan-1-amine (2.1 g, 8.68 mmol) and Et ₃ N (3.7 mL, 26 mmol) in DCM Add TFAA (1.7 mL, 12.1 mmol) dropwise to the solution in (30 mL). After 1 h, water (30 mL) was added, and the mixture was extracted with DCM (30 mL x 2). The combined organic layer was washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with EtOAc (3% to 10%) in PE) to give the title compound (1.7 g, 60%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.34-7.29 (m, 1H), 7.16-7.13 (m, 1H), 5.89 (s, 1H), 3.69 (d, J = 6.1 Hz, 2H), 2.52 ( s, 3H), 1.44 (s, 6H). LC-MS (M+H) ⁺ = 337.8, 339.8.

Step 61-4: 1-(7-Bromo-4,4,5-trimethyl-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethane -1-one

At room temperature, add N-(2-(4-bromo-2-methylphenyl)-2-methylpropyl)-2,2,2-trifluoroacetamide (1.1 g, 3.25 mmol) in Add paraformaldehyde (146 mg, 4.89 mmol) to the pre-mixed AcOH (6.6 mL) and H ₂ SO ₄ (4.4 mL) mixture, and stir the mixture overnight. Cold water (20 mL) was added, and the mixture was extracted with EtOAc (30 mL x 2). The combined organic layer was washed sequentially with saturated NaHCO ₃ (50 mL), brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with EtOAc (3% to 10%) in PE) to give the title compound (160 mg, 14%). LC-MS (M+H) ⁺ = 349.8, 351.8.

Step 61-5: 7-bromo-4,4,5-trimethyl-1,2,3,4-tetrahydroisoquinoline

The 1-(7-bromo-4,4,5-trimethyl-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1-one A mixture of (160 mg, 0.46 mmol) and K ₂ CO ₃ (315 mg, 2.28 mmol) in EtOH (20 mL) and water (10 mL) was stirred at 75°C for 1 h. The mixture was cooled to room temperature and EtOH was evaporated in vacuo. The mixture was extracted with EtOAc (20 mL x 2). The combined organic layer was washed with saturated NaHCO ₃ (50 mL), brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (120 mg, 100%). LC-MS (M+H) ⁺ = 253.9, 255.9.

Step 61-6: 7-Bromo-2,4,4,5-tetramethyl-1,2,3,4-tetrahydroisoquinoline

At room temperature, add 7-bromo-4,4,5-trimethyl-1,2,3,4-tetrahydroisoquinoline (120 mg, 0.472 mmol) in DCM (10 mL) 37% formalin (0.38 mL, 4.72 mmol) and NaBH(OAc) ₃ (200 mg, 0.944 mmol). The mixture was stirred for 1 h and then quenched with water (10 mL). The mixture was extracted with DCM (20 mL x 2). The combined organic layer was washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (120 mg, 95%). LC-MS (M+H) ⁺ = 267.9, 269.9.

Step 61-7: N,N-Dimethyl-4-(5-(2,4,4,5-tetramethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)- 1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide

In a similar manner as in Example 15, Step 15-5, from N,N-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxa Cyclopentaborin-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide and 7-bromo-2,4,4,5-tetramethyl-1, 2,3,4-Tetrahydroisoquinoline Preparation Example 61 (70 mg, 35%). ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.07 (s, 1H), 8.53 (s, 1H), 8.43 (s, 1H), 8.00 (s, 1H), 7.86-7.82 (m, 2H), 7.51 -7.47 (m, 2H), 7.35 (s, 1H), 7.25 (s, 1H), 3.56 (s, 2H), 3.02-2.94 (m, 8H), 2.53 (s, 2H), 2.32 (s, 3H) ), 1.37 (s, 6H). LC-MS (M+H) ⁺ = 453.0.

