CN112243439A - Pyrrolo [2,3-B ] pyridines or pyrrolo [2,3-B ] pyrazines as HPK1 inhibitors and uses thereof - Google Patents

Abstract

Disclosed herein are compounds of formula (AIII) or (III), or stereoisomers thereof, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising the same. Also disclosed are methods of treating HPK 1-related disorders or diseases by using the compounds disclosed herein.

Description

Pyrrolo [2,3-B ] pyridines or pyrrolo [2,3-B ] pyrazines as HPK1 inhibitors and uses thereof

Cross Reference to Related Applications

This application claims the benefit of international patent application No. PCT/CN2018/091009 filed on 6/13/2018, the disclosure of which is hereby incorporated by reference in its entirety for all purposes.

Technical Field

The disclosure herein provides compounds and their compositions and methods of use. The compounds disclosed herein modulate (e.g., inhibit) hematopoietic progenitor 1(HPK1) activity and are useful for treating a variety of diseases, including cancer.

Background

HPK1 regulates a variety of functions of various immune cells and has been shown to have kinase activity in the T Cell Receptor (TCR) [ Liou J., et al, Immunity,2000.12(4): p.399-408], B Cell Receptor (BCR) [ Liou J., et al, Immunity,2000.12(4): p.399-408], transforming growth factor receptor (TGF-. beta.R) [ Wang, W., et al, J Biol Chem,1997.272(36): p.22771-5; activation of either the Zhou, G., et al, J Biol Chem,1999.274(19): pages 13133-8 ], or the Gs-coupled PGE2 receptor (EP2 and EP4) [ Ikegami, R., et al, J Immunol,2001.166(7): pages 4689-96 ] was induced. Overexpression of HPK1 inhibited TCR-induced activation of AP-1-dependent gene transcription in a kinase-dependent manner, suggesting that HPK1 is required to inhibit the Erk MAPK pathway [ Liou J., et al, Immunity,2000.12(4): page 399-.

In vitro HPK1-/-T cells have a lower TCR activation threshold, proliferate robustly, produce enhanced amounts of Th1 cytokines, and HPK 1-/-mice experience more severe autoimmune symptoms [ S.Sawasdsdikosol et al, Immunol Res,2012.54: 262-. In humans, HPK1 was down-regulated in peripheral blood mononuclear cells from psoriatic arthritis patients or T cells from Systemic Lupus Erythematosus (SLE) patients [ Batliwalla F.M., et al, Mol Med,2005.11(1-12): pages 21-9 ], suggesting that attenuation of HPK1 activity may contribute to patient autoimmunity. In addition, HPK1 may also control anti-tumor immunity via T cell-dependent mechanisms. In the Lewis lung cancer tumor model that generated PGE2, tumors developed more slowly in HPK1 knockout mice compared to wild-type mice [ us patent application No. 2007/0087988 ]. HPK 1-deficient T cells are more effective at controlling tumor growth and metastasis than wild-type T cells [ Alzabin, S., et al, Cancer Immunol Immunother,2010.59(3): p.419-29 ]. Similarly, BMDCs from HPK1 knockout mice more efficiently produced T cell responses to eradicate Lewis lung cancer than wild-type BMDCs [ Alzabin, S., et al, J Immunol,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 benzimidazoles, WO 2018049152 a1 discloses pyrazolopyrimidines, WO 2018049191 a1 discloses pyrazolopyridinones, and WO 2018049200 a1 and WO 2018049214 a1 disclose pyrazolopyridines.

Pyrrolo [2,3-b ] pyridine derivatives have not been reported as HPK1 modulators, although WO 2008124849 discloses pyrrolo [2,3-b ] pyridines as Abelson tyrosine kinase, rahn receptor tyrosine kinase, Met receptor tyrosine kinase, Fms-like tyrosine kinase-3, aurora kinase, p 21-activated kinase-4, or 3-phosphoinositide-dependent kinase-1.

Disclosure of Invention

In a first embodiment, disclosed herein are pyrrolo [2,3-b ] pyridine or pyrrolo [2,3-b ] pyrazine derivatives of formula (I). The first embodiment includes the following aspects:

aspect 1: a compound of formula (I)

Or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

wherein

X¹Is C or N;

R¹is hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^1a、-SO₂R^1a、-COR^1a、-CO₂R^1a、-CONR^1aR^1b、-C(＝NR^1a)NR^1bR^1c、-NR^1aR^1b、-NR^1aCOR^1b、-NR^1aCONR^1bR^1c、-NR^1aCO₂R^1b、-NR^1aSONR^1bR^1c、-NR^1aSO₂NR^1bR^1cor-NR^1aSO₂R^1bsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally substituted with halogen, hydroxy, -C _1-8Alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; provided that X is¹In the case of N, R is absent¹；

R^1a、R^1bAnd R^1cEach independently is hydrogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^1dSubstitution; or

(R^1aAnd R^1b)、(R^1bAnd R^1c) Or (R)^1cAnd R^1a) Together with the atom or atoms to which they are attached form a 3 to 9 membered ring containing 0, 1 or 2 further heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulphur as one or more ring members, said ring being optionally substituted with at least one substituent R^1eSubstitution;

wherein R is^1dAnd R^1eEach independently is hydrogen, halogen, -C_1-8Alkyl radical、-C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^1f、-SO₂R^1f、-COR^1f、-CO₂R^1f、-CONR^1fR^1g、-C(＝NR^1f)NR^1gR^1h、-NR^1fR^1g、-NR^1fCOR^1g、-NR^1fCONR^1gR^1h、-NR^1fCO₂R^1g、-NR^1fSONR^1gR^1h、-NR^1fSO₂NR^1gR^1hor-NR^1fSO₂R^1gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR¹ⁱ、-NR¹ⁱR^1jCycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^1f、R^1g、R^1h、R¹ⁱand R^1jEach independently is hydrogen, -C _1-8Alkyl radical, C_1-8alkoxy-C_1-8Alkyl-, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R²and R³Each independently is hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^2a、-SO₂R^2a、-COR^2a、-CO₂R^2a、-CONR^2aR^2b、-C(＝NR^2a)NR^2bR^2c、-NR^2aR^2b、-NR^2aCOR^2b、-NR^2aCONR^2bR^2c、-NR^2aCO₂R^2b、-NR^2aSONR^2bR^2c、-NR^2aSO₂NR^2bR^2cor-NR^2aSO₂R^2bsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally substituted with halogen, hydroxy, -C_1-8Alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^2a、R^2band R^2cEach independently is hydrogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

L¹is a single bond, alkylene, cycloalkylene¹-O-alkylene-a¹、*¹-alkylene-O-)¹、*¹-NH-alkylene-a¹、*¹-alkylene-NH-x¹、*¹-NHC(O)-**¹、*¹-C(O)NH-**¹Alkenylene, or alkynylene;

wherein¹Refers to the position of attachment with Cy1, and¹refers to a group bonded to the main chain (e.g. pyrrolo [2,3-b ]]Pyridine or pyrrolo [2,3-b]Pyrazine ring) attachment position;

L²is a single bond, alkylene, cycloalkylene²-O-alkylene-a²、*²-alkylene-O-)²、*²-NH-alkylene-a²、*²-alkylene-NH-x²、*²-NHC(O)-**²、*²-C(O)NH-**²Alkenylene, or alkynylene;

wherein²Refers to the position of attachment with Cy2, and ²Refers to a group bonded to the main chain (e.g. pyrrolo [2,3-b ]]Pyridine or pyrrolo [2,3-b]Pyrazine ring) attachment position;

cy1 is cycloalkyl, phenyl, 5-or 6-membered heterocyclyl or 5-or 6-membered heteroaryl or 7-to 12-membered bicyclic fused heteroaryl or heterocyclyl, each of which is substituted with one R⁴Substituted and optionally substituted by R⁵Substitution;

n is 0, 1 or 2;

R⁴and R⁵At each occurrence thereof, is independently halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^4a、-SO₂R^4a、-SO₂NR^4aR^4b、-COR^4a、-CO₂R^4a、-CONR^4aR^4b、-C(＝NR^4a)NR^4bR^4c、-NR^4aR^4b、-NR^4aCOR^4b、-NR^4aCONR^4bR^4c、-NR^4aCO₂R^4b、-NR^4aSONR^4bR^4c、-NR^4aSO₂NR^4bR^4cor-NR^4aSO₂R^4bsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^4dSubstitution;

R^4a、R^4band R^4cEach independently is hydrogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^4eSubstitution; or

(R^4aAnd R^4b)、(R^4bAnd R^4c) Or (R)^4cAnd R^4a) Together with the atom or atoms to which they are attached form a 3 to 12 membered ring containing 0, 1 or 2 further heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulphur as one or more ring members, said ring being optionally substituted with at least one substituent R ^4eSubstitution;

R^4dand R^4eEach independently is hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^4f、-SO₂R^4f、-SO₂NR^4fR^4g、-COR^4f、-CO₂R^4f、-CONR^4fR^4g、-C(＝NR^4f)NR^4gR^4h、-NR^4fR^4g、-NR^4fCOR^4g、-NR^4fCONR^4gR^4h、-NR^4fCO₂R^4f、-NR^4fSONR^4fR^4g、-NR^4fSO₂NR^4gR^4hor-NR^4fSO₂R^4gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁴ⁱ、-NR⁴ⁱR^4jCycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^4f、R^4g、R^4h、R⁴ⁱand R^4jEach independently is hydrogen, -C_1-8Alkyl radical, C_1-8alkoxy-C_1-8Alkyl-, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

cy2 is cycloalkylene, heterocyclylene, arylene, or heteroarylene, each of which is optionally substituted with R⁶Substitution;

R⁶is halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^6a、-SO₂R^6a、-SO₂NR^6aR^6b、-COR^6a、-CO₂R^6a、-CONR^6aR^6b、-C(＝NR^6a)NR^6bR^6c、-NR^6aR^6b、-NR^6aCOR^6b、-NR^6aCONR^6bR^6c、-NR^6aCO₂R^6b、-NR^6aSONR^6bR^6c、-NR^6aSO₂NR^6bR^6cor-NR^6aSO₂R^6bsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^6dSubstitution;

R^6a、R^6band R^6cEach independently is hydrogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said-C_1-8Alkyl, -C _2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^6eSubstitution;

R^6dand R^6eEach independently is hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^6f、-SO₂R^6f、-SO₂NR^6fR^6g、-COR^6f、-CO₂R^6f、-CONR^6fR^6g、-C(＝NR^6f)NR^6gR^6h、-NR^6fR^6g、-NR^6fCOR^6g、-NR^6fCONR^6gR^6h、-NR^6fCO₂R^6f、-NR^6fSONR^6fR^6g、-NR^6fSO₂NR^6gR^6hor-NR^6fSO₂R^6gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁶ⁱ、-NR⁶ⁱR^6jCycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^6f、R^6g、R^6h、R⁶ⁱand R^6jEach independently is hydrogen, -C_1-8Alkyl radical, C_1-8alkoxy-C_1-8Alkyl-, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroarylA group;

m is 0, 1, 2, 3 or 4, provided that the valence theory has been met (i.e., the resulting valence is chemically possible);

L³is a single bond or C_1-8An alkylene group;

cy3 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted with R⁷Substituted and optionally substituted by R⁸Substitution;

R⁷and R⁸Each independently is halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^7a、-SO₂R^7a、-SO₂NR^7aR^7b、-COR^7a、-CO₂R^7a、-CONR^7aR^7b、-C(＝NR^7a)NR^7bR^7c、-NR^7aR^7b、-NR^7aCOR^7b、-NR^7aCONR^7bR^7c、-NR^7aCO₂R^7b、-NR^7aSONR^7bR^7c、-NR^7aSO₂NR^7bR^7cor-NR^7aSO₂R^7bsaid-C _1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^7dSubstitution;

R^7a、R^7band R^7cEach independently is hydrogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^7eSubstitution;

R^7dand R^7eEach independently is hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxoSubstituent, -CN, -NO₂、-OR^7f、-SO₂R^7f、-SO₂NR^7fR^7g、-COR^7f、-CO₂R^7f、-CONR^7fR^7g、-C(＝NR^7f)NR^7gR^7h、-NR^7fR^7g、-NR^7fCOR^7g、-NR^7fCONR^7gR^7h、-NR^7fCO₂R^7f、-NR^7fSONR^7fR^7g、-NR^7fSO₂NR^7gR^7hor-NR^7fSO₂R^7gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁷ⁱ、-NR⁷ⁱR^7jCycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^7f、R^7g、R^7h、R⁷ⁱand R^7jEach independently is hydrogen, -C_1-8Alkyl radical, C_1-8alkoxy-C_1-8Alkyl-, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

p is 0, 1, 2 or 3, provided that the valence theory is satisfied.

Aspect 2: a compound according to aspect 1, wherein R²And R³Each independently is hydrogen, halogen or cyano.

Aspect 3: a compound according to aspect 1, wherein R²And R³Is hydrogen.

Aspect 4: the compound according to any one of aspects 1 to 3, wherein L¹Is a single bond, alkylene¹-O-alkylene-a¹、*¹-NH-alkylene-a¹、*¹-NHC(O)-**¹Or¹-C(O)NH-**¹(ii) a And L is²Is a single bond, alkylene, alkenylene, or alkynylene.

Aspect 5: the compound according to aspect 4, wherein L¹Is a single bond, -CH₂-、-(CH₂)₂-、-CH(CH₃)-、-C≡C-、*¹-O-CH(CH₃)-**¹、*¹-O-CH₂-**¹、*¹-NH-CH₂-**¹、*¹-NH-CH(CH₃)-**¹Or¹-NHC(O)-**¹And L is²Is a single bond, -C ≡ C-, or-CH ═ CH-.

Aspect 6: the compound according to aspect 4, wherein L¹And L²Each is a single bond.

Aspect 7: the compound according to any one of aspects 1 to 6, wherein R¹Is hydrogen, -OR^1aor-NR^1aR^1bWherein R is^1aAnd R^1bAs defined for formula (I).

Aspect 8: a compound according to aspect 7, wherein R¹Is hydrogen.

Aspect 9: a compound according to aspect 7, wherein R¹is-OR^1aWherein R is^1aIs hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl.

Aspect 10: a compound according to aspect 7, wherein R¹is-NR^1aR^1bWherein R is^1aAnd R^1bEach independently is hydrogen or-C_1-8Alkyl radical of formula (I), said_1-8Alkyl optionally substituted by at least one substituent R^1dAnd (4) substitution.

Aspect 11: a compound according to aspect 10, wherein R^1dIs heterocyclyl, aryl, or-NR^1fR^1gWherein said heterocyclyl, or aryl is optionally substituted with halogen, -C _1-8Alkyl, -OR¹ⁱor-NR¹ⁱR^1jIs substituted in which R^1f、R^1g、R¹ⁱAnd R^1jEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl.

Aspect 12: a compound according to aspect 11, wherein the aryl is phenyl.

Aspect 13: a compound according to aspect 11, wherein said heterocyclyl is a 4, 5, 6, or 7 membered ring containing as ring members one heteroatom selected from nitrogen, oxygen or optionally oxidised sulfur, preferably tetrahydropyranyl or piperidinyl.

Aspect 14: a compound according to aspect 7, wherein R¹is-NR^1aR^1bWherein R is^1aAnd R^1bTogether with the heteroatom to which they are attached form a 3-to 6-membered ring, said ring comprising 0, 1 or 2 further heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulfur as one or more ring members, said ring being optionally substituted with at least one substituent R^1eIs substituted in which R^1eIs as defined above.

Aspect 15: a compound according to aspect 14, wherein R¹is-NR^1aR^1bWherein R is^1aAnd R^1bTogether with the heteroatom to which they are attached form a 4-, 5-or 6-membered ring, which ring comprises 0 or 1 further heteroatom independently selected from nitrogen, oxygen or optionally oxidised sulphur as one or more ring members, which ring is optionally substituted with at least one substituent R ^1eIs substituted in which R^1eIs as defined above.

Aspect 16: the compound according to aspect 14 or 15, wherein R^1eis-OR^1f、-CONR^1fR^1gor-NR^1fR^1gWherein R is^1fAnd R^1gEach independently is hydrogen, or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl.

Aspect 17: a compound according to any one of aspects 1 to 16, wherein Cy1 is a 5 or 6 membered heterocyclyl containing one or two heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulfur as one or more ring members, said heterocyclyl being substituted with one R⁴Substituted and optionally substituted by R⁵Substituted, and R is in case the heterocycle is 6-membered⁴Relative to the attachment point L¹At the para position (or 4 position) of said heterocyclyl, or Cy1 is a 7-to 10-membered bicyclic fused heterocyclyl containing as one or more ring members one or two or three heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur, said heterocyclyl being optionally substituted with R⁵Is substituted in which R⁵Is halogen, -C_1-8Alkyl, oxo, or aryl.

Aspect 18: a compound according to aspect 17, wherein said 6-membered heterocyclyl is piperidinyl, tetrahydropyridinyl, or piperazinyl or said 7 to 10-membered bicyclic fused heterocyclyl is dihydropyridinooxazine (preferably 2, 3-dihydro-1H-pyrido [2,3-b ] [1,4] oxazine), dihydrobenzoxazoloazepinyl (preferably 5-oxo-3, 4-dihydrobenzo [ f ] [1,4] oxoazepinyl), isoindolinyl (preferably 1-oxo-2-methylisoindoline-5-yl), dihydroisoquinolinyl (preferably 1-oxo-2-methyl-3, 4-dihydroisoquinolin-6-yl), tetrahydroisoquinolinyl (preferably 2-methyl-1-oxo-1, 2,3, 4-tetrahydroisoquinolin-6-yl), benzoazepine (preferably 2,3,4, 5-tetrahydro-1-oxo-2-benzazepin-6-yl), benzoxazepin (preferably 5-oxo-2, 3,4, 5-tetrahydro-1, 4-benzoxazpin-8-yl), dihydrobenzoxazine (preferably 3, 4-dihydro-2H-1, 4-benzoxazin-6-yl).

Aspect 19: the compound according to aspect 18, wherein said 6-membered heterocyclyl is

And n is 0, 1 or 2.

Aspect 20: a compound according to any one of aspects 1 to 16, wherein Cy1 is a 5 or 6 membered heteroaryl group comprising as one or more ring members one or two heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulfur, said heteroaryl group being substituted by one R⁴Substituted and optionally substituted by R⁵Substituted, and R is in the case that the heteroaryl is 6-membered⁴Relative to the attachment point L¹In the para (or 4) position of the heteroaryl group.

Aspect 21: a compound according to aspect 20, wherein the 5 or 6 membered heteroaryl is pyrazolyl, oxazolyl, pyridinyl, or pyrimidinyl.

Aspect 22: the compound according to aspect 21, wherein the 5-membered heteroaryl is

Or said 6-membered heteroaryl is

And n is 0, 1 or 2.

Aspect 23: the compound according to any one of aspects 1-16, wherein Cy1 is in relative relationship to L¹By an R in position 4 of the attached position⁴Is substituted and substituted by R⁵Substituted phenyl, and n is 0, 1 or 2.

Aspect 24: a compound according to any one of aspects 17 to 23, wherein Cy1 is substituted by one R in the 4-position where Cy1 is 6-membered⁴Substituted and n is 0.

Aspect 25: the compound according to any one of aspects 17 to 24, wherein Cy1 is substituted by one R in the 4-position where Cy1 is 6-membered ⁴Is substituted and substituted by R⁵And n is 1; and said R is⁵Is halogen or-C_1-8An alkyl group.

Aspect 26: the compound according to aspect 24 or 25, wherein R⁴Is a halogen.

Aspect 27: the compound according to any one of aspects 17-24, wherein R⁴is-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^4dAnd (4) substitution.

Aspect 28: a compound according to aspect 27, wherein R^4dIs hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^4f、-SO₂R^4f、-SO₂NR^4fR^4g、-COR^4f、-CO₂R^4f、-CONR^4fR^4g、-C(＝NR^4f)NR^4gR^4h、-NR^4fR^4g、-NR^4fCOR^4g、-NR^4fCONR^4gR^4h、-NR^4fCO₂R^4f、-NR^4fSONR^4fR^4g、-NR^4fSO₂NR^4gR^4hor-NR^4fSO₂R^4gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁴ⁱor-NR⁴ⁱR^4jWherein R is^4f、R^4g、R^4h、R⁴ⁱAnd R is^4jEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl. Aspect 29: the compound according to aspect 27 or 28, wherein R⁴Is optionally substituted by cycloalkyl, aryl, heterocyclyl, -OR^4f、-CONR^4fR^4g、-NR^4fR^4gor-NR^4fSO₂R^4gsubstituted-C_1-8Alkyl, preferably-C _1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl, wherein said cycloalkyl, aryl or heterocyclyl is optionally substituted by halogen, -C_1-8Alkyl, OR-OR⁴ⁱIs substituted in which R^4f、R^4gAnd R⁴ⁱEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

Aspect 30: a compound according to aspect 29, wherein said heterocyclyl is optionally substituted with-C_1-8Alkyl or-C_1-8Alkoxy-substituted 4 to 7 membered rings comprising one or two heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulfur, preferably 4, 5, 6 or 7 membered saturated rings comprising one nitrogen or oxygen atom as a ring member.

Aspect 31: according to aspect 29A compound of formula (I) wherein R⁴Is a methyl group, an ethyl group,

Aspect 32: the compound according to aspect 27 or 28, wherein R⁴Is optionally halogen, -C_1-8Alkyl, -OR^4for-NR^4fR^4gSubstituted aryl radicals, in which R is^4fAnd R^4gEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

Aspect 33: a compound according to aspect 32, wherein the aryl is phenyl.

Aspect 34: a compound according to aspect 32, wherein R⁴Is that

Aspect 35: the compound according to aspect 27 or 28, wherein R⁴Is optionally substituted by halogen, oxo, -C _1-8Alkyl, -OR^4for-NR^4fR^4gSubstituted heteroaryl, wherein R^4fAnd R^4gEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

Aspect 36: a compound according to aspect 35, wherein the heteroaryl is a 5, 6 or 7 membered heteroaryl comprising one or two or three heteroatoms independently selected from oxygen, nitrogen or sulphur.

Aspect 37: a compound according to aspect 36, the heteroaryl is pyrrolyl, pyridinyl, pyrimidinyl, pyrazolyl, oxazolyl, or triazolyl.

Aspect 38: a compound according to aspect 35, wherein R⁴Is that

Aspect 39: the compound according to aspect 27 or 28, wherein R⁴Is optionally substituted by halogen, oxo, -C_1-8Alkyl, -OR^4for-NR^4fR^4gSubstituted heterocyclic radical, wherein R^4fAnd R^4gEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

Aspect 40: the compound according to aspect 39, wherein said heterocyclyl is a 4 to 7 membered ring comprising one or two heteroatoms independently selected from nitrogen, oxygen or sulfur, preferably a 4, 5, 6, or 7 membered saturated ring comprising one nitrogen or oxygen atom as a ring member.

Aspect 41: a compound according to aspect 40, wherein said heterocyclyl is piperidinyl, pyrrolidinyl, or azepanyl.

Aspect 42: a compound according to any one of aspects 39-41, wherein R⁴Is that

Aspect 43: the compound according to aspect 27 or 28, wherein R⁴Is optionally substituted by halogen, oxo, -C_1-8Alkyl, -OR^4for-NR^4fR^4gSubstituted cycloalkyl, wherein R^4fAnd R^4gEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

Aspect 44: a compound according to aspect 43, wherein R⁴Is optionally substituted by-C_1-8Alkyl (preferably methyl), -OR^4for-NR^4fR^4gSubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, wherein R is^4fAnd R^4gEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

Aspect 45: the compound according to aspects 43 or 44, wherein R⁴Is that

Aspect 46: a compound according to any one of aspects 17 to 24, wherein

R⁴is-CONR^4aR^4b，

Wherein R is^4aAnd R^4bEach independently is hydrogen, -C_1-8Alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said-C_1-8Each of the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is optionally substituted with at least one substituent R^4eSubstitution;

R^4eis hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO ₂、-OR^4f、-SO₂R^4f、-SO₂NR^4fR^4g、-COR^4f、-CO₂R^4f、-CONR^4fR^4g、-C(＝NR^4f)NR^4gR^4h、-NR^4fR^4g、-NR^4fCOR^4g、-NR^4fCONR^4gR^4h、-NR^4fCO₂R^4f、-NR^4fSONR^4fR^4g、-NR^4fSO₂NR^4gR^4hor-NR^4fSO₂R^4gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁴ⁱ、-NR⁴ⁱR^4jCycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^4f、R^4g、R^4h、R⁴ⁱand R^4jEach independently is hydrogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

Aspect 47: a compound according to aspect 46, wherein

R⁴is-CONR^4aR^4bWherein

R^4aIs hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl; and is

R^4bIs optionally substituted by at least one substituent R^4esubstituted-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl, ethyl or propyl;

R^4eis hydrogen, halogen, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^4f、-SO₂R^4f、-SO₂NR^4fR^4g、-COR^4f、-CO₂R^4f、-CONR^4fR^4g、-C(＝NR^4f)NR^4gR^4h、-NR^4fR^4g、-NR^4fCOR^4g、-NR^4fCONR^4gR^4h、-NR^4fCO₂R^4f、-NR^4fSONR^4fR^4g、-NR^4fSO₂NR^4gR^4hor-NR^4fSO₂R^4gEach of said cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one substituent selected from the group consisting of halogen, -C_1-8Alkyl, -OR⁴ⁱor-NR⁴ⁱR^4jSubstituted with the substituent(s); and is

R^4f、R^4g、R^4h、R⁴ⁱAnd R^4jEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

Aspect 48: a compound according to aspect 47, wherein R^4eIs optionally substituted by-C_1-8Alkyl, hydroxy, or-C _1-8Alkoxy, preferably methyl, substitutedA 4 to 7 membered ring comprising one or two heteroatoms independently selected from nitrogen, oxygen or sulfur, preferably a 4, 5, 6, or 7 membered saturated ring comprising one nitrogen or oxygen atom as a ring member, or a 4, 5, 6, or 7 membered heteroaryl ring comprising one or two heteroatoms selected from nitrogen and oxygen as a ring member.

Aspect 49: a compound according to aspect 48, wherein R^4eIs azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholino, piperazinyl, or pyrazolyl, each of which is optionally substituted with methyl, ethyl, hydroxy, methoxy, amino, or halogen.

Aspect 50: a compound according to aspect 47, wherein R^4eIs optionally substituted by at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁴ⁱor-NR⁴ⁱR^4jPhenyl substituted with the substituent of (1); wherein R is⁴ⁱAnd R^4jEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

Aspect 51: a compound according to aspect 47, wherein R^4eis-OR^4fWherein R is^4fIs hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

Aspect 52: a compound according to aspect 47, wherein R^4eis-NR^4fR^4gWherein R is ^4fAnd R^4gEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

Aspect 53: the compound according to any one of aspects 46-52, wherein

R⁴Is that

Aspect 54: a compound according to aspect 46, wherein

R⁴is-CONR^4aR^4bWherein

R^4aIs hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl; and is

R^4bIs cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with at least one substituent R^4eSubstitution;

R^4eis hydrogen, halogen, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^4f、-SO₂R^4f、-SO₂NR^4fR^4g、-COR^4f、-CO₂R^4f、-CONR^4fR^4g、-C(＝NR^4f)NR^4gR^4h、-NR^4fR^4g、-NR^4fCOR^4g、-NR^4fCONR^4gR^4h、-NR^4fCO₂R^4f、-NR^4fSONR^4fR^4g、-NR^4fSO₂NR^4gR^4hor-NR^4fSO₂R^4gEach of said cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one substituent selected from the group consisting of halogen, -C_1-8Alkyl, -OR⁴ⁱor-NR⁴ⁱR^4jSubstituted with the substituent(s); and is

R^4f、R^4g、R^4h、R⁴ⁱAnd R^4jEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

Aspect 55: a compound according to aspect 54, wherein R^4bIs optionally substituted by at least one substituent R^4eSubstituted monocyclic ring C_3-8Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl), R^4eIs halogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl), -OR ⁴ⁱor-NR⁴ⁱR^4jWherein R is⁴ⁱAnd R^4jEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

Aspect 56: a compound according to aspect 54, wherein R^4bIs optionally substituted by at least one substituent R^4eSubstituted heterocyclic group, said R^4eIs halogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl), -OR⁴ⁱor-NR⁴ⁱR^4jWherein R is⁴ⁱAnd R^4jEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

Aspect 57: a compound according to aspect 56, wherein R^4bIs a 4 to 7 membered ring containing one or two heteroatoms independently selected from nitrogen, oxygen or sulfur, preferably a 4, 5, 6 or 7 membered saturated ring containing one nitrogen or oxygen atom as a ring member.

Aspect 58: a compound according to aspect 57, wherein R^4bIs azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, tetrahydrofuranyl, tetrahydropyranyl, or morpholino.

Aspect 59: a compound according to aspect 54, wherein R⁴Is that

Aspect 60: the compound according to any one of aspects 17-24, wherein R⁴is-CONR^4aR^4b，R^4aAnd R^4bTogether with the nitrogen atom to which they are attached form a 3-to 12-membered ring, which ring comprises as one or more ring members 0, 1 or 2 further heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulfur, which ring is optionally substituted with at least one substituent R ^4eSubstitution;

R^4eis hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^4f、-SO₂R^4f、-SO₂NR^4fR^4g、-COR^4f、-CO₂R^4f、-CONR^4fR^4g、-C(＝NR^4f)NR^4gR^4h、-NR^4fR^4g、-NR^4fCOR^4g、-NR^4fCONR^4gR^4h、-NR^4fCO₂R^4f、-NR^4fSONR^4fR^4g、-NR^4fSO₂NR^4gR^4hor-NR^4fSO₂R^4gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁴ⁱ、-NR⁴ⁱR^4jCycloalkyl, heterocyclyl, aryl, or heteroaryl; and is

R^4f、R^4g、R^4h、R⁴ⁱAnd R^4jEach independently is hydrogen, -C_1-8Alkyl, or C_1-8alkoxy-C_1-8An alkyl group-.

Aspect 61: a compound according to aspect 60, wherein R is^4aAnd R^4bThe ring formed with the nitrogen atom to which they are attached is a monocyclic 3 to 8 membered ring comprising as one or more ring members 0, 1 or 2 further heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulfur, the ring being optionally substituted with at least one substituent R^4eAnd (4) substitution.

Aspect 62: a compound according to aspect 61, wherein R is^4aAnd R^4bThe ring formed with the nitrogen atom to which they are attached is a 4-, 5-, 6-or 7-membered ring containing 0 additional heteroatoms (e.g., azetidinyl, pyrrolidinyl, piperidinyl, and azepanyl), optionally substituted with at least one substituent R ^4eAnd (4) substitution.

Aspect 63: a compound according to aspect 61, wherein R is^4aAnd R^4bThe ring formed with the nitrogen atom to which they are attached is a ring containing 1 additional nitrogen or oxygen heteroA 4-, 5-, 6-or 7-membered ring having an atom as a ring member (e.g. morpholino or piperazinyl), said ring optionally being substituted with at least one substituent R^4eAnd (4) substitution.

Aspect 64: a compound according to any one of aspects 61-63, wherein R^4eis-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl OR ethyl), -OR^4f、-NR^4fR^4gsaid-C_1-8Alkyl is optionally substituted by at least one substituent selected from halogen, -NR⁴ⁱR^4jOr cycloalkyl, wherein R is^4f、R^4g、R⁴ⁱAnd R^4jEach independently is hydrogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl), or C_1-8alkoxy-C_1-8Alkyl- (preferably methoxy-C)_1-6Alkyl-, more preferably methoxy-ethyl-).

Aspect 65: a compound according to aspect 64, wherein R^4eIs methoxy, methoxy-ethoxy-, -NH₂、-N(CH₃)₂、NH(CH₃) Hydroxy, methyl, ethyl, N (CH)₃)₂-(CH₂)₂-, or cyclopropyl-CH₂-。

Aspect 66: the compound according to any one of aspects 61-65, wherein

R⁴Is that

Aspect 67: the compound according to aspect 60, wherein said ring is a bicyclic 7 to 12 membered ring comprising as one or more ring members 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulfur, said ring being optionally substituted with at least one substituent R ^4eAnd (4) substitution.

Aspect 68: a compound according to aspect 60, wherein R^4eis-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl or ethyl) or cycloalkyl (preferablyC_3-8Cycloalkyl, more preferably cyclopropyl).

Aspect 69: a compound according to aspect 67 or 68, wherein the ring is a bicyclic spiro 7-to 12-membered ring.

Aspect 70: a compound according to aspect 69, wherein the ring is azaspiro [3.3] heptane, azaspiro [3.5] nonane, azaspiro [3.4] octane, azaspiro [5.5] undecane, or azaspiro [4.5] decane, each containing 0 or 1 additional nitrogen or oxygen atom as a ring member.

Aspect 71: the compound according to aspect 67 or 68, wherein R⁴Is that

Aspect 72: the compound according to any one of aspects 17-24, wherein R⁴is-SO₂R^4a、-SO₂NR^4aR^4b、-NR^4aSO₂R^4b、-NR^4aCOR^4b、-CO₂R^4a、-COR^4a、-NR^4aR^4bor-NR^4aCONR^4bR^4cWherein

R^4a、R^4bAnd R^4cEach independently is hydrogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl or ethyl), cycloalkyl (preferably monocyclic-C)_3-8Cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), heterocyclyl, aryl (preferably phenyl), or heteroaryl, said-C_1-8Each of the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is optionally substituted with at least one substituent R^4eSubstitution;

R^4eis hydrogen, halogen, -C_1-8Alkyl (preferably-C) _1-6Alkyl, more preferably methyl or ethyl), cycloalkyl (preferably monocyclic-C)_3-8Cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl OR cyclohexyl), heterocyclyl, aryl, heteroaryl, -OR^4for-NR^4fR^4g；

R^4fAnd R^4gEach independently is hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl or ethyl).

Aspect 73: a compound according to aspect 72, wherein R⁴is-SO₂R^4aWherein R is^4ais-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl or ethyl) or cycloalkyl (preferably monocyclic-C)_3-8Cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), said-C_1-8Alkyl and cycloalkyl are each optionally substituted by at least one substituent R as defined in formula (I)^4eAnd (4) substitution.

Aspect 74: a compound according to aspect 73, wherein R⁴Is that

Aspect 75: a compound according to aspect 72, wherein R⁴is-SO₂NR^4aR^4bWherein R is^4aAnd R^4bEach independently is hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl or ethyl).

Aspect 76: a compound according to aspect 75, wherein R⁴Is that

Aspect 77: a compound according to aspect 72, wherein R⁴is-NR^4aSO₂R^4b，

Wherein

R^4aAnd R^4bEach independently is hydrogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl or ethyl), cycloalkyl (preferably monocyclic-C)_3-8Cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), or aryl, preferably phenyl, said-C _1-8Each of the alkyl, cycloalkyl, or aryl groups being optionally substituted with at least one substituent R^4eSubstitution;

R^4eis-OR^4fAnd R is^4fIs hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl or ethyl.

Aspect 78: a compound according to aspect 77, wherein R⁴Is that

Aspect 79: a compound according to aspect 72, wherein R⁴is-NR^4aCOR^4bWherein R is^4aAnd R^4bEach independently is hydrogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl group) of said-C_1-8Alkyl is optionally substituted by R^4eSubstituted, said R^4eIs cycloalkyl (preferably monocyclic-C)_3-8Cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl OR cyclohexyl), heterocyclyl (preferably a monocyclic 4-, 5-OR 6-membered ring containing one nitrogen OR oxygen atom as a ring member), -OR^4for-NR^4fR^4g(ii) a Wherein R is^4fAnd R^4gEach independently is hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl or ethyl).

Aspect 80: a compound according to aspect 79, wherein R⁴Is that

Aspect 81: a compound according to aspect 72, wherein R⁴is-NR^4aCONR^4bR^4cWherein R is^4a、R^4bAnd R^4cEach independently is hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl or ethyl), said-C_1-8Alkyl is optionally substituted by R^4eSubstitution; wherein R is^4eis-NR^4fR^4g；R^4fAnd R^4gEach independently is hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl or ethyl).

Aspect 82: a compound according to aspect 81, wherein R⁴Is that

Aspect 83: a compound according to aspect 72, wherein R⁴is-COR^4aWherein R is^4ais-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl or ethyl) or a heterocyclyl (preferably a monocyclic 4-, 5-or 6-membered ring containing as ring members one nitrogen or oxygen atom), optionally substituted with one R^4eSubstituted, R^4eis-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl or ethyl).

Aspect 84: a compound according to aspect 83, wherein R⁴Is that

Aspect 85: the compound according to any one of aspects 17-24, wherein R⁴is-OR^4a，R^4ais-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl or ethyl or propyl) or heterocyclyl (preferably selected from tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl), said-C_1-8Alkyl or heterocyclyl being optionally substituted by at least one substituent R^4eSubstitution; r^4eIs hydrogen, halogen, cycloalkyl, aryl, -CONR^4fR^4g、-CO₂R^4f、-C(＝NR^4f)NR^4gR^4hor-NR^4fR^4g；R^4f、R^4gAnd R^4hEach independently is hydrogen, or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl).

Aspect 86: a compound according to aspect 85, wherein R⁴Is a methoxy group, an ethoxy group,

Aspect 87: the compound according to any one of aspects 1 to 16, wherein Cy1 is substituted by one R in position 4⁴Substituted phenyl and n is 0, wherein R ⁴is-CONR as defined in any one of aspects 46 to 71^4aR^4b。

Aspect 88: the compound according to any one of aspects 1-87, wherein Cy2 is phenylene, m is 0, 1, or 2, R⁶Is as defined for formula (I).

Aspect 89: a compound according to aspect 88, wherein Cy2 is phenylene, m is 2, one R⁶At a position opposite to the attachment point L²At position 3 of (3), another R⁶At a position opposite to the attachment point L²At position 5 of and L³At a position opposite to the attachment point L²At 4 bits of (1).

Aspect 90: the compound according to aspect 88, wherein Cy2 is phenylene, m is 1, R⁶At a position opposite to the attachment point L²At position 3 or 5 of and L³At a position opposite to the attachment point L²At 4 bits of (1).

Aspect 91: a compound according to any one of aspects 1-87, wherein Cy2 is a 5 or 6 membered heteroarylene comprising one or two heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur, m is 0, 1, or 2, and R is⁶Is as defined for formula (I).

Aspect 92: the compound according to aspect 91, wherein Cy2 is a pyrimidine, pyridine, or pyrazole ring.

Aspect 93: a compound according to any one of aspects 1-87, wherein Cy2 is a 4, 5, 6, or 7 membered heterocyclylene comprising one or two heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur.

Aspect 94: a compound according to aspect 93, wherein Cy2 is a monocyclic 4-, 5-, 6-, or 7-membered saturated heterocyclylene group containing one nitrogen atom as a ring member.

Aspect 95: the compound according to any one of aspects 88-93, wherein

R⁶Is halogen, -C_1-8Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -OR^6a、-COR^6a、-CO₂R^6a、-CONR^6aR^6bor-NR^6aR^6bsaid-C_1-8Each of the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is optionally substituted with at least one substituent R^6dSubstitution;

R^6aand R^6bEach independently is hydrogen, -C_1-8Alkyl, cycloalkyl, or heterocyclyl, said-C_1-8Each of the alkyl, cycloalkyl, or heterocyclyl is optionally substituted with at least one substituent R^6eSubstitution;

R^6dand R^6eEach independently is hydrogen, halogen, -C_1-8Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR^6f、-CONR^6fR^6gor-NR^6fR^6gsaid-C_1-8Each of alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one substituent selected from the group consisting of halogen, -C_1-8Alkyl, -OR⁶ⁱor-NR⁶ⁱR^6jSubstituted with the substituent(s);

R^6f、R^6g、R⁶ⁱand R^6jEach independently is hydrogen, or-C_1-8An alkyl group.

Aspect 96: a compound according to aspect 95, wherein R⁶is-C optionally substituted by halogen, preferably fluorine_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl).

Aspect 97: a compound according to aspect 95, wherein R ⁶Is cycloalkyl (preferably C)_3-8Cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).

Aspect 98: conversion according to aspect 95Compound (I) wherein R⁶is-OR^6aWherein R is^6aIs optionally substituted by at least one substituent R^6esubstituted-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), R^6eIs cycloalkyl (preferably C)_3-8Cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl, OR cyclohexyl), optionally substituted by-OR⁶ⁱSubstituted aryl, heteroaryl (preferably 6-membered heteroaryl containing one or two nitrogen atoms as one or more ring members), -CONR^6fR^6gAnd R^6f，R^6gAnd R⁶ⁱEach independently is hydrogen, or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl).