Example 62 : 2-(7-(3-(4-(dimethylaminomethanyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methyl -3,4-Dihydroisoquinoline-2(1H)-yl)ethyl acetate

Step 62-1: Tertiary butyl 5-bromo-3-(4-(dimethylaminomethanyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

The tertiary butyl 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (4.0 g, 9.5 mmol), (4-(dimethylaminomethyl (Phenyl)phenyl)boronic acid (1.8 g, 9.5 mmol), Pd(dppf)Cl ₂ (350 mg, 0.47 mmol), and K ₂ CO ₃ (2.0 g, 14.2 mmol) were added to the two 㗁𠮿 (100 mL) and water (20 mL). The reaction mixture was heated to reflux overnight and then cooled to room temperature. The solvent was removed in vacuo, and the residue was purified by silica gel column chromatography (eluted with EtOAc) to give the title compound (1.86 g, 56%). LC-MS (M+H) ⁺ = 444.0.

Step 62-2: Tertiary butyl 3-(4-(dimethylaminomethanyl)phenyl)-5-(4,4,5,5-tetramethyl-1,3,2-di Oxaloborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

Under nitrogen, the tertiary butyl 5-bromo-3-(4-(dimethylaminomethanyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (1.86 g, 5.4 mmol), BPD (1.65 g, 6.5 mmol), Pd(dppf)Cl ₂ (200 mg, 0.27 mmol), and AcOK (800 mg, 8.1 mmol) are added to the second 㗁𠮿 (50 mL), And the mixture was heated to reflux overnight. After cooling to room temperature, the mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (eluted with MeOH (5%) in DCM) to give the title compound (1.0 g, 50%). LC-MS (M+H) ⁺ = 492.0.

Step 62-3: 2-(7-Bromo-5-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1-ol

To 7-bromo-5-methyl-1,2,3,4-tetrahydroisoquinoline (0.5 g, 2.21 mmol) and 2-bromoethane-1-ol (415 mg, 3.32 mmol) in MeCN ( Add K ₂ CO ₃ (610 mg) to the solution in 20 mL). The mixture was stirred at room temperature overnight. Water (20 mL) was added, and the mixture was extracted with EtOAc (20 mL x 3). The combined organic layer was washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound (564 mg, 95%). LC-MS (M+H) ⁺ = 296.9, 271.9.

Step 62-4: 2-(7-bromo-5-methyl-3,4-dihydroisoquinolin-2(1H)-yl) ethyl acetate

To 2-(7-bromo-5-methyl-3,4-dihydroisoquinoline-2(1H)-yl)ethane-1-ol (564 mg, 2.09 mmol) and NaOH (84 mg, 2.09 mmol) To the mixture in CCl ₄ (20 mL), add dropwise a solution of acetyl chloride (164 mg, 2.09 mmol) in CCl ₄ (1 mL). The mixture was stirred at room temperature for 8 h. Water (20 mL) was added, and the mixture was extracted with EtOAc (20 mL x 3). The combined organic layer was washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography (eluted with EtOAc (50%) in PE) to give the title compound (400 mg, 61%). LC-MS (M+H) ⁺ = 311.8, 313.8.

Step 62-5: 2-(7-(3-(4-(dimethylaminomethanyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-5- Methyl-3,4-dihydroisoquinoline-2(1H)-yl) ethyl acetate

To tertiary butyl 3-(4-(dimethylaminomethanyl)phenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxolane Borin-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (314 mg, 0.641 mmol) and 2-(7-bromo-5-methyl-3,4- A solution of dihydroisoquinoline-2(1H)-yl) ethyl acetate (200 mg, 0.641 mmol) in dichloromethane (10 mL) and H ₂ O (10 mL) was added XPhos Pd G2 (50 mg, 0.064 mmol) and K ₃ PO ₄ (272 mg, 1.282 mmol). The mixture was stirred at 60°C under N ₂ overnight and cooled to room temperature. Water (20 mL) was added, and the mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO _4, filtered and concentrated. The residue was purified by silica gel column chromatography (eluted with MeOH (5%) in DCM), and then further purified by preparative TLC (DCM: MeOH = 10:1) to give Example 62 (8 mg, 3%). ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.05 (s, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.41 (d, J = 1.8 Hz, 1H), 8.00 (s, 1H), 7.84 (d, J = 8.1 Hz, 2H), 7.49 (d, J = 8.2 Hz, 2H), 7.41 (s, 1H), 7.29 (s, 1H), 4.22 (t, J = 5.7 Hz, 2H), 3.69 (s, 2H), 3.01 (s, 6H), 2.83-2.76 (m, 2H), 2.76-2.65 (m, 4H), 2.27 (s, 3H), 2.03 (s, 3H). LC-MS (M+H) ⁺ = 496.9

Biological assay

HPK kinase activity was measured at 1 mM ATP in

In the assay based on the time-resolved fluorescence resonance energy transfer (TR-FRET) method, the compounds disclosed in the present invention were tested for their inhibition of HPK1 kinase (aa1-346, Life Technologies) activity. The assay was performed in a 384-well small-volume black reaction plate in a reaction mixture in a buffer, the reaction mixture containing HPK1 kinase, 1 mM ATP, 0.5 μM STK1 substrate and 0-10 μM compound, the buffer Contains 50 mM HEPES, 0.01% BSA, 0.1 mM orthovanadate, 10 mM MgCl ₂ , 1 mM DTT (pH = 7.0), 0.005% Tween-20). The kinase is reacted with the compound disclosed in the invention or DMSO at room temperature for 60 minutes, and ATP and STK1 substrate are added to initiate the reaction. After reacting at room temperature for 120 minutes, add an equal volume of stop/detection solution according to the manufacturer's instructions (CisBio). The stop/detection solution contains STK antibody-cryptate and XL665-conjugated streptavidin in detection buffer. Record the TR-FRET signal on the PHERAstar FS microplate reader (BMG Labtech) (after excitation with a wavelength of 337 nm, the ratio of fluorescence emission at 665 nm to that at 620 nm). The phosphorylation of the STK1 substrate causes the STK antibody-cryptate to bind to the biotinylated STK1 substrate, making the fluorescence donor (Eu3+ cryptate) close to the acceptor (streptavidin-XL665), resulting in a highly fluorescent Optical resonance energy transfer. Based on the fluorescence ratio of 665 nm wavelength to 620 nm wavelength, the inhibition of HPK1 by the compound is calculated when the concentration increases. The data was fitted to a four-parameter logistic equation by Graphpad Prism software to derive the IC50 of each compound. The compounds disclosed in the present invention show enzyme activity values as shown in Table 1.

[Table 1]. The enzyme activity IC ₅₀ (nM) of the compound disclosed in the present invention Compound number Enzyme activity IC ₅₀ ( nM ) Compound number Enzyme activity IC ₅₀ ( nM ) 1 107 2 78 3 29 4 73 5 16 6 50 7 160 8 72 9 91 10 125 11 81 12 53 13 67 14 115 15 726 16 594 17 119 18 45 19 37 20 827 twenty one 47 22A 306 22B 6036 23A 106 23B 202 twenty four 118 25 117 26 8.2 27 52 28 105 29 twenty one 30 43 31 1437 32 63 33 516 34 42 35 38 36 36 37 26 38 52 39 30 40 7.3 41 twenty one 42 35 43 15 44A 45 44B 43 45 73 46 37 47 15 48 49 49 18 50A 41 50B 12 51 15 52 17 53 37 54A 13 54B 52 55 19 56 34 57 25 58 27 59 14 60 36 61 27 62 63 * - Indicates that no data is available.

It should be understood that even though the present invention refers to prior art publications, the content does not constitute an admission that publications form part of the general knowledge of any country in the field.

The disclosures of all publications, patents, patent applications and published patent applications mentioned in the present invention by identifying citation are hereby incorporated into the present invention in their entirety by reference.