Aspect 99: the compound according to aspect 98, wherein R⁶Is methoxy, ethoxy, isopropoxy,

Aspect 100: a compound according to aspect 95, wherein R⁶is-OR^6aWherein R is^6aIs cycloalkyl (preferably C)_3-8Cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).

Aspect 101: a compound according to aspect 95, wherein R⁶is-NR^6aR^6bAnd R is^6aAnd R^6bEach independently is hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), heterocyclyl, benzyl, cycloalkyl (preferably cyclopropyl), or alkoxyalkyl.

Aspect 102: a compound according to aspect 95, wherein R⁶is-COOR^6aAnd R is^6aIs hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

Aspect 103: a compound according to aspect 95, wherein R⁶is-COR^6aAnd R is^6aIs hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethylI-propyl or n-propyl) or a heterocyclic group (preferably a monocyclic 5 or 6 membered heterocyclic group comprising one or two heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulphur, more preferably morpholino).

Aspect 104: a compound according to aspect 95, wherein R⁶Is optionally substituted by at least one substituent R^6dSubstituted heteroaryl (preferably monocyclic 5 or 6 membered heteroaryl comprising one or two heteroatoms independently selected from nitrogen or oxygen).

Aspect 105: the compound according to aspect 104, wherein R^6dis-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl) or phenyl, optionally substituted by-C_1-8Alkyl, -OR⁶ⁱor-NR⁶ⁱR^6jIs substituted in which R⁶ⁱAnd R^6jEach independently is hydrogen, or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

Aspect 106: the compound according to aspect 104 or 105, wherein R ⁶Is that

Aspect 107: a compound according to aspect 95, wherein R⁶Is optionally substituted by at least one R^6dA substituted heterocyclic group.

Aspect 108: a compound according to aspect 95, wherein R⁶Is a monocyclic 3-to 8-membered heterocyclic group comprising as one or more ring members 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur.

Aspect 109: a compound according to aspect 95, wherein R⁶Are 4-, 5-, 6-, or 7-membered heterocyclic groups containing one nitrogen heteroatom as a ring member (e.g., azetidinyl, pyrrolidinyl, piperidinyl, and azepanyl).

Aspect 110: a compound according to aspect 95, wherein R⁶Is a 4-, 5-, 6-or 7-membered heterocyclyl group (e.g., morpholino or piperazinyl) containing one nitrogen and 1 additional nitrogen or oxygen heteroatom as ring members.

Aspect 111: a compound according to aspect 95, wherein R⁶Is a bicyclic 5-to 12-membered heterocyclyl comprising as one or more ring members 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulfur.

Aspect 112: the compound according to aspect 111, wherein R⁶Is a bicyclic spiro 7-to 12-membered heterocyclyl.

Aspect 113: the compound according to aspect 112, wherein R⁶Is azaspiro [3.3 ]Heptane, azaspiro [3.5 ]]Nonane, azaspiro [3.4 ]]Octane, azaspiro [5.5 ]]Undecane, or azaspiro [4.5 ]]Decanes, each containing 0 or 1 further nitrogen or oxygen atoms.

Aspect 114: the compound according to aspect 112, wherein R⁶Is 2-oxa-6-azaspiro [3.3]Heptane.

Aspect 115: a compound according to aspect 95, wherein R⁶is-CONR^6aR^6bWherein R is^6aAnd R^6bEach independently is-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), aryl or heteroaryl, each optionally substituted with at least one R^6eSubstituted, R^6eis-OR^6f、-NR^6fR^6gAryl, or heteroaryl, and R^6fAnd R^6gEach independently is hydrogen, or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

Aspect 116: the compound according to aspect 115, wherein R⁶Is that

Aspect 117: the compound according to any one of aspects 1-116, wherein L³Is a single bond or C_1-3Alkylene (e.g., -CH)₂-、-CH₂CH₂-or-CH (CH)₃)-)。

Aspect 118: a compound according to aspect 117, wherein L³Is a single bond.

Aspect 119: a compound according to any one of aspects 1-118, wherein Cy3 is a monocyclic 4-, 5-, 6-, or 7-membered heterocyclyl or a bicyclic 5-to 12-membered heterocyclyl, each of which comprises one or two heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as one or more ring members.

Aspect 120: a compound according to aspect 119, wherein Cy3 is a monocyclic 4-, 5-, 6-, or 7-membered heterocyclyl comprising one or two nitrogen atoms as one or more ring members.

Aspect 121: a compound according to any one of aspects 1-118, wherein Cy3 is monocyclic 4-, 5-, 6-, or 7-membered heteroaryl or bicyclic 7-to 12-membered heteroaryl, each of which comprises one or two heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur.

Aspect 122: the compound according to any one of aspects 119-121, wherein Cy3 is represented by R⁷Substituted and optionally substituted by R⁸And p is 0 or 1.

Aspect 123: the compound according to any one of aspects 119-122, wherein R⁷is-C_1-8Alkyl, heterocyclyl, -NR^7aR^7bOR-OR^7asaid-C_1-8Alkyl or heterocyclyl is optionally substituted by one R^7dThe substitution is carried out by the following steps,

wherein R is^7dis-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), cycloalkyl (preferably C)_3-6Cycloalkyl, more preferably cyclopropyl) OR-OR^7fsaid-C_1-8Alkyl, OR cycloalkyl optionally substituted by at least one substituent selected from halogen, -OR⁷ⁱor-NR⁷ⁱR^7jSubstituted with the substituent(s);

R^7aor R^7bIs hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl);

wherein R is ^7f、R⁷ⁱAnd R^7jEach independently is hydrogen, -C_1-8Alkyl (preferably-C)_1-6An alkyl group, a carboxyl group,more preferably methyl, ethyl, isopropyl or n-propyl).

Aspect 124: the compound according to any one of aspects 119-123, wherein p is 0 and R is⁷is-OR^7aWherein R is^7aIs hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

Aspect 125: the compound according to any one of aspects 119-123, wherein p is 0 and R is⁷Is optionally substituted by one R^7dsubstituted-C_1-8Alkyl radical, wherein R^7dis-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), cycloalkyl (preferably C)_3-6Cycloalkyl, more preferably cyclopropyl) OR-OR^7fWherein R is^7fIs hydrogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

Aspect 126: the compound according to aspect 125, wherein p is 0, and R⁷Is methyl, cyclopropylmethyl, or hydroxyethyl.

Aspect 127: the compound according to any one of aspects 119-123, wherein p is 0 and R is⁷Is a heterocyclic group optionally substituted with one R^7dThe substitution is carried out by the following steps,

wherein R is^7dis-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), said-C_1-8Alkyl is optionally substituted by at least one substituent selected from halogen, -OR ⁷ⁱor-NR⁷ⁱR^7jWherein R is⁷ⁱAnd R^7jEach independently is hydrogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl).

Aspect 128: a compound according to aspect 127, wherein said heterocyclyl is a monocyclic 5 or 6 membered heterocyclyl comprising one or two heteroatoms selected from nitrogen, oxygen or optionally oxidised sulfur as one or more ring members.

Aspect 129: the compound according to aspect 128, wherein said heterocyclyl is a monocyclic 6-membered heterocyclyl comprising one nitrogen or oxygen as a ring member.

Aspect 130: a compound according to aspect 128, wherein said heterocyclyl is piperidinyl or tetrahydropyranyl.

Aspect 131: the compound according to any one of aspects 119-123, wherein p is 1, and

R⁸is-C_1-8Alkyl, -CN, -OR^7aor-CONR^7aR^7b，

Wherein R is^7aAnd R^7bEach independently is hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), said-C_1-8Alkyl optionally substituted by at least one substituent R^7eThe substitution is carried out by the following steps,

R^7eis phenyl, heteroaryl, heterocyclyl, each of which is optionally substituted with at least one substituent selected from the group consisting of halogen, -C_1-8Alkyl, -OR⁷ⁱor-NR⁷ⁱR^7jThe substituent (b) of (a) is substituted,

R⁷ⁱand R^7jEach independently is hydrogen or-C _1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

Aspect 132: a compound according to aspect 131, wherein p is 1, and R⁸is-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

Aspect 133: a compound according to aspect 131, wherein p is 1, and

R⁸is-OR^7aWherein R is^7aIs hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

Aspect 134: a compound according to aspect 131, wherein p is 1, and

R⁸is-CONR^7aR^7b，

Wherein R is^7aIs hydrogen, and R^7bIs optionally substituted by at least one substituent R^7esubstituted-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl),

R^7eis phenyl, heteroaryl (preferably a 5 or 6 membered heteroaryl comprising one or two nitrogens as one or more ring members, more preferably pyridinyl or pyrimidinyl), heterocyclyl (preferably a monocyclic 4, 5, 6, or 7 membered heterocyclyl or a bicyclic 7 to 12 membered heterocyclyl, each comprising one or two heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulphur, more preferably piperidinyl or piperazinyl), each of said heterocyclyl, phenyl or heteroaryl being optionally substituted with at least one substituent selected from halogen, -C _1-8Alkyl, -OR⁷ⁱor-NR⁷ⁱR^7jThe substituent (b) of (a) is substituted,

R⁷ⁱand R^7jEach independently is hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

Aspect 135: the compound according to any one of aspects 119-123, wherein p is 1 and R is⁷is-OR^7aWherein R is^7aIs hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), and R⁸As defined in any of aspects 131-134.

Aspect 136: the compound according to any one of aspects 119-123, wherein p is 1 and R is⁷Is optionally substituted by one R^7dsubstituted-C_1-8Alkyl radical, wherein R^7dis-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), cycloalkyl (preferably C)_3-6Cycloalkyl, more preferably cyclopropyl) OR-OR^7fWherein R is^7fIs hydrogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), and R⁸As defined in any of aspects 131-134.

Aspect 137: a compound according to aspect 136, wherein p is 1, and R⁷Is methyl, cyclopropylmethyl, or hydroxyethyl.

Aspect 138: compounds according to any one of aspects 119-123Wherein p is 1, and R⁷Is a heterocyclic group optionally substituted with one R ^7dThe substitution is carried out by the following steps,

wherein R is^7dis-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), said-C_1-8Alkyl is optionally substituted by at least one substituent selected from halogen, -OR⁷ⁱor-NR⁷ⁱR^7jWherein R is⁷ⁱAnd R^7jEach independently is hydrogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl), and

R⁸as defined in any of aspects 131-134.

Aspect 139: a compound according to aspect 138, wherein said heterocyclyl is a monocyclic 5 or 6 membered heterocyclyl comprising one or two heteroatoms selected from nitrogen, oxygen or optionally oxidised sulfur as one or more ring members.

Aspect 140: a compound according to aspect 138, wherein said heterocyclyl is a monocyclic 6-membered heterocyclyl containing one nitrogen or oxygen as a ring member.

Aspect 141: a compound according to aspect 138, wherein said heterocyclyl is piperidinyl or tetrahydropyranyl.

In a second embodiment, disclosed herein are pyrrolo [2,3-b ] pyridine or pyrrolo [2,3-b ] pyrazine derivatives of formula (II):

wherein each variable in formula (II) is as defined for formula (I).

In a third embodiment, disclosed herein are pyrrolo [2,3-b ] pyridine or pyrrolo [2,3-b ] pyrazine derivatives of formula (AIII), (III), (AIV), or (IV). The third embodiment includes the following aspects:

Aspect 1: a compound of formula (AIII):

or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

wherein

X¹Is C or N;

R¹is hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^1a、-SO₂R^1a、-COR^1a、-CO₂R^1a、-CONR^1aR^1b、-C(＝NR^1a)NR^1bR^1c、-NR^1aR^1b、-NR^1aCOR^1b、-NR^1aCONR^1bR^1c、-NR^1aCO₂R^1b、-NR^1aSONR^1bR^1c、-NR^1aSO₂NR^1bR^1cor-NR^1aSO₂R^1bsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally substituted with halogen, hydroxy, -C_1-8Alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; provided that X is¹In the case of N, R is absent¹；

R^1a、R^1bAnd R^1cEach independently is hydrogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^1dSubstitution; or

(R^1aAnd R^1b)、(R^1bAnd R^1c) Or (R)^1cAnd R^1a) Together with the atom or atoms to which they are attached form a 3 to 9 membered ring containing 0, 1 or 2 further heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulphur as one or more ring membersSaid ring being optionally substituted by at least one substituent R^1eSubstitution;

wherein R is ^1dAnd R^1eEach independently is hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^1f、-SO₂R^1f、-COR^1f、-CO₂R^1f、-CONR^1fR^1g、-C(＝NR^1f)NR^1gR^1h、-NR^1fR^1g、-NR^1fCOR^1g、-NR^1fCONR^1gR^1h、-NR^1fCO₂R^1g、-NR^1fSONR^1gR^1h、-NR^1fSO₂NR^1gR^1hor-NR^1fSO₂R^1gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR¹ⁱ、-NR¹ⁱR^1jCycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^1f、R^1g、R^1h、R¹ⁱand R^1jEach independently is hydrogen, -C_1-8Alkyl radical, C_1-8alkoxy-C_1-8Alkyl-, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R²and R³Each independently is hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^2a、-SO₂R^2a、-COR^2a、-CO₂R^2a、-CONR^2aR^2b、-C(＝NR^2a)NR^2bR^2c、-NR^2aR^2b、-NR^2aCOR^2b、-NR^2aCONR^2bR^2c、-NR^2aCO₂R^2b、-NR^2aSONR^2bR^2c、-NR^2aSO₂NR^2bR^2cor-NR^2aSO₂R^2bsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally substituted with halogen, hydroxy, -C_1-8Alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^2a、R^2band R^2cEach independently is hydrogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

L¹is a single bond, alkylene, cycloalkylene¹-O-alkylene-a ¹、*¹-alkylene-O-)¹、*¹-NH-alkylene-a¹、*¹-alkylene-NH-x¹、*¹-NHC(O)-**¹、*¹-C(O)NH-**¹Alkenylene, or alkynylene;

wherein¹Refers to the position of attachment with Cy1, and¹refers to a group bonded to the main chain (e.g. pyrrolo [2,3-b ]]Pyridine or pyrrolo [2,3-b]Pyrazine ring) attachment position;

L²is a single bond, alkylene, cycloalkylene²-O-alkylene-a²、*²-alkylene-O-)²、*²-NH-alkylene-a²、*²-alkylene-NH-x²、*²-NHC(O)-**²、*²-C(O)NH-**²Alkenylene, or alkynylene;

wherein²Refers to a position attached to a phenyl group, and²refers to a group bonded to the main chain (e.g. pyrrolo [2,3-b ]]Pyridine or pyrrolo [2,3-b]Pyrazine ring) attachment position;

cy1 is cycloalkyl, phenyl, 5-or 6-membered heterocyclyl, 5-or 6-membered heteroaryl, or 7-to 12-membered bicyclic fused heteroaryl or heterocyclyl, each of which is substituted with one R⁴Substituted and optionally substituted by R⁵Substitution;

n is 0, 1 or 2;

R⁴and R⁵At each occurrence thereof, is independently halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^4a、-SO₂R^4a、-SO₂NR^4aR^4b、-COR^4a、-CO₂R^4a、-CONR^4aR^4b、-C(＝NR^4a)NR^4bR^4c、-NR^4aR^4b、-NR^4aCOR^4b、-NR^4aCONR^4bR^4c、-NR^4aCO₂R^4b、-NR^4aSONR^4bR^4c、-NR^4aSO₂NR^4bR^4cor-NR^4aSO₂R^4bsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^4dSubstitution;

R^4a、R^4band R^4cEach independently is hydrogen, -C _1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^4eSubstitution; or

(R^4aAnd R^4b)、(R^4bAnd R^4c) Or (R)^4cAnd R^4a) Together with the atom or atoms to which they are attached form a 3 to 12 membered ring containing 0, 1 or 2 further heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulphur as one or more ring members, said ring being optionally substituted with at least one substituent R^4eSubstitution;

R^4dand R^4eEach independently is hydrogen, halogen, -C_1-8Alkyl, -C_2-8An alkenyl group,-C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^4f、-SO₂R^4f、-SO₂NR^4fR^4g、-COR^4f、-CO₂R^4f、-CONR^4fR^4g、-C(＝NR^4f)NR^4gR^4h、-NR^4fR^4g、-NR^4fCOR^4g、-NR^4fCONR^4gR^4h、-NR^4fCO₂R^4f、-NR^4fSONR^4fR^4g、-NR^4fSO₂NR^4gR^4hor-NR^4fSO₂R^4gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁴ⁱ、-NR⁴ⁱR^4jCycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^4f、R^4g、R^4h、R⁴ⁱand R^4jEach independently is hydrogen, -C_1-8Alkyl radical, C_1-8alkoxy-C_1-8Alkyl-, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R⁶is halogen, -C _1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^6a、-SO₂R^6a、-SO₂NR^6aR^6b、-COR^6a、-CO₂R^6a、-CONR^6aR^6b、-C(＝NR^6a)NR^6bR^6c、-NR^6aR^6b、-NR^6aCOR^6b、-NR^6aCONR^6bR^6c、-NR^6aCO₂R^6b、-NR^6aSONR^6bR^6c、-NR^6aSO₂NR^6bR^6cor-NR^6aSO₂R^6bsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^6dSubstitution;

R^6a、R^6band R^6cEach independently is hydrogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^6eSubstitution;

R^6dand R^6eEach independently is hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^6f、-SO₂R^6f、-SO₂NR^6fR^6g、-COR^6f、-CO₂R^6f、-CONR^6fR^6g、-C(＝NR^6f)NR^6gR^6h、-NR^6fR^6g、-NR^6fCOR^6g、-NR^6fCONR^6gR^6h、-NR^6fCO₂R^6f、-NR^6fSONR^6fR^6g、-NR^6fSO₂NR^6gR^6hor-NR^6fSO₂R^6gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁶ⁱ、-NR⁶ⁱR^6jCycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^6f、R^6g、R^6h、R⁶ⁱand R^6jEach independently is hydrogen, -C_1-8Alkyl radical, C_1-8alkoxy-C_1-8Alkyl-, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

m is 0, 1, 2, 3 or 4, provided that valency theory is satisfied;

L³Is a single bond or C_1-8An alkylene group;

X²and X³Each independently is CH or N, provided that X²And X³Are not all CH;

t is 0, 1, 2, or 3;

s is 0, 1, 2, or 3;

R⁷and R⁸Each independently is halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^7a、-SO₂R^7a、-SO₂NR^7aR^7b、-COR^7a、-CO₂R^7a、-CONR^7aR^7b、-C(＝NR^7a)NR^7bR^7c、-NR^7aR^7b、-NR^7aCOR^7b、-NR^7aCONR^7bR^7c、-NR^7aCO₂R^7b、-NR^7aSONR^7bR^7c、-NR^7aSO₂NR^7bR^7cor-NR^7aSO₂R^7bsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^7dSubstitution;

R^7a、R^7band R^7cEach independently is hydrogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^7eSubstitution;

R^7dand R^7eEach independently is hydrogen, halogen, -C_1-8Alkyl and substituted benzeneC_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^7f、-SO₂R^7f、-SO₂NR^7fR^7g、-COR^7f、-CO₂R^7f、-CONR^7fR^7g、-C(＝NR^7f)NR^7gR^7h、-NR^7fR^7g、-NR^7fCOR^7g、-NR^7fCONR^7gR^7h、-NR^7fCO₂R^7f、-NR^7fSONR^7fR^7g、-NR^7fSO₂NR^7gR^7hor-NR^7fSO₂R^7gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁷ⁱ、-NR⁷ⁱR^7jCycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^7f、R^7g、R^7h、R⁷ⁱAnd R^7jEach independently is hydrogen, -C_1-8Alkyl radical, C_1-8alkoxy-C_1-8Alkyl-, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

p is 0, 1, 2 or 3, provided that the valence theory is satisfied, and

with the proviso that the compound is not 5- (4- (4-hydroxymethylpiperidin-1-ylmethyl) -3-hydroxyphenyl) -3- (2-methoxyphenyl) -1H-pyrrolo [2,3-b ] pyridine; 5- (4- (4-methyl-1, 4-diazepan-1-ylmethyl) -3-hydroxyphenyl) -3- (2-methoxyphenyl) -1H-pyrrolo [2,3-b ] pyridine; 5- (4- (4-hydroxypiperidin-1-yl) -3-fluoro-5-dimethylcarbamoylphenyl) -3- (2-methoxyphenyl) -1H-pyrrolo [2,3-b ] pyridine; or 5- (4- (4-methylpiperazin-1-yl) -3-fluoro-5-dimethylcarbamoylphenyl) -3- (2-methoxyphenyl) -1H-pyrrolo [2,3-b ] pyridine.

Aspect 2: a compound according to aspect 1, which is a compound of formula (III)

Or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

wherein

X¹Is C or N;

R¹is hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^1a、-SO₂R^1a、-COR^1a、-CO₂R^1a、-CONR^1aR^1b、-C(＝NR^1a)NR^1bR^1c、-NR^1aR^1b、-NR^1aCOR^1b、-NR^1aCONR^1bR^1c、-NR^1aCO₂R^1b、-NR^1aSONR^1bR^1c、-NR^1aSO₂NR^1bR^1cor-NR^1aSO₂R^1bsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally substituted with halogen, hydroxy, -C _1-8Alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; provided that X is¹In the case of N, R is absent¹；

R^1a、R^1bAnd R^1cEach independently is hydrogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^1dSubstitution; or

(R^1aAnd R^1b)、(R^1bAnd R^1c) Or (R)^1cAnd R^1a) With one to which they are attachedOr a plurality of atoms together form a 3 to 9 membered ring, said ring comprising 0, 1 or 2 further heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulfur as one or more ring members, said ring optionally being substituted with at least one

A substituent R^1eSubstitution;

wherein R is^1dAnd R^1eEach independently is hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^1f、-SO₂R^1f、-COR^1f、-CO₂R^1f、-CONR^1fR^1g、-C(＝NR^1f)NR^1gR^1h、-NR^1fR^1g、-NR^1fCOR^1g、-NR^1fCONR^1gR^1h、-NR^1fCO₂R^1g、-NR^1fSONR^1gR^1h、-NR^1fSO₂NR^1gR^1hor-NR^1fSO₂R^1gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR¹ⁱ、-NR¹ⁱR^1jCycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^1f、R^1g、R^1h、R¹ⁱAnd R^1jEach independently is hydrogen, -C_1-8Alkyl radical, C_1-8alkoxy-C_1-8Alkyl-, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R²and R³Each independently is hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^2a、-SO₂R^2a、-COR^2a、-CO₂R^2a、-CONR^2aR^2b、-C(＝NR^2a)NR^2bR^2c、-NR^2aR^2b、-NR^2aCOR^2b、-NR^2aCONR^2bR^2c、-NR^2aCO₂R^2b、-NR^2aSONR^2bR^2c、-NR^2aSO₂NR^2bR^2cor-NR^2aSO₂R^2bsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally substituted with halogen, hydroxy, -C_1-8Alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^2a、R^2band R^2cEach independently is hydrogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, ring

Alkyl, heterocyclyl, aryl, or heteroaryl;

L¹is a single bond, alkylene, cycloalkylene¹-O-alkylene-a¹、*¹-alkylene-O-)¹、*¹-NH-alkylene-a¹、*¹-alkylene-NH-x¹、*¹-NHC(O)-**¹、*¹-C(O)NH-**¹Alkenylene, or alkynylene;

wherein¹Refers to the position of attachment with Cy1, and¹refers to a position of attachment to the backbone;

L²is a single bond, alkylene, cycloalkylene²-O-alkylene-a²、*²-alkylene-O-)²、*²-NH-alkylene-a²、*²-alkylene-NH-x²、*²-NHC(O)-**²、*²-C(O)NH-**²Alkenylene, or alkynylene;

wherein²Refers to a position attached to a phenyl group, and²refers to a position of attachment to the backbone; cy1 is cycloalkyl, phenyl, 5-or 6-membered heterocyclyl, 5-or 6-membered heteroaryl, or 7-to 12-membered bicyclic fused heteroaryl or heterocyclyl, each of which From being an R⁴Substituted and optionally substituted by R⁵Substitution;

n is 0, 1 or 2;

R⁴and R⁵At each occurrence thereof, is independently halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^4a、-SO₂R^4a、-SO₂NR^4aR^4b、-COR^4a、-CO₂R^4a、-CONR^4aR^4b、-C(＝NR^4a)NR^4bR^4c、-NR^4aR^4b、-NR^4aCOR^4b、-NR^4aCONR^4bR^4c、-NR^4aCO₂R^4b、-NR^4aSONR^4bR^4c、-NR^4aSO₂NR^4bR^4cor-NR^4aSO₂R^4bsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^4dSubstitution;

R^4a、R^4band R^4cEach independently is hydrogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^4eSubstitution; or

(R^4aAnd R^4b)、(R^4bAnd R^4c) Or (R)^4cAnd R^4a) Together with the atom or atoms to which they are attached form a 3 to 12 membered ring containing 0, 1 or 2 further heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulphur as one or more ring members, said ring being optionally substituted with at least one substituent R^4eSubstitution;

R^4dand R^4eEach independently is hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO ₂、-OR^4f、-SO₂R^4f、-SO₂NR^4fR^4g、-COR^4f、-CO₂R^4f、-CONR^4fR^4g、-C(＝NR^4f)NR^4gR^4h、-NR^4fR^4g、-NR^4fCOR^4g、-NR^4fCONR^4gR^4h、-NR^4fCO₂R^4f、-NR^4fSONR^4fR^4g、-NR^4fSO₂NR^4gR^4hor-NR^4fSO₂R^4gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁴ⁱ、-NR⁴ⁱR^4jCycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^4f、R^4g、R^4h、R⁴ⁱand R^4jEach independently is hydrogen, -C_1-8Alkyl radical, C_1-8alkoxy-C_1-8Alkyl-, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R⁶is halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^6a、-SO₂R^6a、-SO₂NR^6aR^6b、-COR^6a、-CO₂R^6a、-CONR^6aR^6b、-C(＝NR^6a)NR^6bR^6c、-NR^6aR^6b、-NR^6aCOR^6b、-NR^6aCONR^6bR^6c、-NR^6aCO₂R^6b、-NR^6aSONR^6bR^6c、-NR^6aSO₂NR^6bR^6cor-NR^6aSO₂R^6bsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^6dSubstitution;

R^6a、R^6band R^6cEach independently is hydrogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^6eSubstitution;

R^6dand R^6eEach independently is hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO ₂、-OR^6f、-SO₂R^6f、-SO₂NR^6fR^6g、-COR^6f、-CO₂R^6f、-CONR^6fR^6g、-C(＝NR^6f)NR^6gR^6h、-NR^6fR^6g、-NR^6fCOR^6g、-NR^6fCONR^6gR^6h、-NR^6fCO₂R^6f、-NR^6fSONR^6fR^6g、-NR^6fSO₂NR^6gR^6hor-NR^6fSO₂R^6gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁶ⁱ、-NR⁶ⁱR^6jCycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^6f、R^6g、R^6h、R⁶ⁱand R^6jEach independently is hydrogen, -C_1-8Alkyl radical, C_1-8alkoxy-C_1-8Alkyl-, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

m is 0, 1, 2, 3 or 4, provided that valency theory is satisfied;

L³is a single bond or C_1-8An alkylene group;

X²and X³Each independently is CH or N, provided that X²And X³Are not all CH;

t is 0, 1, 2, or 3;

R⁷and R⁸Each independently is halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^7a、-SO₂R^7a、-SO₂NR^7aR^7b、-COR^7a、-CO₂R^7a、-CONR^7aR^7b、-C(＝NR^7a)NR^7bR^7c、-NR^7aR^7b、-NR^7aCOR^7b、-NR^7aCONR^7bR^7c、-NR^7aCO₂R^7b、-NR^7aSONR^7bR^7c、-NR^7aSO₂NR^7bR^7cor-NR^7aSO₂R^7bsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^7dSubstitution;

R^7a、R^7band R^7cEach independently is hydrogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R ^7eSubstitution;

R^7dand R^7eEach independently is hydrogen, halogen-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^7f、-SO₂R^7f、-SO₂NR^7fR^7g、-COR^7f、-CO₂R^7f、-CONR^7fR^7g、-C(＝NR^7f)NR^7gR^7h、-NR^7fR^7g、-NR^7fCOR^7g、-NR^7fCONR^7gR^7h、-NR^7fCO₂R^7f、-NR^7fSONR^7fR^7g、-NR^7fSO₂NR^7gR^7hor-NR^7fSO₂R^7gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁷ⁱ、-NR⁷ⁱR^7jCycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^7f、R^7g、R^7h、R⁷ⁱand R^7jEach independently is hydrogen, -C_1-8Alkyl radical, C_1-8alkoxy-C_1-8Alkyl-, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

p is 0, 1, 2 or 3, provided that the valence theory is satisfied, and

with the proviso that the compound is not 5- (4- (4-hydroxymethylpiperidin-1-ylmethyl) -3-hydroxyphenyl) -3- (2-methoxyphenyl) -1H-pyrrolo [2,3-b ] pyridine; 5- (4- (4-methyl-1, 4-diazepan-1-ylmethyl) -3-hydroxyphenyl) -3- (2-methoxyphenyl) -1H-pyrrolo [2,3-b ] pyridine; 5- (4- (4-hydroxypiperidin-1-yl) -3-fluoro-5-dimethylcarbamoylphenyl) -3- (2-methoxyphenyl) -1H-pyrrolo [2,3-b ] pyridine; or 5- (4- (4-methylpiperazin-1-yl) -3-fluoro-5-dimethylcarbamoylphenyl) -3- (2-methoxyphenyl) -1H-pyrrolo [2,3-b ] pyridine.

Aspect 3: the compound according to aspect 1 or 2Wherein R is²And R³Each independently is hydrogen, halogen or cyano.

Aspect 4: the compound according to aspect 1 or 2, wherein R²And R³Each is hydrogen.

Aspect 5: the compound according to any one of aspects 1 to 4, wherein L¹Is a single bond, alkylene¹-O-alkylene-a¹、*¹-NH-alkylene-a¹、*¹-NHC(O)-**¹Or¹-C(O)NH-**¹(ii) a And L is²Is a single bond, alkylene, alkenylene, or alkynylene.

Aspect 6: the compound according to aspect 5, wherein L¹Is a single bond, -CH₂-、-(CH₂)₂-、-CH(CH₃)-、-C≡C-、*¹-O-CH(CH₃)-**¹、*¹-O-CH₂-**¹、*¹-NH-CH₂-**¹、*¹-NH-CH(CH₃)-**¹Or¹-NHC(O)-**¹And L is²Is a single bond, -C ≡ C-, or-CH ═ CH-.

Aspect 7: the compound according to aspect 5, wherein L¹And L²Each is a single bond.

Aspect 8: a compound according to any one of aspects 1 to 7, wherein R¹Is hydrogen, -OR^1aor-NR^1aR^1bWherein R is^1aAnd R^1bAs defined for formula (III).

Aspect 9: a compound according to aspect 8, wherein R¹Is hydrogen.

Aspect 10: a compound according to aspect 8, wherein R¹is-OR^1aWherein R is^1aIs hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl.

Aspect 11: a compound according to aspect 8, wherein R¹is-NR^1aR^1bWherein R is^1aAnd R^1bEach independently is hydrogen or-C_1-8Alkyl radical of formula (I), said_1-8Alkyl optionally substituted by at least one substituent R^1dAnd (4) substitution.

Aspect 12: a compound according to aspect 11, wherein R ^1dIs heterocyclyl, aryl, or-NR^1fR^1gWherein said heterocyclyl, or aryl is optionally substituted with halogen, -C_1-8Alkyl, -OR¹ⁱor-NR¹ⁱR^1jIs substituted in which R^1f、R^1g、R¹ⁱAnd R^1jEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl.

Aspect 13: a compound according to aspect 12, wherein the aryl is phenyl.

Aspect 14: a compound according to aspect 12, wherein said heterocyclyl is a 4, 5, 6 or 7 membered ring containing as ring members one heteroatom selected from nitrogen, oxygen or optionally oxidised sulfur, preferably tetrahydropyranyl or piperidinyl.

Aspect 15: a compound according to aspect 8, wherein R¹is-NR^1aR^1bWherein R is^1aAnd R^1bTogether with the heteroatom to which they are attached form a 3-to 6-membered ring, said ring comprising 0, 1 or 2 further heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulfur as one or more ring members, said ring being optionally substituted with at least one substituent R^1eIs substituted in which R^1eIs as defined above.

Aspect 16: a compound according to aspect 15, wherein R¹is-NR^1aR^1bWherein R is^1aAnd R^1bTogether with the heteroatom to which they are attached form a 4-, 5-or 6-membered ring, which ring comprises 0 or 1 further heteroatom independently selected from nitrogen, oxygen or optionally oxidised sulphur as one or more ring members, which ring is optionally substituted with at least one substituent R ^1eIs substituted in which R^1eIs as defined above.

Aspect 17: the compound according to aspect 15 or 16, wherein R^1eis-OR^1f、-CONR^1fR^1gor-NR^1fR^1gWherein R is^1fAnd R^1gEach independently is hydrogen, or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl.

Aspect 18: a compound according to any one of aspects 1 to 17, wherein Cy1 is a 5 or 6 membered heterocyclyl containing one or two heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulfur as one or more ring members, said heterocyclyl being substituted with one R⁴Substituted and optionally substituted by R⁵Substituted, and R is in case the heterocycle is 6-membered⁴Relative to the attachment point L¹At the para position (or 4 position) of said heterocyclyl, or Cy1 is a 7-to 10-membered bicyclic fused heterocyclyl containing as one or more ring members one or two or three heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur, said heterocyclyl being optionally substituted with R⁵Is substituted in which R⁵Is halogen, -C_1-8Alkyl, oxo, or aryl.

Aspect 19: a compound according to aspect 18, wherein said 6-membered heterocyclyl is piperidinyl, tetrahydropyridinyl, or piperazinyl or said 7 to 10-membered bicyclic fused heterocyclyl is dihydropyridinooxazine (preferably 2, 3-dihydro-1H-pyrido [2,3-b ] [1,4] oxazine), dihydrobenzoxazoloazepinyl (preferably 5-oxo-3, 4-dihydrobenzo [ f ] [1,4] oxoazepinyl), isoindolinyl (preferably 1-oxo-2-methylisoindoline-5-yl), dihydroisoquinolinyl (preferably 1-oxo-2-methyl-3, 4-dihydroisoquinolin-6-yl), tetrahydroisoquinolinyl (preferably 2-methyl-1-oxo-1, 2,3, 4-tetrahydroisoquinolin-6-yl), benzoazepine (preferably 2,3,4, 5-tetrahydro-1-oxo-2-benzazepin-6-yl), benzoxazepin (preferably 5-oxo-2, 3,4, 5-tetrahydro-1, 4-benzoxazpin-8-yl), dihydrobenzoxazine (preferably 3, 4-dihydro-2H-1, 4-benzoxazin-6-yl).

Aspect 20: the compound according to aspect 19, wherein said 6-membered heterocyclyl is

And n is 0, 1 or 2.

Aspect 21: the compound according to any one of aspects 1 to 17, wherein Cy1 is a cyclic amino acid comprising oneOr two 5-or 6-membered heteroaryl groups as one or more ring members, independently selected from heteroatoms of nitrogen, oxygen or optionally oxidised sulfur, said heteroaryl groups being substituted by one R⁴Substituted and optionally substituted by R⁵Substituted, and R is in the case that the heteroaryl is 6-membered⁴Relative to the attachment point L¹In the para (or 4) position of the heteroaryl group.

Aspect 22: a compound according to aspect 21, wherein the 5 or 6 membered heteroaryl is pyrazolyl, oxazolyl, pyridinyl, or pyrimidinyl.

Aspect 23: a compound according to aspect 22, wherein the 5-membered heteroaryl is

Or said 6-membered heteroaryl is

And n is 0, 1 or 2.

Aspect 24: the compound according to any one of aspects 1-17, wherein Cy1 is in relative relationship to L¹By an R in position 4 of the attached position⁴Is substituted and substituted by R⁵Substituted phenyl, and n is 0, 1 or 2.

Aspect 25: the compound according to any one of aspects 18 to 24, wherein Cy1 is substituted by one R in the 4-position where Cy1 is 6-membered⁴Substituted and n is 0.

Aspect 26: a compound according to any one of aspects 18 to 25, wherein Cy1 is substituted by one R in the 4-position where Cy1 is 6-membered ⁴Is substituted and substituted by R⁵And n is 1; and said R is⁵Is halogen or-C_1-8An alkyl group.

Aspect 27: the compound according to aspect 25 or 26, wherein R⁴Is a halogen.

Aspect 28: according to any of aspects 18 to 25A compound of (I), wherein R⁴is-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^4dAnd (4) substitution.

Aspect 29: a compound according to aspect 28, wherein R^4dIs hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^4f、-SO₂R^4f、-SO₂NR^4fR^4g、-COR^4f、-CO₂R^4f、-CONR^4fR^4g、-C(＝NR^4f)NR^4gR^4h、-NR^4fR^4g、-NR^4fCOR^4g、-NR^4fCONR^4gR^4h、-NR^4fCO₂R^4f、-NR^4fSONR^4fR^4g、-NR^4fSO₂NR^4gR^4hor-NR^4fSO₂R^4gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁴ⁱor-NR⁴ⁱR^4jWherein R is^4f、R^4g、R^4h、R⁴ⁱAnd R is^4jEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

Aspect 30: the compound according to aspect 28 or 29, wherein R⁴Is optionally substituted by cycloalkyl, aryl, heterocyclyl, -OR^4f、-CONR^4fR^4g、-NR^4fR^4gor-NR^4fSO₂R^4gsubstituted-C_1-8Alkyl, preferably-C _1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propylPropyl, wherein the cycloalkyl, aryl or heterocyclyl is optionally substituted with halogen, -C_1-8Alkyl, OR-OR⁴ⁱIs substituted in which R^4f、R^4gAnd R⁴ⁱEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

Aspect 31: a compound according to aspect 30, wherein said heterocyclyl is optionally substituted with-C_1-8Alkyl or-C_1-8Alkoxy-substituted 4 to 7 membered rings comprising one or two heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulfur, preferably 4, 5, 6 or 7 membered saturated rings comprising one nitrogen or oxygen atom as a ring member.

Aspect 32: a compound according to aspect 30, wherein R⁴Is a methyl group, an ethyl group,

Aspect 33: the compound according to aspect 28 or 29, wherein R⁴Is optionally halogen, -C_1-8Alkyl, -OR^4for-NR^4fR^4gSubstituted aryl radicals, in which R is^4fAnd R^4gEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

Aspect 34: a compound according to aspect 33, wherein the aryl is phenyl.

Aspect 35: a compound according to aspect 33, wherein R⁴Is that

Aspect 36: the compound according to aspect 28 or 29, wherein R⁴Is optionally substituted by halogen, oxo, -C _1-8Alkyl, -OR^4for-NR^4fR^4gSubstituted heteroaryl, wherein R^4fAnd R^4gEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

Aspect 37: a compound according to aspect 36, wherein the heteroaryl is a 5, 6 or 7 membered heteroaryl comprising one or two or three heteroatoms independently selected from oxygen, nitrogen or sulphur.

Aspect 38: the compound according to aspect 35 or 37, the heteroaryl is pyrrolyl, pyridinyl, pyrimidinyl, pyrazolyl, oxazolyl, or triazolyl.

Aspect 39: a compound according to aspect 36, wherein R⁴Is that

Aspect 40: the compound according to aspect 28 or 29, wherein R⁴Is optionally substituted by halogen, oxo, -C_1-8Alkyl, -OR^4for-NR^4fR^4gSubstituted heterocyclic radical, wherein R^4fAnd R^4gEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

Aspect 41: the compound according to aspect 40, wherein said heterocyclyl is a 4 to 7 membered ring comprising one or two heteroatoms independently selected from nitrogen, oxygen or sulfur, preferably a 4, 5, 6, or 7 membered saturated ring comprising one nitrogen or oxygen atom as a ring member.

Aspect 42: a compound according to aspect 51, wherein said heterocyclyl is piperidinyl, pyrrolidinyl, or azepanyl.