Although the foregoing invention has been described in detail by means of illustrations and examples for the purpose of clear understanding, it will be clear to those skilled in the art that certain minor modifications or modifications can be implemented. Therefore, the description and examples should not be construed as limiting the scope of the present invention.

no

no

Claims (13)

A compound of chemical formula (I)

(I) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R ¹ , R ² and R ³ are each independently hydrogen, halogen, -C _1-8 alkyl, -C _2-8 alkene Group, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, pendant oxy, -CN, -NO ₂ , -OR ^a , -SO ₂ R ^a , -COR ^a , -CO ₂ R ^a , -CONR ^a R ^b , -C(=NR ^a )NR ^b R ^c , -NR ^a R ^b , -NR ^a COR ^b , -NR ^a CONR ^b R ^c , -NR ^a CO ₂ R ^b , -NR ^a SONR ^b R ^c , -NR ^a SO ₂ NR ^b R ^c , or -NR ^a SO ₂ R ^b , the -C _1-8 alkyl group, -C _2-8 alkenyl group, -C _{2 -8alkynyl} , cycloalkyl, heterocyclyl, aryl, or heteroaryl are optionally composed of halogen, hydroxy, -C _1-8 alkoxy, cycloalkyl, heterocyclyl, aryl, or hetero Aryl substitution; R ^a , R ^b , and R ^c are each independently hydrogen, -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, Aryl or heteroaryl; n is 0 or 1; each time R ⁴ and R ⁵ appear, they are independent halogen, -C _1-8 alkyl, -C _2-8 alkenyl, -C _{2- 8} alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, ^{_{oxo, -CN, -NO 2, -OR 4a}} , -SO 2 R 4a, -SO 2 NR 4a R 4b, -COR ^4a , -CO ₂ R ^4a , -CONR ^4a R ^4b , -C(=NR ^4a )NR ^4b R ^4c , -NR ^4a R ^4b , -NR ^4a COR ^4b , -NR ^4a CONR ^4b R ^4c , -NR ^4a CO ₂ R ^4b , -NR ^4a SONR ^4b R ^4c , -NR ^4a SO ₂ NR ^4b R ^4c , or -NR ^4a SO ₂ R ^4b , the -C _1-8 alkyl group, -C _2-8 alkenyl group,- C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are optionally substituted with at least one substituent R ^4d ; or when on adjacent carbon atoms of the phenyl ring, R ⁴ and R ⁵ and its attached two intervening carbon atoms together form a 5-membered to 8-membered ring containing 0, 1 or 2 heteroatoms as one or more ring members, the heteroatoms are independently selected from nitrogen, oxygen or Oxidized sulfur is required, and the ring is optionally substituted by at least one substituent R ^4e ; R ^4a , R ^4b , and R ^4c are each independently hydrogen, -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C _1-8 Alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are optionally substituted with at least one substituent R ^4e ; or (R ^4a And R ^4b ), (R ^4b and R ^4c ), or (R ^4c and R ^4a ) together with one or more of its attached atoms to form a 3- to 12-membered ring, the ring containing 0, 1 or 2 Additional heteroatoms are used as one or more ring members, the heteroatoms are independently selected from nitrogen, oxygen or optionally oxidized sulfur, and the rings are optionally substituted by at least one substituent R ^4e ; R ^4d and R ^4e are each independent Of hydrogen, halogen, -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, pendant oxy, -CN , -NO ₂ , -OR ^4f , -SO ₂ R ^4f , -SO ₂ NR ^4f R ^4g , -COR ^4f , -CO ₂ R ^4f , -CONR ^4f R ^4g , -C(=NR ^4f )NR ^4g R ^4h , -NR ^4f R ^4g , -NR ^4f COR ^4g , -NR ^4f CONR ^4g R ^4h , -NR ^4f CO ₂ R ^4f , -NR ^4f SONR ^4f R ^4g , -NR ^4f SO ₂ NR ^4g R ^4h , or -NR ^4f SO ₂ R ^4g , the -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are all as needed Substituted by at least one substituent selected from halogen, -C _1-8 alkyl, -OR ⁴ⁱ , -NR ⁴ⁱ R ^4j , cycloalkyl, heterocyclyl, aryl, or heteroaryl; R ^4f , R ^4g , R ^4h , R ⁴ⁱ and R ^4j are each independently hydrogen, -C _1-8 alkyl, C _1-8 alkoxy-C _1-8 alkyl-, -C _2-8 alkenyl, -C _{2 -8} Alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl; L ¹ is a single bond, alkylene, cycloalkylene, * ¹ -O-alkylene-** ¹ , * ¹ - alkylene -O - ** ^1, * ¹ -NH- alkylene - * ^1, * ¹ - alkylene ^{-NH - ** 1, * 1 -NHC} (O) - ** 1, * ¹ -C(O)NH-** ¹ , alkenylene, or alkynylene; where * ¹ refers to the position attached to Cy1, and ** ¹ refers to the position attached to the main chain; Cy1 is A fused heterocyclic group, a fused heteroaryl group, a fused aryl group, a fused cycloalkyl group, a fused cycloalkenyl group, or a fused cycloalkynyl group each optionally substituted by R ⁶ ; m is 0, 1, 2, 3 or 4; each time R ⁶ appears, each is an independent halogen, -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclic Group, aryl, heteroaryl, pendant oxygen Base, -CN, -NO ₂ , -OR ^6a , -SO ₂ R ^6a , -SO ₂ NR ^6a R ^6b , -COR ^6a , -CO ₂ R ^6a , -CONR ^6a R ^6b , -C(=NR ^6a ) NR ^6b R ^6c , -NR ^6a R ^6b , -NR ^6a COR ^6b , -NR ^6a CONR ^6b R ^6c , -NR ^6a CO ₂ R ^6b , -NR ^6a SONR ^6b R ^6c , -NR ^6a SO ₂ NR ^6b R ^6c , Or -NR ^6a SO ₂ R ^6b , the -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl The groups are optionally substituted with at least one substituent R ^6d ; or in the case of m series 2, two original R ⁶ and the attached carbon atoms together form 4 members, 5 members, 6 members, 7 members or 8 members A ring comprising 0, 1 or 2 heteroatoms as one or more ring members, the heteroatoms are independently selected from nitrogen, oxygen or optionally oxidized sulfur, and the ring optionally consists of at least one substituent R ^6e Substitution; R ^6a , R ^6b , R ^6c are each independently hydrogen, -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclic, aryl , Or heteroaryl, the -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group are optional Substituting at least one substituent R ^6e ; R ^6d and R ^6e are each independently hydrogen, halogen, -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, Heterocyclic group, aryl group, heteroaryl group, pendant oxy group, -CN, -NO ₂ , -OR ^6f , -SO ₂ R ^6f , -SO ₂ NR ^6f R ^6g , -COR ^6f , -CO ₂ R ^6f , -CONR ^6f R ^6g , -C(=NR ^6f )NR ^6g R ^6h , -NR ^6f R ^6g , -NR ^6f COR ^6g , -NR ^6f CONR ^6g R ^6h , -NR ^6f CO ₂ R ^6f , -NR ^6f SONR ^6f R ^6g , -NR ^6f SO ₂ NR ^6g R ^6h , or -NR ^6f SO ₂ R ^6g , the -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, ring The alkyl group, heterocyclic group, aryl group, or heteroaryl group are optionally selected from halogen, -C _1-8 alkyl group, -OR ⁶ⁱ , -NR ⁶ⁱ R ^6j , cycloalkyl, heterocyclic group, Substituent substitution of aryl or heteroaryl; R ^6f , R ^6g , R ^6h , R ⁶ⁱ , R ^6j are each independent hydrogen , Pendant oxy, -C _1-8 alkyl, C _1-8 alkoxy-C _1-8 alkyl-, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, hetero Cyclic, aryl, or heteroaryl. The compound according to claim 1, wherein R ¹ , R ² and R ³ are each hydrogen or -C _1-8 alkyl (preferably methyl). The compound according to claim 1, wherein n is 0, and R ⁴ is -C _1-8 alkyl or -CONR ^4a R ^4b , wherein the -C _1-8 alkyl is optionally composed of at least one substituent R ^{4d is} substituted, and R ^4a and R ^4b are as defined. The compound according to claim 1, wherein n is 0, and R ⁴ is -CONR ^4a R ^4b , wherein R ^4a and R ^4b are each independently hydrogen or -C _1-8 alkyl, preferably methyl Or ethyl. The compound of claim 1, wherein n is 0, and R ⁴ is -CONR ^4a R ^4b , wherein R ^4a and R ^{4b together} with the nitrogen atom to which they are attached form a 3- to 12-membered ring, the ring comprising 0, 1 or 2 additional heteroatoms are used as one or more ring members, the heteroatoms are independently selected from nitrogen, oxygen or optionally oxidized sulfur, and the rings are optionally substituted by at least one substituent R ^4e . The compound according to claim 5, wherein n is 0, and R ⁴ is -CONR ^4a R ^4b , wherein R ^4a and R ^4b and their attached nitrogen atoms together form 3 members, 4 members, 5 members, 6 members , A 7-membered or 8-membered monocyclic ring, the ring contains 0 or 1 additional heteroatoms as ring members, the heteroatoms are independently selected from nitrogen, oxygen or optionally oxidized sulfur, and the ring is optionally substituted by at least one The group R ^{4e is} substituted. The compound according to claim 1, wherein n is 0, and R ⁴ is optionally a -C _1-8 alkyl group substituted with at least one substituent R ^4d , preferably methyl or ethyl. The compound according to claim 1, wherein n is 1, and when it is on the adjacent carbon atom of the phenyl ring, R ⁴ and R ⁵ and the two intervening carbon atoms attached to it together form a nitrogen atom as A 5-membered, 6-membered, 7-membered or 8-membered ring of ring members is ^optionally substituted with at least one substituent R ^4e , wherein R ^4e is as defined for formula (I). The compound according to claim 1, wherein L ¹ is a single bond. The compound according to claim 1, wherein Cy1 is a bicyclic fused heterocyclic group, a bicyclic fused heteroaryl group, a bicyclic fused aryl group, a bicyclic fused cycloalkyl group, and a bicyclic fused ring substituted by R ⁶ as necessary. Cycloalkenyl or bicyclic fused cycloalkynyl. Or a pharmaceutically acceptable salt or stereoisomer thereof, the compound is selected from

1 2 3 4

5 6 7 8

9 10 11 12

13 14 15 16

17 18 19 20

twenty one 22A 22B 23A

23B twenty four 25 26

27 28 29 30

31 32 33 34

35 36 37 38

39 40 41 42

43 44A 44B 45

46 47 48 49

50A 50B 51 52

53 54A 54B 55

56 57 58 59

60 61 62 63

64 65 66 67

68 69 70 71

72 73 73 74

75 76 77 78

79 80 81 82

83 84 85 86

87 88 89 90

91 92 93 94

95 96 97 98

99 100 101 102

103 104 105

106 107 108 . A pharmaceutical composition comprising a therapeutically effective amount of a compound as described in any one of claims 1 to 11 of the application, its stereoisomers or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable Of excipients. A method for a subject, treating or preventing a disorder or disease that is responsive to the inhibition of HPK1 activity, the method comprising administering to the subject a compound as described in any one of claim 1 to claim 12 , Or its stereoisomer, or its pharmaceutically acceptable salt as HPK1 kinase inhibitor.