Aspect 43: a compound according to any one of aspects 40-42, wherein R⁴Is that

Aspect 44: the compound according to aspect 28 or 29, wherein R⁴Is optionally substituted by halogen, oxo, -C_1-8Alkyl, -OR^4for-NR^4fR^4gSubstituted cycloalkyl, wherein R^4fAnd R^4gEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

Aspect 45: a compound according to aspect 44, wherein R⁴Is optionally substituted by-C_1-8Alkyl (preferably methyl), -OR^4for-NR^4fR^4gSubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, wherein R is^4fAnd R^4gEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

Aspect 46: the compound according to aspect 44 or 45, wherein R⁴Is that

Aspect 47: a compound according to any one of aspects 18 to 25, wherein

R⁴is-CONR^4aR^4b，

Wherein R is^4aAnd R^4bEach independently is hydrogen, -C_1-8Alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said-C_1-8Each of the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is optionally substituted with at least one substituent R^4eSubstitution;

R^4eis hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO ₂、-OR^4f、-SO₂R^4f、-SO₂NR^4fR^4g、-COR^4f、-CO₂R^4f、-CONR^4fR^4g、-C(＝NR^4f)NR^4gR^4h、-NR^4fR^4g、-NR^4fCOR^4g、-NR^4fCONR^4gR^4h、-NR^4fCO₂R^4f、-NR^4fSONR^4fR^4g、-NR^4fSO₂NR^4gR^4hor-NR^4fSO₂R^4gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁴ⁱ、-NR⁴ⁱR^4jCycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^4f、R^4g、R^4h、R⁴ⁱand R^4jEach independently is hydrogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

Aspect 48: a compound according to aspect 47, wherein

R⁴is-CONR^4aR^4bWherein

R^4aIs hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl; and is

R^4bIs optionally substituted by at least one substituent R^4esubstituted-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl, ethyl or propyl;

R^4eis hydrogen, halogen, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^4f、-SO₂R^4f、-SO₂NR^4fR^4g、-COR^4f、-CO₂R^4f、-CONR^4fR^4g、-C(＝NR^4f)NR^4gR^4h、-NR^4fR^4g、-NR^4fCOR^4g、-NR^4fCONR^4gR^4h、-NR^4fCO₂R^4f、-NR^4fSONR^4fR^4g、-NR^4fSO₂NR^4gR^4hor-NR^4fSO₂R^4gThe cycloalkyl, heterocyclyl, aryl, or heteroaryl groupEach optionally substituted by at least one member selected from halogen, -C_1-8Alkyl, -OR⁴ⁱor-NR⁴ⁱR^4jSubstituted with the substituent(s); and is

R^4f、R^4g、R^4h、R⁴ⁱAnd R^4jEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

Aspect 49: a compound according to aspect 48, wherein R^4eIs optionally substituted by-C_1-8Alkyl, hydroxy, or-C _1-8Alkoxy, preferably methyl, substituted 4 to 7 membered ring containing one or two heteroatoms independently selected from nitrogen, oxygen or sulfur, preferably a 4, 5, 6, or 7 membered saturated ring containing one nitrogen or oxygen atom as a ring member, or a 4, 5, 6, or 7 membered heteroaryl ring containing one or two heteroatoms selected from nitrogen and oxygen as a ring member.

Aspect 50: a compound according to aspect 49, wherein R^4eIs azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholino, piperazinyl, or pyrazolyl, each of which is optionally substituted with methyl, ethyl, hydroxy, methoxy, amino, or halogen.

Aspect 51: a compound according to aspect 48, wherein R^4eIs optionally substituted by at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁴ⁱor-NR⁴ⁱR^4jPhenyl substituted with the substituent of (1); wherein R is⁴ⁱAnd R^4jEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

Aspect 52: a compound according to aspect 48, wherein R^4eis-OR^4fWherein R is^4fIs hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

Aspect 53: a compound according to aspect 48, wherein R^4eis-NR^4fR^4gWherein R is ^4fAnd R^4gEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferablyAnd is selected from methyl or ethyl.

Aspect 54: a compound according to any one of aspects 47 to 53, wherein R⁴Is that

Aspect 55: a compound according to aspect 47, wherein

R⁴is-CONR^4aR^4bWherein

R^4aIs hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl; and is

R^4bIs cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with at least one substituent R^4eSubstitution;

R^4eis hydrogen, halogen, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^4f、-SO₂R^4f、-SO₂NR^4fR^4g、-COR^4f、-CO₂R^4f、-CONR^4fR^4g、-C(＝NR^4f)NR^4gR^4h、-NR^4fR^4g、-NR^4fCOR^4g、-NR^4fCONR^4gR^4h、-NR^4fCO₂R^4f、-NR^4fSONR^4fR^4g、-NR^4fSO₂NR^4gR^4hor-NR^4fSO₂R^4gEach of said cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one substituent selected from the group consisting of halogen, -C_1-8Alkyl, -OR⁴ⁱor-NR⁴ⁱR^4jSubstituted with the substituent(s); and is

R^4f、R^4g、R^4h、R⁴ⁱAnd R^4jEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6An alkyl group, a carboxyl group,more preferably methyl or ethyl.

Aspect 56: a compound according to aspect 55, wherein R^4bIs optionally substituted by at least one substituent R^4eSubstituted monocyclic ring C_3-8Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl), R^4eIs halogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl), -OR ⁴ⁱor-NR⁴ⁱR^4jWherein R is⁴ⁱAnd R^4jEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

Aspect 57: a compound according to aspect 55, wherein R^4bIs optionally substituted by at least one substituent R^4eSubstituted heterocyclic group, said R^4eIs halogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl), -OR⁴ⁱor-NR⁴ⁱR^4jWherein R is⁴ⁱAnd R^4jEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

Aspect 58: a compound according to aspect 57, wherein R^4bIs a 4 to 7 membered ring containing one or two heteroatoms independently selected from nitrogen, oxygen or sulfur, preferably a 4, 5, 6 or 7 membered saturated ring containing one nitrogen or oxygen atom as a ring member.

Aspect 59: a compound according to aspect 58, wherein R^4bIs azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, tetrahydrofuranyl, tetrahydropyranyl, or morpholino.

Aspect 60: a compound according to aspect 55, wherein R⁴Is that

Aspect 61: a compound according to any one of aspects 18 to 25, wherein R⁴is-CONR^4aR^4b，R^4aAnd R^4bTogether with the nitrogen atom to which they are attached form a 3-to 12-membered ring, which ring comprises as one or more ring members 0, 1 or 2 further heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulfur, which ring is optionally substituted with at least one substituent R ^4eSubstitution;

R^4eis hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^4f、-SO₂R^4f、-SO₂NR^4fR^4g、-COR^4f、-CO₂R^4f、-CONR^4fR^4g、-C(＝NR^4f)NR^4gR^4h、-NR^4fR^4g、-NR^4fCOR^4g、-NR^4fCONR^4gR^4h、-NR^4fCO₂R^4f、-NR^4fSONR^4fR^4g、-NR^4fSO₂NR^4gR^4hor-NR^4fSO₂R^4gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁴ⁱ、-NR⁴ⁱR^4jCycloalkyl, heterocyclyl, aryl, or heteroaryl; and is

R^4f、R^4g、R^4h、R⁴ⁱAnd R^4jEach independently is hydrogen, -C_1-8Alkyl, or C_1-8alkoxy-C_1-8An alkyl group-.

Aspect 62: a compound according to aspect 61, wherein R is^4aAnd R^4bThe ring formed with the nitrogen atom to which they are attached is a monocyclic 3 to 8 membered ring comprising as one or more ring members 0, 1 or 2 further heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulfur, the ring being optionally substituted with at least one substituent R^4eAnd (4) substitution.

Aspect(s)63: a compound according to aspect 62, wherein R is^4aAnd R^4bThe ring formed with the nitrogen atom to which they are attached is a 4-, 5-, 6-or 7-membered ring containing 0 additional heteroatoms (e.g., azetidinyl, pyrrolidinyl, piperidinyl, and azepanyl), optionally substituted with at least one substituent R ^4eAnd (4) substitution.

Aspect 64: a compound according to aspect 62, wherein R is^4aAnd R^4bThe ring formed with the nitrogen atom to which they are attached is a 4-, 5-, 6-or 7-membered ring containing 1 additional nitrogen or oxygen heteroatom as a ring member (e.g. morpholino or piperazinyl), optionally substituted with at least one substituent R^4eAnd (4) substitution.

Aspect 65: a compound according to any one of aspects 62-64, wherein R^4eis-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl OR ethyl), -OR^4f、-NR^4fR^4gsaid-C_1-8Alkyl is optionally substituted by at least one substituent selected from halogen, -NR⁴ⁱR^4jOr cycloalkyl, wherein R is^4f、R^4g、R⁴ⁱAnd R^4jEach independently is hydrogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl), or C_1-8alkoxy-C_1-8Alkyl- (preferably methoxy-C)_1-6Alkyl-, more preferably methoxy-ethyl-).

Aspect 66: a compound according to aspect 65, wherein R^4eIs methoxy, methoxy-ethoxy-, -NH₂、-N(CH₃)₂、NH(CH₃) Hydroxy, methyl, ethyl, N (CH)₃)₂-(CH₂)₂-, or cyclopropyl-CH₂-。

Aspect 67: the compound according to any one of aspects 62-66, wherein R⁴Is that

Aspect 68: a compound according to aspect 61, wherein said ring is a bicyclic 7 to 12 membered ring comprising as one or more ring members 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulfur, said ring being optionally substituted with at least one substituent R ^4eAnd (4) substitution.

Aspect 69: a compound according to aspect 61, wherein R^4eis-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl or ethyl) or cycloalkyl (preferably C)_3-8Cycloalkyl, more preferably cyclopropyl).

Aspect 70: a compound according to aspect 68 or 69, wherein the ring is a bicyclic spiro 7-to 12-membered ring.

Aspect 71: a compound according to aspect 70, wherein the ring is azaspiro [3.3] heptane, azaspiro [3.5] nonane, azaspiro [3.4] octane, azaspiro [5.5] undecane, or azaspiro [4.5] decane, each containing 0 or 1 additional nitrogen or oxygen atom as a ring member.

Aspect 72: the compound according to aspect 68 or 69, wherein R⁴Is that

Aspect 73: a compound according to any one of aspects 18 to 25, wherein R⁴is-SO₂R^4a、-SO₂NR^4aR^4b、-NR^4aSO₂R^4b、-NR^4aCOR^4b、-CO₂R^4a、-COR^4a、-NR^4aR^4bor-NR^4aCONR^4bR^4cWherein

R^4a、R^4bAnd R^4cEach independently is hydrogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl or ethyl), cycloalkyl (preferably monocyclic-C)_3-8Cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), heterocyclylAryl (preferably phenyl), or heteroaryl, said-C_1-8Each of the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is optionally substituted with at least one substituent R^4eSubstitution;

R^4eis hydrogen, halogen, -C_1-8Alkyl (preferably-C) _1-6Alkyl, more preferably methyl or ethyl), cycloalkyl (preferably monocyclic-C)_3-8Cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl OR cyclohexyl), heterocyclyl, aryl, heteroaryl, -OR^4f、-CO₂R^4for-NR^4fR^4g；

R^4fAnd R^4gEach independently is hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl or ethyl).

Aspect 74: a compound according to aspect 73, wherein R⁴is-SO₂R^4aWherein R is^4ais-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl or ethyl) or cycloalkyl (preferably monocyclic-C)_3-8Cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), said-C_1-8The alkyl group and the cycloalkyl group are each optionally substituted with at least one substituent R as defined in aspect 1^4eAnd (4) substitution.

Aspect 75: the compound according to aspect 74, wherein R⁴Is that

Aspect 76: a compound according to aspect 73, wherein R⁴is-SO₂NR^4aR^4bWherein R is^4aAnd R^4bEach independently is hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl or ethyl).

Aspect 77: a compound according to aspect 76, wherein R⁴Is that

Aspect 78: a compound according to aspect 73, wherein R⁴is-NR^4aSO₂R^4b，

Wherein

R^4aAnd R^4bEach independently is hydrogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl or ethyl), cycloalkyl (preferably monocyclic-C)_3-8Cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), or aryl, preferably phenyl, said-C _1-8Each of the alkyl, cycloalkyl, or aryl groups being optionally substituted with at least one substituent R^4eSubstitution;

R^4eis-OR^4fAnd R is^4fIs hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl or ethyl.

Aspect 79: a compound according to aspect 78, wherein R⁴Is that

Aspect 80: a compound according to aspect 73, wherein R⁴is-NR^4aCOR^4bWherein R is^4aAnd R^4bEach independently is hydrogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl group) of said-C_1-8Alkyl is optionally substituted by R^4eSubstituted, said R^4eIs cycloalkyl (preferably monocyclic-C)_3-8Cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl OR cyclohexyl), heterocyclyl (preferably a monocyclic 4-, 5-OR 6-membered ring containing one nitrogen OR oxygen atom as a ring member), -OR^4for-NR^4fR^4g(ii) a Wherein R is^4fAnd R^4gEach independently is hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl or ethyl).

Aspect 81: a compound according to aspect 80, wherein R⁴Is that

Aspect 82: a compound according to aspect 73, wherein R⁴is-NR^4aCONR^4bR^4cWherein R is^4a、R^4bAnd R^4cEach independently is hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl or ethyl), said-C_1-8Alkyl is optionally substituted by R^4eSubstitution; wherein R is^4eis-NR^4fR^4g；R^4fAnd R^4gEach independently is hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl or ethyl).

Aspect 83: a compound according to aspect 82, wherein R⁴Is that

Aspect 84: a compound according to aspect 73, wherein R⁴is-COR^4aWherein R is^4ais-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl or ethyl) or a heterocyclyl (preferably a monocyclic 4-, 5-or 6-membered ring containing as ring members one nitrogen or oxygen atom), optionally substituted with one R^4eSubstituted, R^4eis-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl or ethyl).

Aspect 85: a compound according to aspect 84, wherein R⁴Is that

Aspect 86: a compound according to any one of aspects 18 to 25, wherein R⁴is-OR^4a，R^4ais-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl or ethyl or propyl) or heterocyclyl (preferably selected from tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl), said-C_1-8Alkyl or heterocyclyl being optionally substituted by at least one substituent R^4eSubstitution; r^4eIs hydrogen, halogen, cycloalkyl, aryl, -CONR^4fR^4g、-CO₂R^4f、-C(＝NR^4f)NR^4gR^4hor-NR^4fR^4g；R^4f、R^4gAnd R^4hEach independently is hydrogen, or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl).

Aspect 87: a compound according to aspect 86, wherein R⁴Is a methoxy group, an ethoxy group,

Aspect 88: the compound according to any one of aspects 1 to 17, wherein Cy1 is substituted by one R in position 4⁴Substituted phenyl and n is 0, wherein R ⁴is-CONR as defined in any one of aspects 46 to 71^4aR^4b。

Aspect 89: the compound according to any one of aspects 1-88, wherein m is 0, 1 or 2, R⁶Is as defined in formula (III).

Aspect 90: a compound according to aspect 89, wherein m is 2, one R⁶At a position opposite to the attachment point L²At position 3 of (3), another R⁶At a position opposite to the attachment point L²At position 5.

Aspect 91: a compound according to aspect 89, wherein m is 1, R⁶At a position opposite to the attachment point L²At position 3 or 5.

Aspect 92: the compound according to any one of aspects 89-91, wherein

R⁶Is halogen, -C_1-8Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, nitro, -OR^6a、-COR^6a、-CO₂R^6a、-CONR^6aR^6bor-NR^6aR^6bsaid-C_1-8Each of the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is optionally substituted with at least one substituent R^6dSubstitution;

R^6aand R^6bEach independently is hydrogen, -C_1-8Alkyl, cycloalkyl, or heterocyclyl, said-C_1-8Each of the alkyl, cycloalkyl, or heterocyclyl is optionally substituted with at least one substituent R^6eSubstitution;

R^6dand R^6eEach independently is hydrogen, halogen, -C_1-8Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR^6f、-CONR^6fR^6gor-NR^6fR^6gsaid-C_1-8Each of alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one substituent selected from the group consisting of halogen, -C _1-8Alkyl, -OR⁶ⁱor-NR⁶ⁱR^6jSubstituted with the substituent(s);

R^6f、R^6g、R⁶ⁱand R^6jEach independently is hydrogen, or-C_1-8An alkyl group.

Aspect 93: the compound according to aspect 92, wherein R⁶is-C optionally substituted by halogen (preferably fluorine) or heteroaryl_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl).

Aspect 94: the compound according to aspect 92, wherein R⁶Is cycloalkyl (preferably C)_3-8Cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).

Aspect 95: the compound according to aspect 92, wherein R⁶is-OR^6aWherein R is^6aIs hydrogen or is optionally substituted by at least one substituent R^6esubstituted-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), R^6eIs cycloalkyl (preferably C)_3-8Cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl, OR cyclohexyl), optionally substituted by-OR⁶ⁱSubstituted aryl, heteroaryl(preferably a 6-membered heteroaryl group containing one or two nitrogen atoms as one or more ring members), -CONR^6fR^6gAnd R is^6f、R^6gAnd R⁶ⁱEach independently is hydrogen, or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl).

Aspect 96: a compound according to aspect 95, wherein R⁶Is methoxy, ethoxy, isopropoxy,

Aspect 97: the compound according to aspect 92, wherein R ⁶is-OR^6aWherein R is^6aIs cycloalkyl (preferably C)_3-8Cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).

Aspect 98: the compound according to aspect 92, wherein R⁶is-NR^6aR^6bAnd R is^6aAnd R^6bEach independently is hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), heterocyclyl, benzyl, cycloalkyl (preferably cyclopropyl), or alkoxyalkyl.

Aspect 99: the compound according to aspect 92, wherein R⁶is-COOR^6aAnd R is^6aIs hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

Aspect 100: the compound according to aspect 92, wherein R⁶is-COR^6aAnd R is^6aIs hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl) or heterocyclyl (preferably monocyclic 5-or 6-membered heterocyclyl comprising one or two heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulphur, more preferably morpholino).

Aspect 101: the compound according to aspect 92, wherein R⁶Is optionally substituted by at least one substituent R^6dSubstituted heteroaryl (preferably containing one or two heteroatoms independently selected from nitrogen or oxygen)Monocyclic 5 or 6 membered heteroaryl).

Aspect 102: the compound according to aspect 101, wherein R^6dis-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl) or phenyl, optionally substituted by-C_1-8Alkyl, -OR⁶ⁱor-NR⁶ⁱR^6jIs substituted in which R⁶ⁱAnd R^6jEach independently is hydrogen, or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

Aspect 103: the compound according to aspect 101 or 102, wherein R⁶Is that

Aspect 104: the compound according to aspect 92, wherein R⁶Is optionally substituted by at least one R^6dA substituted heterocyclic group.

Aspect 105: the compound according to aspect 92, wherein R⁶Is a monocyclic 3-to 8-membered heterocyclic group containing as one or more ring members 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur.

Aspect 106: the compound according to aspect 92, wherein R⁶Are 4-, 5-, 6-, or 7-membered heterocyclic groups containing one nitrogen as a ring member (e.g., azetidinyl, pyrrolidinyl, piperidinyl, and azepanyl).

Aspect 107: a compound according to aspect 93, wherein R⁶Is a 4-, 5-, 6-or 7-membered heterocyclyl group (e.g., morpholino or piperazinyl) containing one nitrogen and 1 additional nitrogen or oxygen heteroatom as ring members.

Aspect 108: the compound according to aspect 92, wherein R⁶Is a bicyclic 5-to 12-membered heterocyclyl comprising as one or more ring members 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulfur.

Aspect 109: a compound according to aspect 108, wherein R⁶Is a bicyclic spiro 7-to 12-membered heterocyclyl.

Aspect 110: root of herbaceous plantA compound according to aspect 109, wherein R⁶Is azaspiro [3.3]Heptane, azaspiro [3.5 ]]Nonane, azaspiro [3.4 ]]Octane, azaspiro [5.5 ]]Undecane, or azaspiro [4.5 ]]Decanes, each containing 0 or 1 further nitrogen or oxygen atoms.

Aspect 111: the compound according to aspect 109, wherein R⁶Is 2-oxa-6-azaspiro [3.3]Heptane.

Aspect 112: the compound according to aspect 92, wherein R⁶is-CONR^6aR^6bWherein R is^6aAnd R^6bEach independently is-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), aryl or heteroaryl, each optionally substituted with at least one R^6eSubstituted, R^6eis-OR^6f、-NR^6fR^6gAryl, or heteroaryl, and R^6fAnd R^6gEach independently is hydrogen, or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

Aspect 113: the compound according to aspect 112, wherein R ⁶Is that

Aspect 114: the compound according to any one of aspects 1 to 113, wherein L³Is a single bond or C_1-3Alkylene (e.g., -CH)₂-、-CH₂CH₂-or-CH (CH)₃)-)。

Aspect 115: the compound according to aspect 114, wherein L³Is a single bond.

Aspect 116: the compound according to any one of aspects 1 to 115, wherein

Is partially

Aspect 117: the compound according to any one of aspects 1-116, wherein

Is partially

Aspect 118: the compound according to aspect 116 or 117, wherein p is 0 or 1.

Aspect 119: the compound according to any one of aspects 117-118, wherein

R⁷is-C_1-8Alkyl, heterocyclyl, -NR^7aR^7bOR-OR^7asaid-C_1-8Alkyl or heterocyclyl is optionally substituted by one R^7dThe substitution is carried out by the following steps,

wherein R is^7dis-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), cycloalkyl (preferably C)_3-6Cycloalkyl, more preferably cyclopropyl) OR-OR^7fsaid-C_1-8Alkyl, OR cycloalkyl optionally substituted by at least one substituent selected from halogen, -OR⁷ⁱor-NR⁷ⁱR^7jSubstituted with the substituent(s);

R^7aor R^7bIs hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl);

wherein R is^7f、R⁷ⁱAnd R^7jEach independently is hydrogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

Aspect 120: the compound according to any one of aspects 117-119, wherein p is 0 and R is ⁷is-OR^7aWherein R is^7aIs hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

Aspect 121: the compound according to any one of aspects 117-119, wherein p is 0 and R is⁷Is optionally covered byA R^7dsubstituted-C_1-8Alkyl radical, wherein R^7dis-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), cycloalkyl (preferably C)_3-6Cycloalkyl, more preferably cyclopropyl) OR-OR^7fWherein R is^7fIs hydrogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

Aspect 122: the compound according to aspect 120, wherein p is 0, and R⁷Is methyl, cyclopropylmethyl, or hydroxyethyl.

Aspect 123: the compound according to any one of aspects 117-119, wherein p is 0 and R is⁷Is a heterocyclic group optionally substituted with one R^7dThe substitution is carried out by the following steps,

wherein R is^7dis-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), said-C_1-8Alkyl is optionally substituted by at least one substituent selected from halogen, -OR⁷ⁱor-NR⁷ⁱR^7jWherein R is⁷ⁱAnd R^7jEach independently is hydrogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl).

Aspect 124: a compound according to aspect 123, wherein said heterocyclyl is a monocyclic 5 or 6 membered heterocyclyl comprising as one or more ring members one or two heteroatoms selected from nitrogen, oxygen or optionally oxidised sulfur.

Aspect 125: a compound according to aspect 124, wherein said heterocyclyl is a monocyclic 6-membered heterocyclyl containing one nitrogen or oxygen as a ring member.

Aspect 126: a compound according to aspect 124, wherein said heterocyclyl is piperidinyl (preferably piperidin-4-yl) or tetrahydropyranyl.

Aspect 127: the compound according to any one of aspects 117-119, wherein p is 1, and

R⁸is-C_1-8Alkyl, -CN, -OR^7aor-CONR^7aR^7b，

Wherein R is^7aAnd R^7bEach independently is hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), said-C_1-8Alkyl optionally substituted by at least one substituent R^7eThe substitution is carried out by the following steps,

R^7eis phenyl, heteroaryl, heterocyclyl, each of which is optionally substituted with at least one substituent selected from the group consisting of halogen, -C_1-8Alkyl, -OR⁷ⁱor-NR⁷ⁱR^7jThe substituent (b) of (a) is substituted,

R⁷ⁱand R^7jEach independently is hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

Aspect 128: a compound according to aspect 127, wherein p is 1, and R⁸is-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

Aspect 129: a compound according to aspect 127, wherein p is 1, and R ⁸is-OR^7aWherein R is^7aIs hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

Aspect 130: a compound according to aspect 127, wherein p is 1, and

R⁸is-CONR^7aR^7b，

Wherein R is^7aIs hydrogen, and R^7bIs optionally substituted by at least one substituent R^7esubstituted-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl),

R^7eis phenyl, heteroaryl (preferably a 5 or 6 membered heteroaryl comprising one or two nitrogens as one or more ring members, more preferably pyridinyl or pyrimidinyl), heterocyclyl (preferably a monocyclic 4, 5, 6, or 7 membered heterocyclyl or a bicyclic 7 to 12 membered heterocyclyl each comprising one or two heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulphur, more preferably piperidinyl or piperazinyl), said heterocyclyl, phenyl, orHeteroaryl is each optionally substituted by at least one substituent selected from the group consisting of halogen, -C_1-8Alkyl, -OR⁷ⁱor-NR⁷ⁱR^7jThe substituent (b) of (a) is substituted,

R⁷ⁱand R^7jEach independently is hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

Aspect 131: the compound according to any one of aspects 117-119, wherein p is 1 and R is⁷is-OR^7aWherein R is^7aIs hydrogen or-C _1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), and R⁸As defined in any of aspects 125-128.

Aspect 132: the compound according to any one of aspects 117-119, wherein p is 1 and R is⁷Is optionally substituted by one R^7dsubstituted-C_1-8Alkyl radical, wherein R^7dis-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), cycloalkyl (preferably C)_3-6Cycloalkyl, more preferably cyclopropyl) OR-OR^7fWherein R is^7fIs hydrogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), and R⁸As defined in any of aspects 125-128.

Aspect 133: the compound according to aspect 132, wherein p is 1, and R⁷Is methyl, cyclopropylmethyl, or hydroxyethyl.

Aspect 134: the compound according to any one of aspects 117-119, wherein p is 1 and R is⁷Is a heterocyclic group optionally substituted with one R^7dThe substitution is carried out by the following steps,

wherein R is^7dis-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), said-C_1-8Alkyl is optionally substituted by at least one substituent selected from halogen, -OR⁷ⁱor-NR⁷ⁱR^7jWherein R is⁷ⁱAnd R^7jEach independently is hydrogen, -C _1-8Alkyl radical(preferably-C)_1-6Alkyl, more preferably methyl), and

R⁸as defined in any of aspects 125-128.

Aspect 135: a compound according to aspect 135, wherein said heterocyclyl is a monocyclic 5 or 6 membered heterocyclyl comprising one or two heteroatoms selected from nitrogen, oxygen or optionally oxidised sulfur as one or more ring members.

Aspect 136: the compound according to aspect 135, wherein said heterocyclyl is a monocyclic 6-membered heterocyclyl comprising one nitrogen or oxygen as a ring member.

Aspect 137: a compound according to aspect 134, wherein said heterocyclyl is piperidinyl or tetrahydropyranyl.

Aspect 138: the compound according to any one of aspects 117-137, wherein

Is partially

Aspect 139: the compound according to any one of aspects 117-137, wherein

Is partially

The compounds of the formula (AIV) or (IV) correspond to compounds of the formula (AIII) or (III), in which L¹、L²And L³Each is a single bond, Cy1 is a phenyl ring, and R is⁴is-CONR in the 4 position^4aR^4bAnd R is²And R³Is hydrogen.

Aspect 140: a compound of formula (AIV):

or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

wherein

X¹Is C or N;

R¹is hydrogen, halogen, or-C_1-8An alkyl group; provided that X is¹In the case of N, R is absent ¹；

Cy1 is cycloalkyl, phenyl, 5-or 6-membered heterocyclyl, 5-or 6-membered heteroaryl, or 7-to 12-membered bicyclic fused heteroaryl or heterocyclyl, each of which is substituted with one R⁴Substituted and optionally substituted by R⁵Substitution;

n is 0, 1 or 2;

R⁵at each occurrence thereof, is independently halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^4a、-SO₂R^4a、-SO₂NR^4aR^4b、-COR^4a、-CO₂R^4a、-CONR^4aR^4b、-C(＝NR^4a)NR^4bR^4c、-NR^4aR^4b、-NR^4aCOR^4b、-NR^4aCONR^4bR^4c、-NR^4aCO₂R^4b、-NR^4aSONR^4bR^4c、-NR^4aSO₂NR^4bR^4cor-NR^4aSO₂R^4bsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^4dSubstitution;

R^4a、R^4band R^4cEach independently is hydrogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, ringEach of the alkyl, heterocyclyl, aryl, or heteroaryl groups is optionally substituted with at least one substituent R^4eSubstitution; or

(R^4aAnd R^4b)、(R^4bAnd R^4c) Or (R)^4cAnd R^4a) Together with the atom or atoms to which they are attached form a 3 to 12 membered ring containing 0, 1 or 2 further heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulphur as one or more ring members, said ring being optionally substituted with at least one substituent R^4eSubstitution;

R^4dAnd R^4eEach independently is hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^4f、-SO₂R^4f、-SO₂NR^4fR^4g、-COR^4f、-CO₂R^4f、-CONR^4fR^4g、-C(＝NR^4f)NR^4gR^4h、-NR^4fR^4g、-NR^4fCOR^4g、-NR^4fCONR^4gR^4h、-NR^4fCO₂R^4f、-NR^4fSONR^4fR^4g、-NR^4fSO₂NR^4gR^4hor-NR^4fSO₂R^4gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁴ⁱ、-NR⁴ⁱR^4jCycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^4f、R^4g、R^4h、R⁴ⁱand R^4jEach independently is hydrogen, -C_1-8Alkyl radical, C_1-8alkoxy-C_1-8Alkyl-, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R⁶is halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^6a、-SO₂R^6a、-SO₂NR^6aR^6b、-COR^6a、-CO₂R^6a、-CONR^6aR^6b、-C(＝NR^6a)NR^6bR^6c、-NR^6aR^6b、-NR^6aCOR^6b、-NR^6aCONR^6bR^6c、-NR^6aCO₂R^6b、-NR^6aSONR^6bR^6c、-NR^6aSO₂NR^6bR^6cor-NR^6aSO₂R^6bsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^6dSubstitution;

R^6a、R^6band R^6cEach independently is hydrogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^6eSubstitution;

R^6dAnd R^6eEach independently is hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^6f、-SO₂R^6f、-SO₂NR^6fR^6g、-COR^6f、-CO₂R^6f、-CONR^6fR^6g、-C(＝NR^6f)NR^6gR^6h、-NR^6fR^6g、-NR^6fCOR^6g、-NR^6fCONR^6gR^6h、-NR^6fCO₂R^6f、-NR^6fSONR^6fR^6g、-NR^6fSO₂NR^6gR^6hor-NR^6fSO₂R^6gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁶ⁱ、-NR⁶ⁱR^6jCycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^6f、R^6g、R^6h、R⁶ⁱand R^6jEach independently is hydrogen, -C_1-8Alkyl radical, C_1-8alkoxy-C_1-8Alkyl-, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

m is 0, 1, 2, 3 or 4, provided that valency theory is satisfied;

X²and X³Each independently is CH or N, provided that X²And X³Are not all CH;

t is 0, 1, 2, or 3;

s is 0, 1, 2, or 3;

R⁷and R⁸Each independently is halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^7a、-SO₂R^7a、-SO₂NR^7aR^7b、-COR^7a、-CO₂R^7a、-CONR^7aR^7b、-C(＝NR^7a)NR^7bR^7c、-NR^7aR^7b、-NR^7aCOR^7b、-NR^7aCONR^7bR^7c、-NR^7aCO₂R^7b、-NR^7aSONR^7bR^7c、-NR^7aSO₂NR^7bR^7cor-NR^7aSO₂R^7bsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally substituted with at least oneSubstituent R^7dSubstitution;

R^7a、R^7band R^7cEach independently is hydrogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C _2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^7eSubstitution;

R^7dand R^7eEach independently is hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^7f、-SO₂R^7f、-SO₂NR^7fR^7g、-COR^7f、-CO₂R^7f、-CONR^7fR^7g、-C(＝NR^7f)NR^7gR^7h、-NR^7fR^7g、-NR^7fCOR^7g、-NR^7fCONR^7gR^7h、-NR^7fCO₂R^7f、-NR^7fSONR^7fR^7g、-NR^7fSO₂NR^7gR^7hor-NR^7fSO₂R^7gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁷ⁱ、-NR⁷ⁱR^7jCycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^7f、R^7g、R^7h、R⁷ⁱand R^7jEach independently is hydrogen, -C_1-8Alkyl radical, C_1-8alkoxy-C_1-8Alkyl-, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

p is 0, 1, 2 or 3, provided that the valence theory is satisfied.

Aspect 141: a compound of formula (IV)

Or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

wherein

X¹Is C or N;

R¹is hydrogen, halogen, or-C_1-8An alkyl group; provided that X is¹In the case of N, R is absent¹；

Cy1 is cycloalkyl, phenyl, 5-or 6-membered heterocyclyl, 5-or 6-membered heteroaryl, or 7-to 12-membered bicyclic fused heteroaryl or heterocyclyl, each of which is substituted with one R ⁴Substituted and optionally substituted by R⁵Substitution;

n is 0, 1 or 2;

R⁵at each occurrence thereof, is independently halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^4a、-SO₂R^4a、-SO₂NR^4aR^4b、-COR^4a、-CO₂R^4a、-CONR^4aR^4b、-C(＝NR^4a)NR^4bR^4c、-NR^4aR^4b、-NR^4aCOR^4b、-NR^4aCONR^4bR^4c、-NR^4aCO₂R^4b、-NR^4aSONR^4bR^4c、-NR^4aSO₂NR^4bR^4cor-NR^4aSO₂R^4bsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^4dSubstitution;

R^4a、R^4band R^4cEach independently is hydrogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkylHeterocyclyl, aryl, or heteroaryl, said-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^4eSubstitution; or

(R^4aAnd R^4b)、(R^4bAnd R^4c) Or (R)^4cAnd R^4a) Together with the atom or atoms to which they are attached form a 3 to 12 membered ring containing 0, 1 or 2 further heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulphur as one or more ring members, said ring being optionally substituted with at least one substituent R^4eSubstitution;

R^4dand R^4eEach independently is hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO ₂、-OR^4f、-SO₂R^4f、-SO₂NR^4fR^4g、-COR^4f、-CO₂R^4f、-CONR^4fR^4g、-C(＝NR^4f)NR^4gR^4h、-NR^4fR^4g、-NR^4fCOR^4g、-NR^4fCONR^4gR^4h、-NR^4fCO₂R^4f、-NR^4fSONR^4fR^4g、-NR^4fSO₂NR^4gR^4hor-NR^4fSO₂R^4gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁴ⁱ、-NR⁴ⁱR^4jCycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^4f、R^4g、R^4h、R⁴ⁱand R^4jEach independently is hydrogen, -C_1-8Alkyl radical, C_1-8alkoxy-C_1-8Alkyl-, -C_2-8Alkenyl, -C_2-8Alkynyl, ringAlkyl, heterocyclyl, aryl, or heteroaryl;

R⁶is halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^6a、-SO₂R^6a、-SO₂NR^6aR^6b、-COR^6a、-CO₂R^6a、-CONR^6aR^6b、-C(＝NR^6a)NR^6bR^6c、-NR^6aR^6b、-NR^6aCOR^6b、-NR^6aCONR^6bR^6c、-NR^6aCO₂R^6b、-NR^6aSONR^6bR^6c、-NR^6aSO₂NR^6bR^6cor-NR^6aSO₂R^6bsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^6dSubstitution;

R^6a、R^6band R^6cEach independently is hydrogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^6eSubstitution;

R^6dand R^6eEach independently is hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO ₂、-OR^6f、-SO₂R^6f、-SO₂NR^6fR^6g、-COR^6f、-CO₂R^6f、-CONR^6fR^6g、-C(＝NR^6f)NR^6gR^6h、-NR^6fR^6g、-NR^6fCOR^6g、-NR^6fCONR^6gR^6h、-NR^6fCO₂R^6f、-NR^6fSONR^6fR^6g、-NR^6fSO₂NR^6gR^6hor-NR^6fSO₂R^6gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁶ⁱ、-NR⁶ⁱR^6jCycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^6f、R^6g、R^6h、R⁶ⁱand R^6jEach independently is hydrogen, -C_1-8Alkyl radical, C_1-8alkoxy-C_1-8Alkyl-, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

m is 0, 1, 2, 3 or 4, provided that valency theory is satisfied;

X²and X³Each independently is CH or N, provided that X²And X³Are not all CH;

t is 0, 1, 2, or 3;

R⁷and R⁸Each independently is halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^7a、-SO₂R^7a、-SO₂NR^7aR^7b、-COR^7a、-CO₂R^7a、-CONR^7aR^7b、-C(＝NR^7a)NR^7bR^7c、-NR^7aR^7b、-NR^7aCOR^7b、-NR^7aCONR^7bR^7c、-NR^7aCO₂R^7b、-NR^7aSONR^7bR^7c、-NR^7aSO₂NR^7bR^7cor-NR^7aSO₂R^7bsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heteroThe cyclic, aryl or heteroaryl radical each being optionally substituted by at least one substituent R^7dSubstitution;

R^7a、R^7band R^7cEach independently is hydrogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R ^7eSubstitution;

R^7dand R^7eEach independently is hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^7f、-SO₂R^7f、-SO₂NR^7fR^7g、-COR^7f、-CO₂R^7f、-CONR^7fR^7g、-C(＝NR^7f)NR^7gR^7h、-NR^7fR^7g、-NR^7fCOR^7g、-NR^7fCONR^7gR^7h、-NR^7fCO₂R^7f、-NR^7fSONR^7fR^7g、-NR^7fSO₂NR^7gR^7hor-NR^7fSO₂R^7gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁷ⁱ、-NR⁷ⁱR^7jCycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^7f、R^7g、R^7h、R⁷ⁱand R^7jEach independently is hydrogen, -C_1-8Alkyl radical, C_1-8alkoxy-C_1-8Alkyl-, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

p is 0, 1, 2 or 3, provided that the valence theory is satisfied.

Aspect 142: the compound according to any one of aspects 140-141, wherein n is 1; and R is⁵Is halogen or-C_1-8An alkyl group.

Aspect 143: the compound according to any one of aspects 140-142, wherein-CONR in formulae (AIV) and (IV)^4aR^4bIn part (A) of

R^4aAnd R^4bEach independently is hydrogen, -C_1-8Alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said-C_1-8Each of the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is optionally substituted with at least one substituent R^4eSubstitution;

R^4eis hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C _2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^4f、-SO₂R^4f、-SO₂NR^4fR^4g、-COR^4f、-CO₂R^4f、-CONR^4fR^4g、-C(＝NR^4f)NR^4gR^4h、-NR^4fR^4g、-NR^4fCOR^4g、-NR^4fCONR^4gR^4h、-NR^4fCO₂R^4f、-NR^4fSONR^4fR^4g、-NR^4fSO₂NR^4gR^4hor-NR^4fSO₂R^4gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁴ⁱ、-NR⁴ⁱR^4jCycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^4f、R^4g、R^4h、R⁴ⁱand R^4jEach independently is hydrogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

Aspect 144: a compound according to aspect 143, wherein-CONR is in formulae (AIV) and (IV)^4aR^4bIn the section (a) above, the section (b),

R^4ais hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl; and is

R^4bIs optionally substituted by at least one substituent R^4esubstituted-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl, ethyl or propyl;

R^4eis hydrogen, halogen, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^4f、-SO₂R^4f、-SO₂NR^4fR^4g、-COR^4f、-CO₂R^4f、-CONR^4fR^4g、-C(＝NR^4f)NR^4gR^4h、-NR^4fR^4g、-NR^4fCOR^4g、-NR^4fCONR^4gR^4h、-NR^4fCO₂R^4f、-NR^4fSONR^4fR^4g、-NR^4fSO₂NR^4gR^4hor-NR^4fSO₂R^4gEach of said cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one substituent selected from the group consisting of halogen, -C_1-8Alkyl, -OR⁴ⁱor-NR⁴ⁱR^4jSubstituted with the substituent(s); and is

R^4f、R^4g、R^4h、R⁴ⁱAnd R^4jEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

Aspect 145: the compound according to aspect 144, wherein R^4eIs optionally substituted by-C_1-8Alkyl, hydroxy, or-C_1-8Alkoxy, preferably methyl, substituted 4 to 7 membered ring containing one or two heteroatoms independently selected from nitrogen, oxygen or sulfur, preferably a 4, 5, 6, or 7 membered saturated ring containing one nitrogen or oxygen atom as a ring member, or a 4, 5, 6, or 7 membered saturated ring containing one or two heteroatoms selected from nitrogen and oxygen as a ring member,Or a 7 membered heteroaryl ring.

Aspect 146: a compound according to aspect 145, wherein R^4eIs azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholino, piperazinyl, or pyrazolyl, each of which is optionally substituted with methyl, ethyl, hydroxy, methoxy, amino, or halogen.

Aspect 147: the compound according to aspect 144, wherein R^4eIs optionally substituted by at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁴ⁱor-NR⁴ⁱR^4jPhenyl substituted with the substituent of (1); wherein R is⁴ⁱAnd R^4jEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

Aspect 148: the compound according to aspect 144, wherein R^4eis-OR^4fWherein R is^4fIs hydrogen or-C_1-8Alkyl, preferably-C _1-6Alkyl, more preferably methyl or ethyl.

Aspect 149: the compound according to aspect 144, wherein R^4eis-NR^4fR^4gWherein R is^4fAnd R^4gEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

Aspect 150: a compound according to aspect 143, wherein-CONR in formulae (AIV) and (IV)^4aR^4bIn the section (a) above, the section (b),

R^4ais hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl; and is

R^4bIs cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with at least one substituent R^4eSubstitution;

R^4eis hydrogen, halogen, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^4f、-SO₂R^4f、-SO₂NR^4fR^4g、-COR^4f、-CO₂R^4f、-CONR^4fR^4g、-C(＝NR^4f)NR^4gR^4h、-NR^4fR^4g、-NR^4fCOR^4g、-NR^4fCONR^4gR^4h、-NR^4fCO₂R^4f、-NR^4fSONR^4fR^4g、-NR^4fSO₂NR^4gR^4hor-NR^4fSO₂R^4gEach of said cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one substituent selected from the group consisting of halogen, -C_1-8Alkyl, -OR⁴ⁱor-NR⁴ⁱR^4jSubstituted with the substituent(s); and is

R^4f、R^4g、R^4h、R⁴ⁱAnd R^4jEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

Aspect 151: a compound according to aspect 150, wherein R^4bIs optionally substituted by at least one substituent R^4eSubstituted monocyclic ring C_3-8Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl), R ^4eIs halogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl), -OR⁴ⁱor-NR⁴ⁱR^4jWherein R is⁴ⁱAnd R^4jEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

Aspect 152: a compound according to aspect 150, wherein R^4bIs optionally substituted by at least one substituent R^4eSubstituted heterocyclic group, said R^4eIs halogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl), -OR⁴ⁱor-NR⁴ⁱR^4jWherein R is⁴ⁱAnd R^4jEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

Aspect 153: the compound according to aspect 152, wherein R^4bIs one or two of the compounds are independently selected fromA 4-to 7-membered ring containing a heteroatom in nitrogen, oxygen or sulfur, preferably a 4-, 5-, 6-or 7-membered saturated ring containing one nitrogen or oxygen atom as a ring member.

Aspect 154: a compound according to aspect 153, wherein R^4bIs azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, tetrahydrofuranyl, tetrahydropyranyl, or morpholino.

Aspect 155: the compound according to any one of aspects 140-142, wherein-CONR in formulae (AIV) and (IV)^4aR^4bIn the section (a) above, the section (b),

R^4aand R^4bTogether with the nitrogen atom to which they are attached form a 3-to 12-membered ring, which ring comprises as one or more ring members 0, 1 or 2 further heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulfur, which ring is optionally substituted with at least one substituent R ^4eSubstitution;

R^4eis hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^4f、-SO₂R^4f、-SO₂NR^4fR^4g、-COR^4f、-CO₂R^4f、-CONR^4fR^4g、-C(＝NR^4f)NR^4gR^4h、-NR^4fR^4g、-NR^4fCOR^4g、-NR^4fCONR^4gR^4h、-NR^4fCO₂R^4f、-NR^4fSONR^4fR^4g、-NR^4fSO₂NR^4gR^4hor-NR^4fSO₂R^4gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁴ⁱ、-NR⁴ⁱR^4jCycloalkyl, heterocyclyl, aryl, or heteroaryl; and is

R^4f、R^4g、R^4h、R⁴ⁱAnd, andR^4jeach independently is hydrogen, -C_1-8Alkyl, or C_1-8alkoxy-C_1-8An alkyl group-.

Aspect 156: the compound according to aspect 155, wherein R is substituted with R^4aAnd R^4bThe ring formed with the nitrogen atom to which they are attached is a monocyclic 3 to 8 membered ring comprising as one or more ring members 0, 1 or 2 further heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulfur, the ring being optionally substituted with at least one substituent R^4eAnd (4) substitution.

Aspect 157: the compound according to aspect 156, wherein R is^4aAnd R^4bThe ring formed with the nitrogen atom to which they are attached is a 4-, 5-, 6-or 7-membered ring containing 0 additional heteroatoms (e.g., azetidinyl, pyrrolidinyl, piperidinyl, and azepanyl), optionally substituted with at least one substituent R ^4eAnd (4) substitution.

Aspect 158: the compound according to aspect 156, wherein R is^4aAnd R^4bThe ring formed with the nitrogen atom to which they are attached is a 4-, 5-, 6-or 7-membered ring containing 1 additional nitrogen or oxygen heteroatom as a ring member (e.g. morpholino or piperazinyl), optionally substituted with at least one substituent R^4eAnd (4) substitution.

Aspect 159: the compound according to any one of aspects 156-158, wherein R^4eis-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl OR ethyl), -OR^4f、-NR^4fR^4gsaid-C_1-8Alkyl is optionally substituted by at least one substituent selected from halogen, -NR⁴ⁱR^4jOr cycloalkyl, wherein R is^4f、R^4g、R⁴ⁱAnd R^4jEach independently is hydrogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl), or C_1-8alkoxy-C_1-8Alkyl- (preferably methoxy-C)_1-6Alkyl-, more preferably methoxy-ethyl-).

Aspect 160: the compound according to aspect 159, wherein R^4eIs methoxy, methoxy-ethoxy-, -NH₂、-N(CH₃)₂、NH(CH₃) Hydroxy, methyl, ethyl, N (CH)₃)₂-(CH₂)₂-, or cyclopropyl-CH₂-。

Aspect 161: a compound according to aspect 155, wherein said ring is a bicyclic 7 to 12 membered ring comprising as one or more ring members 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulfur, said ring being optionally substituted with at least one substituent R ^4eAnd (4) substitution.

Aspect 162: the compound according to aspect 155, wherein R^4eis-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl or ethyl) or cycloalkyl (preferably C)_3-8Cycloalkyl, more preferably cyclopropyl).

Aspect 163: a compound according to aspect 161 or 162, wherein the ring is a bicyclic spiro 7-to 12-membered ring.

Aspect 164: a compound according to aspect 163, wherein the ring is azaspiro [3.3] heptane, azaspiro [3.5] nonane, azaspiro [3.4] octane, azaspiro [5.5] undecane, or azaspiro [4.5] decane, each containing 0 or 1 additional nitrogen or oxygen atoms as ring members.

Aspect 165: the compound according to any one of aspects 143-164, wherein-CONR in the formulae (AIV) and (IV)^4aR^4bIs partially

a)

b)

c)

d)

Aspect 166: the compound according to aspect 140-165, wherein the compound has the formula

Aspect 167: the compound according to any one of aspects 140-166, wherein

R⁶Is halogen, -C_1-8Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, nitro, -OR^6a、-COR^6a、-CO₂R^6a、-CONR^6aR^6bor-NR^6aR^6bsaid-C_1-8Each of the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is optionally substituted with at least one substituent R^6dSubstitution;

R^6aand R^6bEach independently is hydrogen, -C_1-8Alkyl, cycloalkyl, or heterocyclyl, said-C _1-8Each of the alkyl, cycloalkyl, or heterocyclyl is optionally substituted with at least one substituent R^6eSubstitution;

R^6dand R^6eEach independently is hydrogen, halogen, -C_1-8Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR^6f、-CONR^6fR^6gor-NR^6fR^6gsaid-C_1-8Each of alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one substituent selected from the group consisting of halogen, -C_1-8Alkyl, -OR⁶ⁱor-NR⁶ⁱR^6jSubstituted with the substituent(s);

R^6f、R^6g、R⁶ⁱand R^6jEach independently is hydrogen, or-C_1-8An alkyl group.

Aspect 168: a compound according to aspect 167, wherein R⁶Is that

a) -C optionally substituted by halogen (preferably fluorine) or heteroaryl_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl); or

b) Cycloalkyl (preferably C)_3-8Cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl);

c)-OR^6awherein R is^6aIs hydrogen or is optionally substituted by at least one substituent R^6esubstituted-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), R^6eIs cycloalkyl (preferably C)_3-8Cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl, OR cyclohexyl), optionally substituted by-OR⁶ⁱSubstituted aryl, heteroaryl (preferably 6-membered heteroaryl containing one or two nitrogen atoms as one or more ring members), -CONR ^6fR^6gAnd R is^6f、R^6gAnd R⁶ⁱEach independently is hydrogen, or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl); or

d)-OR^6aWherein R is^6aIs cycloalkyl (preferably C)_3-8Cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl); or

e)-NR^6aR^6bAnd R is^6aAnd R^6bEach independently is hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), heterocyclyl, benzyl, cycloalkyl (preferably cyclopropyl), or alkoxyalkyl; or

f) Optionally substituted by at least one substituent R^6dSubstituted heteroaryl (preferably monocyclic 5 or 6 membered heteroaryl comprising one or two heteroatoms independently selected from nitrogen or oxygen), wherein R is^6dis-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl) or phenyl, optionally substituted by-C_1-8Alkyl, -OR⁶ⁱor-NR⁶ⁱR^6jIs substituted in which R⁶ⁱAnd R^6jEach independently is hydrogen, or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl);

g) optionally substituted by at least one R^6dA substituted heterocyclic group.

Aspect 169: the compound according to aspect 168, wherein R⁶Is a monocyclic 3-to 8-membered heterocyclic group containing as one or more ring members 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur.

Aspect 170: the compound according to aspect 168, wherein R⁶Are 4-, 5-, 6-, or 7-membered heterocyclic groups containing one nitrogen as a ring member (e.g., azetidinyl, pyrrolidinyl, piperidinyl, and azepanyl).

Aspect 171: the compound according to aspect 168, wherein R⁶Is a 4-, 5-, 6-or 7-membered heterocyclyl group (e.g., morpholino or piperazinyl) containing one nitrogen and 1 additional nitrogen or oxygen heteroatom as ring members.

Aspect 172: the compound according to aspect 112, wherein R⁶Is that

a) Halogen; CN; a nitro group;

b) methyl, trifluoromethyl;

c) methoxy, ethoxy, isopropoxy, trifluoromethoxy, hydroxy, oxetan-3-yloxy, oxetanyl, and the like,

d)

e) A cyclopropyl group;

f) methylamino, ethylamino, benzylamino, (2-methoxyethyl) (methyl) amino, isopropylamino, propylamino, cyclopropylamino, ((tetrahydrofuran-2-yl) methyl) amino; or

g) (R) -3-hydroxypyrrolidin-1-yl, (S) -3-hydroxypyrrolidin-1-yl, (1-methyl-1H-pyrazol-4-yl) methyl, 1H-pyrazol-4-yl, 5-oxopyrrolidin-3-yl, or tetrahydrofuran-3-yl.

Aspect 173: the compound according to any one of aspects 140-172, wherein

Is partially

Aspect 174: the compound according to any one of aspects 141-172, wherein

Is partially

Aspect 175: the compound according to aspect 173 or 174, wherein p is 0 or 1.

Aspect 176: the compound according to any one of aspects 173-175, wherein p is 0 and R is⁷Is optionally substituted by one R^7dsubstituted-C_1-8Alkyl radical, wherein R^7dis-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), cycloalkyl (preferably C)_3-6Cycloalkyl, more preferably cyclopropyl) OR-OR^7fWherein R is^7fIs hydrogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

Aspect 177: a compound according to aspect 176, wherein p is 0, and R⁷Is methyl, cyclopropylmethyl, or hydroxyethyl.

Aspect 178: the compound according to any one of aspects 173-175, wherein p is 0 and R is⁷Is a heterocyclic group optionally substituted with one R^7dThe substitution is carried out by the following steps,

wherein R is^7dis-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), said-C_1-8Alkyl is optionally substituted by at least one substituent selected from halogen, -OR⁷ⁱor-NR⁷ⁱR^7jSubstituted by a substituent of (a), whichIn R⁷ⁱAnd R^7jEach independently is hydrogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl).

Aspect 179: a compound according to aspect 178, wherein said heterocyclyl is a monocyclic 5 or 6 membered heterocyclyl comprising as one or more ring members one or two heteroatoms selected from nitrogen, oxygen or optionally oxidised sulfur.

Aspect 180: the compound according to aspect 179, wherein said heterocyclyl is a monocyclic 6-membered heterocyclyl comprising one nitrogen or oxygen as ring member.

Aspect 181: a compound according to aspect 179, wherein said heterocyclyl is piperidinyl (preferably piperidin-4-yl) or tetrahydropyranyl.

Aspect 182: a compound according to aspect 127, wherein p is 1, and

R⁸is-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl) or R⁸is-OR^7aWherein R is^7aIs hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

Aspect 183: the compound according to any one of aspects 117-119, wherein p is 1 and R is⁷Is optionally substituted by one R^7dsubstituted-C_1-8Alkyl radical, wherein R^7dis-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), cycloalkyl (preferably C)_3-6Cycloalkyl, more preferably cyclopropyl) OR-OR^7fWherein R is^7fIs hydrogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), and R⁸As defined in any of aspects 125-128.

Aspect 184: the compound according to aspect 183, wherein p is 1, and R⁷Is methyl, cyclopropylmethyl, or hydroxyethyl.

Aspect 185: the compound according to any one of aspects 173-184, wherein

Is partially

Aspect 186: a compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, selected from the exemplary compounds disclosed herein.

The inventors of the present invention have found that wherein Cy1 is phenyl and R⁴A compound of formula (AIII) or (III) in the 4-position of the phenyl ring, especially wherein R⁴Has been limited to-CONR^4aR^4bThe compound of formula (AIV) or (IV) shows an enzymatic activity of inhibiting HPK1 kinase. In contrast, wherein R⁴The compound at position 2 has no enzymatic activity to inhibit HPK1 kinase.

The inventors of the present invention have further found that

A moiety is attached to the 4-position of the phenyl ring in formula (III) and R on the moiety⁷By substitution and/or coupling of R in position 3 or 5 of said phenyl ring⁶Substitutions also produce or increase enzyme binding or enzyme activity that modulates (or inhibits) HPK1 kinase.

In a fourth embodiment, disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

In a fifth embodiment, disclosed herein is a method of inhibiting HPK1 activity, the method comprising administering to a subject a compound disclosed herein, or a pharmaceutically acceptable salt thereof, comprising a compound of formula (I), a compound of formula (II), or a compound of formula (III), or a particular compound exemplified herein.

In a sixth embodiment, disclosed herein is a method of treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, as an HPK1 kinase inhibitor, wherein the compound disclosed herein comprises a compound of formula (I), a compound of formula (II), or a compound of formula (III), or a specific compound exemplified herein.

In one aspect of the sixth embodiment, the disease or disorder is associated with inhibition of HPK1 interaction. Preferably, the disease or disorder is cancer.

Detailed Description

The following terms have the indicated meanings throughout the specification:

as used herein (including the appended aspects), singular forms of words such as "a," "an," and "the" include their corresponding plural referents unless the context clearly dictates otherwise.

The term "or" is used to mean, and is used interchangeably with, the term "and/or," unless the context clearly dictates otherwise.

The term "alkyl" refers to a hydrocarbon group selected from straight and branched chain saturated hydrocarbon groups containing 1 to 18 (such as 1 to 12, further such as 1 to 10, further such as 1 to 8, or 1 to 6, or 1 to 4) carbon atoms. Examples of alkyl groups containing 1 to 6 carbon atoms (i.e., C) _1-6Alkyl) includes, but is 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 sec-butyl ("s-Bu"), 1-dimethylethyl or tert-butyl ("t-Bu"), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-isopropyl ("i-Pr"), 2-butyl or n-butyl ("n-Bu"), 2-methyl-1-butyl ("t-Bu"), 1-pentyl, 2-, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl and 3, 3-dimethyl-2-butyl.

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

The term "haloalkyl" refers to an alkyl in which one or more hydrogens are replaced with one or more halogen atoms (such as fluorine, chlorineBromine and iodine). Examples of haloalkyl groups include halo C_1-8Alkyl, halo C_1-6Alkyl or halo C_1-4Alkyl, but not limited to-CF₃、-CH₂Cl、-CH₂CF₃、-CHCl₂、CF₃And the like.

The term "alkenyl" refers to a hydrocarbon group selected from straight and branched chain hydrocarbon groups containing at least one C ═ C double bond and 2 to 18 (such as 2 to 8, further such as 2 to 6) carbon atoms. Alkenyl (e.g. C) _2-6Alkenyl) include, but are not limited to, vinyl (ethenyl or vinyl), prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-2-enyl, but-3-enyl, but-1, 3-dienyl, 2-methylbut-1, 3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl and hex-1, 3-dienyl.

The term "alkynyl" refers to a hydrocarbon radical selected from straight and branched chain hydrocarbon radicals containing at least one C ≡ C triple bond and 2 to 18 (such as 2 to 8, further such as 2 to 6) carbon atoms. Alkynyl (e.g., C)_2-6Alkynyl) include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl.

The term "alkyloxy" or "alkoxy" means an alkyl group, as defined above, appended to the parent molecular moiety through an oxygen atom. Alkyloxy (e.g. C)_1-6Alkyloxy or C_1-4Alkyl oxy) includes, but is not limited to, methoxy, ethoxy, isopropoxy, propoxy, n-butoxy, t-butoxy, pentoxy, hexoxy, and the like.

The term "alkoxy-alkyl-" refers to an alkyl group as defined above further substituted with an alkoxy group as defined above. Alkoxy-alkyl- (e.g. C) _1-8alkoxy-C_1-8Examples of alkyl-) include, but are not limited to, methoxymethyl, ethoxymethyl, isopropoxymethyl, or propoxymethyl, and the like.

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

For example, a cycloalkyl group may contain 3 to 12 (such as 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, cycloalkyl groups may be selected from monocyclic groups comprising 3 to 12 (such as 3 to 10, further such as 3 to 8, 3 to 6) carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Specifically, a saturated monocyclic cycloalkyl group (e.g., C)_3-8Cycloalkyl) groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In a preferred embodiment, cycloalkyl is a monocyclic ring (abbreviated as C) containing 3 to 6 carbon atoms _3-6Cycloalkyl) including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of bicyclic cycloalkyl groups include those having 7 to 12 ring atoms arranged as selected from [4,4 ] ring atoms]、[4,5]、[5,5]、[5,6]Or [6,6 ]]Condensed bicyclic rings in ring systems, or arranged to be selected from bicyclo [2.2.1]Heptane, bicyclo [2.2.2]Octane and bicyclo [3.2.2]Bridged bicyclic rings in nonanes. Other examples of bicyclic cycloalkyl groups include those arranged as a group selected from [5,6 ]]And [6,6 ]]Bicyclic rings in ring systems (such as

) Wherein the wavy lines indicate attachment points. The ring may be saturated or have at least one double bond (i.e., partially unsaturated), but is not fully conjugated, and is not aromatic, as aromatic is defined herein.

The term "spirocycloalkyl" refers to a cyclic structure containing carbon atoms and formed from at least two rings that share an atom. The term "7 to 12 membered spirocycloalkyl" refers to a cyclic structure containing 7 to 12 carbon atoms and formed from at least two rings that share an atom.

The term "fused cycloalkyl" refers to a fused ring containing carbon atoms and formed from two or more rings that share two adjacent atoms. The term "4-to 10-membered fused cycloalkyl" refers to a fused ring containing 4 to 10 ring carbon atoms and formed from two or more rings that share two adjacent atoms.

Examples 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-membered cycloalkyl, benzo C_4-6Cycloalkenyl, 2, 3-dihydro-1H-indenyl, 1,2,3, 4-tetrazolyl, 1, 4-dihydronaphthyl, and the like. A preferred embodiment is an 8 to 9 membered fused ring, which refers to a cyclic structure containing 8 to 9 ring atoms in the above examples.

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

The term "cycloalkenyl" refers to a non-aromatic cyclic alkyl group of 3 to 10 carbon atoms having a single or multiple ring and having at least one double bond and preferably 1 to 2 double bonds. In one embodiment cycloalkenyl is cyclopentenyl (1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl) or cyclohexenyl (1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl), preferably cyclohexenyl.

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

The term "aryl", used alone or in combination with other terms, refers to a group selected from:

5-and 6-membered carbocyclic aromatic rings, for example phenyl;

-bicyclic ring systems, such as 7 to 12 membered bicyclic ring systems, wherein at least one ring is carbocyclic and aromatic, e.g. naphthyl and indanyl; and

-tricyclic ring systems, such as 10-to 15-membered tricyclic ring systems, wherein at least one ring is carbocyclic and aromatic, e.g. fluorenyl.

Term "Aromatic hydrocarbon rings "and" aryl "are used interchangeably throughout the disclosure herein. In some embodiments, the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C)_5-10Aryl). Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphthalen-1-yl, naphthalen-2-yl, anthracenyl, phenanthrenyl, and the like. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphthalene-1-yl or naphthalene-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

The term "heteroaryl" refers to a group selected from:

-a 5, 6 or 7 membered aromatic monocyclic ring comprising at least one heteroatom, such as 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, in some embodiments 1 to 2 heteroatoms, said heteroatoms being selected from nitrogen (N), sulfur (S) and oxygen (O), the remaining ring atoms being carbon;

-a 7-to 12-membered bicyclic ring comprising at least one heteroatom, such as 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, or in other embodiments 1 or 2 heteroatoms, selected from N, O and S, the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in an aromatic ring; and

-an 11-to 14-membered tricyclic ring comprising at least one heteroatom, such as 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, or in other embodiments 1 or 2 heteroatoms, selected from N, O and S, the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in an 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 is no greater than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is no greater than 1. When a heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. The nitrogen atoms in one or more rings of the heteroaryl group can be oxidized to form an N-oxide. The term "C-linked heteroaryl" as used herein means that the heteroaryl is linked to the core molecule through a bond from a C-atom of the heteroaryl ring.

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

Examples of heteroaryl or monocyclic or bicyclic aromatic heterocyclic rings include, but are not limited to (as numbered from the attachment position of indicated priority 1) pyridyl (such as 2-pyridyl, 3-pyridyl or 4-pyridyl), cinnolinyl, pyrazinyl, 2, 4-pyrimidinyl, 3, 5-pyrimidinyl, 2, 4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl (such as 1,2, 3-thiadiazolyl, 1,2, 4-thiadiazolyl or 1,3, 4-thiadiazolyl), tetrazolyl, thienyl (such as thien-2-yl, thien-3-yl), triazinyl, benzothienyl, furyl (furyl or furanyl), benzofuranyl, benzimidazolyl, indolyl, isoindolyl, thionylyl, Indolinyl, oxadiazolyl (such as 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl or 1,3, 4-oxadiazolyl), phthalazinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl (such as 1,2, 3-triazolyl, 1,2, 4-triazolyl or 1,3, 4-triazolyl), quinolinyl, isoquinolinyl, pyrazolyl, pyrrolopyridinyl (such as 1H-pyrrolo [2,3-b ] pyridin-5-yl), pyrazolopyridinyl (such as 1H-pyrazolo [3,4-b ] pyridin-5-yl), benzoxazolyl (such as benzo [ d ] oxazol-6-yl), pteridinyl, purinyl, 1-oxa-2, 3-oxadiazolyl, 1-oxa-2, 4-oxadiazolyl, 1-oxa-2, 5-oxadiazolyl, 1-oxa-3, 4-oxadiazolyl, 1-thia-2, 3-oxadiazolyl, 1-thia-2, 4-oxadiazolyl, 1-thia-2, 5-oxadiazolyl, 1-thia-3, 4-oxadiazolyl, furazanyl (such as furazan-2-yl, furazan-3-yl), benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, benzothiazolyl (such as benzo [ d ] thiazol-6-yl), indazolyl (such as 1H-indazol-5-yl), and 5,6,7, 8-tetrahydroisoquinoline.

"heterocyclyl", "heterocycle" or "heterocyclic" are interchangeable and refer to a non-aromatic heterocyclic group that contains one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members and the remaining ring members are carbon, including monocyclic rings, fused rings, bridged rings, and spirocycles, i.e., containing monocyclic heterocyclic groups, bridged heterocyclic groups, spiroheterocyclic groups, and fused heterocyclic groups. The term "optionally oxidized sulfur" as used herein means S, SO or SO₂。

The term "monocyclic heterocyclyl" refers to a monocyclic group in which at least one ring member is a heteroatom selected from nitrogen, oxygen or optionally oxidized sulfur. The heterocyclic ring may be saturated or partially saturated.

Exemplary monocyclic 4-to 9-membered heterocyclic groups include, but are not limited to (as numbered from the attachment position specifying priority 1) pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrazolidin-2-yl, pyrazolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2, 5-piperazinyl, pyranyl, morpholinyl, morpholino, morpholinyl, morpholin-2-yl, morpholin-3-yl, oxiranyl, aziridin-1-yl, aziridin-2-yl, azocane-1-yl, azocane-2-yl, and the like, Azetidin-3-yl, azetidin-4-yl, azetidin-5-yl, thiepanyl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, oxetanyl, thietanyl, 1, 2-dithianyl, 1, 3-dithianyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, oxathiolanyl, piperazinyl, homopiperazinyl, homopiperidinyl, azepan-1-yl, azepan-2-yl, azepan-3-yl, azepan-4-yl, oxepanyl, thiepanyl, 1, 4-oxathianyl, azetidinyl, 1, 4-dioxepanyl, 1, 4-oxathiepanyl, 1, 4-oxazepanyl, 1, 4-dithiacycloheptyl, 1, 4-thiazepanyl and 1, 4-diazepanyl, 1, 4-dithiacyclonyl, 1, 4-azathiepanyl, oxazepinyl, diazepinyl, thiazepinyl, dihydrothienyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, 1, 4-dioxanyl, 1, 3-dioxolanyl, pyrazolinyl, Pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinyl, imidazolinyl, pyrimidinonyl, or 1, 1-dioxo-thiomorpholinyl.

The term "spiroheterocyclyl" refers to a 5-to 20-membered polycyclic heterocyclyl group having rings attached through one common carbon atom (referred to as spiro atom) containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon. One or more rings of the spiroheterocyclic group may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably, the spiroheterocyclyl group is 6 to 14 membered, and more preferably 7 to 12 membered. The spiro heterocyclic group is classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group, or a multi-spiro heterocyclic group, according to the number of common spiro atoms, and preferably means a mono-spiro heterocyclic group or a di-spiro heterocyclic group, and more preferably a 4-membered/4-membered, 3-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered mono-spiro heterocyclic group. Representative examples of spiro heterocyclic groups include, but are not limited to, the following: 2, 3-dihydrospiro [ indene-1, 2 '-pyrrolidine ] (e.g., 2, 3-dihydrospiro [ indene-1, 2' -pyrrolidin ] -1 '-yl), 1, 3-dihydrospiro [ indene-2, 2' -pyrrolidine ] (e.g., 1, 3-dihydrospiro [ indene-2, 2 '-pyrrolidin ] -1' -yl), azaspiro [2.4] heptane (e.g., 5-azaspiro [2.4] heptane-5-yl), azaspiro [3.4] octane (e.g., 6-azaspiro [3.4] octane-6-yl), 2-oxa-6-azaspiro [3.4] octane (e.g., 2-oxa-6-azaspiro [3.4] octane-6-yl), azaspiro [3.4] octane (e.g., 6-azaspiro [3.4] oct-6-yl), azaspiro [3.4] octane (e.g., 6-azaspiro [3.4] oct-6-yl), 1, 7-dioxaspiro [4.5] decane, 2-oxa-7-aza-spiro [4.4] nonane (e.g., 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 heterocyclic group" refers to a 5 to 20 membered polycyclic heterocyclic group wherein each ring in the system shares an adjacent pair of atoms (carbon and carbon atoms or carbon and nitrogen atoms) with another ring, comprising one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, the remaining ring members being carbon. One or more rings of the fused heterocyclic group may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably, the fused heterocyclyl is 6 to 14 membered, preferably 7 to 12 membered and more preferably 7 to 10 membered. The fused heterocyclic group is classified into a bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic fused heterocyclic group, and more preferably a 5-membered/5-membered, or 5-membered/6-membered bicyclic fused heterocyclic group, depending on the number of the ring-forming members. Representative examples of fused heterocycles include, but are not limited to, the following: octahydrocyclopenta [ c ] pyrrole (e.g., octahydrocyclopenta [ c ] pyrrol-2-yl), octahydropyrrolo [3,4-c ] pyrrolyl, octahydroisoindolyl, isoindolinyl (e.g., isoindolin-2-yl or isoindolin-5-yl), octahydrobenzo [ b ] [1,4] dioxine, dihydropyridooxazinyl (e.g., 2, 3-dihydro-1H-pyrido [2,3-b ] [1,4] oxazinyl), or dihydrobenzoxazepinyl (e.g., 5-oxo-3, 4-dihydrobenzo [ f ] [1,4] oxazepinyl), benzoxazepinyl (e.g., 2,3,4, 5-tetrahydro-1-oxo-2-benzazepin-6-yl), Benzoxazepine group (e.g., 5-oxo-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-8-yl), dihydroisoquinolinyl group (e.g., 1-oxo-2-methyl-3, 4-dihydroisoquinolin-6-yl), tetrahydroisoquinolinyl group (e.g., 2-methyl-1-oxo-1, 2,3, 4-tetrahydroisoquinolin-6-yl), dihydrobenzoxazine (e.g., 3, 4-dihydro-2H-1, 4-benzoxazin-6-yl).

The term "bridged heterocyclyl" refers to a 5-to 14-membered polycyclic heterocycloalkyl group in which each two rings in the system share two unconnected atoms, containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon. One or more rings bridging the heterocyclyl group may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. Preferably, the bridged heterocyclyl is 6 to 14 membered, and more preferably 7 to 10 membered. Depending on the number of membered rings, the bridged heterocyclyl group is a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl group, and preferably refers to a bicyclic, tricyclic or tetracyclic bridged heterocyclyl group, and more preferably a bicyclic or tricyclic bridged heterocyclyl group. Representative examples of bridged heterocyclic groups include, but are not limited to, the following: 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 "alkylene" refers to a divalent alkyl group as defined above. The term "alkenylene" refers to a divalent alkenyl group as defined above. The term "alkynylene" refers to a divalent alkynyl group as defined above. The term "cycloalkylene" refers to a divalent cycloalkyl group as defined above. The term "heterocyclylene" refers to a divalent heterocyclic group as defined above. The term "arylene" refers to a divalent aryl group as defined above. The term "heteroarylene" refers to a divalent heteroarylene group as defined above.

The compounds disclosed herein may contain asymmetric centers and, thus, may exist as enantiomers. "enantiomer" refers to two stereoisomers of a compound that are nonsuperimposable mirror images of each other. Where the compounds disclosed herein have two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers belong to a broader class of stereoisomers. It is intended to include all such possible stereoisomers as substantially pure resolved enantiomers, racemic mixtures thereof, and mixtures of diastereomers. All stereoisomers of the compounds disclosed herein and/or pharmaceutically acceptable salts thereof are intended to be included. Unless otherwise specifically mentioned, reference to one isomer applies to any possible isomer. Whenever the isomeric composition is unspecified, all possible isomers are included.

The term "substantially pure" as used herein means that the stereoisomer of interest contains no more than 35% (such as no more than 30%, further such as no more than 25%, even further such as no more than 20%) by weight of any other stereoisomer(s). In some embodiments, the term "substantially pure" means that the stereoisomer of interest contains no more than 10% (e.g., no more than 5%, such as no more than 1%) by weight of any other stereoisomer(s).

When the compounds disclosed herein contain olefinic double bonds, such double bonds are intended to include both E and Z geometric isomers, unless otherwise specified.

When the compounds disclosed herein contain a disubstituted cyclohexyl or cyclobutyl group, the substituents found on the cyclohexyl or cyclobutyl ring can be formed in both the cis and trans forms. Cis formation means that both substituents are found on the carbon at the upper side of the 2 substituent positions, while trans 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. The desired product of each step or series of steps is isolated and/or purified (hereinafter isolated) by techniques commonly used in the art to the desired degree of homogeneity. Typically, such separation involves heterogeneous extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography may involve any number of methods, including, for example: reverse phase and normal phase; size exclusion; ion exchange; high, medium and low pressure liquid chromatography and apparatus; small-scale analysis; simulated moving bed ("SMB") and preparative thin or thick layer chromatography, as well as small scale thin layer and flash chromatography. Those skilled in the art will apply the techniques most likely to achieve the desired separation.

"diastereoisomers" refer to stereoisomers of compounds having two or more chiral centers, but which are not mirror images of each other. Separation of diastereomeric mixtures into their individual diastereomers can be based on their physicochemical differences, for example, by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization. Enantiomers can be separated by: the enantiomeric mixtures are converted into diastereomeric mixtures by reaction with an appropriate optically active compound (e.g. a chiral auxiliary, such as a chiral alcohol or Mosher's acid chloride), the diastereomers are separated and the individual diastereomers are converted (e.g. hydrolyzed) into the corresponding pure enantiomers. Enantiomers can also be separated by using a chiral HPLC column.

Single stereoisomers, e.g. substantially pure enantiomers, can be obtained by resolving racemic mixtures using optically active resolving agents using methods such as diastereomer formation (Eliel, E. and Wilen, S. stereospecificity of Organic Compounds.New York: John Wiley & Sons, Inc., 1994; Lochmuller, C.H., et al, "Chromatographic resolution of enantiomers: Selective review," J.Chromatographer, 113(3) (1975): page 283-302). The racemic mixture of chiral compounds of the present invention can be separated and isolated by any suitable method, including: (1) forming ionic diastereoisomeric salts with chiral compounds and separating by fractional crystallization or other methods; (2) forming diastereomeric compounds with a chiral derivatizing agent, separating the diastereomers and converting to pure stereoisomers; and (3) direct separation of substantially pure or enriched stereoisomers under chiral conditions. See: wainer, Irving W., editors Stereochemistry: Analytical Methods and Pharmacology.New York: Marcel Dekker, Inc., 1993.

"pharmaceutically acceptable salts" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting the free base functionality with a suitable organic acid or by reacting the acidic group with a suitable base.

Additionally, if the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, such as a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and/or water and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize the various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts without undue experimentation.

As defined herein, "pharmaceutically acceptable salts thereof" include at least one salt of a compound of formula (I) and salts of stereoisomers of a compound of formula (I), such as salts of enantiomers and/or salts of diastereomers.

The terms "administering", "treating" and "treatment", when applied to an animal, human, experimental subject, cell, tissue, organ or biological fluid, mean the contact of an exogenous agent, therapeutic agent, diagnostic agent or composition with the animal, human, subject, cell, tissue, organ or biological fluid. Treatment of a cell encompasses contact of the agent with the cell, and contact of the agent with a fluid, wherein the fluid is in contact with the cell. The terms "administration" and "treatment" also mean in vitro and ex vivo treatment of, for example, a cell by an agent, diagnostic agent, binding compound, or by another cell. The term "subject" herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit) and most preferably a human.

The term "effective amount" or "therapeutically effective amount" refers to an amount of an active ingredient, such as a compound, that is sufficient to effect such treatment of a disease or at least one clinical symptom of the disease or disorder when the compound is administered to a subject to treat the disease or such treatment of the disease, disorder, or symptom. The "therapeutically effective amount" may vary from: the compound, the disease, disorder, and/or symptoms of the disease or disorder, the severity of the disease, disorder, and/or symptoms of the disease or disorder, the age of the subject to be treated, and/or the weight of the subject to be treated. In any given instance, appropriate amounts will be apparent to those skilled in the art, or may be determined by routine experimentation. In some embodiments, a "therapeutically effective amount" is an amount of at least one compound disclosed herein and/or at least one stereoisomer thereof and/or at least one pharmaceutically acceptable salt thereof that is effective to "treat" (as defined above) a disease or disorder in a subject. In the context of combination therapy, a "therapeutically effective amount" refers to the total amount of the combination of subjects that is effective to treat a disease, disorder or condition.

Pharmaceutical compositions comprising a compound disclosed herein can be administered to a subject in need thereof via oral, inhalation, rectal, parenteral, or topical administration. For oral administration, the pharmaceutical composition may be a conventional solid formulation such as tablets, powders, granules, capsules and the like, a liquid formulation such as an aqueous or oily suspension, or other liquid formulations such as syrups, solutions, suspensions and the like; for parenteral administration, the pharmaceutical composition may be a solution, an aqueous solution, an oil suspension concentrate, a lyophilized powder, or the like. Preferably, the formulation of the pharmaceutical composition is selected from the group consisting of tablets, coated tablets, capsules, suppositories, nasal sprays or injections, more preferably tablets or capsules. The pharmaceutical composition may be administered as a single unit with the correct dosage. In addition, the pharmaceutical composition may further comprise additional active ingredients.

All formulations of the pharmaceutical compositions disclosed herein can be produced by conventional methods in the pharmaceutical arts. For example, the active ingredient may be mixed with one or more excipients and the desired formulation prepared. By "pharmaceutically acceptable excipient" is meant a conventional pharmaceutical carrier suitable for use in the desired pharmaceutical formulation, for example: diluents, vehicles such as water, various organic solvents, and the like, fillers such as starch, sucrose, and the like, binders such as cellulose derivatives, alginates, gelatin, and polyvinylpyrrolidone (PVP); humectants, such as glycerol; disintegrating agents such as agar, calcium carbonate and sodium bicarbonate; absorption enhancers, such as quaternary ammonium compounds; surfactants such as cetyl alcohol; absorbent carriers such as kaolin and bentonite; lubricants such as talc, calcium stearate, magnesium stearate, polyethylene glycol, and the like. In addition, the pharmaceutical composition may further comprise other pharmaceutically acceptable excipients such as dispersants, stabilizers, thickeners, complexing agents, buffers, permeation enhancers, polymers, flavoring agents, sweeteners, and dyes.

The term "disease" refers to any disease, disorder, disease, symptom, or indication, and may be interchangeable with the terms "condition" or "disorder".

Throughout this specification and the aspects that follow, unless the context requires otherwise, the terms "comprise" and variations such as "comprises" and "comprising" are intended to specify the presence of the stated features but do not preclude the presence or addition of one or more other features. As used herein, the term "comprising" may be substituted with the term "comprising", "including" or sometimes with "having".

Throughout the specification and in subsequent aspects, the term "C" is used_n-m"indicates ranges including endpoints, where n and m are integers and indicate carbon number. Examples include C_1-8、C_1-6And the like.

Unless explicitly defined elsewhere in this document, all other technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

General Synthesis

The compounds disclosed herein (including salts thereof) can be prepared using known organic synthesis techniques and can be synthesized according to any of a variety of possible synthetic routes.

The reactions used to prepare the compounds disclosed herein can be carried out in a suitable solvent that can be readily selected by one of skill in the art of organic synthesis. Suitable solvents may be substantially non-reactive with the starting materials, intermediates, or products at the temperature at which the reaction is carried out (e.g., a temperature that may be within the boiling point range of the solvent). A given reaction may be carried out in one solvent or a mixture of solvents.

The selection of suitable protecting groups can be readily determined by one skilled in the art.

The reaction may be monitored according to any suitable method known in the art, such as NMR, UV, HPLC, LC-MS, and TLC. The compounds can be purified by a variety of methods, including HPLC and normal phase silica chromatography.

Chiral analytical HPLC was used for retention time analysis of different chiral examples, and the conditions were divided into the following methods according to the column, mobile phase, and solvent ratio used.

Scheme I

Wherein Pr₁And Pr₂Are conventional protecting groups in organic synthesis, and the other variables are defined in formula (I), (II), (AIII), (III), (AIV) or (IV) as disclosed herein.

For example, compounds of formula (I), (II), (AIII), (III), (AIV), or (IV) may be formed as shown in scheme I. Compound (I) may be reacted with a boronic acid under a palladium catalysed reaction to give compound (II), compound (II) may be protected to give compound (III), compound (III) may be halogenated with N-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide to give compound (IV), compound (IV) may be used for further coupling under a transition metal and with a Cy1 group which may be an aryl, heterocyclic or the like to give compound (v), compound (v) is deprotected to give compound (vi) (i.e. formula (I), (II), (AIII), (III), (AIV) or (IV)).

Scheme II

For example, compounds of formula (I), (II), (AIII), (III), (AIV), or (IV) may be formed as shown in scheme I. Compound (I) may be reacted with a boronic acid having a heterocyclic ring under a palladium catalysed reaction to give compound (II), compound (II) may be protected to give compound (III), compound (III) may be halogenated with N-chlorosuccinamide, N-bromosuccinamide or N-iodosuccinamide to give compound (IV), compound (IV) may be used for the next step of coupling under a transition metal and with a R8 group which may be an aryl, heterocyclic ring or the like to give compound (v), compound (v) is deprotected to give compound (vi) (i.e. formula (I), (II), (AIII), (III), (AIV) or (IV)).

Abbreviations

BPD bis (pinacolato) diboron

DMSO dimethyl sulfoxide

Eq. equivalents

r.t. room temperature

THF tetrahydrofuran

NBS N-bromosuccinimide

NIS N-iodosuccinimide

XPhos Pd G2 chloro (2-dicyclohexylphosphino-2 ', 4 ', 6 ' -triisopropyl-1, 1 ' -biphenyl) [2- (2 ' -amino group)

-1, 1' -biphenyl) ] palladium (II)

TFA trifluoroacetic acid

TLC thin layer chromatography

Pd(dppf)Cl₂[1, 1' -bis (diphenylphosphino) ferrocene ]Palladium dichloride (II)

PhNTf 2N-phenyl-bis (trifluoromethanesulfonimide)

PE Petroleum Ether

T3P propylphosphonic anhydride

TEA Triethylamine

TBDMS tert-butyldimethylsilyl group

TBAF tetrabutylammonium fluoride

Tol toluene

THP tetrahydro-2H-pyran-2-yl

TsOH p-toluenesulfonic acid

SEM (2- (trimethylsilyl) ethoxy) methyl

TBDMS tert-butyldimethylsilyl group

AcOK Potassium acetate

EA/EtOAc ethyl acetate

Pd(OAc)₂Palladium acetate

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

Et₃N-Triethylamine

DMF N, N-dimethylformamide

HATU hexafluorophosphate 1- [ bis (dimethylamino) methylene ] -1H-1,2, 3-triazolo [4,5-b ]

Pyridinium 3-oxide

Example A

Example 1: 5- (4- (4-Methylpiperazin-1-yl) phenyl) -3-phenyl-1H-pyrrolo [2,3-b ] pyridine (Compound 1)

Step 1: 5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (Compound 1-1)

To 5-bromo-1H-pyrrolo [2,3-b ]]Pyridine (501mg, 2.5mmol, 1.0 equiv.) and (4- (4-methylpiperazin-1-yl) phenyl) boronic acid (560mg, 2.5mmol, 1.0 equiv.) to a mixture of dioxane (25mL) and water (2mL) was added K ₂CO₃(527mg, 3.8mmol, 1.5 equiv.) and Pd (dppf) Cl₂(93mg, 0.13mmol, 0.05 equiv.). The reaction mixture was stirred at 100 ℃ under nitrogen for 4 h. The mixture was cooled to room temperature and diluted with ethyl acetate (50mL), washed with brine (30mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give compound 1-1(560mg, 75%) which was used in the next step without further purification.

Step 2: 3-bromo-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (compound 1-2)

To 5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]NBS (376mg, 2.1mmol, 1.1 equiv.) was added portionwise to a solution of pyridine (0.56g, 1.9mmol, 1.0 equiv.) in THF (40 mL). The reaction mixture was stirred at room temperature overnight. Will be provided withThe mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: MeOH ═ 20:1) to give compound 1-2(360mg, 51%).¹H NMR(400MHz,DMSO-d6)δ:12.10(s,1H),8.56(d,J＝2.1Hz,1H),7.94(d,J＝1.9Hz,1H),7.74(d,J＝2.6Hz,1H),7.65(d,J＝8.7Hz,2H),7.10(d,J＝8.7Hz,2H),3.35(brs,4H),3.03(brs,4H),2.62(s,3H)。LC-MS(M+H)⁺＝371.0,373.0。

And step 3: 3-bromo-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester (Compound 1-3)

To 3-bromo-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]To a mixture of pyridine (100mg, 0.27mmol, 1.0 equiv.) and di-tert-butyl dicarbonate (65mg, 0.30mmol, 1.1 equiv.) in THF (10mL) was added triethylamine (0.11mL, 0.81mmol, 3.0 equiv.). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (20mL), washed with brine (20mL), dried over sodium sulfate, and concentrated under reduced pressure to give compound 1-3(110mg, 87%). LC-MS (M + H) ⁺＝471.1,473.1。

And 4, step 4: 5- (4- (4-Methylpiperazin-1-yl) phenyl) -3-phenyl-1H-pyrrolo [2,3-b ] pyridine (Compound 1)

To 3-bromo-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]Pyridine-1-carboxylic acid tert-butyl ester (50mg, 0.13mmol, 1.0 equiv.) and phenylboronic acid (18mg, 0.15mmol, 1.1 equiv.) in dioxane (10mL) and water (1mL) was added XPhos Pd G2(5mg, 0.05 equiv.) and K₂CO₃(28mg, 0.20mmol, 1.5 equiv.). The mixture was stirred under nitrogen at 90 ℃ overnight. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (30mL), washed with brine (30mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with dichloromethane: MeOH ═ 20: 1) to give compound 1(2mg, 4%).¹H NMR(400MHz,CD₃OD)δ:8.53(d,J＝15.1Hz,2H),7.75(s,1H),7.71(d,J＝7.7Hz,2H),7.66(d,J＝8.0Hz,2H),7.47(t,J＝7.4Hz,2H),7.31(t,J＝7.3Hz,1H),7.17(d,J＝8.0Hz,2H),3.94(d,J＝13.2Hz,2H),3.64(d,J＝10.5Hz,2H),3.30-3.24(m,2H),3.10(t,J＝11.4Hz,2H),2.99(s,3H)。LC-MS(M+H)⁺＝369.1。

Example 2: 3- (4-methoxyphenyl) -5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (Compound 2)

Prepared from 3-bromo-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that described in example 1, step 4]Pyridine-1-carboxylic acid tert-butyl ester and (4-methoxyphenyl) boronic acid compound 2(4mg, 9%) was prepared.¹H NMR(400MHz,CD₃OD)δ:8.52(d,J＝10.6Hz,2H),7.68-7.58(m,5H),7.16(d,J＝8.1Hz,2H),7.05(d,J＝7.7Hz,2H),3.94(d,J＝11.9Hz,2H),3.84(s,3H),3.64(d,J＝10.8Hz,2H),3.30-3.23(m,2H),3.12(d,J＝11.3Hz,2H),2.99(s,3H)。LC-MS(M+H)⁺＝399.2。

Example 3: 3- (4-chlorophenyl) -5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (Compound 3)

Prepared from 3-bromo-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that described in example 1, step 4]Pyridine-1-carboxylic acid tert-butyl ester and (4-chlorophenyl) boronic acid compound 3(2mg, 8%) was prepared.¹H NMR(400MHz,DMSO-d6)δ:12.07(s,1H),8.54(s,1H),8.17(s,1H),7.80(s,2H),7.61(d,J＝8.1Hz,2H),7.34(d,J＝7.4Hz,3H),7.08(d,J＝8.2Hz,2H),3.31-3.19(m,4H),2.83(brs,4H)。LC-MS(M+H)⁺＝403.1。

Example 4: 3- (2-fluorophenyl) -5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (Compound 4)

As described in step 4 of example 1In a similar manner from 3-bromo-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]Pyridine-1-carboxylic acid tert-butyl ester and (2-fluorophenyl) boronic acid compound 4(3mg, 8%) was prepared.¹H NMR(400MHz,DMSO-d6)δ:12.03(s,1H),9.72(bs,1H),8.54(s,1H),8.36(s,1H),7.96(s,1H),7.82(d,J＝7.8Hz,2H),7.69(d,J＝8.0Hz,2H),7.49(d,J＝7.8Hz,2H),7.13(d,J＝8.0Hz,2H),3.91(s,2H),3.55(d,J＝11.7Hz,2H),3.20(d,J＝10.0Hz,2H),3.00(t,J＝12.2Hz,2H),2.88(s,3H)。LC-MS(M+H)⁺＝387.1。

Example 5: 3- (2-fluoro-4-methoxyphenyl) -5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (Compound 5)

Prepared from 3-bromo-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that described in example 1, step 4]Pyridine-1-carboxylic acid tert-butyl ester and (2-fluoro-4-methoxyphenyl) boronic acid compound 5(3mg, 4%) was prepared.¹H NMR(400MHz,DMSO-d6)δ:11.98(s,1H),9.64(bs,1H),8.53(d,J＝1.8Hz,1H),8.12(s,1H),7.73-7.60(m,4H),7.12(d,J＝8.7Hz,2H),6.98(dd,J＝12.7,2.3Hz,1H),6.91(dd,J＝8.6,2.3Hz,1H),3.92(d,J＝13.2Hz,2H),3.82(s,3H),3.54(s,2H),3.23-3.13(m,2H),2.99(t,J＝12.1Hz,2H),2.88(d,J＝3.6Hz,3H)。LC-MS(M+H)⁺＝417.2。

Example 6: 3- (4-Isopropoxyphenyl) -5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine hydrochloride (Compound 6)

Prepared from 3-bromo-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that described in example 1, step 4 ]Pyridine-1-carboxylic acid tert-butyl ester and (4-isopropoxyphenyl) boronic acid compound 6(46mg, 46%) was prepared.¹H NMR(400MHz,DMSO-d6)δ:11.91(s,1H),10.46(s,1H),8.53(s,1H),8.34(s,1H),7.78(s,1H),7.71-7.63(m,3H),7.13(d,J＝8.4Hz,2H),7.00(d,J＝8.4Hz,2H),4.64(dt,J＝11.9,5.9Hz,1H),3.91(d,J＝12.6Hz,2H),3.52(d,J＝11.3Hz,2H),3.14(dt,J＝24.6,11.5Hz,4H),2.84(d,J＝4.2Hz,3H),1.30(d,J＝5.9Hz,2H)。LC-MS(M+H)⁺＝427.2。

Example 7: 3- (3-methoxyphenyl) -5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine hydrochloride (Compound 7)

Prepared from 3-bromo-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that described in example 1, step 4]Pyridine-1-carboxylic acid tert-butyl ester and (3-methoxyphenyl) boronic acid compound 7(28mg, 44%) was prepared.¹H NMR(400MHz,DMSO-d6)δ12.13(s,1H),10.81(s,1H),8.56(d,J＝1.6Hz,1H),8.41(s,1H),7.95(d,J＝2.2Hz,1H),7.69(d,J＝8.6Hz,2H),7.42-7.36(m,2H),7.28(s,1H),7.13(d,J＝8.7Hz,2H),6.86(dd,J＝7.4,4.0Hz,1H),3.90(d,J＝10.1Hz,2H),3.83(s,3H),3.50(d,J＝9.0Hz,2H),3.21-3.10(m,4H),2.82(d,J＝4.6Hz,3H)。LC-MS(M+H)⁺＝399.2。

Example 8: 3- (4- (benzyloxy) phenyl) -5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (compound 8)

Prepared from 3-bromo-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that described in example 1, step 4]Pyridine-1-carboxylic acid tert-butyl ester and (4- (benzyloxy) phenyl) boronic acid preparation compound 8(25mg, 37%).¹H NMR(400MHz,DMSO-d6)δ:12.20(s,1H),8.57(d,J＝5.0Hz,1H),8.45(d,J＝15.9Hz,1H),7.84(d,J＝2.9Hz,1H),7.71(d,J＝6.5Hz,4H),7.48(d,J＝7.3Hz,2H),7.41(t,J＝7.4Hz,2H),7.34(t,J＝7.2Hz,1H),7.12(t,J＝7.9Hz,4H),5.16(s,2H),3.90(d,J＝9.9Hz,2H),3.51(d,J＝8.4Hz,2H),3.17(t,J＝7.4Hz,4H),2.83(s,3H)。LC-MS(M+H)⁺＝475.2。

Example 9: 3- (4-ethoxyphenyl) -5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine hydrochloride (Compound 9)

Prepared from 3-bromo-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that described in example 1, step 4]Pyridine-1-carboxylic acid tert-butyl ester and (4-ethoxyphenyl) boronic acid compound 9(33mg, 49%) was prepared. ¹H NMR(400MHz,DMSO-d6)δ12.05(s,1H),10.82(s,1H),8.55(d,J＝1.5Hz,1H),8.40(s,1H),7.81(d,J＝2.0Hz,1H),7.69(d,J＝8.6Hz,4H),7.13(d,J＝8.7Hz,2H),7.02(d,J＝8.6Hz,2H),4.07(q,J＝6.9Hz,2H),3.90(d,J＝10.1Hz,2H),3.51(d,J＝9.1Hz,2H),3.22-3.10(m,4H),2.83(d,J＝4.6Hz,3H),1.36(t,J＝6.9Hz,3H)。LC-MS(M+H)⁺＝413.2。

Example 10: 3- (4- (cyclopropylmethoxy) phenyl) -5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (Compound 10)

Prepared from 3-bromo-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that described in example 1, step 4]Pyridine-1-carboxylic acid tert-butyl ester and (4- (cyclopropylmethoxy) phenyl) boronic acid compound 10(12mg, 18%) was prepared.¹H NMR(400MHz,DMSO-d6)δ11.83(s,1H),8.49(s,1H),8.28(s,1H),7.76(d,J＝2.0Hz,1H),7.67(d,J＝8.5Hz,2H),7.61(d,J＝8.5Hz,2H),7.06(d,J＝8.4Hz,2H),7.01(d,J＝8.5Hz,2H),3.85(d,J＝6.9Hz,2H),3.25(s,4H),2.66(s,4H),2.37(s,3H),1.22(t,J＝9.8Hz,1H),0.59(t,J＝6.4Hz,2H),0.34(d,J＝4.6Hz,2H)。LC-MS(M+H)⁺＝439.2。

Example 11: 5- (4- (4-Methylpiperazin-1-yl) phenyl) -3- (p-tolyl) -1H-pyrrolo [2,3-b ] pyridine (Compound 11)

Prepared from 3-bromo-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that described in example 1, step 4]Tert-butyl pyridine-1-carboxylate and p-tolylboronic acid prepared compound 11(6mg, 9%).¹H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.50(d,J＝1.9Hz,1H),8.31(d,J＝1.8Hz,1H),7.82(d,J＝2.3Hz,1H),7.66(d,J＝8.0Hz,2H),7.61(d,J＝8.7Hz,2H),7.26(d,J＝8.0Hz,2H),7.06(d,J＝8.8Hz,2H),3.22(s,4H),2.59(s,4H),2.34(s,3H),2.32(s,3H)。LC-MS(M+H)⁺＝383.2。

Example 12: n, N-dimethyl-4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 12)

Prepared from 3-bromo-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that described in example 1, step 4]Pyridine-1-carboxylic acid tert-butyl ester and (4- (dimethylcarbamoyl) phenyl) boronic acid compound 12(15mg, 22%) was prepared.¹H NMR(400MHz,DMSO-d6)δ12.03(s,1H),8.53(s,1H),8.39(s,1H),7.99(d,J＝1.9Hz,1H),7.85(d,J＝8.0Hz,2H),7.63(d,J＝8.4Hz,2H),7.49(d,J＝8.0Hz,2H),7.06(d,J＝8.4Hz,2H),3.22(app s,4H),3.00(s,6H),2.57(app s,4H),2.30(s,3H)。LC-MS(M+H)⁺＝440.2。

Example 13: 4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) aniline hydrochloride (Compound 13)

Prepared from 3-bromo-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that described in example 1, step 4]Pyridine-1-carboxylic acid tert-butyl esterButyl ester and (4-aminophenyl) boronic acid gave compound 13(18mg, 26%).¹H NMR(400MHz,DMSO-d6)δ12.10(s,1H),10.64(s,1H),8.56(s,1H),8.42(s,1H),7.97(s,1H),7.91(d,J＝7.5Hz,2H),7.71(d,J＝7.3Hz,2H),7.43(s,2H),7.14(d,J＝7.3Hz,2H),3.92(d,J＝11.8Hz,2H),3.51(s,2H),3.13(d,J＝13.0Hz,4H),2.85(s,3H)。LC-MS(M+H)⁺＝384.2。

Example 14: 5- (4- (4-Methylpiperazin-1-yl) phenyl) -3- (pyridin-4-yl) -1H-pyrrolo [2,3-b ] pyridine (Compound 14)

Prepared from 3-bromo-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that described in example 1, step 4]Pyridine-1-carboxylic acid tert-butyl ester and pyridin-4-ylboronic acid compound 14(10mg, 15%) was prepared.¹H NMR(400MHz,DMSO-d6)δ12.26(s,1H),8.56(brs,3H),8.49(s,1H),8.23(s,1H),7.83(s,2H),7.68(d,J＝6.1Hz,2H),7.08(d,J＝6.2Hz,2H),3.29(s,4H),2.74(s,4H),2.42(s,3H)。LC-MS(M+H)⁺＝370.2。

Example 15: 3- (3-chloro-4-methoxyphenyl) -5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (compound 15)

Prepared from 3-bromo-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that described in example 1, step 4]Pyridine-1-carboxylic acid tert-butyl ester and (3-chloro-4-methoxyphenyl) boronic acid compound 15(10mg, 15%) was prepared.¹H NMR(400MHz,DMSO-d6)δ11.97-11.89(m,1H),8.53-8.45(m,1H),8.30-8.25(m,1H),7.89-7.84(m,1H),7.78-7.75(m,1H),7.75-7.69(m,1H),7.68-7.62(m,2H),7.23-7.18(m,1H),7.15-7.08(m,2H),3.90-3.87(m,4H),3.54-3.48(m,1H),3.25-3.11(m,2H),3.07-3.04(m,4H),2.91-2.79(m,3H)。LC-MS(M+H)⁺＝433.1。

Example 16: 3- (2-Methoxypyrimidin-5-yl) -5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (Compound 16)

Compound 16(2mg, 3%) was prepared from (2-methoxypyrimidin-5-yl) boronic acid in a similar manner to that described in example 1, step 4. ¹H NMR(400MHz,CD₃OD)δ8.92(s,2H),8.49(s,1H),8.33(s,1H),7.79(s,1H),7.59(t,J＝9.2Hz,2H),7.11(d,J＝8.4Hz,2H),4.06(s,3H),3.33(s,4H),2.86(s,4H),2.53(s,3H)。LC-MS(M+H)⁺＝401.2。

Example 17: n, N-dimethyl-4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) aniline (Compound 17)

Compound 17(2mg, 3%) was prepared from (4- (dimethylamino) phenyl) boronic acid in a similar manner to that described in example 1, step 4.¹H NMR(400MHz,DMSO-d6)δ11.71(s,1H),8.47(d,J＝2.0Hz,1H),8.26(d,J＝1.8Hz,1H),7.67(d,J＝2.3Hz,1H),7.61-7.55(m,4H),7.04(d,J＝8.8Hz,2H),6.84(d,J＝8.8Hz,2H),3.22-3.16(m,4H),2.93(s,6H),2.47(s,4H),2.24(s,3H)。LC-MS(M+H)⁺＝412.2。

Example 18: n, N-dimethyl-1- (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methylamine (compound 18)

Compound 18(5mg, 7%) was prepared from (4- ((dimethylamino) methyl) phenyl) boronic acid in a similar manner to that described in example 1, step 4.¹H NMR(400MHz,CD₃OD)δ8.36(d,J＝1.6Hz,1H),8.30(d,J＝1.9Hz,1H),7.72(d,J＝8.0Hz,2H),7.66(d,J＝3.4Hz,1H),7.47(t,J＝7.4Hz,4H),7.00(d,J＝8.6Hz,2H),4.09(s,2H),3.25(s,4H),2.84-2.76(m,4H),2.68(s,6H),2.46(s,3H)。LC-MS(M+H)⁺＝426.2。

Example 19: 5- (4- (4-Methylpiperazin-1-yl) phenyl) -3- (4- (piperidin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (Compound 19)

Compound 19(5mg, 7%) was prepared from (4- (piperidin-1-yl) phenyl) boronic acid in a similar manner to that described in example 1, step 4.¹H NMR(400MHz,DMSO-d6)δ11.78(s,1H),8.49(s,1H),8.28(s,1H),7.71(s,1H),7.60(t,J＝7.6Hz,4H),7.04(dd,J＝20.6,8.4Hz,4H),3.15(d,J＝4.9Hz,4H),2.76(s,4H),2.43(s,3H),1.64(d,J＝3.1Hz,4H),1.55(d,J＝4.4Hz,2H)。LC-MS(M+H)⁺＝452.2。

Example 20: 7- (1-methyl-1H-pyrazol-4-yl) -2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazine (compound 20)

Compound 20(4mg, 6%) was prepared from (1-methyl-1H-pyrazol-4-yl) boronic acid and compound 106-5 in a similar manner to that described in example 1, step 4.¹H NMR(400MHz,DMSO-d6)δ11.95(s,1H),8.79(s,1H),8.30(s,1H),8.15-8.03(m,4H),7.10(d,J＝8.7Hz,2H),3.93(s,3H),3.33(s,3H),2.67(s,4H),2.38(s,4H)。LC-MS(M+H)⁺＝373.2。

Example 21: 5- (4- (4-Methylpiperazin-1-yl) phenyl) -3- (4- (2- (oxetan-3-yl) ethyl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (Compound 21)

In a similar manner to that described in step 4 of example 1Manner compound 21(10mg, 4%) was prepared from 4,4,5, 5-tetramethyl-2- (4- (2- (oxetan-3-yl) ethyl) phenyl) -1,3, 2-dioxaborolan. LC-MS (M + H)⁺＝453.2。

Example 22: n, N-dimethyl-1- (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) ethan-1-amine (Compound 22)

Compound 22(10mg, 4%) was prepared from (4- (1- (dimethylamino) ethyl) phenyl) boronic acid in a similar manner to that described in example 1, step 4.¹H NMR(400MHz,DMSO-d6)δ11.93(s,1H),8.51(d,J＝1.9Hz,1H),8.35(d,J＝1.7Hz,1H),7.88(d,J＝2.2Hz,1H),7.76(d,J＝7.9Hz,2H),7.62(d,J＝8.7Hz,2H),7.43(d,J＝7.6Hz,2H),7.05(d,J＝8.8Hz,2H),3.58(s,1H),3.20(d,J＝4.7Hz,4H),2.52(s,4H),2.27(brs,9H),1.40(d,J＝5.3Hz,3H)。LC-MS(M+H)⁺＝440.2。

Example 23: n, N-dimethyl-5- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) picolinamide (Compound 23)

Compound 23(10mg, 5%) was prepared from N, N-dimethyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) picolinamide in a similar manner to that described in example 1, step 4.¹H NMR(400MHz,DMSO-d6)δ12.19(s,1H),9.04(d,J＝1.5Hz,1H),8.56(d,J＝1.8Hz,1H),8.44(s,1H),8.34(dd,J＝8.1,2.1Hz,1H),8.15(d,J＝2.5Hz,1H),7.66(dd,J＝11.4,8.5Hz,3H),7.07(d,J＝8.7Hz,2H),3.26(s,4H),3.07(s,3H),3.04(s,3H),2.68(s,4H),2.38(s,3H)。LC-MS(M+H)⁺＝441.2。

Example 24: 3-fluoro-N, N-dimethyl-4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 24)

Compound 24(70mg, 36%) was prepared from (4- (dimethylcarbamoyl) -2-fluorophenyl) boronic acid in a similar manner to that described in example 1, step 4. ¹H NMR(400MHz,DMSO-d6)δ12.19(s,1H),8.56(s,1H),8.24(s,1H),7.88(d,J＝9.9Hz,2H),7.61(d,J＝8.1Hz,2H),7.41(d,J＝11.1Hz,1H),7.35(d,J＝7.8Hz,1H),7.05(d,J＝7.8Hz,2H),3.23(s,4H),3.01(s,6H),2.59(s,4H),2.32(s,3H)。LC-MS(M+H)⁺＝458.2。

Example 25: 1- (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) propan-1-one (Compound 25)

Compound 25(10mg, 11%) was prepared from (4-propionylphenyl) boronic acid in a similar manner to that described in example 1, step 4.¹H NMR(400MHz,DMSO-d6)δ12.14(s,1H),8.54(d,J＝2.0Hz,1H),8.44(d,J＝1.8Hz,1H),8.10(d,J＝2.7Hz,1H),8.04(d,J＝8.5Hz,2H),7.96(d,J＝8.5Hz,2H),7.65(d,J＝8.8Hz,2H),7.07(d,J＝8.8Hz,2H),3.23(s,4H),3.07(q,J＝7.2Hz,2H),2.58(s,4H),2.31(s,3H),1.12(t,J＝7.2Hz,3H)。LC-MS(M+H)⁺＝425.2。

Example 26: 5- (4- (4-Methylpiperazin-1-yl) phenyl) -3- (4- (1-methylpyrrolidin-2-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (Compound 26)

Step 1: 2- (4-bromophenyl) pyrrolidine (Compound 26-1)

To a solution of tert-butyl 2- (4-bromophenyl) pyrrolidine-1-carboxylate (500mg, 1.53mmol) in dichloromethane (15mL) was added CF₃COOH (5 mL). The mixture was stirred at room temperature for 2 h. Reducing the mixtureConcentration under reduced pressure afforded 2- (4-bromophenyl) pyrrolidine TFA salt (800mg, crude).

Step 2: 2- (4-bromophenyl) -1-methylpyrrolidine (Compound 26-2)

To a solution of 2- (4-bromophenyl) pyrrolidine (800mg, 2.4mmol, 1.0 equiv.) and HCHO (0.3mL, 3.6mmol, 1.5 equiv.) in dichloromethane (25mL) was added NaBH (OAc)₃(480mg, 2.4mmol, 1.0 equiv.). The mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (20mL) and NaHCO₃The solution (20mL) was washed, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane: MeOH ═ 20:1) to give compound 26-2(300mg, 83%).

And step 3: 1-methyl-2- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) pyrrolidine (Compound 26-3)

To a solution of 2- (4-bromophenyl) -1-methylpyrrolidine (300mg, 1.25mmol, 1.0 equiv.) and 4,4,4 ', 4 ', 5,5,5 ', 5 ' -octamethyl-2, 2 ' -bis (1,3, 2-dioxaborolan) (350mg, 1.38mmol, 1.1 equiv.) in dioxane (20mL) was added Pd (dppf) Cl₂(65mg, 0.088mmol, 0.07 equiv.) and AcOK (245mg, 2.5mmol, 2.0 equiv.). The mixture was refluxed under nitrogen for 5 h. The mixture was cooled to room temperature and diluted with EA (30mL), washed with brine (20mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane: MeOH ═ 20:1) to give compound 26-2(120mg, 34%). LC-MS (M + H)⁺＝288.2。

And 4, step 4: 5- (4- (4-Methylpiperazin-1-yl) phenyl) -3- (4- (1-methylpyrrolidin-2-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (Compound 26)

Compound 26(40mg, 21%) was prepared from 1-methyl-2- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) pyrrolidine in a similar manner to that described in example 1, step 4.¹H NMR(400MHz,DMSO-d6)δ11.95(s,1H),8.52(s,1H),8.35(s,1H),7.88(s,1H),7.76(d,J＝7.1Hz,2H),7.68-7.59(m,2H),7.48(s,2H),7.06(d,J＝6.9Hz,2H),3.25(s,6H),2.64(s,4H),2.35(s,3H),2.24(s,4H),1.91(s,4H)。LC-MS(M+H)⁺＝452.2。

Example 27: 5- (4- (4-Methylpiperazin-1-yl) phenyl) -3- (4- (pyrrolidin-2-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine hydrochloride (Compound 27)

Step 1: tert-butyl 2- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) pyrrolidine-1-carboxylate (Compound 27-1)

Compound 27-1(380mg, 100% as a black oil) was prepared from tert-butyl 2- (4-bromophenyl) pyrrolidine-1-carboxylate in a similar manner to that described in example 26, step 3.

Step 2: 2- (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) pyrrolidine-1-carboxylic acid tert-butyl ester (Compound 27-2)

Compound 27-2 was prepared as a white solid (200mg, 37%) from tert-butyl 2- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) pyrrolidine-1-carboxylate in a similar manner to that described in example 26, step 4.

And step 3: 5- (4- (4-Methylpiperazin-1-yl) phenyl) -3- (4- (pyrrolidin-2-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (Compound 27)

2- (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) phenyl) pyrrolidine-1-carboxylic acid tert-butyl ester (200mg, 0.37mmol) in HCl/ethanol (20mL) was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure to give compound 27(40mg, 9%).¹H NMR(400MHz,DMSO-d6)δ12.32(s,1H),11.15(s,1H),10.28(s,1H),9.08(s,1H),8.60(s,1H),8.51(s,1H),8.02(s,1H),7.89(d,J＝8.1Hz,2H),7.72(d,J＝8.5Hz,2H),7.64(d,J＝8.1Hz,2H),7.14(d,J＝8.6Hz,2H),4.57(s,1H),3.91(d,J＝8.4Hz,2H),3.50(d,J＝6.7Hz,2H),3.34(d,J＝31.6Hz,2H),3.19(t,J＝10.0Hz,4H),2.82(d,J＝4.4Hz,3H),2.38(t,J＝14.7Hz,1H),2.18-1.96(m,3H)。LC-MS(M+H)⁺＝438.2。

Example 28: 4- (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) pyrrolidin-2-one (compound 28)

Step 1: 3- (4-bromophenyl) acrylic acid tert-butyl ester (Compound 28-1)

To a mixture of 1-bromo-4-iodobenzene (2g, 7.1mmol, 1.0 equiv.) and tert-butyl acrylate (2.0mL, 14.1mmol, 2.0 equiv.) in CH₃Addition of Pd (OAc) to a solution in CN (50mL)₂(45mg, 0.17mmol, 0.025 equiv.), tri-o-tolylphosphine (200mg, 0.7mmol, 0.1 equiv.), and Et₃N (5.0mL, 35.3mmol, 5.0 equiv.). The mixture was refluxed under nitrogen for 4 h. The mixture was concentrated under reduced pressure. The residue was diluted with EA (50mL), washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give compound 28-1(2.2g, crude). LC-MS (M + H)⁺＝283.0。

Step 2: tert-butyl 3- (4-bromophenyl) -4-nitrobutanoate (Compound 28-2)

To tert-butyl 3- (4-bromophenyl) acrylate (2.2g, 7.8mmol, 1.0 eq) in CH₃NO₂To the solution in (11mL) was added DBU (1.4mL, 9.3mmol, 1.2 equiv). The mixture was refluxed for 3 h. The mixture was diluted with water (30mL) and extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (2 × 40mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (eluting with petroleum ether: EA ═ 10: 1) to give compound 28-2(2g, 99%).

And step 3: 4- (4-bromophenyl) pyrrolidin-2-one (Compound 28-3)

To a solution of tert-butyl 3- (4-bromophenyl) -4-nitrobutyrate (1.5g, 4.4mmol, 1.0 equiv.) in AcOH (30mL) was added Zn powder (1.4g, 21.8mmol, 5.0 equiv.). The mixture was refluxed overnight. The mixture was cooled, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluting with dichloromethane: MeOH ═ 20: 1) to give compound 28-3(400mg, 40%). LC-MS (M + H)⁺＝239.9,241.9。

And 4, step 4: 4- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) pyrrolidin-2-one (compound 28-4)

Compound 28-4(220mg, 46%) was prepared from 4- (4-bromophenyl) pyrrolidin-2-one in a similar manner to that described in example 26, step 3. LC-MS (M + H)⁺＝288.1。

And 5: 4- (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) pyrrolidin-2-one (compound 28)

Compound 28(20mg, 13%) was prepared from 4- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) pyrrolidin-2-one in a similar manner to that described in example 1, step 4.¹H NMR(400MHz,DMSO-d6)δ11.91(d,J＝2.0Hz,1H),8.51(d,J＝2.0Hz,1H),8.33(d,J＝1.8Hz,1H),7.85(d,J＝2.5Hz,1H),7.73(d,J＝8.2Hz,3H),7.62(d,J＝8.7Hz,2H),7.39(d,J＝8.2Hz,2H),7.06(d,J＝8.8Hz,2H),3.70-3.60(m,2H),3.30-3.19(m,6H),2.71-2.54(m,4H),2.41-2.27(m,4H)。LC-MS(M+H)⁺＝452.2。

Example 29: 3- (4- ((4-Methylpiperazin-1-yl) methyl) phenyl) -5- (4- (4-Methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (Compound 29)

Compound 29(15mg, 15%) was prepared from 1-methyl-4- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) piperazine in a similar manner to that described in example 1, step 4.¹H NMR(400MHz,DMSO-d6)δ11.93(s,1H),8.51(s,1H),8.34(s,1H),7.87(s,1H),7.74(d,J＝7.8Hz,2H),7.62(d,J＝8.4Hz,2H),7.38(d,J＝7.8Hz,2H),7.06(d,J＝8.5Hz,2H),3.54(s,2H),3.94-3.23(m,8H),2.59(s,8H),2.37(s,3H),2.32(s,3H)。LC-MS(M+H)⁺＝481.3。

Example 30: 3- (4- ((3-Methoxyazetidin-1-yl) methyl) phenyl) -5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (Compound 30)

Compound 30(9mg, 9%) was prepared from (4- ((3-methoxyazetidin-1-yl) methyl) phenyl) boronic acid in a similar manner to that described in example 1, step 4.¹H NMR(400MHz,DMSO-d6)δ11.98(s,1H),8.52(s,1H),8.35(s,1H),7.92(s,1H),7.79(d,J＝7.8Hz,2H),7.64(d,J＝8.2Hz,2H),7.45(d,J＝7.7Hz,2H),7.09(d,J＝8.4Hz,2H),4.12(brs,1H),4.01(brs,2H),3.89(brs,2H),3.42(brs,2H),3.42(brs,7H),3.21(s,3H),2.86(s,4H)。LC-MS(M+H)⁺＝468.2。

Example 31: 1- (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) ethan-1-one (Compound 31)

Compound 31(9mg, 9%) was prepared from (4-acetylphenyl) boronic acid in a similar manner to that described in example 1, step 4.¹H NMR(400MHz,DMSO-d6)δ12.16(s,1H),8.55(d,J＝1.6Hz,1H),8.44(d,J＝1.6Hz,1H),8.11(d,J＝2.4Hz,1H),8.03(d,J＝8.4Hz,2H),7.97(d,J＝8.0Hz,2H),7.65(d,J＝8.4Hz,2H),7.06(d,J＝8.4Hz,2H),3.22(brs,4H),2.60(s,3H),2.55(brs,4H),2.29(s,3H)。LC-MS(M+H)⁺＝411.1。

Example 32: 5- (4- (4-Methylpiperazin-1-yl) phenyl) -3- (4- (1- (pyrrolidin-1-yl) ethyl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (Compound 32)

Compound 32(6mg, 6%) was prepared from 1- (1- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) ethyl) pyrrolidine in a similar manner to that described in example 1, step 4.¹H NMR(400MHz,DMSO-d6)12.02(s,1H),8.53(s,1H),8.38(s,1H),7.95(s,1H),7.85(brs,2H),7.66-7.64(m,4H),7.08(d,J＝8.5Hz,2H),4.42(brs,1H),3.33(brs,6H),3.14-2.97(m,4H),2.88(s,4H),1.91-1.82(m,5H),1.67(s,3H)。LC-MS(M+H)⁺＝466.2。

Example 33: 7- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazine TFA salt (Compound 33)

Step 1: 1-methyl-4- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -1H-pyrazole (Compound 33-1)

To a solution of 4- (4-bromophenyl) -1-methyl-1H-pyrazole (237mg, 1.0mmol, 1.0 equiv.) in dioxane (30mL) under nitrogen was added 4,4,4 ', 4 ', 5,5,5 ', 5 ' -octamethyl-2, 2 ' -bis (1,3, 2-dioxaborolan) (260mg, 1.05mmol, 1.05 equiv.), Pd (dppf) Cl₂(51mg, 0.07mmol, 0.07 equiv.) and AcOK (15mg, 1.5mmol, 1.5 equiv.). The reaction mixture was refluxed overnight. It was cooled to room temperature and diluted with ethyl acetate (40mL), washed with brine (40mL), over Na₂SO₄Dried, evaporated under vacuum to give compound 33-1(370mg,>100%) which was used directly in the next step.

Step 2: 7- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazine TFA salt (Compound 33)

Compound 33(25mg, 25%) was prepared from (4- (1-methyl-1H-pyrazol-4-yl) phenyl) boronic acid in a similar manner to that described in example 1, step 4.¹H NMR(400MHz,DMSO-d6)δ12.25(d,J＝2.7Hz,1H),9.74(s,1H),8.86(s,1H),8.41(d,J＝2.8Hz,1H),8.31(d,J＝8.3Hz,2H),8.20-8.10(m,3H),7.92(s,1H),7.65(d,J＝8.4Hz,2H),7.19(d,J＝8.9Hz,2H),4.01(d,J＝13.3Hz,2H),3.56(d,J＝12.0Hz,2H),3.21(d,J＝10.9Hz,2H),3.06(t,J＝12.4Hz,2H),2.90(s,3H)。LC-MS(M+H)⁺＝449.2。

Example 34: n-methyl-1- (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) ethan-1-amine (Compound 34)

Compound 34(28mg, 32%) was prepared from (4- (1- (methylamino) ethyl) phenyl) boronic acid in a similar manner to that described in example 1, step 4. ¹H NMR(400MHz,DMSO-d6)δ12.01(s,1H),8.53(d,J＝1.6Hz,1H),8.37(d,J＝2.0Hz,1H),7.95(d,J＝2.4Hz,1H),7.86(d,J＝8.4Hz,2H),7.63(d,J＝8.8Hz,2H),7.58(d,J＝8.4Hz,2H),7.06(d,J＝8.8Hz,2H),4.31-4.26(m,1H),3.21(brs,4H),2.54(s,4H),2.42(s,3H),2.28(s,3H),1.58(d,J＝6.8Hz,3H)。LC-MS(M+H)⁺＝426.2。

Example 35: 3- (4-methoxyphenyl) -5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (compound 35)

Step 1: 3-methyl-4- (4-methylpiperazin-1-yl) aniline (compound 35-1)

To a solution of 1-methyl-4- (2-methyl-4-nitrophenyl) piperazine (3.2g, 13.6mmol) in ethanol (260mL) was added Pd/C (32 mg). The mixture was stirred at room temperature for 4h under a hydrogen atmosphere. The mixture was filtered and concentrated under reduced pressure to give compound 35-1(2.8g, 90%). LC-MS (M + H)⁺＝206.1。

Step 2: 1- (4-bromo-2-methylphenyl) -4-methylpiperazine (compound 35-2)

To 3-methyl-4- (4-methylpiperazin-1-yl) aniline (1.3g, 6.0mmol, 1 eq) in hydrobromic acid (in H) at 0 deg.C₂61% in O, 9mL) was added sodium nitrite (443mg, 6.42mmol, 1.1 equiv) dropwise in H₂Solution in O (2.3 mL). The mixture was stirred for 1 h. The mixture was then poured into a solution of CuBr (1.84g, 12.5mmol, 2.0 equiv.) in HBr (8mL) at 0 ℃. The resulting mixture was stirred at 60 ℃ overnight. After cooling, the mixture was basified with NaOH solution (2M) and extracted with dichloromethane (3 × 30 mL). The combined organic phases are passed over sulfuric acidSodium dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: MeOH ═ 50:1) to give compound 35-2(133mg, 10%). LC-MS (M + H) ⁺＝269.0,271.0。

And step 3: 1-methyl-4- (2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) piperazine (Compound 35-3)

Compound 35-3(70mg, 45%) was prepared from 1- (4-bromo-2-methylphenyl) -4-methylpiperazine in a similar manner to that described in example 26, step 3.

And 4, step 4: 5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (compound 35-4)

Prepared in a similar manner to that described in example 1, step 1 from 1-methyl-4- (2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) piperazine and 5-bromo-1H-pyrrolo [2,3-b ] p]Pyridine preparation compound 35-4(120mg, 100%). LC-MS (M + H)⁺＝307.1。

And 5: 3-bromo-5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (compound 35-5)

Prepared from 5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that described in example 1, step 2]Pyridine preparation compound 35-5(40mg, 27%). LC-MS (M + H)⁺＝385.1,387.1。

Step 6: 3- (4-methoxyphenyl) -5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (compound 35)

Compound 35(9mg, 25%) was prepared from (4-methoxyphenyl) boronic acid in a similar manner to that described in example 1, step 4. ¹H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.51(d,J＝1.9Hz,1H),8.31(d,J＝1.8Hz,1H),7.78(d,J＝2.4Hz,1H),7.69(d,J＝8.6Hz,2H),7.59(s,1H),7.58-7.53(m,1H),7.16(d,J＝8.2Hz,1H),7.03(d,J＝8.7Hz,2H),3.80(s,3H),3.25(s,4H),3.11(s,4H),2.78(s,3H),2.36(s,3H)。LC-MS(M+H)⁺＝413.2。

Example 36: (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (morpholino) methanone (Compound 36)

Step 1: 3- (4- (methoxycarbonyl) phenyl) -5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester (compound 36-1)

Prepared in the same manner as described in example 1, step 4 from 3-bromo-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ]]Pyridine-1-carboxylic acid tert-butyl ester and (4- (methoxycarbonyl) phenyl) boronic acid compound 36-1(430mg, 96%) was prepared. LC-MS (M + H)⁺＝527.2。

Step 2: methyl 4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzoate (Compound 36-2)

Compound 36-2(660mg, crude) was prepared from tert-butyl 3- (4- (methoxycarbonyl) phenyl) -5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine-1-carboxylate in a similar manner to that described in example 27, step 3.

And step 3: 4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzoic acid (Compound 36-3)

To 4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) benzoic acid methyl ester (660mg, 1.2mmol, 1.0 equiv.) to a solution in a mixture of THF (10mL), methanol (10mL) and water (20mL) was added LiOH H ₂O (170mg, 6.0mmol, 5.0 equiv.). The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was acidified with HCl (4M) to pH 2-3 and the precipitate was collected by filtration to give compound 36-3(400mg, 63%).

And 4, step 4: (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (morpholino) methanone

To 4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] under nitrogen]Pyridin-3-yl) benzoic acid (100mg, 0.24mmol, 1.0 equiv.) and morpholine (63mg, 0.73mmol, 3.0 equiv.) were added to a solution of HATU (92mg, 0.24mmol, 1.0 equiv.) in DMF (5 mL). Will be provided withThe reaction mixture was stirred at room temperature overnight. The mixture was diluted with water (30mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (3 × 30mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane: MeOH ═ 8:1) to give compound 36(11mg, 10%).¹H NMR(400MHz,DMSO-d6)δ12.03(s,1H),8.52(d,J＝1.5Hz,1H),8.39(d,J＝1.2Hz,1H),7.99(d,J＝2.2Hz,1H),7.87(d,J＝8.1Hz,2H),7.63(d,J＝8.6Hz,2H),7.49(d,J＝8.1Hz,2H),7.05(d,J＝8.6Hz,2H),3.62(s,4H),3.55(s,2H),3.33(s,6H),3.20(s,4H),2.25(s,3H)。LC-MS(M+H)⁺＝482.2。

Example 37: n- (4-methoxyphenyl) -4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 37)

Compound 37(3mg, 27%) was prepared from 4-methoxyaniline in a similar manner to that described in example 36, step 4. ¹H NMR(400MHz,DMSO-d6)δ12.11(s,1H),10.12(s,1H),8.55(s,1H),8.44(s,1H),8.10-7.99(m,3H),7.95(d,J＝8.0Hz,2H),7.70(dd,J＝12.0,8.7Hz,4H),7.11(d,J＝8.3Hz,2H),6.94(d,J＝8.7Hz,2H),3.76(s,3H),3.30-3.26(m,4H),2.48-2.41(m,4H)。LC-MS(M+H)⁺＝518.2。

Example 38: n-methyl-4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 38)

Compound 38(8mg, 7%) was prepared from methylamine hydrochloride in a similar manner to that described in example 36, step 4.¹H NMR(400MHz,DMSO-d6)δ12.06(s,1H),8.53(s,1H),8.43(d,J＝4.6Hz,1H),8.40(s,1H),8.02(d,J＝2.4Hz,1H),7.90(q,J＝8.4Hz,4H),7.64(d,J＝8.6Hz,2H),7.07(d,J＝8.6Hz,2H),3.25(s,4H),2.81(d,J＝4.4Hz,3H),2.64(s,4H),2.35(s,3H)。LC-MS(M+H)⁺＝426.2。

Example 39: (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (piperidin-1-yl) methanone (Compound 39)

Compound 39(8mg, 13%) was prepared from piperidine in a similar manner to that described in example 36, step 4.¹H NMR(400MHz,DMSO-d6)δ12.06(s,1H),8.54(s,1H),8.41(s,1H),7.99(s,1H),7.86(d,J＝7.9Hz,2H),7.68(d,J＝8.3Hz,2H),7.45(d,J＝7.9Hz,2H),7.11(d,J＝8.4Hz,2H),3.40(s,8H),3.13(s,4H),2.69(s,3H),1.58(m,6H)。LC-MS(M+H)⁺＝480.2。

Example 40: (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (pyrrolidin-1-yl) methanone (Compound 40)

Compound 40(5mg, 6%) was prepared from pyrrolidine in a similar manner to that described in example 36, step 4.¹H NMR(400MHz,DMSO-d6)δ12.04(s,1H),8.53(d,J＝1.9Hz,1H),8.40(d,J＝1.7Hz,1H),7.99(d,J＝2.5Hz,1H),7.85(d,J＝8.2Hz,2H),7.62(dd,J＝12.9,8.5Hz,4H),7.07(d,J＝8.7Hz,2H),3.49(t,J＝6.5Hz,4H),3.25(s,4H),2.64(s,4H),2.35(s,3H),1.95-1.78(m,4H)。LC-MS(M+H)⁺＝466.2。

Example 41: azetidin-1-yl (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone (Compound 41)

Compound was prepared from azetidine in a similar manner to that described in example 36, step 4Substance 41(3mg, 4%).¹H NMR(400MHz,DMSO-d6)δ12.13-11.99(m,1H),8.58-8.49(m,1H),8.43-8.38(m,1H),8.06-8.00(m,1H),7.91-7.85(m,2H),7.74-7.67(m,2H),7.67-7.60(m,2H),7.10-7.02(m,2H),4.44-4.31(m,2H),4.14-4.00(m,2H),3.31-3.28(m,3H),3.26-3.13(m,4H),2.56(s,2H),2.34-2.27(m,4H)。LC-MS(M+H)⁺＝452.2。

Example 42: (4-Methylpiperazin-1-yl) (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone (Compound 42)

Compound 42(5mg, 6%) was prepared from 1-methylpiperazine in a similar manner to that described in example 36, step 4.¹H NMR(400MHz,CD₃OD)δ8.41-8.28(m,2H),7.77-7.70(m,2H),7.70-7.64(m,1H),7.54-7.46(m,2H),7.46-7.38(m,2H),7.05-6.95(m,2H),3.80-3.41(m,4H),3.31-3.24(m,3H),2.91-2.77(m,4H),2.54-2.40(m,7H),2.31-2.22(m,4H)。LC-MS(M+H)⁺＝495.2。

Example 43: (4- (2- (dimethylamino) ethyl) piperazin-1-yl) (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone (Compound 43)

Compound 43(8mg, 12%) was prepared from N, N-dimethyl-2- (piperazin-1-yl) ethan-1-amine in a similar manner to that described in example 36, step 4.¹H NMR(400MHz,DMSO-d6)δ12.08-12.01(m,1H),8.56-8.49(m,1H),8.44-8.37(m,1H),8.02-7.96(m,1H),7.89-7.81(m,2H),7.69-7.59(m,2H),7.51-7.42(m,2H),7.10-7.03(m,2H),3.71-3.42(m,5H),3.25-3.14(m,5H),2.90-2.74(m,2H),2.64-2.51(m,13H),2.31-2.20(m,3H)。LC-MS(M+H)⁺＝552.3。

Example 44: n- (3- (dimethylamino) propyl) -N-methyl-4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 44)

From N in a manner analogous to that described in step 4 of example 36₁,N₁,N₃-trimethylpropane-1, 3-diamine preparation compound 44(10mg, 15%).¹H NMR(400MHz,DMSO-d6)δ12.05(s,1H),8.53(d,J＝1.8Hz,1H),8.39(d,J＝1.7Hz,1H),7.99(d,J＝2.4Hz,1H),7.86(d,J＝8.1Hz,2H),7.63(d,J＝8.6Hz,2H),7.50(s,2H),7.07(d,J＝8.7Hz,2H),3.40-3.60(m,2H),3.19-3.29(m,4H),3.00(s,3H),2.90-2.97(m,2H),2.55-2.76(m,8H),2.24-2.46(m,5H),1.92-1.99(m,2H)。LC-MS(M+H)⁺＝511.3。

Example 45: (3-Methoxyazetidin-1-yl) (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone (Compound 45)

Compound 45(30mg, 26%) was prepared from 3-methoxyazetidine in a similar manner to that described in example 36, step 4.¹H NMR(400MHz,DMSO-d6)δ12.08(s,1H),8.53(d,J＝1.8Hz,1H),8.41(d,J＝1.7Hz,1H),8.03(d,J＝2.5Hz,1H),7.88(d,J＝8.3Hz,2H),7.72(d,J＝8.3Hz,2H),7.65(d,J＝8.6Hz,2H),7.08(d,J＝8.7Hz,2H),4.52(s,1H),4.26(d,J＝4.7Hz,2H),4.21(s,1H),3.87(s,1H),3.31-3.25(m,4H),3.24(s,3H),2.71(d,J＝28.4Hz,4H),2.42(s,3H)。LC-MS(M+H)⁺＝482.2。

Example 46: 4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (3- (piperidin-1-yl) propyl) benzamide (compound 46)

In the step of example 36Compound 46(10mg, 15%) was prepared from 3- (piperidin-1-yl) propan-1-amine in a similar manner as described in step 4.¹H NMR(400MHz,DMSO-d6)δ12.13-12.04(m,1H),9.96(s,1H),8.74-8.61(m,1H),8.54(s,1H),8.40(s,1H),8.03(s,1H),7.96(d,J＝7.9Hz,2H),7.89(d,J＝7.9Hz,2H),7.65(d,J＝8.1Hz,2H),7.08(d,J＝8.2Hz,2H),3.31-3.17(m,5H),3.02(s,3H),2.82(s,2H),2.67(s,3H),2.39(s,4H),1.95(s,2H),1.74(s,5H),1.39(s,2H)。LC-MS(M+H)⁺＝537.3。

Example 47: n- (2- (dimethylamino) ethyl) -4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 47)

From N in a manner analogous to that described in step 4 of example 36₁,N₁-dimethylethane-1, 2-diamine compound 47(15mg, 21%) was prepared.¹H NMR(400MHz,DMSO-d6)δ12.11(s,1H),8.81(s,1H),8.54(s,1H),8.41(s,1H),8.05(s,1H),8.01(d,J＝8.3Hz,2H),7.91(d,J＝8.1Hz,2H),7.66(d,J＝8.3Hz,2H),7.10(d,J＝8.4Hz,2H),3.63(q,J＝5.2Hz,2H),3.34(brs,4H),3.17(s,2H),2.90(brs,4H),2.75(s,6H),2.52(s,3H)。LC-MS(M+H)⁺＝483.3。

Example 48: n- (2-methoxyethyl) -4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 48)

Compound 48(20mg, 29%) was prepared from 2-methoxyethyl-1-amine in a similar manner to that described in example 36, step 4.¹H NMR(400MHz,DMSO-d6)δ12.08(s,1H),8.54(brs,2H),8.41(s,1H),8.04(s,1H),7.95(d,J＝8.0Hz,2H),7.89(d,J＝6.9Hz,2H),7.66(d,J＝7.3Hz,2H),7.09(d,J＝7.4Hz,2H),3.48-3.47(m,5H),3.33-3.28(m,6H),2.83(bs,4H),2.48(s,3H)。LC-MS(M+H)⁺＝470.3。

Example 49: (4-hydroxypiperidin-1-yl) (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone (compound 49)

Compound 49(12mg, 17%) was prepared from piperidin-4-ol in a similar manner to that described in example 36, step 4.¹H NMR(400MHz,DMSO-d6)δ12.04(s,1H),8.53(d,J＝1.6Hz,1H),8.40(s,1H),7.98(d,J＝2.4Hz,1H),7.85(d,J＝8.1Hz,2H),7.65(d,J＝8.5Hz,2H),7.45(d,J＝8.0Hz,2H),7.08(d,J＝8.6Hz,2H),4.81(d,J＝3.7Hz,1H),4.01(brs,1H),3.75(brs,2H),3.30-3.13(m,6H),2.77(brs,4H),2.44(s,3H),1.77(s,2H),1.39(s,2H)。LC-MS(M+H)⁺＝496.3。

Example 50: 4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- ((tetrahydrofuran-2-yl) methyl) benzamide (Compound 50)

Compound 50(15mg, 21%) was prepared from (tetrahydrofuran-2-yl) methylamine in a similar manner to that described in example 36, step 4.¹H NMR(400MHz,DMSO-d6)δ12.07(s,1H),8.53(brs,2H),8.41(s,1H),8.03(d,J＝2.3Hz,1H),7.95(d,J＝8.2Hz,2H),7.88(d,J＝8.3Hz,2H),7.65(d,J＝8.6Hz,2H),7.07(d,J＝8.7Hz,2H),4.08-3.93(m,1H),3.82-3.77(m,1H),3.67-3.61(m,1H),3.41-3.29(m,2H),3.26(brs,4H),2.67(brs,4H),2.37(s,3H),1.97-1.88(m,1H),1.83(dd,J＝13.7,6.9Hz,2H),1.69-1.55(m,1H)。LC-MS(M+H)⁺＝496.3。

Example 51: n- (3-Hydroxycyclopentyl) -4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (Compound 51)

Compound 51(14mg, 21%) was prepared from 3-aminocyclopentan-1-ol in a similar manner to that described in example 36, step 4.¹H NMR(400MHz,DMSO-d6)δ12.06(s,1H),8.53(s,1H),8.40(s,1H),8.29(d,J＝7.3Hz,1H),8.02(s,1H),7.92(d,J＝8.0Hz,2H),7.87(d,J＝8.1Hz,2H),7.64(d,J＝8.3Hz,2H),7.07(d,J＝8.4Hz,2H),4.72(d,J＝3.2Hz,1H),4.30-4.18(m,1H),4.13(brs,1H),3.25(brs,4H),2.67(brs,4H),2.37(s,3H),2.16(dd,J＝13.1,6.7Hz,1H),2.04-1.95(m,1H),1.88(bs,1H),1.72(brs,1H),1.62(brs,1H),1.54(brs,1H)。LC-MS(M+H)⁺＝496.3。

Example 52: (3-Hydroxyazetidin-1-yl) (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone (Compound 52)

Compound 52(10mg, 14%) was prepared from azetidin-3-ol in a similar manner to that described in example 36, step 4.¹H NMR(400MHz,DMSO-d6)δ12.08(s,1H),8.53(s,1H),8.41(s,1H),8.03(d,J＝2.4Hz,1H),7.88(d,J＝8.1Hz,2H),7.70(d,J＝8.3Hz,2H),7.64(d,J＝8.6Hz,2H),7.07(d,J＝8.7Hz,2H),5.78(d,J＝4.8Hz,1H),4.53(brs,2H),4.27(brs,1H),4.10(brs,1H),3.82(brs,1H),3.26(brs,4H),2.67(brs,4H),2.37(s,3H)。LC-MS(M+H)⁺＝468.2。

Example 53: (4- (cyclopropylmethyl) piperazin-1-yl) (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone (Compound 53)

Compound 53(18mg, 23%) was prepared from 1- (cyclopropylmethyl) piperazine in a similar manner to that described in example 36, step 4.¹H NMR(400MHz,DMSO-d6)δ12.04(s,1H),8.53(d,J＝1.6Hz,1H),8.40(s,1H),7.98(d,J＝2.5Hz,1H),7.86(d,J＝8.0Hz,2H),7.64(d,J＝8.6Hz,2H),7.47(d,J＝8.0Hz,2H),7.06(d,J＝8.6Hz,2H),3.54(bs,4H),3.33(s,4H),3.23(s,4H),2.60(bs,4H),2.32(s,3H),2.25(bs,2H),0.84(bs,1H),0.47(d,J＝7.7Hz,2H),0.09(d,J＝4.4Hz,2H)。LC-MS(M+H)⁺＝535.4。

Example 54: 4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (tetrahydro-2H-pyran-4-yl) benzamide (compound 54)

Compound 54(8mg, 11%) was prepared from tetrahydro-2H-pyran-4-amine in a similar manner to that described in example 36, step 4.¹H NMR(400MHz,DMSO-d6)δ12.07(s,1H),8.54(d,J＝1.6Hz,1H),8.40(s,1H),8.30(d,J＝7.6Hz,1H),8.03(d,J＝2.4Hz,1H),7.94(d,J＝8.2Hz,2H),7.88(d,J＝8.3Hz,2H),7.65(d,J＝8.5Hz,2H),7.08(d,J＝8.6Hz,2H),4.03(brs,1H),3.91-3.88(m,2H),3.43-3.29(m,6H),2.76(brs,4H),2.43(s,3H),1.7-1.76(m,2H),1.68-1.52(m,2H)。LC-MS(M+H)⁺＝496.3。

Example 55: 4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- ((1-methylpiperidin-4-yl) methyl) benzamide (compound 55)

Compound 55(5mg, 7%) was prepared from (1-methylpiperidin-4-yl) methylamine in a similar manner to that described in example 36, step 4.¹H NMR(400MHz,DMSO-d6)δ12.09(s,1H),8.62(s,1H),8.54(d,J＝1.8Hz,1H),8.40(s,1H),8.03(d,J＝2.5Hz,1H),7.96(d,J＝8.3Hz,2H),7.88(d,J＝8.3Hz,2H),7.64(d,J＝8.6Hz,2H),7.07(d,J＝8.6Hz,2H),3.28(s,4H),3.21(s,2H),2.79(bs,4H),2.67(s,3H),2.64(s,5H),2.37(s,3H),1.85-1.77(m,2H),1.62-1.34(m,2H)。LC-MS(M+H)⁺＝523.3。

Example 56: (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (2-oxa-6-azaspiro [3.3] hept-6-yl) methanone (Compound 56)

Prepared from 2-oxa-6-azaspiro [3.3] in a similar manner to that described in step 4 of example 36]Heptane preparation compound 56(13mg, 18%).¹H NMR(400MHz,DMSO-d6)δ12.14(s,1H),8.59(s,1H),8.46(s,1H),8.09(d,J＝2.3Hz,1H),7.94(d,J＝8.1Hz,2H),7.75(d,J＝8.1Hz,2H),7.69(d,J＝8.5Hz,2H),7.12(d,J＝8.6Hz,2H),4.76(s,4H),4.60(s,2H),4.29(s,2H),3.29(app s,4H),2.65(app s,4H),2.37(s,3H)。LC-MS(M+H)⁺＝494.3。

Example 57: n- (2- (dimethylamino) ethyl) -N-methyl-4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide hydrochloride (Compound 57)

From N in a manner analogous to that described in step 4 of example 36₁,N₁,N₂-trimethylethane-1, 2-diamine compound 57(9mg, 13%) was prepared.¹H NMR(400MHz,DMSO-d6)δ12.05(s,1H),10.06(s,1H),8.53(s,1H),8.40(s,1H),8.00(s,1H),7.86(brs,2H),7.65(brs,2H),7.53(brs,2H),7.08(bs,2H),3.4-3.12(m,8H),3.08-2.93(m,5H),2.76-2.67(m,8H),2.26-2.03(m,3H)。LC-MS(M+H)⁺＝497.3。

Example 58: (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (7-oxa-2-azaspiro [3.5] non-2-yl) methanone (Compound 58)

Prepared from 7-oxa-2-azaspiro [3.5 ] in a similar manner to that described in step 4 of example 36]Nonane preparation of compound 58(11mg, 14%).¹H NMR(400MHz,DMSO-d6)δ12.08(d,J＝2.0Hz,1H),8.53(d,J＝1.9Hz,1H),8.40(d,J＝1.6Hz,1H),8.02(d,J＝2.6Hz,1H),7.88(d,J＝8.3Hz,2H),7.74(d,J＝8.3Hz,2H),7.64(d,J＝8.7Hz,2H),7.06(d,J＝8.8Hz,2H),4.13(s,2H),3.81(s,2H),3.56-3.55(m,2H),3.50-3.49(m,2H),3.23(brs,4H),2.60(brs,4H),2.32(s,3H),1.72(t,J＝5.0Hz,4H)。LC-MS(M+H)⁺＝522.3。

Example 59: (4- (dimethylamino) piperidin-1-yl) (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone (Compound 59)

Compound 59(20mg, 26%) was prepared from N, N-dimethylpiperidin-4-amine in a similar manner to that described in example 36, step 4.¹H NMR(400MHz,DMSO-d6)δ12.05(s,1H),8.53(s,1H),8.39(s,1H),7.99(d,J＝2.3Hz,1H),7.86(d,J＝8.0Hz,2H),7.63(d,J＝8.5Hz,2H),7.48(d,J＝8.0Hz,2H),7.06(d,J＝8.6Hz,2H),4.49(brs,1H),3.21(brs,4H),3.02-2.82(m,4H),2.53(brs,4H),2.41(s,6H),2.27(s,3H),1.91(brs,2H),1.49(brs,2H)。LC-MS(M+H)⁺＝523.4。

Example 60: n-methyl-4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (3- (piperidin-1-yl) propyl) benzamide (compound 60)

Compound 60(20mg, 22%) was prepared from N-methyl-3- (piperidin-1-yl) propan-1-amine in a similar manner to that described in example 36, step 4.¹H NMR(400MHz,DMSO-d6)δ12.07(s,1H),8.53(s,1H),8.39(s,1H),8.00(s,1H),7.86(d,J＝8.0Hz,2H),7.64(d,J＝8.4Hz,2H),7.50(brs,2H),7.07(d,J＝8.4Hz,2H),3.52(brs,2H),3.34(brs,4H),3.26(brs,4H),3.00(brs,3H),2.67(brs,4H),2.36(brs,3H),2.01(brs,2H),1.74-1.23(m,8H)。LC-MS(M+H)⁺＝551.2。

Example 61: (3- (2-methoxyethoxy) azetidin-1-yl) (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone (Compound 61)

Compound 61(11mg, 12%) was prepared from 3- (2-methoxyethoxy) azetidine in a similar manner to that described in example 36, step 4.¹H NMR(400MHz,DMSO-d6)δ12.08(s,1H),8.53(d,J＝1.6Hz,1H),8.41(s,1H),8.04(d,J＝2.4Hz,1H),7.88(d,J＝8.0Hz,2H),7.71(d,J＝8.4Hz,2H),7.64(d,J＝8.4Hz,2H),7.07(d,J＝8.4Hz,2H),4.52(brs,1H),4.37(brs,1H),4.26(brs,1H),4.20(brs,1H),3.87(brs,1H),3.54-3.51(m,2H),3.47-3.45(m,2H),3.25(brs,7H),2.67(brs,4H),2.38(s,3H)。LC-MS(M+H)⁺＝526.2。

Example 62: (3, 3-Dimethylazetidin-1-yl) (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone (Compound 62)

Compound 62(29mg, 36%) was prepared from 3, 3-dimethylazetidine in a similar manner to that described in example 36, step 4.¹H NMR(400MHz,DMSO-d6)δ12.08(d,J＝2.2Hz,1H),8.53(d,J＝2.0Hz,1H),8.40(d,J＝1.9Hz,1H),8.02(d,J＝2.5Hz,1H),7.87(d,J＝8.3Hz,2H),7.71(d,J＝8.3Hz,2H),7.64(d,J＝8.7Hz,2H),7.06(d,J＝8.8Hz,2H),4.05(s,2H),3.75(s,2H),3.24(brs,4H),2.60(brs,4H),2.33(s,3H),1.26(s,6H)。LC-MS(M+H)⁺＝480.2。

Example 63: N-Ethyl-N-methyl-4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (Compound 63)

Compound 63(30mg, 39%) was prepared from N-methylethylamine in a similar manner to that described in example 36, step 4.¹H NMR(400MHz,DMSO-d6)δ12.04(s,1H),8.53(d,J＝1.7Hz,1H),8.40(s,1H),7.99(d,J＝2.3Hz,1H),7.85(d,J＝8.1Hz,2H),7.63(d,J＝8.6Hz,2H),7.46(d,J＝7.2Hz,2H),7.06(d,J＝8.7Hz,2H),3.47(brs,2H),3.23(brs,4H),2.97(s,3H),2.58(brs,4H),2.31(s,3H),1.13(brs,3H)。LC-MS(M+H)⁺＝454.3。

Example 64: n-methyl-4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (3- (pyrrolidin-1-yl) propyl) benzamide (compound 64)

Compound 64(20mg, 22%) was prepared from N-methyl-3- (pyrrolidin-1-yl) propan-1-amine in a similar manner to that described in example 36, step 4.¹H NMR(400MHz,DMSO-d6)δ12.05(s,1H),8.53(d,J＝1.8Hz,1H),8.39(s,1H),7.99(s,1H),7.86(d,J＝8.1Hz,2H),7.63(d,J＝8.6Hz,2H),7.50(bs,2H),7.06(d,J＝8.7Hz,2H),3.53(brs,1H),3.33(brs,4H),3.22(s,4H),3.00(s,6H),2.56(brs,4H),2.29(s,3H),1.90-1.74(m,6H)。LC-MS(M+H)⁺＝537.3。

Example 65: (3- (dimethylamino) azetidin-1-yl) (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone (Compound 65)

Compound 65(22mg, 31%) was prepared from N, N-dimethylazetidin-3-amine in a similar manner to that described in example 36, step 4.¹H NMR(400MHz,DMSO-d6)δ12.08(s,1H),8.53(d,J＝1.9Hz,1H),8.40(s,1H),8.03(d,J＝2.6Hz,1H),7.88(d,J＝8.3Hz,2H),7.72(d,J＝8.4Hz,2H),7.64(d,J＝8.7Hz,2H),7.07(d,J＝8.9Hz,2H),4.37(brs,1H),4.15(brs,1H),4.07(brs,1H),3.86(brs,1H),3.24(s,4H),3.11(brs,1H),2.64(brs,4H),2.35(s,3H),2.11(s,6H)。LC-MS(M+H)⁺＝495.3。

Example 66: 4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (3- (pyrrolidin-1-yl) propyl) benzamide (compound 66)

Compound 66(15mg, 15%) was prepared from 3- (pyrrolidin-1-yl) propan-1-amine in a similar manner to that described in example 36, step 4.¹H NMR(400MHz,DMSO-d6)δ12.08(s,1H),8.65(s,1H),8.54(d,J＝1.6Hz,1H),8.40(s,1H),8.03(d,J＝2.4Hz,1H),7.95(d,J＝8.4Hz,2H),7.90(d,J＝8.2Hz,2H),7.64(d,J＝8.6Hz,2H),7.07(d,J＝8.6Hz,2H),3.38-3.33(m,6H),3.25(brs,4H),3.11(brs,2H),2.62(brs,4H),2.34(s,3H),1.92(brs,6H)。LC-MS(M+H)⁺＝523.3。

Example 67: n- (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) acetamide TFA salt (Compound 67)

To a solution of compound 13(70mg, 0.14mmol, 1.0 equiv.) in DMF (3ml) was added acetic acid (17mg, 0.29mmol, 2.0 equiv.) and HATU (66mg, 0.17mmol, 1.2 equiv.). The reaction mixture was stirred at room temperature for 12 h. The mixture was diluted with water (20mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane: MeOH ═ 8:1) to give compound 67(8mg, 10%).¹H NMR(400MHz,DMSO-d6)δ11.93(s,1H),10.00(s,1H),9.84(s,1H),8.53(s,1H),8.37(s,1H),7.84(s,1H),7.75-7.63(m,6H),7.13(d,J＝8.4Hz,2H),3.93(d,J＝13.1Hz,2H),3.55(d,J＝11.5Hz,2H),3.20(d,J＝10.2Hz,2H),3.01(t,J＝12.3Hz,2H),2.89(s,3H),2.07(s,3H)。LC-MS(M+H)⁺＝426.2。

Example 68: 2-cyclopentyl-N- (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) acetamide (Compound 68)

Compound 68(3mg, 7%) was prepared from 2-cyclopentylacetic acid and compound 13 in a similar manner to that described in example 67.¹H NMR(400MHz,DMSO-d6)δ11.88(s,1H),9.92(s,1H),8.51(s,1H),8.35(s,1H),7.81(s,1H),7.72-7.68(m,3H),7.66(d,J＝8.1Hz,2H),7.09(d,J＝8.3Hz,2H),3.00(s,4H),2.60(s,2H),2.41-2.18(m,4H),1.76(s,2H),1.62(s,2H),1.53(s,2H),1.23(s,3H)。LC-MS(M+H)⁺＝494.2。

Example 69: n- (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) -2- (pyrrolidin-1-yl) acetamide (compound 69)

Compound 69(11mg, 6%) was prepared from 2- (pyrrolidin-1-yl) acetic acid and compound 13 in a similar manner to that described in example 67.¹H NMR(400MHz,CDCl₃)δ9.45(s,1H),9.19(s,1H),8.57(d,J＝1.8Hz,1H),8.33(d,J＝1.8Hz,1H),7.66(dd,J＝22.0,8.6Hz,4H),7.56(d,J＝8.7Hz,2H),7.50(s,1H),7.05(d,J＝8.7Hz,2H),3.33(s,6H),2.73(s,4H),2.67(s,4H),2.41(s,3H),1.89(s,4H)。LC-MS(M+H)⁺＝495.0。

Example 70: 3- (dimethylamino) -N- (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) propionamide (Compound 70)

To be in factCompound 70(11mg, 6%) was prepared from 3- (dimethylamino) propionic acid and compound 13 in a similar manner to that described in example 67.¹H NMR(400MHz,DMSO-d6)δ11.88(s,1H),10.21(s,1H),8.50(s,1H),8.34(s,1H),7.83(s,1H),7.77-7.51(m,6H),7.06(d,J＝8.5Hz,2H),3.24(s,4H),3.08(s,2H),2.72(brs,2H),2.64(brs,4H),2.58(s,6H),2.35(s,3H)。LC-MS(M+H)⁺＝483.0。

Example 71: 2- (dimethylamino) -N- (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) acetamide (Compound 71)

Compound 71(12mg, 8%) was prepared from dimethylglycine and compound 13 in a similar manner to that described in example 67.¹H NMR(400MHz,DMSO-d6)δ11.83(s,1H),8.50(s,1H),8.32(d,J＝3.9Hz,2H),7.78(s,1H),7.65-7.63(m,4H),7.56(d,J＝8.1Hz,2H),7.10(d,J＝8.3Hz,2H),3.33(brs,4H),3.06(brs,4H),2.95(s,6H),2.65(s,3H)。LC-MS(M+H)⁺＝455.2。

Example 72: n- (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) -4- (pyrrolidin-1-yl) butanamide (compound 72)

Compound 72(98mg, 45%) was prepared from 4- (pyrrolidin-1-yl) butyric acid and compound 13 in a similar manner to that described in example 67.¹H NMR(400MHz,DMSO-d6)δ11.89(s,1H),10.12(s,1H),8.50(d,J＝1.6Hz,1H),8.34(s,1H),7.82(d,J＝2.4Hz,1H),7.77-7.67(m,4H),7.63(d,J＝8.6Hz,2H),7.06(d,J＝8.7Hz,2H),3.26(s,4H),3.10(s,4H),2.67(s,4H),2.46(t,J＝7.2Hz,4H),2.37(s,3H),1.99-1.92(m,6H)。MS(ESI)m/e(M+1)⁺523.0。

Example 73: n, N-dimethyl-4- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) benzamide (compound 73)

Step 1: 2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazine (compound 73-1)

The title compound (500mg, crude) was prepared from 2-bromo-5H-pyrrolo [2,3-b ] pyrazine and (4- (4-methylpiperazin-1-yl) phenyl) boronic acid in a similar manner to that described in example 1, step 1.

Step 2: 7-bromo-2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazine (compound 73-2)

Prepared from 2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] in a similar manner to that described in example 1, step 2]Pyrazine the title compound was prepared (210mg, 33%). LC-MS (M + H)⁺＝372.0,374.0。

And step 3: 7-bromo-2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazine-5-carboxylic acid tert-butyl ester (compound 73-3)

The title compound (390mg, crude) was prepared from 7-bromo-2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazine in a similar manner to that described in example 1, step 3.

And 4, step 4: n, N-dimethyl-4- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) benzamide

Prepared from 7-bromo-2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] in a similar manner to that described in example 1, step 4 ]Tert-butyl pyrazine-5-carboxylate and (4- (dimethylcarbamoyl) phenyl) boronic acid compound 73(10mg, 36%) was prepared.¹H NMR(400MHz,DMSO-d6)δ12.34(s,1H),8.84(s,1H),8.48(d,J＝2.2Hz,1H),8.38(d,J＝8.1Hz,2H),8.09(d,J＝8.6Hz,2H),7.50(d,J＝8.1Hz,2H),7.11(d,J＝8.7Hz,2H),3.30(app s,4H),3.01(s,6H),2.63(app s,4H),2.32(s,3H)。LC-MS(M+H)⁺＝441.2。

Example 74: n- (2- (dimethylamino) ethyl) -3-fluoro-N-methyl-4- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) benzamide (compound 74)

Step 1: 2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazine (compound 74-1)

The title compound (900mg, > 100%) was prepared from 2-bromo-5H-pyrrolo [2,3-b ] pyrazine in a similar manner to that described in example 1, step 1.

Step 2: 7-bromo-2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazine (compound 74-2)

The title compound (460mg, 40%) was prepared from 2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazine in a similar manner to that described in example 1, step 2.

And step 3: 7-bromo-2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazine-5-carboxylic acid tert-butyl ester (compound 74-3)

The title compound (540mg, 93%) was prepared from 7-bromo-2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazine in a similar manner to that described in example 1, step 3.

And 4, step 4: 3-fluoro-4- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) benzoic acid methyl ester (Compound 74-4)

The title compound (40mg, 39%) was prepared from tert-butyl 7-bromo-2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazine-5-carboxylate in a similar manner to that described in example 1, step 4.

And 5: 3-fluoro-4- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) benzoic acid (compound 74-5)

The title compound (90mg, > 100%) was prepared from methyl 3-fluoro-4- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) benzoate in a similar manner to the one described in example 36, step 3.

Step 6: n- (2- (dimethylamino) ethyl) -3-fluoro-N-methyl-4- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) benzamide

From N in a manner analogous to that described in step 4 of example 36₁,N₁,N₂Trimethylethane-1, 2-diamine compound 74(1mg, 2%) was prepared.¹H NMR(400MHz,CD₃OD)δ9.17(t,J＝7.7Hz,1H),8.79(s,1H),8.29(d,J＝2.6Hz,1H),8.13(d,J＝8.8Hz,2H),7.46(dd,J＝19.2,10.1Hz,2H),7.19(d,J＝8.9Hz,2H),4.09-3.97(m,2H),3.96-3.90(m,2H),3.65(d,J＝17.2Hz,2H),3.48(d,J＝6.1Hz,2H),3.30(s,6H),3.17(s,3H),3.13-3.00(m,4H),3.00(s,3H)。LC-MS(M+H)⁺＝516.2。

Example 75: (4- (2- (dimethylamino) ethyl) piperazin-1-yl) (4- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) methanone (Compound 75)

Step 1: 7- (4- (methoxycarbonyl) phenyl) -2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazine-5-carboxylic acid tert-butyl ester (compound 75-1)

The title compound (800mg, 57%) was prepared from compound 74-3 in a similar manner to that described in example 1, step 4.

Step 2: 4- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) benzoic acid methyl ester (Compound 75-2)

Compound 75-1(800mg, 1.52mmol, 1.0 equiv.) was dissolved in HCl/dioxane (20 ml). It was stirred at room temperature overnight. The solvent was removed under vacuum to give the crude product (900mg, crude) which was used in the next step without purification. LC-MS (M + H)⁺＝428.2。

And step 3: 4- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) benzoic acid (Compound 75-3)

Compound 75-2(900mg, 1.64mmol, 1.0 equiv.) is dissolved in methanol (50ml) and then LiOH (100mg, 40mmol, 24 equiv.) and water (50ml) are addedAnd (3) mixing. The reaction mixture was refluxed for 12 h. MTBE (30ml) was added, separated with aqueous phase and adjusted to pH 5-6 by 2N HCl, filtered and washed with water, dried in vacuo to give compound 75-3(800mg,>100％)。LC-MS(M+H)⁺＝414.2。

and 4, step 4: (4- (2- (dimethylamino) ethyl) piperazin-1-yl) (4- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) methanone

Compound 75(10mg, 14%) was prepared from N, N-dimethyl-2- (piperazin-1-yl) ethan-1-amine in a similar manner to that described in example 36, step 4. ¹H NMR(400MHz,CD₃OD)δ8.65(d,J＝3.5Hz,1H),8.33(d,J＝8.0Hz,2H),8.14(s,1H),8.04(d,J＝8.8Hz,2H),7.43(d,J＝8.0Hz,2H),7.09(d,J＝8.8Hz,2H),3.90(d,J＝12.4Hz,2H),3.90-3.60(m,3H),3.56(d,J＝12.7Hz,3H),3.32-3.23(m,2H),3.14-2.97(m,3H),2.90(s,3H),2.84(s,6H),2.90-2.75(m,2H),2.75-2.56(m,5H)。LC-MS(M+H)⁺＝553.3。

Example 76: (3-Methoxyazetidin-1-yl) (4- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) methanone (Compound 76)

Example 76 was prepared from compound 75-3 and 3-methoxyazetidine. 7mg, 6%, yellow solid.¹H NMR(400MHz,DMSO-d6)δ12.39(d,J＝2.4Hz,1H),8.85(s,1H),8.52(d,J＝2.7Hz,1H),8.42(d,J＝8.2Hz,2H),8.10(d,J＝8.7Hz,2H),7.73(d,J＝8.2Hz,2H),7.12(d,J＝8.7Hz,2H),4.53(s,1H),4.15-4.30(m,3H),3.87(s,1H),3.27-3.32(m,4H),3.24(s,3H),2.50-2.90(m,4H),2.30-2.45(m,3H)。

Example 77: n-methyl-4- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -N- (3- (pyrrolidin-1-yl) propyl) benzamide (compound 77)

Compound 77(9mg, 10%) was prepared from compound 75-3 and N-methyl-3- (pyrrolidin-1-yl) propan-1-amine.¹H NMR(400MHz,DMSO-d6)δ12.40(d,J＝2.7Hz,1H),8.88(s,1H),8.51(d,J＝2.7Hz,1H),8.40(d,J＝8.3Hz,2H),8.14(d,J＝8.8Hz,2H),7.53(brs,2H),7.18(d,J＝8.9Hz,2H),3.97(brs,2H),3.55(brs,6H),3.18(brs,5H),3.01(s,6H),2.83(s,3H),2.01(brs,4H),1.91(brs,2H)。LC-MS(M+H)⁺＝538.2。

Example 78: n- (2- (dimethylamino) ethyl) -4- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) benzamide (compound 78)

From compounds 75-3 and N₁,N₁Dimethyl ethane-1, 2-diamine compound 78(15mg, 18%) was prepared.¹H NMR(400MHz,DMSO-d6)δ12.44(s,1H),8.89(s,1H),8.80(s,1H),8.56(d,J＝2.9Hz,1H),8.46(d,J＝8.4Hz,2H),8.14(d,J＝8.8Hz,2H),8.01(d,J＝8.3Hz,2H),7.18(d,J＝8.8Hz,2H),3.98(brs,2H),3.66(q,J＝5.6Hz,2H),3.45-3.42(m,2H),3.31-3.28(m,2H),3.25-3.08(m,2H),2.85(s,6H),2.83(s,3H),2.78(s,2H)。LC-MS(M+H)⁺＝484.3。

Example 79: n- (2- (dimethylamino) ethyl) -N-methyl-4- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) benzamide (compound 79)

From compounds 75-3 and N₁,N₁,N₂Trimethylethane-1, 2-diamine compound 79(14mg, 19%) was prepared.¹H NMR(400MHz,DMSO-d6)δ12.41(s,1H),8.87(s,1H),8.51(d,J＝2.7Hz,1H),8.40(d,J＝8.1Hz,2H),8.13(d,J＝8.4Hz,2H),7.62(bs,2H),7.17(d,J＝8.6Hz,2H),3.84(brs,4H),3.28-3.11(m,8H),3.05(s,3H),2.84(s,6H),2.78(s,3H)。LC-MS(M+H)⁺＝498.3。

Example 80: n- (3- (dimethylamino) propyl) -N-methyl-4- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) benzamide (compound 80)

From compounds 75-3 and N₁,N₁,N₃-trimethylpropane-1, 3-diamine preparation compound 80(16mg, 18%).¹H NMR(400MHz,DMSO-d6)δ12.43(s,1H),8.88(s,1H),8.51(s,1H),8.40(d,J＝6.9Hz,2H),8.14(d,J＝7.3Hz,2H),7.55(bs,2H),7.17(d,J＝8.0Hz,2H),3.96(brs,2H),3.49(brs,4H),3.20(brs,4H),3.09(brs,2H),3.01(s,3H),2.81(s,3H),2.77(brs,6H),2.03(brs,2H)。LC-MS(M+H)⁺＝512.3。

Example 81: (4- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) (2-oxa-6-azaspiro [3.3] hept-6-yl) methanone (Compound 81)

From the compounds 75-3 and 2-oxa-6-azaspiro [3.3]Heptane compound 81(5mg, 7%) was prepared.¹H NMR(400MHz,DMSO-d6)δ12.47(d,J＝2.5Hz,1H),8.93(s,1H),8.59(d,J＝2.9Hz,1H),8.48(d,J＝8.3Hz,2H),8.19(d,J＝8.8Hz,2H),7.77(d,J＝8.4Hz,2H),7.22(d,J＝8.9Hz,2H),4.77(s,4H),4.63(s,2H),4.30(s,2H),3.51(app s,4H),3.13(app s,4H),2.72(s,3H)。LC-MS(M+H)⁺＝495.3。

Example 82: (4- (dimethylamino) piperidin-1-yl) (4- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) methanone (Compound 82)

Preparation of Compounds from Compound 75-3 and N, N-dimethylpiperidin-4-amineSubstance 82(5mg, 6%).¹H NMR(400MHz,DMSO-d6)δ12.36(s,1H),8.85(s,1H),8.49(d,J＝2.4Hz,1H),8.40(d,J＝8.0Hz,2H),8.09(d,J＝8.6Hz,2H),7.51(d,J＝8.1Hz,2H),7.11(d,J＝8.6Hz,2H),4.57(brs,1H),3.12-2.84(m,4H),2.62(brs,10H),2.35(s,3H),2.00-1.99(m,4H),1.61-1.59(m,2H),1.23(brs,2H)。LC-MS(M+H)⁺＝524.4。

Example 83: (3- (dimethylamino) azetidin-1-yl) (4- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) methanone (Compound 83)

Compound 83(9mg, 13%) was prepared from compound 75-3 and N, N-dimethylazetidin-3-amine.¹H NMR(400MHz,DMSO-d6)δ12.40(s,1H),8.85(s,1H),8.51(d,J＝2.7Hz,1H),8.42(d,J＝8.2Hz,2H),8.10(d,J＝8.7Hz,2H),7.73(d,J＝8.3Hz,2H),7.12(d,J＝8.7Hz,2H),4.39(brs,1H),4.19(brs,1H),4.07(brs,1H),3.88(brs,1H),3.35(brs,4H),3.15(brs,1H),2.77(brs,4H),2.44(s,3H),2.14(s,6H)。LC-MS(M+H)⁺＝496.3。

Example 84: n- (4- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) -4- (pyrrolidin-1-yl) butanamide (compound 84)

Compound 84(110mg, 40%) was prepared from compound 122-1 in a similar manner to example 122.¹H NMR(400MHz,DMSO-d6)δ12.16(s,1H),10.12(s,1H),8.81(s,1H),8.52-8.12(m,3H),8.08(d,J＝8.3Hz,2H),7.67(d,J＝8.2Hz,2H),7.10(d,J＝8.1Hz,2H),3.25(s,4H),2.75(s,2H),2.55(s,6H),2.32(s,6H),2.26(s,3H)。MS(ESI)m/e(M+1)⁺484.0。

Example 85: 3- (dimethylamino) -N- (4- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) propionamide (Compound 85)

Compound 85(10mg, 8%) was prepared from compound 122-1 in a similar manner to that in example 122.¹H NMR(400MHz,DMSO-d6)δ12.16(s,1H),10.12(s,1H),8.81(s,1H),8.52-8.12(m,3H),8.08(d,J＝8.3Hz,2H),7.67(d,J＝8.2Hz,2H),7.10(d,J＝8.1Hz,2H),3.25(s,4H),2.75(s,2H),2.55(s,6H),2.32(s,6H),2.26(s,3H)。MS(ESI)m/e(M+1)⁺484.0。

Example 86: 7- (4- (1-methyl-1H-pyrazol-5-yl) phenyl) -2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazine TFA salt (Compound 86)

Compound 86(15mg, 5%) was prepared from (4- (1-methyl-1H-pyrazol-5-yl) phenyl) boronic acid in a similar manner to that in example 1, step 4.¹H NMR(400MHz,DMSO-d6)δ12.37(d,J＝2.7Hz,1H),9.69(s,1H),8.88(s,1H),8.52(d,J＝2.8Hz,1H),8.46(d,J＝8.3Hz,2H),8.15(d,J＝8.8Hz,2H),7.62(d,J＝8.3Hz,2H),7.49(d,J＝1.7Hz,1H),7.19(d,J＝8.9Hz,2H),6.46(d,J＝1.7Hz,1H),4.01(d,J＝13.6Hz,2H),3.93(s,3H),3.56(d,J＝12.1Hz,2H),3.20(d,J＝10.8Hz,2H),3.05(t,J＝12.2Hz,2H),2.89(s,3H)。LC-MS(M+H)⁺＝449.2。

Example 87: 7- (4-methoxyphenyl) -2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazine (compound 87)

Compound 87(28mg, 12%) was prepared from (4-methoxyphenyl) boronic acid in a similar manner to that described in example 1, step 4.¹H NMR(400MHz,DMSO-d6)δ12.10(d,J＝2.5Hz,1H),8.80(s,1H),8.28-8.24(m,2H),8.23(s,1H),8.06(d,J＝8.8Hz,2H),7.09(d,J＝8.9Hz,2H),7.04(d,J＝8.8Hz,2H),3.80(s,3H),3.29-3.20(m,4H),2.49-2.43(m,4H),2.24(s,3H)。LC-MS(M+H)⁺＝400.2。

Example 88: n, N-dimethyl-1- (4- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) methylamine (compound 88)

Compound 88(10mg, 14%) was prepared from (4- ((dimethylamino) methyl) phenyl) boronic acid in a similar manner to that described in example 1, step 4.¹H NMR(400MHz,DMSO-d6)δ12.24(s,1H),8.82(s,1H),8.38(d,J＝2.5Hz,1H),8.29(d,J＝8.0Hz,2H),8.08(d,J＝8.7Hz,2H),7.41(d,J＝7.8Hz,2H),7.10(d,J＝8.8Hz,2H),3.62(s,2H),3.27(s,4H),2.52(s,4H),2.31(s,6H),2.27(s,3H)。LC-MS(M+H)⁺＝427.2。

Example 89: 7- (1-methyl-1H-pyrazol-5-yl) -2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazine (compound 89)

Compound 89(26mg, 33%) was prepared from (1-methyl-1H-pyrazol-5-yl) boronic acid in a similar manner to that in example 1, step 4. ¹H NMR(400MHz,DMSO-d6)δ12.45(s,1H),8.88(s,1H),8.16(s,1H),8.04(d,J＝8.8Hz,2H),7.50(d,J＝1.6Hz,1H),7.07(d,J＝8.8Hz,2H),6.77(d,J＝2.0Hz,1H),4.03(s,3H),3.26(brs,4H),2.56(brs,4H),2.29(s,3H)。LC-MS(M+H)⁺＝374.1。

Example 90: 3- (4-methoxyphenyl) -5- (2- (4-methylpiperazin-1-yl) pyrimidin-5-yl) -1H-pyrrolo [2,3-b ] pyridine (compound 90)

Step 1: 2-chloro-5- (4-methylpiperazin-1-yl) pyrimidine (Compound 90-1)

To a solution of 5-bromo-2-chloropyrimidine (1.5g, 7.7mmol, 1.0 eq) in dioxane (60mL) was added 1-methylpiperazine (1.56g, 15.6mmol, 2.0 eq). The mixture was refluxed for 2 h. The solvent was removed under reduced pressure. The residue was diluted with ethyl acetate (60mL), washed with brine (40mL), dried over sodium sulfate and concentrated under reduced pressure to give the title compound (1.7g, 100%).

Step 2: 5- (4-methylpiperazin-1-yl) -2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine (Compound 90-2)

The title compound (400mg, 24%) was prepared from 2-chloro-5- (4-methylpiperazin-1-yl) pyrimidine in a similar manner to the procedure in example 26, step 3. LC-MS (M + H)⁺＝305.2。

And step 3: 5- (2- (4-Methylpiperazin-1-yl) pyrimidin-5-yl) -1H-pyrrolo [2,3-b ] pyridine (compound 90-3)

The title compound (540mg, 100%) was prepared from 5- (4-methylpiperazin-1-yl) -2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine and 5-bromo-1H-pyrrolo [2,3-b ] pyridine in a similar manner to that in example 1, step 1.

And 4, step 4: 3-bromo-5- (2- (4-methylpiperazin-1-yl) pyrimidin-5-yl) -1H-pyrrolo [2,3-b ] pyridine (compound 90-4)

Prepared in a similar manner to that in example 1, step 2 from 5- (2- (4-methylpiperazin-1-yl) pyrimidin-5-yl) -1H-pyrrolo [2,3-b]Pyridine preparation the title compound (160mg, 23%). LC-MS (M + H)⁺＝373.0,375.0。

And 5: 3- (4-methoxyphenyl) -5- (2- (4-methylpiperazin-1-yl) pyrimidin-5-yl) -1H-pyrrolo [2,3-b ] pyridine (compound 90)

Prepared in a similar manner to that in example 1, step 4 from 3-bromo-5- (2- (4-methylpiperazin-1-yl) pyrimidin-5-yl) -1H-pyrrolo [2,3-b]Pyridine and (4-methoxyphenyl) boronic acid preparation of compound 90(10mg, 16%).¹H NMR(400MHz,DMSO-d6)δ11.95-11.88(m,1H),8.87-8.81(m,2H),8.55-8.50(m,1H),8.42-8.35(m,1H),7.83-7.78(m,1H),7.76-7.68(m,2H),7.05-6.98(m,2H),3.80(s,4H),3.80(s,3H),2.72(ds,4H)。LC-MS(M+H)⁺＝401.0。

Example 91: 3- (4-methoxyphenyl) -5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b ] pyridine (compound 91)

Step 1: 5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b ] pyridine (compound 91-1)

The title compound (230mg, crude) was prepared from 5-bromo-1H-pyrrolo [2,3-b ] pyridine and (1-methyl-1H-pyrazol-4-yl) boronic acid in a similar manner to that in example 1, step 1.

Step 2: 3-bromo-5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b ] pyridine (compound 91-2)

Prepared in a similar manner to that in example 1, step 2 from 5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b ] ]Pyridine preparation the title compound (100mg, 31%). LC-MS (M + H)⁺＝277.0,279.0。

And step 3: 3- (4-methoxyphenyl) -5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b ] pyridine (compound 91)

Prepared in a similar manner to that in example 1, step 4 from 3-bromo-5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b]Pyridine and (4-methoxyphenyl) boronic acid prepared compound 91(12mg, 11%).¹H NMR(400MHz,DMSO-d6)δ11.78(s,1H),8.51(d,J＝1.9Hz,1H),8.30(d,J＝1.7Hz,1H),8.23(s,1H),7.95(s,1H),7.74(d,J＝2.5Hz,1H),7.68(d,J＝8.7Hz,2H),7.02(d,J＝8.7Hz,2H),3.88(s,3H),3.80(s,3H)。LC-MS(M+H)⁺＝305.1。

Example 92: 5- (1-Ethyl-1H-pyrazol-4-yl) -3- (4-methoxyphenyl) -1H-pyrrolo [2,3-b ] pyridine (compound 92)

Step 1: 5- (1-Ethyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b ] pyridine (compound 92-1)

The title compound (252mg, crude) was prepared from (1-ethyl-1H-pyrazol-4-yl) boronic acid in a similar manner to that in example 1, step 1.

Step 2: 3-bromo-5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b ] pyridine (compound 92-2)

Prepared in a similar manner to that in example 1, step 2 from 5- (1-ethyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b]Pyridine preparation the title compound (300mg, 87%). LC-MS (M + H)⁺＝291.0,293.0。

And step 3: 5- (1-Ethyl-1H-pyrazol-4-yl) -3- (4-methoxyphenyl) -1H-pyrrolo [2,3-b ] pyridine (compound 92)

Compound 92(10mg, 9%) was prepared from (4-methoxyphenyl) boronic acid in a similar manner to that in example 1, step 4. ¹H NMR(400MHz,DMSO-d6)δ11.90(s,1H),8.55(d,J＝1.7Hz,1H),8.38(s,1H),8.31(s,1H),7.98(s,1H),7.77(d,J＝2.1Hz,1H),7.69(d,J＝8.8Hz,2H),7.03(d,J＝8.8Hz,2H),4.17(q,J＝7.3Hz,2H),3.81(s,3H),1.43(t,J＝7.3Hz,3H)。LC-MS(M+H)⁺＝319.1。

Example 93: 4- (2- (1-Ethyl-1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -N, N-dimethylbenzamide (Compound 93)

Compound 93(10mg, 10%) was prepared from (4- (dimethylcarbamoyl) phenyl) boronic acid in a similar manner to that in example 1, step 4.¹H NMR(400MHz,DMSO-d6)δ12.30(s,1H),8.68(s,1H),8.46(d,J＝6.5Hz,2H),8.37(d,J＝7.9Hz,2H),8.16(s,1H),7.49(d,J＝7.9Hz,2H),4.23(q,J＝7.2Hz,2H),3.01(s,6H),1.45(t,J＝7.2Hz,3H)。LC-MS(M+H)⁺＝361.1。

Example 94: 3- (4-methoxyphenyl) -5- (1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b ] pyridine (compound 94)

Step 1: 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ] pyridine (compound 94-1)

The title compound (9.0g, 73%) was prepared from 5-bromo-1H-pyrrolo [2,3-b ] pyridine in a similar manner to that in example 26, step 26-3.

Step 2: 4- (4-bromo-1H-pyrazol-1-yl) -1-methylpiperidine (compound 94-2)

To a solution of 4- (4-bromo-1H-pyrazol-1-yl) piperidine (390mg, 1.7mmol, 1.0 equiv.) and iodomethane (265mg, 1.9mmol, 1.1 equiv.) in DMF (5mL) was added triethylamine (0.73mL, 5.1mmol, 3.0 equiv.). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with water (25mL) and extracted with ethyl acetate (4 × 20 mL). The combined organic layers were washed with brine (20mL), dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (160mg, 38%). LC-MS (M + H) ⁺＝230.0,232.0。

And step 3: 5- (1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b ] pyridine (compound 94-3)

Prepared in a similar manner to that in example 1, step 1 from 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ]]Pyridine preparation the title compound (55mg, 30%). LC-MS (M + H)⁺＝282.1。

And 4, step 4: 3-bromo-5- (1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b ] pyridine (compound 94-4)

The title compound (30mg, 43%) was prepared from 5- (1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b ] pyridine in a similar manner to that in example 1, step 2.

And 5: 3- (4-methoxyphenyl) -5- (1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b ] pyridine (compound 94)

Compound 94(5mg, 16%) was prepared from (4-methoxyphenyl) boronic acid in a similar manner to that in example 1, step 4.¹H NMR(400MHz,DMSO-d6)δ11.82-11.74(m,1H),8.57-8.51(m,1H),8.41-8.36(m,1H),8.36-8.31(m,1H),8.03-7.94(m,1H),7.76-7.71(m,1H),7.71-7.65(m,2H),7.06-6.99(m,2H),4.34-4.19(m,1H),3.83-3.77(m,3H),3.33-3.28(m,3H),3.19-3.04(m,2H),2.46-2.39(m,2H),2.23-2.07(m,4H)。LC-MS(M+H)⁺＝388.2。

Example 95: (4- (5- (4- (2- (4-methylpiperazin-1-yl) ethyl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (2-oxa-6-azaspiro [3.3] hept-6-yl) methanone (Compound 95)

Step 1: 1- (4-bromophenylethyl) -4-methylpiperazine (compound 95-1)

To 1-bromo-4- (2-bromoethyl) benzene (5g, 18.9mmol, 1.0 equiv.) and 1-methylpiperazine (3.6g, 36.0mmol, 2.0 equiv.) in CH ₃Addition of K to CN (50mL)₂CO₃(3.9g, 28.3mmol, 1.5 equiv.). The reaction mixture was refluxed for 2 h. The mixture was cooled and diluted with ethyl acetate (50mL), washed with brine (80mL), dried over sodium sulfate and concentrated under reduced pressure to give the title compound (4.7g, 89%). LC-MS (M + H)⁺＝283.0,285.0。

Step 2: 1-methyl-4- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenethyl) piperazine (compound 95-2)

The title compound (300mg, crude) was prepared from 1- (4-bromophenylethyl) -4-methylpiperazine in a similar manner to that in example 26, step 26-3.

And step 3: 5- (4- (2- (4-methylpiperazin-1-yl) ethyl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (compound 95-3)

The title compound (580mg, crude) was prepared from 5-bromo-1H-pyrrolo [2,3-b ] pyridine in a similar manner to that in example 1, step 1.

And 4, step 4: 3-bromo-5- (4- (2- (4-methylpiperazin-1-yl) ethyl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (compound 95-4)

The title compound (260mg, 36%) was prepared from 5- (4- (2- (4-methylpiperazin-1-yl) ethyl) phenyl) -1H-pyrrolo [2,3-b ] pyridine in a similar manner to that in example 1, step 2.

And 5: methyl 4- (5- (4- (2- (4-methylpiperazin-1-yl) ethyl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzoate (Compound 95-5)

The title compound (130mg, 36%) was prepared from (4- (methoxycarbonyl) phenyl) boronic acid in a similar manner to that in example 1, step 4. LC-MS (M + H)⁺＝456.2。

Step 6: 4- (5- (4- (2- (4-methylpiperazin-1-yl) ethyl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzoic acid (Compound 95-6)

The title compound (200mg, crude) was prepared from methyl 4- (5- (4- (2- (4-methylpiperazin-1-yl) ethyl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzoate in a similar manner to the manner in example 36, step 3.

And 7: (4- (5- (4- (2- (4-methylpiperazin-1-yl) ethyl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (2-oxa-6-azaspiro [3.3] hept-6-yl) methanone (Compound 95)

Prepared from 4- (5- (4- (2- (4-methylpiperazin-1-yl) ethyl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that in example 36 step 4]Pyridin-3-yl) benzoic acid preparation of compound 95(21mg, 9%).¹H NMR(400MHz,DMSO-d6)δ12.15(s,1H),8.57(d,J＝1.5Hz,1H),8.46(s,1H),8.06(d,J＝2.4Hz,1H),7.89(d,J＝8.1Hz,2H),7.70(d,J＝8.0Hz,4H),7.36(d,J＝8.0Hz,2H),4.70(s,4H),4.55(s,2H),4.23(s,2H),2.74(s,11H),2.44(s,4H)。LC-MS(M+H)⁺＝522.2。

Example 96: N-cyclopropyl-N-methyl-4- (5- (4- (2- (4-methylpiperazin-1-yl) ethyl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 96)

Prepared from 4- (5- (4- (2- (4-methylpiperazin-1-yl) ethyl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that in example 36 step 4 ]Pyridin-3-yl) benzoic acid preparation of compound 96(3mg, 3%).¹H NMR(400MHz,CD₃OD)δ8.55(s,1H),8.47(s,1H),7.79(s,1H),7.72(d,J＝8.0Hz,2H),7.60(d,J＝7.9Hz,2H),7.55(d,J＝7.4Hz,2H),7.34(d,J＝8.0Hz,2H),3.42(s,4H),3.36(s,3H),3.20-3.16(m,3H),3.00(dd,J＝16.0,6.6Hz,5H),2.90(s,1H),2.84(s,3H),0.59(s,2H),0.46(s,2H)。LC-MS(M+H)⁺＝494.2。

Example 97: n, N-dimethyl-4- (2- (4- (2- (4-methylpiperazin-1-yl) ethyl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) benzamide (compound 97)

Step 1: 2- (4- (2- (4-methylpiperazin-1-yl) ethyl) phenyl) -5H-pyrrolo [2,3-b ] pyrazine (Compound 97-1)

From 1-methyl-4- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenethyl) piperazine and 2-bromo-5H-pyrrolo [2,3-b ] in a similar manner to that in example 1, step 1]Pyrazine the title compound was prepared (800mg, crude). LC-MS (M + H)⁺＝322.2。

Step 2: 7-bromo-2- (4- (2- (4-methylpiperazin-1-yl) ethyl) phenyl) -5H-pyrrolo [2,3-b ] pyrazine (compound 97-2)

The title compound (240mg, 24%) was prepared from 2- (4- (2- (4-methylpiperazin-1-yl) ethyl) phenyl) -5H-pyrrolo [2,3-b ] pyrazine in a similar manner to that in example 1, step 2.

And step 3: 7-bromo-2- (4- (2- (4-methylpiperazin-1-yl) ethyl) phenyl) -5H-pyrrolo [2,3-b ] pyrazine-5-carboxylic acid tert-butyl ester (compound 97-3)

The title compound (240mg, 80%) was prepared from 7-bromo-2- (4- (2- (4-methylpiperazin-1-yl) ethyl) phenyl) -5H-pyrrolo [2,3-b ] pyrazine in a similar manner to that in example 1, step 3.

And 4, step 4: n, N-dimethyl-4- (2- (4- (2- (4-methylpiperazin-1-yl) ethyl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) benzamide (compound 97)

Compound 97(42mg, 17%) was prepared from (4- (dimethylcarbamoyl) phenyl) boronic acid in a similar manner to that in example 1, step 4.¹H NMR(400MHz,DMSO-d6)δ12.44(s,1H),8.90(s,1H),8.53(d,J＝2.5Hz,1H),8.39(d,J＝8.3Hz,2H),8.12(d,J＝8.1Hz,2H),7.51(d,J＝8.3Hz,2H),7.42(d,J＝8.2Hz,2H),3.01(s,6H),2.84(s,3H),2.67(s,8H),2.36(s,4H)。LC-MS(M+H)⁺＝469.2。

Example 98: (4- (2- (4- (2- (4-methylpiperazin-1-yl) ethyl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) (2-oxa-6-azaspiro [3.3] hept-6-yl) methanone (Compound 98)

Prepared from 4- (2- (4- (2- (4-methylpiperazin-1-yl) ethyl) phenyl) -5H-pyrrolo [2,3-b ] in a similar manner to that in example 36 step 4]Pyrazin-7-yl) benzoic acid preparation of compound 98(7mg, 2%).¹H NMR(400MHz,DMSO-d6)δ12.50(s,1H),8.93(s,1H),8.59(d,J＝2.5Hz,1H),8.42(d,J＝8.3Hz,2H),8.17(d,J＝7.8Hz,2H),7.72(d,J＝8.3Hz,2H),7.46(d,J＝7.9Hz,2H),4.71(s,4H),4.57(s,2H),4.24(s,2H),3.49(ds,4H),3.01(s,4H),2.96(s,4H),2.80(s,3H)。LC-MS(M+H)⁺＝523.2。

Example 99: n, N-dimethyl-4- [ 4-methyl-5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide (compound 99)

Step 1: 1-methyl-4- (2-methyl-4- [ 4-methyl-1H-pyrrolo [2,3-b ] pyridin-5-yl ] phenyl) piperazine (compound 99-1)

Prepared from 5-bromo-4-methyl-1H-pyrrolo [2,3-b ] in a similar manner to that described in step 4 of example 106]Pyridine and 1-methyl-4- [ 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ]Piperazine prepared the title compound (150mg, 46.8%). LC-MS (M + H)⁺＝321.2。

Step 2: 1- (4- [ 3-iodo-4-methyl-1H-pyrrolo [2,3-b ] pyridin-5-yl ] -2-methylphenyl) -4-methylpiperazine (compound 99-2)

Prepared from 1-methyl-4- (2-methyl-4- [ 4-methyl-1H-pyrrolo [2,3-b ] in a similar manner to that described in step 5 of example 106]Pyridin-5-yl]Phenyl) piperazine the title compound (120mg, 44.6%) was prepared. LC-MS (M + H)⁺＝447.2。

And step 3: n, N-dimethyl-4- [ 4-methyl-5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide (compound 99)

Prepared from [4- (dimethylcarbamoyl) phenyl in a similar manner to that described in step 6 of example 106]Boronic acid and 1- (4- [ 3-iodo-4-methyl-1H-pyrrolo [2,3-b ]]Pyridin-5-yl]-2-methylphenyl) -4-methylpiperazine preparation compound 99(12.4mg, 11.8%).¹H NMR(400MHz,DMSO-d6)δ11.88(d,J＝2.7Hz,1H),8.07(s,1H),7.56-7.51(m,3H),7.44(d,J＝7.8Hz,2H),7.22-7.15(m,2H),7.08(d,J＝8.1Hz,1H),3.33(s,2H),2.99(brs,6H),2.89(br s,4H),2.49-2.42(m,2H),2.30(s,3H),2.25(s,3H),2.22(s,3H)。LC-MS(M+H)⁺＝468.3。

Example 100: 4- (2-chloro-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (Compound 100)

Step 1: 5-bromo-2-chloro-1H-pyrrolo [2,3-b ] pyridine (Compound 100-1)

Reacting 5-bromo-1, 3-dihydro-2H-pyrrolo [2,3-b ]]Pyridin-2-one (500mg, 2.3mmol, 1.0 equiv.) in POCl₃The mixture in (10mL) was refluxed for 4 h. After cooling, the mixture was poured into ice-water and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (20mL), dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (560mg, 97%). LC-MS (M + H) ⁺＝230.9,232.9。

Step 2: 2-chloro-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (compound 100-2)

The title compound (480mg, 61%) was prepared from 5-bromo-2-chloro-1H-pyrrolo [2,3-b ] pyridine in a similar manner to that in example 1, step 1.

And step 3: 3-bromo-2-chloro-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (compound 100-3)

The title compound (320mg, 54%) was prepared from 2-chloro-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine in a similar manner to that in example 1, step 2.

And 4, step 4: 3-bromo-2-chloro-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester (compound 100-4)

The title compound (400mg, 100%) was prepared from 3-bromo-2-chloro-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine in a similar manner to that in example 1, step 3.

And 5: 4- (2-chloro-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (Compound 100)

Compound 100(3mg, 2%) was prepared from (4- (dimethylcarbamoyl) phenyl) boronic acid in a similar manner to that in example 1, step 4.¹H NMR(400MHz,DMSO-d6)δ12.85(s,1H),8.54(s,1H),8.11(s,1H),7.75(d,J＝6.7Hz,2H),7.60(d,J＝6.9Hz,2H),7.55(d,J＝6.7Hz,2H),7.05(d,J＝7.4Hz,2H),3.30(s,3H),3.22(s,4H),3.01(s,6H),2.33(s,4H)。LC-MS(M+H)⁺＝474.2。

Example 101: 1- (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) ethan-1-ol (Compound 101)

To compound 31(190mg, 0.46mmol) in MeOH (20mL) was added NaBH in portions₄(24mg, 0.63 mmol). The mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 101(145mg, 75.9%).¹H NMR(400MHz,DMSO-d6)δ11.91(s,1H),8.51(s,1H),8.34(s,1H),7.84(s,1H),7.71(d,J＝8.0Hz,2H),7.63(d,J＝8.4Hz,2H),7.42(d,J＝8.0Hz,2H),7.07(d,J＝8.4Hz,2H),5.15(d,J＝4.0Hz,1H),4.75(t,J＝5.2Hz,1H),3.29(brs,4H),2.77(brs,4H),2.44(s,3H),1.36(d,J＝6.3Hz,3H)。LC-MS(M+H)⁺＝413.1。

Example 102: n, N-dimethyl-4- (2- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) ethyl) benzamide (compound 102)

Step 1: 3-iodo-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (compound 102-1)

Prepared in a similar manner to that in example 1, step 2 from 5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]Pyridine and NIS prepared the title compound (3.2g, 65.6%). LC-MS (M + H)⁺＝419.2。

Step 2: 3-iodo-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester (compound 102-2)

Prepared in a similar manner to that in example 1, step 3 from 3-iodo-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]Pyridine preparation the title compound (1.5g, 87%). LC-MS (M + H)⁺＝519.2。

And step 3: methyl 4- ((5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) ethynyl) benzoate (Compound 102-3)

3-iodine-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]Pyridine-1-carboxylic acid tert-butyl ester (1.3g, 2.5mmol), methyl 4-acetylenylbenzoate (480mg, 3mmol), Pd (pph)₃)₂Cl₂(176mg, 0.25mmol), CuI (91mg, 0.5mmol) and Et₃Mixture of N (5mL) in DMF (30mL) in N₂Stirring was continued for 6h at 100 ℃. The mixture was then cooled and diluted with EA (100mL), washed with brine (100mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (500mg, 46%). LC-MS (M + H)⁺＝451.1。

And 4, step 4: 4- ((5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) ethynyl) benzoic acid (Compound 102-4)

Reacting 4- ((5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) ethynyl) benzoic acid methyl ester (350mg, 0.64mmol) and NaOH (127mg, 3.18mmol) in MeOH (15mL) and H₂The mixture in O (15mL) was stirred at 60 ℃ for 4 h. The mixture was cooled and acidified with HCl to pH 5-6. The mixture was concentrated, and the residue was purified by silica gel column chromatography to give the title compound (300mg, 100%). LC-MS (M + H)⁺＝437.1。

And 5: n, N-dimethyl-4- ((5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) ethynyl) benzamide (compound 102-5)

Prepared from 4- ((5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2, 3-b) in a similar manner to that in example 36 step 4]Pyridin-3-yl) ethynyl) benzoic acid and dimethylamine hydrochloride salt compound (110mg, 34%) was prepared.¹H NMR(400MHz,DMSO-d6)δ12.23(s,1H),8.58(d,J＝2.0Hz,1H),8.21(d,J＝2.0Hz,1H),7.98(d,J＝2.8Hz,1H),7.65(t,J＝8.4Hz,4H),7.45(d,J＝8.4Hz,2H),7.08(d,J＝8.8Hz,2H),3.26(brs,4H),2.99(s,3H),2.94(s,3H),2.73(brs,4H),2.41(s,3H)。LC-MS(M+H)⁺＝464.2。

Step 6: n, N-dimethyl-4- (2- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) ethyl) benzamide (compound 102)

Mixing N, N-dimethyl-4- ((5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) ethynyl) benzamide (200mg, 0.43mmol) and PtO₂(100mg) mixture in MeOH (20mL) in H at room temperature₂Stirring was continued overnight. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 102(35mg, 17.3%).¹H NMR(400MHz,DMSO-d6)δ11.31(s,1H),8.41(d,J＝1.6Hz,1H),8.06(d,J＝1.6Hz,1H),7.56(d,J＝8.8Hz,2H),7.34-7.24(m,4H),7.24(s,1H),7.03(d,J＝8.8Hz,2H),3.18(t,J＝4.4Hz,4H),3.03(q,J＝12.1Hz,4H),2.95(s,3H),2.86(s,3H),2.49(s,4H),2.24(s,3H)。LC-MS(M+H)⁺＝468.2。

Example 103: 4- (5- (4-methoxy-2-methyl-3- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (Compound 103)

Step 1: 1- (3-bromo-6-methoxy-2-methylphenyl) -4-methylpiperazine (compound 103-1)

To a solution of 1- (2-methoxy-6-methylphenyl) -4-methylpiperazine (2.8g, 12.7mmol) in EtOH (50mL) was added Br dropwise₂(2.24g, 14 mmol). The mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was taken up in water (30mL) and saturated NaHCO ₃The solution (30mL) was diluted and extracted with EA (100 mL). The organic layer was separated, washed with brine (30mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (3.7g, 99%). LC-MS (M + H)⁺＝299.1。

Step 2: 5- (4-methoxy-2-methyl-3- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (compound 103-2)

Prepared in a similar manner to that in example 1, step 1 from 1- (3-bromo-6-methoxy-2-methylphenyl) -4-methylpiperazine and 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b]Pyridine preparation the title compound (1.2g, 29%). LC-MS (M + H)⁺＝337.1。

And step 3: 3-bromo-5- (4-methoxy-2-methyl-3- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (compound 103-3)

Prepared in a similar manner to that in example 1, step 2 from 5- (4-methoxy-2-methyl-3- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]Pyridine preparation the title compound (450mg, 30%). LC-MS (M + H)⁺＝415.1。

And 4, step 4: 3-bromo-5- (4-methoxy-2-methyl-3- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester (compound 103-4)

Prepared in a similar manner to that in example 1, step 3 from 3-bromo-5- (4-methoxy-2-methyl-3- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ]Pyridine preparation the title compound (250mg, 45%). LC-MS (M + H)⁺＝515.1。

And 5: 4- (5- (4-methoxy-2-methyl-3- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (Compound 103)

Prepared in a similar manner to that in example 1, step 4 from 3-bromo-5- (4-methoxy-2-methyl-3- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]Pyridine-1-carboxylic acid tert-butyl ester preparation of compound 103(15mg, 16%).¹H NMR(400MHz,DMSO-d6)δ12.06(s,1H),8.19(s,1H),8.15(s,1H),8.02(s,1H),7.80(d,J＝8.0Hz,2H),7.45(d,J＝8.0Hz,2H),7.08(d,J＝8.4Hz,1H),6.92(d,J＝8.4Hz,1H),3.81(s,3H),3.50-3.30(m,2H),2.98(s,6H),2.70-2.68(m,4H),2.22(s,6H),2.15-2.05(m,2H)。LC-MS(M+H)⁺＝484.2。

Example 104: 5- (3- (4- (2-oxa-6-azaspiro [3.3] heptane-6-carbonyl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) -2- (4-methylpiperazin-1-yl) benzonitrile (Compound 104)

Step 1: 5-bromo-2- (4-methylpiperazin-1-yl) benzonitrile (Compound 104-1)

The title compound (0.95g, 68%) was prepared from 2- (4-methylpiperazin-1-yl) benzonitrile in a similar manner to that in example 103, step 1. LC-MS (M + H)⁺＝280.1。

Step 2: 2- (4-Methylpiperazin-1-yl) -5- (1H-pyrrolo [2,3-b ] pyridin-5-yl) benzonitrile (Compound 104-2)

The title compound (250mg, 18%) was prepared from 5-bromo-2- (4-methylpiperazin-1-yl) benzonitrile in a similar manner to that in example 1, step 1. LC-MS (M + H)⁺＝318.1。

And step 3: 5- (3-bromo-1H-pyrrolo [2,3-b ] pyridin-5-yl) -2- (4-methylpiperazin-1-yl) benzonitrile (Compound 104-3)

Prepared in a similar manner to that in example 1, step 2 from 2- (4-methylpiperazin-1-yl) -5- (1H-pyrrolo [2, 3-b)]Pyridin-5-yl) benzonitrile the title compound (160mg, 46%) was prepared. LC-MS (M + H)⁺＝396.1。

And 4, step 4: 3-bromo-5- (3-cyano-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester (compound 104-4)

Prepared in a similar manner to that in step 3 of example 1 from 5- (3-bromo-1H-pyrrolo [2, 3-b)]Pyridin-5-yl) -2- (4-methylpiperazin-1-yl) benzonitrile the title compound (100mg, 50%) was prepared. LC-MS (M + H)⁺＝496.1。

And 5: 5- (3-cyano-4- (4-methylpiperazin-1-yl) phenyl) -3- (4- (methoxycarbonyl) phenyl) -1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester (compound 104-5)

Prepared in a similar manner to that in example 1, step 4 from 3-bromo-5- (3-cyano-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]Pyridine-1-carboxylic acid tert-butyl ester the title compound (60mg, 48%) was prepared. LC-MS (M + H)⁺＝552.1。

Step 6: 4- (5- (3-cyano-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzoic acid (Compound 104-6)

Prepared from 5- (3-cyano-4- (4-methylpiperazin-1-yl) phenyl) -3- (4- (methoxycarbonyl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that in example 36 step 3 ]Pyridine-1-carboxylic acid tert-butyl ester the title compound (30mg, 62.5%) was prepared. LC-MS (M + H)⁺＝438.1。

And 7: 5- (3- (4- (2-oxa-6-azaspiro [3.3] heptane-6-carbonyl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) -2- (4-methylpiperazin-1-yl) benzonitrile (Compound 104)

Prepared from 4- (5- (3-cyano-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that in example 36 step 4]Pyridin-3-yl) benzoic acid preparation of compound 104(15mg, 41.7%).¹H NMR(400MHz,DMSO-d6)δ12.20(s,1H),8.61(d,J＝2.0Hz,1H),8.54(d,J＝1.6Hz,1H),8.26(d,J＝2.0Hz,1H),8.07(dd,J＝2.4,2.0Hz,2H),7.92(d,J＝8.4Hz,2H),7.70(d,J＝8.0Hz,2H),7.34(d,J＝8.8Hz,1H),4.70(s,4H),4.55(s,2H),4.24(s,2H),3.41(app s,4H),3.14(m,4H),2.71(s,3H)。LC-MS(M+H)⁺＝519.2。

Example 105: ethyl 5- (3- (4- (dimethylcarbamoyl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) -2- (4-methylpiperazin-1-yl) benzoate (Compound 105)

Step 1: 5-bromo-2- (4-methylpiperazin-1-yl) benzoic acid (Compound 105-1)

Compound 104-1(700mg, 2.5mmol) in NaOH (5M, 5mL) and EtOH (5mL) was stirred at reflux for 24 h. The mixture was cooled and acidified with HCl to pH 5-6. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (550mg, 73.5%).

Step 2: 5-bromo-2- (4-methylpiperazin-1-yl) benzoic acid ethyl ester (Compound 105-2)

To a solution of 5-bromo-2- (4-methylpiperazin-1-yl) benzoic acid (550mg, 1.84mmol) in EtOH (40mL) was added H ₂SO₄(2 drops). The mixture was stirred at reflux overnight. The mixture was concentrated under reduced pressure, the residue diluted with EA (100mL) and saturated NaHCO₃The solution (50mL), water (30mL), brine (50mL) was washed, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (275mg, 46%).

And step 3: ethyl 2- (4-methylpiperazin-1-yl) -5- (1H-pyrrolo [2,3-b ] pyridin-5-yl) benzoate (Compound 105-3)

The title compound (250mg, 82%) was prepared from ethyl 5-bromo-2- (4-methylpiperazin-1-yl) benzoate in a similar manner to that in example 1, step 1. LC-MS (M + H)⁺＝365.1。

And 4, step 4: ethyl 5- (3-bromo-1H-pyrrolo [2,3-b ] pyridin-5-yl) -2- (4-methylpiperazin-1-yl) benzoate (Compound 105-4)

Prepared in a similar manner to that in example 1, step 2 from 2- (4-methylpiperazin-1-yl) -5- (1H-pyrrolo [2, 3-b)]Pyridin-5-yl) benzoic acid Ethyl ester the title compound (220mg, 72%) was prepared. LC-MS (M + H)⁺＝443.1。

And 5: 3-bromo-5- (3- (ethoxycarbonyl) -4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester (compound 105-5)

Prepared in a similar manner to that in step 3 of example 1 from 5- (3-bromo-1H-pyrrolo [2, 3-b) ]Pyridin-5-yl) -2- (4-methylpiperazin-1-yl) benzoic acid ethyl ester the title compound (120mg, 44%) was prepared. LC-MS (M + H)⁺＝543.1。

Step 6: ethyl 5- (3- (4- (dimethylcarbamoyl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) -2- (4-methylpiperazin-1-yl) benzoate (Compound 105)

Prepared in a similar manner to that in example 1, step 4 from 3-bromo-5- (3- (ethoxycarbonyl) -4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]Pyridine-1-carboxylic acid tert-butyl ester preparation of compound 105(630mg, 51%).¹H NMR(400MHz,CDCl₃)δ8.50(s,1H),8.32(s,1H),8.12(s,1H),7.70-7.67(m,3H),7.63(s,1H),7.54(d,J＝8.0Hz,2H),7.15(d,J＝8.4Hz,1H),4.37(q,J＝7.2Hz,2H),3.69-3.43(m,4H),3.15(s,3H),3.09(s,3H),2.89(s,3H),2.07-1.61(m,4H),1.40(t,J＝7.2Hz,3H)。LC-MS(M+H)⁺＝512.2。

Example 106: n, N-dimethyl-5- [2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] pyridine-2-carboxamide (Compound 106)

Step 1: 5-bromopyridine-2-carbonyl chloride (Compound 106-1)

To a solution of 5-bromopyridine-2-carboxylic acid (1g, 4.70mmol, 1 eq) in dichloromethane (20mL) was added oxalyl dichloride (762mg, 5.70mmol, 1.21 eq) dropwise at room temperature. DMF (0.2mL, 2.56mmol, 0.54 equiv.) was then added and the resulting mixture was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure to give the title compound (1.0g, 88.9%) which was used in the next step without further purification.

Step 2: 5-bromo-N, N-dimethylpyridine-2-carboxamide (Compound 106-2)

To a solution of dimethylamine hydrochloride (345mg, 4.02mol, 0.96 eq) and N, N-diisopropyl-ethylamine (1.3g, 9.52mol, 2.27 eq) in dichloromethane (50mL) was added dropwise a solution of 5-bromopyridine-2-carbonyl chloride (1g, 4.20mol, 1 eq) in dichloromethane. The resulting mixture was stirred at room temperature for 4 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with petroleum ether: ethyl acetate ═ 1: 1) to give the title compound (750mg, 74.1%). LCMS (M + H)⁺＝229.1。

And step 3: n, N-dimethyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine-2-carboxamide (Compound 106-3)

5-bromo-N, N-dimethylpyridine-2-carboxamide (100mg, 0.41mmol, 1 equiv.), 4,4,4 ', 4 ', 5,5,5 ', 5 ' -octamethyl-2, 2 ' -bis (1,3, 2-dioxaborolan) (146mg, 0.55mmol, 1.32 equiv.), KOAc (130mg, 1.26mmol, 3.03 equiv.), Pd (dppf) Cl was added to a 10mL sealed tube at room temperature under a nitrogen atmosphere₂CH₂Cl₂(37mg, 0.04mmol, 0.10 equiv.) and dioxane (3 mL). The resulting mixture was stirred at 100 ℃ under a nitrogen atmosphere for 3 h. After cooling, the mixture was concentrated under reduced pressure to give the title compound (150mg, 69.8%). LCMS (M-18+ H) ⁺＝195.1。

And 4, step 4: 1-methyl-4- (4- [ 5H-pyrrolo [2,3-b ] pyrazin-2-yl ] phenyl) piperazine (compound 106-4)

2-bromo-5H-pyrrolo [2,3-b ] was added to a 30mL sealed tube under a nitrogen atmosphere]Pyrazine (1.5g, 7.20mmol, 1 equiv.), 1-methyl-4- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Piperazine (1.8g, 5.66mmol, 0.79 eq), Cs₂CO₃(4g, 11.66mmol, 1.62 equiv.), Pd (dppf) Cl₂ CH₂Cl₂(600mg, 0.70mmol, 0.10 equiv.), dioxane (20mL) and H₂O (2 mL). Mixing the obtained mixture at 100Stirring was carried out at deg.C under nitrogen atmosphere for 16 h. The mixture was allowed to cool to room temperature and diluted with water (20 mL). The precipitated solid was collected by filtration and washed with water. The crude product was recrystallized from MeOH to give the title compound (900mg, 40.5%). LCMS (M + H)⁺＝294.2。

And 5: 1- (4- [ 7-iodo-5H-pyrrolo [2,3-b ] pyrazin-2-yl ] phenyl) -4-methylpiperazine (compound 106-5)

To a 50mL round bottom flask was added 1-methyl-4- (4- [ 5H-pyrrolo [2,3-b ]]Pyrazin-2-yl radicals]Phenyl) piperazine (900mg, 2.91mmol, 1 eq, 95), KOH (600mg, 10.16mmol, 3.49 eq), and DMF (15 mL). The resulting mixture was stirred at room temperature for 40min, and then cooled to

In that

Addition of I in portions ₂(800mg, 2.99mmol, 1.03 equiv.). The resulting mixture was stirred at room temperature for another 3 h. Saturated Na was added dropwise to the mixture₂S₂O₃Solution, the precipitated solid was collected by filtration and washed with water (3 × 5mL) to give the title compound (1.1g, 85.5%). LCMS (M + H)⁺＝503.2。

Step 6: n, N-dimethyl-5- [2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] pyridine-2-carboxamide (Compound 106)

1- (4- [ 7-iodo-5H-pyrrolo [2,3-b ] was added to a 25mL sealed tube under a nitrogen atmosphere]Pyrazin-2-yl radicals]Phenyl) -4-methylpiperazine (250mg, 0.57mmol, 1.49 equivalents), N-dimethyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine-2-carboxamide (150mg, 0.38mmol, 1 equivalent), K₃PO₄(115mg, 0.51mmol, 1.35 equiv.), Pd AMPHOS (40mg, 0.05mmol, 0.14 equiv.), i-PrOH (10mL) and H₂O (2.5 mL). The reaction mixture is added in

The reaction mixture was irradiated with microwaves for 1 hour under a nitrogen atmosphere. Tong (Chinese character of 'tong')Insoluble solids were filtered off by filtration and rinsed with ethyl acetate (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and further purified by preparative HPLC to give compound 106(48mg, 27.8%).¹H NMR(400MHz,DMSO-d6)δ12.45(s,1H),9.58-9.52(m,1H),8.87(s,1H),8.79-8.74(m,1H),8.60(s,1H),8.13-8.07(m,2H),7.70-7.65(m,1H),7.13-7.08(m,2H),3.29-3.22(m,4H),3.06(d,J＝7.0Hz,6H),2.50-2.46(m,4H),2.25(s,3H)。LCMS(M+H)⁺＝442.2。

Example 107: n, N-dimethyl-5- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) pyrimidine-2-carboxamide (Compound 107)

Compound 107(37mg, 18.1%) was prepared from compound 106-5 in a similar manner to that described in example 106.¹H NMR(400MHz,DMSO-d6,ppm)δ12.63(s,1H),9.77(s,2H),8.92(s,1H),8.72(d,J＝2.4Hz,1H),8.11(d,J＝8.6Hz,2H),7.12(d,J＝8.6Hz,2H),3.38-3.23(m,4H),3.06(s,3H),2.89(s,3H),2.68-2.62(m,4H),2.36(s,3H)。LCMS(M+H)⁺＝443.3。HPLC:254nm,99.0％。

Example 108: 1- [4- [7- (4-Methanesulfonylphenyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl ] phenyl ] -4-methylpiperazine (compound 108)

Prepared from 7-iodo-2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] in a similar manner to that described in example 106 step 6]Pyrazine preparation compound 108(28.6mg, 31.4%).¹H NMR(400MHz,DMSO-d6,ppm)δ12.49(s,1H),8.87(s,1H),8.64-8.57(m,3H),8.10(d,J＝8.8Hz,2H),8.02-7.95(m,2H),7.09(d,J＝8.9Hz,2H),3.29-3.22(m,7H),2.50-2.47(m,4H),2.25(s,3H)。LCMS(M+H)⁺＝448.1。HPLC:254nm,99.2％。

Example 109: n, N-diethyl-4- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) benzamide (compound 109)

Step 1: n, N-diethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide (compound 109-1)

To a 100mL sealed tube was added 4-bromo-N, N-diethylbenzamide (800mg, 2.979mmol, 1 equiv.), 4,4,4 ', 4 ', 5,5,5 ', 5 ' -octamethyl-2, 2 ' -bis (1,3, 2-dioxaborolan) (955.42mg, 3.574mmol, 1.20 equiv.), KOAc (876.97mg, 8.936mmol, 3 equiv.), Pd (dppf) Cl₂CH₂Cl₂(307.25mg, 0.357mmol, 0.12 eq.) and dioxane (40.00 mL). Mixing the mixture in

Stirring was continued for 12h under a nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with ethyl acetate: petroleum ether ═ 15: 85) to give the title compound (650mg, 61.81%). LCMS (M + H) ⁺＝469.3。

Step 2: n, N-diethyl-4- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) benzamide (compound 109)

Prepared from 7-iodo-2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] in a similar manner to that described in example 106 step 6]Pyrazine preparation compound 109(20mg, 7.1%).¹H NMR(400MHz,DMSO-d6)δ12.30(s,1H),8.83(s,1H),8.45(s,1H),8.38(d,J＝8.0Hz,2H),8.08(d,J＝8.6Hz,2H),7.43(d,J＝8.0Hz,2H),7.09(d,J＝8.6Hz,2H),3.35-2.99(m,8H),2.50-2.44(m,4H),2.24(s,3H),1.15(brs,6H)。LCMS(M+H)⁺＝469.3。HPLC:254nm,99.8％。

Example 110: n- (4- [2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] phenyl) methanesulfonamide (compound 110)

Step 1: n- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] methanesulfonamide (compound 110-1)

The title compound (100mg, 82.0%) was prepared from N- (4-bromophenyl) methanesulfonamide in a similar manner to that described in example 109, step 1. LCMS (M + H)⁺＝296.1。

Step 2: n- (4- [2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] phenyl) methanesulfonamide (compound 110)

Prepared from 7-iodo-2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] in a similar manner to that described in example 106 step 6]Pyrazine preparation compound 110(26.3mg, 23.9%).¹H NMR(400MHz,DMSO-d6)δ12.17(d,J＝3.0Hz,1H),9.69(s,1H),8.81(s,1H),8.35-8.24(m,3H),8.13-8.05(m,2H),7.34-7.26(m,2H),7.13-7.07(m,2H),3.29-3.22(m,4H),3.01(s,3H),2.56-2.50(m,4H),2.27(s,3H)。LCMS(M+H)⁺＝463.1。

Example 111: 2- (4- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) oxazole (compound 111)

Step 1: 2- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] -1, 3-oxazole

The title product (1.1g, 91.44%) was prepared from 2- (4-bromophenyl) -1, 3-oxazole in a similar manner to that described in example 109, step 1. LCMS (M + H)⁺＝272.1。

Step 2: 2- (4- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) oxazole (compound 111)

Prepared from 7-iodo-2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] in a similar manner to that described in example 106 step 6]Pyrazine estersPreparation of compound 111(8.4mg, 5.5%).¹H NMR(300MHz,DMSO-d6)δ8.85(s,1H),8.52-8.48(m,3H),8.20(s,1H),8.10-8.00(m,4H),7.40(s,1H),7.10-7.055(m,2H),3.30-3.20(m,4H),2.52-2.47(m,4H),2.20(s,3H)。LCMS(M+H)⁺＝437.2。HPLC:254nm,97.8％。

Example 112: N-cyclopropyl-N-methyl-4- [2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] benzamide (compound 112)

Step 1: 4-bromo-N-cyclopropyl-N-methylbenzamide (Compound 112-1)

In a 50mL round bottom flask, 4-bromobenzoic acid (500mg, 2.36mmol, 1 equivalent), N-diisopropyl-ethylamine (964.4mg, 7.09mmol, 3 equivalents), HATU (1040.3mg, 2.60mmol, 1.1 equivalents), and N-methylcyclopropylamine (194.6mg, 2.60mmol, 1.10 equivalents) were combined at room temperature in DMF (8 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 4 h. The reaction was then quenched with water and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (3 × 30mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with petroleum ether: ethyl acetate ═ 1: 1) to give the title compound (650mg, 95.2%). LCMS (M + H) ⁺＝253.9。

Step 2: N-cyclopropyl-N-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide (compound 112-2)

The title compound (430mg, 96.6%) was prepared from 4-bromo-N-cyclopropyl-N-methylbenzamide in a similar manner to that described in example 109, step 1. LCMS (M + H)⁺＝302.1。

And step 3: N-cyclopropyl-N-methyl-4- [2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] benzamide (compound 112)

Prepared from 7-iodo-2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pir in a similar manner to that described in example 106 step 6Pyrrolo [2,3-b]Pyrazine preparation compound 112(24.6mg, 11.5%).¹HNMR(400MHz,DMSO-d6)δ12.31(d,J＝3.0Hz,1H),8.83(s,1H),8.48(d,J＝2.9Hz,1H),8.42-8.35(m,2H),8.08(d,J＝8.8Hz,2H),7.59(d,J＝8.1Hz,2H),7.10(d,J＝8.9Hz,2H),3.31-3.29(m,4H),3.01-2.98(m,4H),2.58-2.55(m,4H),2.30(s,3H),0.59(d,J＝6.9Hz,2H),0.47(brs,2H)。LCMS(M+H)⁺＝467.2。HPLC:254nm,98.9％。

Example 113: n- [3- (dimethylamino) propyl ] -N-methyl-4- [2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] benzamide (compound 113)

Step 1: 4-bromo-N- [3- (dimethylamino) propyl ] -N-methylbenzamide (Compound 113-1)

The title compound (300mg, 68.9%) was prepared from 4-bromobenzoic acid in a similar manner to that described in example 112, step 1. LCMS (M + H)⁺＝299.0。

Step 2: n- [3- (dimethylamino) propyl ] -N-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide (compound 113-2)

Prepared from 4-bromo-N- [3- (dimethylamino) propyl group in a similar manner to that described in step 1 of example 109]-N-methylbenzamide the title compound (160mg, 37.0%) was prepared. LCMS (M + H)⁺＝347.2。

And step 3: n- [3- (dimethylamino) propyl ] -N-methyl-4- [2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] benzamide (compound 113)

Prepared from 7-iodo-2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] in a similar manner to that described in example 106 step 6]Pyrazine preparation compound 113(5.7mg, 3.2%).¹HNMR(400MHz,DMSO-d6)δ8.83(s,1H),8.46(s,1H),8.38(d,J＝8.2Hz,2H),8.08(d,J＝8.9Hz,2H),7.46(d,J＝7.5Hz,2H),7.09(d,J＝8.8Hz,2H),3.35-3.30(m,2H),3.28-3.23(m,4H),2.98(s,3H),2.51-2.48(m,4H),2.24(s,3H),2.18-1.96(m,8H),1.73-1.68(m,2H)。LCMS(M+H)⁺＝512.3。HPLC:254nm,99.6％。

Example 114: n- (3-methoxypropyl) -N-methyl-4- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) benzamide (compound 114)

Step 1: 4-bromo-N- (3-methoxypropyl) -N-methylbenzamide (Compound 114-1)

The title compound (600mg, 83.9%) was prepared from 4-bromobenzoic acid in a similar manner to that described in example 112, step 1. LCMS (M + H)⁺＝286.2。

Step 2: n- (3-methoxypropyl) -N-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide (compound 114-2)

The title compound (600mg, 83.9%) was prepared from 4-bromo-N- (3-methoxypropyl) -N-methylbenzamide in a similar manner to that described in example 109, step 1. LCMS (M + H) ⁺＝334.2。

And step 3: n- (3-methoxypropyl) -N-methyl-4- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) benzamide (compound 114)

Prepared from 7-iodo-2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] in a similar manner to that described in example 106 step 6]Pyrazine preparation compound 114(7.8mg, 5%).¹H NMR(300MHz,DMSO-d6)δ12.32(d,J＝2.9Hz,1H),8.84(s,1H),8.47(d,J＝2.7Hz,1H),8.38(d,J＝8.1Hz,2H),8.09(d,J＝8.7Hz,2H),7.49-7.40(m,2H),7.10(d,J＝8.7Hz,2H),3.28-3.12(m,4H),2.97(s,3H),2.56-2.50(m,4H),2.51-2.44(m,7H),2.28(s,3H),1.82-1.76(m,2H)。LCMS(M+H)⁺＝499.3。HPLC:254nm,94.3％。

Example 115: n- (2-methoxyethyl) -N-methyl-4- [2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] benzamide (compound 115)

Step 1: 4-bromo-N- (2-methoxyethyl) -N-methylbenzamide (Compound 115-1)

The title compound was prepared from 4-bromobenzoic acid in a similar manner to that described in example 112, step 1. LCMS (M + H)⁺＝272.0。

Step 2: n- (2-methoxyethyl) -N-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide (compound 115-2)

The title compound was prepared from 4-bromo-N- (2-methoxyethyl) -N-methylbenzamide in a similar manner to that described in example 109, step 1. LCMS (M + H)⁺＝485.3。

And step 3: n- (2-methoxyethyl) -N-methyl-4- [2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] benzamide (compound 115)

Prepared from 7-iodo-2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] in a similar manner to that described in example 106 step 6]Pyrazine preparation compound 115(50mg, 17.8%).¹H NMR(300MHz,DMSO-d6)δ12.33(s,1H),8.85(s,1H),8.60-8.29(m,3H),8.10(d,J＝8.3Hz,2H),7.49(d,J＝7.9Hz,2H),7.11(d,J＝8.4Hz,2H),3.75-3.48(m,4H),3.38-3.11(m,7H),3.03(s,3H),2.57-2.49(m,4H),2.26(s,3H)。LCMS(M+H)⁺＝485.3。

Example 116: 7- (2 '-fluoro- [1, 1' -biphenyl ] -4-yl) -2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazine (compound 116)

Step 1: 4 '-bromo-2-fluoro-1, 1' -biphenyl (compound 116-1)

In a 30mL sealed tube, 2- (2-fluorophenyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (500mg, 2.25mmol, 1 eq.), 1-bromo-4-iodobenzene (637.0mg, 2.25mmol, 1.00 eq.), Pd (dppf) Cl₂.CH₂Cl₂(39.0mg, 0.05mmol, 0.12 equiv.), NaHCO₃(378.3mg, 4.50mmol, 2 equiv.) in dioxane (15mL) and H₂The mixture in O (3mL) was in an oil bath

The mixture was stirred for 16h under a nitrogen atmosphere. The mixture was concentrated and the residue was purified by silica gel column chromatography (eluting with ethyl acetate: hexane ═ 1: 99) to give 4 '-bromo-2-fluoro-1, 1' -biphenyl (314mg, 55.5%).

Step 2: 2- (2 '-fluoro- [1, 1' -biphenyl ] -4-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (Compound 116-2)

The title product was prepared from 4 '-bromo-2-fluoro-1, 1' -biphenyl in a similar manner to that described in example 109, step 1 (110mg, 90.1%). LCMS (M + H) ⁺＝299.0。

And step 3: 7- (2 '-fluoro- [1, 1' -biphenyl ] -4-yl) -2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazine (compound 116)

Prepared from 7-iodo-2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] in a similar manner to that described in example 106 step 6]Pyrazine preparation compound 116(6mg, 1.8%).¹H NMR(300MHz,DMSO-d6)δ12.26(s,1H),8.82(s,1H),8.48-8.38(m,3H),8.08(d,J＝8.8Hz,2H),7.68-7.25(m,6H),7.08(d,J＝8.9Hz,2H),3.28-3.19(m,4H),2.47-2.41(m,4H),2.22(s,3H)。LCMS(M+H)⁺＝464.1。

Example 117: 7- (2 '-methyl- [1, 1' -biphenyl ] -4-yl) -2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazine (Compound 117)

Step 1: 4 '-bromo-2-methyl-1, 1' -biphenyl (compound 117-1)

To a 20mL sealed tube were added (2-methylphenyl) boronic acid (100mg, 0.699mmol, 1 equiv.) and 1, 4-dibromobenzene (173.51mg, 0.699 m) in toluene (4mL) and MeOH (1mL)mol, 1.00 equivalent), K₂CO₃(203.30mg, 1.397mmol, 2 equiv.), Pd (PPh)₃)₄(101.99mg, 0.084mmol, 0.12 equiv.). The resulting mixture was stirred at 100 ℃ overnight. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with dichloromethane: petroleum ether ═ 1: 3) to give the title compound (110mg, 63.1%).

Step 2: 4,4,5, 5-tetramethyl-2- (2 '-methyl- [1, 1' -biphenyl ] -4-yl) -1,3, 2-dioxaborolan (compound 117-2)

The title product was prepared from 4 '-bromo-2-methyl-1, 1' -biphenyl in a similar manner to that described in example 109, step 1 (200mg, 40.0%).

And step 3: 7- (2 '-methyl- [1, 1' -biphenyl ] -4-yl) -2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazine (Compound 117)

Prepared from 7-iodo-2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] in a similar manner to that described in example 106 step 6]Pyrazine preparation of compound 117(20.6mg, 15.6%).¹H NMR(400MHz,DMSO-d6)δ12.26(d,J＝2.9Hz,1H),8.84(s,1H),8.44(d,J＝2.7Hz,1H),8.42-8.35(m,2H),8.13-8.05(m,2H),7.47-7.40(m,2H),7.36-7.24(m,4H),7.14-7.07(m,2H),3.29-3.22(m,4H),2.51-2.45(m,4H),2.32(s,3H),2.25(s,3H)。LCMS(M+H)⁺＝460.3。

Example 118: 7- (2 '-methoxy- [1, 1' -biphenyl ] -4-yl) -2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazine (compound 118)

Step 1: 4 '-bromo-2-methoxy-1, 1' -biphenyl (compound 118-1)

The title product was prepared from (2-methoxyphenyl) boronic acid and 1, 4-dibromobenzene (10mg, 1.1%) in a similar manner to that described in example 117, step 1.

Step 2: 2- (2 '-methoxy- [1, 1' -biphenyl ] -4-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (compound 118-2)

The title product was prepared from 4 '-bromo-2-methoxy-1, 1' -biphenyl in a similar manner to that described in example 109, step 1 (500mg, 69.7%).

And step 3: 7- (2 '-methoxy- [1, 1' -biphenyl ] -4-yl) -2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazine (compound 118)

Prepared from 7-iodo-2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] in a similar manner to that described in example 106 step 6]Pyrazine and 2- (2 '-methoxy- [1, 1' -biphenyl)]-4-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan compound 118(27.9mg) was prepared.¹H NMR(400MHz,DMSO-d6)δ12.26(s,1H),8.84(s,1H),8.43(s,1H),8.37(d,J＝7.9Hz,2H),8.10(d,J＝8.4Hz,2H),7.58(d,J＝8.0Hz,2H),7.41-7.31(m,2H),7.17-7.08(m,2H),7.11-7.02(m,2H),3.81(s,3H),3.41-3.18(m,4H),2.49-2.47(m,4H),2.24(s,3H)。LCMS(M+H)⁺＝476.2。HPLC:254nm,96.5％。

Example 119: n, N-dimethyl-4- [2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] benzene-1-sulfonamide (compound 119)

Step 1: n, N-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzene-1-sulfonamide (Compound 119-1)

The title compound (600mg, 40.2%) was prepared from 4-bromo-N, N-dimethylbenzene-1-sulfonamide in a similar manner to that described in example 109, step 1. LCMS (M + H)⁺＝312.1。

Step 2: n, N-dimethyl-4- [2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] benzene-1-sulfonamide (compound 119)

Prepared from 7-iodo-2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] in a similar manner to that described in example 106 step 6]Pyrazine preparation compound 119(54mg, 12.8%).¹H NMR(400MHz,DMSO-d6)δ12.21(s,1H),8.87(s,1H),8.66-8.57(m,3H),8.15-8.07(m,2H),7.85-7.79(m,2H),7.13-7.05(m,2H),3.32-3.21(m,4H),2.67(s,6H),2.51-2.45(m,4H),2.25(s,3H)。LCMS(M+H)⁺＝477.1。

Example 120: n, N-dimethyl-2- (4- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenoxy) ethan-1-amine (compound 120)

Step 1: dimethyl ([2- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy ] ethyl ]) amine (compound 120-1)

In that

To a solution of 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol (500mg, 2.16mmol, 1 eq) in DMF (10mL) was added NaH (272mg, 6.80mmol, 3.15 eq, 60% in oil). Mixing the mixture in

Stirring for 30 min. In that

To the mixture was added (2-chloroethyl) dimethylamine hydrochloride (360mg, 2.37mmol, 1.10 equiv.). The reaction mixture was stirred at room temperature for 2h and then heated to

And stirred for another 2 h. The reaction mixture was slowly quenched with water (20mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (on CH)₂Cl₂MeOH eluted in 15min, gradient from 0% to 15%) to give the title compound (480mg, 74.8%). LCMS (M + H)⁺＝291.6。

Step 2: n, N-dimethyl-2- (4- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenoxy) ethan-1-amine

Prepared from 7-iodo-2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] in a similar manner to that described in example 106 step 6 ]Pyrazine preparation of compound 120(20.4mg, 17.9%).¹H NMR(400MHz,DMSO-d6)δ12.13(d,J＝2.9Hz,1H),8.80(s,1H),8.31-8.20(m,3H),8.16-8.02(m,2H),7.14-7.04(m,4H),4.33-4.24(m,2H),3.34-3.26(m,4H),2.87-2.61(m,10H),2.50-2.34(m,5H)。LCMS(M+H)⁺＝457.3。

Example 121: 2- (4- [2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] phenoxy) ethan-1-amine (compound 121)

Step 1: n- [2- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy ] ethyl ] carbamic acid tert-butyl ester (Compound 121-1)

The title compound (130mg, 25.3%) was prepared from tert-butyl N- (2-chloroethyl) carbamate in a similar manner to that described in example 120, step 1. LCMS (M + H)⁺＝364.1。

Step 2: n- [2- (4- [2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] phenoxy) ethyl ] carbamic acid tert-butyl ester (compound 121-2)

Prepared from 7-iodo-2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] in a similar manner to that described in example 106 step 6]Pyrazine the title compound was prepared (80mg, 42.2%). LCMS (M + H)⁺＝529.4。

And step 3: 2- (4- [2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] phenoxy) ethan-1-amine (compound 121)

To N- [2- (4- [2- [4- (4-methylpiperazin-1-yl) phenyl ] at room temperature]-5H-pyrrolo [2,3-b]Pyrazin-7-yl]Phenoxy) ethyl]To a solution of tert-butyl carbamate (80mg, 0.15mmol, 1 eq) in MeOH (6mL) was added dropwise a HCl solution (4M, 2mL, 65.82mmol, 434.98 equiv.). The resulting mixture was stirred at room temperature for 4 h. The mixture was concentrated under reduced pressure and the remaining solution was taken up in saturated NaHCO₃The solution was adjusted to pH 8. The resulting mixture was extracted with dichloromethane (3 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC to give compound 121(10.5mg, 15.4%).¹H NMR(400MHz,DMSO-d6)δ8.79(s,1H),8.27-8.18(m,3H),8.06(d,J＝8.9Hz,2H),7.12-7.06(m,2H),7.06-7.00(m,2H),4.06-3.93(m,2H),3.29-3.21(m,4H),2.90(t,J＝5.8Hz,2H),2.50-2.45(m,4H),2.24(s,3H)。LCMS(M+H)⁺＝429.2。HPLC:254nm,95.3％。

Example 122: 2- (dimethylamino) -N- (4- [2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] phenyl) acetamide (Compound 122)

Step 1: 4- [2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] aniline (compound 122-1)

The title compound (50mg, 13.2%) was prepared from 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline in a similar manner to that described in example 106, step 6. LCMS (M + H)⁺＝385.2。

Step 2: 2- (dimethylamino) -N- (4- [2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] phenyl) acetamide (Compound 122)

To a 20mL round bottom flask was added 4- [2- [4- (4-methylpiperazin-1-yl) phenyl ] phenyl]-5H-pyrrolo [2,3-b]Pyrazin-7-yl]Aniline (130mg, 0.14mmol, 1 eq), 2- (dimethylamino) acetic acid (17.7mg, 0.16mmol, 1.20 eq), N-diisopropyl-ethylamine (27.8mg, 0.20mmol, 1.5 eq), HATU (65.4mg, 0.16mmol, 1.2 eq) and DMF (8 mL). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and further purified by preparative HPLC to give Compound 122(32.4mg, 50.3%).¹H NMR(300MHz,DMSO-d6)δ12.16(s,1H),9.73(s,1H),8.81(s,1H),8.32(s,1H),8.30-8.20(m,2H),8.13-8.04(m,2H),7.80-7.71(m,2H),7.16-7.06(m,2H),3.31-3.21(m,4H),3.10(s,2H),2.51-2.44(m,4H),2.31(s,6H),2.24(s,3H)。LCMS(M+H)⁺＝470.2。

Example 123: 2- (dimethylamino) -N-methyl-N- (4- [2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] phenyl) acetamide (compound 123)

Step 1: n- (4-bromophenyl) -2- (dimethylamino) -N-methylacetamide (Compound 123-1)

The title compound (500mg, 61.2%) was prepared from 2- (dimethylamino) acetic acid and 4-bromo-N-methylaniline in a similar manner to that described in example 112, step 1. LCMS (M + H)⁺＝273.2。

Step 2: 2- (dimethylamino) -N-methyl-N- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] acetamide (Compound 123-2)

The title compound (250mg, 42.3%) was prepared from N- (4-bromophenyl) -2- (dimethylamino) -N-methylacetamide in a similar manner to that described in example 109, step 1.

And step 3: 2- (dimethylamino) -N-methyl-N- (4- [2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] phenyl) acetamide (compound 123)

Prepared from 1- (4- [ 7-iodo-5H-pyrrolo [2,3-b ] in a similar manner to that described in step 6 of example 106]Pyrazin-2-yl radicals]Phenyl) -4-methylpiperazine prepared compound 123(26.4mg, 22.6%).¹H NMR(300MHz,DMSO-d6)δ12.30(s,1H),8.84(s,1H),8.48-8.34(m,3H),8.08(d,J＝8.6Hz,2H),7.40(d,J＝8.1Hz,2H),7.09(d,J＝8.7Hz,2H),3.30-3.16(m,7H),2.93(s,2H),2.49-2.43(m,4H),2.24(s,3H),2.15-2.05(m,6H)。LCMS(M+H)⁺＝484.2。

Example 124: 3-methyl-1- (4- [2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] phenyl) urea (compound 124)

Step 1: 3-methyl-1- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] urea (compound 124-1)

In a 25mL round bottom flask, a mixture of 2- (4-isocyanatophenyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (200mg, 0.78mmol, 1 eq), methylamine (25.3mg, 0.77mmol, 1.00 eq) in THF (8mL) was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to give the title compound (200mg, 54.8%), which was used in the next step without further purification. LCMS (M + H)⁺＝277.4。

Step 2: 3-methyl-1- (4- [2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] phenyl) urea (compound 124)

Prepared from 7-iodo-2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] in a similar manner to that described in example 106 step 6]Pyrazine preparation compound 124(14.1mg, 14.5%).¹H NMR(400MHz,DMSO-d6)δ12.08(d,J＝2.8Hz,1H),8.79(s,1H),8.49(s,1H),8.24(d,J＝2.8Hz,1H),8.19-8.11(m,2H),8.07(d,J＝8.8Hz,2H),7.50-7.43(m,2H),7.10(d,J＝8.9Hz,2H),6.02(d,J＝4.7Hz,1H),3.26-3.23(m,4H),2.66(d,J＝4.6Hz,3H),2.49-2.46(m,4H),2.24(s,3H)。LCMS(M+H)⁺＝442.2。

Example 125: 3, 3-dimethyl-1- (4- [2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] phenyl) urea (compound 125)

Step 1: 3, 3-dimethyl-1- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] urea (Compound 125-1)

In a similar manner to that described in step 1 of example 124 The title compound (200mg, 88.9%) was prepared from 2- (4-isocyanatophenyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan. LCMS (M + H)⁺＝291.4。

Step 2: 3, 3-dimethyl-1- (4- [2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] phenyl) urea (compound 125)

Prepared from 7-iodo-2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] in a similar manner to that described in example 106 step 6]Pyrazine preparation compound 125(14.2mg, 8.7%).¹H NMR(400MHz,DMSO-d6)δ12.09(d,J＝2.9Hz,1H),8.79(s,1H),8.31-8.23(m,2H),8.16(d,J＝8.7Hz,2H),8.07(d,J＝8.8Hz,2H),7.54(d,J＝8.8Hz,2H),7.10(d,J＝8.8Hz,2H),3.25(s,4H),2.95(s,6H),2.52-2.50(m,4H),2.24(s,3H)。LCMS(M+H)⁺＝456.3。

Example 126: 1- (2- (dimethylamino) ethyl) -3- (4- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) urea (compound 126)

Step 1: 3- [2- (dimethylamino) ethyl ] -1- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] urea (compound 126-1)

The title compound (200mg, crude) was prepared from 2- (4-isocyanatophenyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan in a similar manner to that described in example 124, step 1 and was used in the next step without further purification. LCMS (M + H)⁺＝334.2。

Step 2: 1- (2- (dimethylamino) ethyl) -3- (4- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) urea (compound 126)

Prepared from 7-iodo-2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] in a similar manner to that described in example 106 step 6]Pyrazine preparation compound 126(14.1mg, 14.5%).¹H NMR(400MHz,DMSO-d6)δ12.08(s,1H),8.80(s,1H),8.67(s,1H),8.25(d,J＝2.7Hz,1H),8.17(d,J＝8.6Hz,2H),8.08(d,J＝8.8Hz,2H),7.47(d,J＝8.7Hz,2H),7.10(d,J＝8.8Hz,2H),6.11(s,1H),3.30-3.17(m,6H),2.50-2.45(m,4H),2.43-2.33(m,2H),2.28-2.19(m,9H)。LCMS(M+H)⁺＝499.2。

Example 127: 1, 3-dimethyl-1- (4- [2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] phenyl) urea (compound 127)

Step 1: 1- (4-bromophenyl) -1, 3-dimethylurea (compound 127-1)

To a solution of 4-bromo-N-methylaniline (500mg, 2.55mmol, 1 eq) in dichloromethane (20mL) was added triphosgene (321mg, 1.03mmol, 0.40 eq) in portions at 0 ℃. The resulting mixture was stirred at 0 ℃ for 3 h. Methylamine (90mg, 2.75mmol, 1.08 equivalents) was added to the mixture. The resulting mixture was stirred at room temperature for an additional 15 h. The reaction mixture was slowly quenched with water (10mL) and extracted with dichloromethane (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with petroleum ether/ethyl acetate 40: 60) to give the title compound (550mg, 84.1%). LCMS (M + H)⁺＝292.9。

Step 2: 1, 3-dimethyl-1- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] urea (Compound 127-2)

The title compound (200mg, 79.3%) was prepared from 1- (4-bromophenyl) -1, 3-dimethylurea in a similar manner to that described in example 109, step 1. LCMS (M + H)⁺＝291.1。

And step 3: 1, 3-dimethyl-1- (4- [2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] phenyl) urea (compound 127)

Prepared from 7-iodo-2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] in a similar manner to that described in example 106 step 6]Pyrazine preparation compound 127(38.1mg, 22.3%).¹H NMR(300MHz,DMSO-d6)δ8.83(s,1H),8.39(s,1H),8.36-8.30(m,2H),8.09(d,J＝8.7Hz,2H),7.37-7.31(m,2H),7.10(d,J＝8.7Hz,2H),5.92(d,J＝4.6Hz,1H),3.34(s,4H),3.20(s,3H),2.59(d,J＝4.4Hz,3H),2.50-2.45(m,4H),2.25(s,3H)。LCMS(M+H)⁺＝456.4。HPLC:254nm,97.7％。

Example 128: n, N-dimethyl-2- (4- [2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] phenoxy) acetamide (compound 128)

Step 1: n, N-dimethyl-2- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy ] acetamide (Compound 128-1)

The title compound (800mg, 47.9%) was prepared from 2-chloro-N, N-dimethylacetamide in a similar manner to the method described in example 120, step 1. LCMS (M + H)⁺＝306.0。

Step 2: n, N-dimethyl-2- (4- [2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] phenoxy) acetamide (compound 128)

Prepared from 7-iodo-2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] in a similar manner to that described in example 106 step 6 ]Pyrazine preparation compound 128(50mg, 33.7%).¹H NMR(400MHz,DMSO-d6)δ12.09(s,1H),8.79(s,1H),8.26(s,1H),8.24-8.17(m,2H),8.10-8.03(m,2H),7.12-7.06(m,2H),7.06-6.98(m,2H),4.84(s,2H),3.29-3.14(m,4H),3.04(s,3H),2.87(s,3H),2.50-2.44(m,4H),2.24(s,3H)。LCMS(M+H)⁺＝471.1。

Example 129: n, N-dimethyl-3- (4- [2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] phenoxy) propionamide (compound 129)

Step 1: 3- (4-bromophenoxy) propionic acid (compound 129-1)

To 3-phenoxypropionic acid (500mg, 2.86mmol, 1 equiv.) and NaOH (240.7mg, 5.72mmol, 2.00 equiv.) in H₂NBS (535.5mg, 2.86mmol, 1.00 equiv.) was added portionwise to the mixture in O (4.7 mL). The mixture was stirred at room temperature overnight. The mixture was acidified with HCl (1M) to pH 2. The resulting mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give the title compound (500mg, 44.7%). LCMS (M + H)⁺＝244.0。

Step 2: 3- (4-bromophenoxy) -N, N-dimethylpropionamide (Compound 129-2)

To a solution of 3- (4-bromophenoxy) propionic acid (500mg, 1.28mmol, 1 equiv.), dimethylamine (69.2mg, 1.46mmol, 1.14 equiv.), and N, N-diisopropyl-ethylamine (522.1mg, 3.84mmol, 3 equiv.) in DMF (20.0mL) was added HATU (614.4mg, 1.54mmol, 1.2 equiv.). The mixture was stirred at room temperature for 3 h. Subjecting the mixture to hydrogenation with H₂Diluted O (200mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column on silica gel (eluting with dichloromethane: methanol ═ 20: 80) to give the title compound (300mg, 75.4%). LCMS (M + H) ⁺＝274.1。

And step 3: n, N-dimethyl-3- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy ] acrylamide (Compound 129-3)

The title compound (590mg, 98.5%) was prepared from 3- (4-bromophenoxy) -N, N-dimethylpropionamide in a similar manner to that described in example 109, step 1. LCMS (M + H)⁺＝320.2。

And 4, step 4: n, N-dimethyl-3- (4- [2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] phenoxy) propionamide (compound 129)

Prepared from 7-iodo-2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] in a similar manner to that described in example 106 step 6]Pyrazine preparation compound 129(30mg, 11.5%).¹H NMR(400MHz,DMSO-d6)δ12.09(s,1H),8.80(s,1H),8.29-8.20(m,3H),8.07(d,J＝8.4Hz,2H),7.09(d,J＝8.5Hz,2H),7.03(d,J＝8.3Hz,2H),4.25(t,J＝6.4Hz,2H),3.32-3.21(m,4H),3.02(s,3H),2.89-2.78(m,5H),2.51-2.45(m,4H),2.24(s,3H)。LCMS(M+H)⁺＝485.3。

Example 130: dimethyl ([2- [ (5- [2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] pyridin-2-yl) oxy ] ethyl ]) amine (compound 130)

Step 1: [2- [ (5-Bromopyridin-2-yl) oxy ] ethyl ] dimethylamine (Compound 130-1)

To a solution of 2- (dimethylamino) ethan-1-ol (400mg, 4.26mmol, 1.58 equiv) in DMF (20mL) at 0 deg.C was added sodium hydride (60% in oil, 400mg, 16.3mmol, 6 equiv) in portions. The mixture was stirred for 15 min. To the mixture was added 5-bromo-2-fluoropyridine (500mg, 2.70mmol, 1 eq). The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 15 h. The reaction mixture was quenched with water (20mL) and extracted with dichloromethane (3 × 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (500mg, crude). The crude product was used directly in the next step without further purification. LCMS (M + H) ⁺＝245.0。

Step 2: dimethyl (2- [ [5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl ] oxy ] ethyl) amine (compound 130-2)

Prepared from [2- [ (5-bromopyridin-2-yl) oxy ] in a similar manner to that described in step 1 of example 109]Ethyl radical]Dimethylamine the title compound (500mg, crude) was prepared. LCMS (M + H)⁺＝293.1。

And step 3: dimethyl ([2- [ (5- [2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] pyridin-2-yl) oxy ] ethyl ]) amine (compound 130)

Prepared from 7-iodo-2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] in a similar manner to that described in example 106 step 6]Pyrazine preparation Compound 130(21.2 mg)，20.8％)。¹H NMR(300MHz,DMSO-d6)δ12.22(s,1H),9.16(d,J＝2.4Hz,1H),8.83(s,1H),8.55-8.48(m,1H),8.37(s,1H),8.07(d,J＝8.8Hz,2H),7.10(d,J＝8.8Hz,2H),6.92(d,J＝8.4Hz,1H),4.43-4.36(m,2H),3.30-3.21(m,4H),2.70-2.61(m,2H),2.50-2.43(m,4H),2.24-2.20(m,9H)。LCMS(M+H)⁺＝458.2。

Example 131: 1- (2-aminoethyl) -5- [2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1, 2-dihydropyridin-2-one (compound 131)

Step 1: n- [2- [ 2-oxo-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-dihydropyridin-1-yl ] ethyl ] carbamic acid tert-butyl ester (Compound 131-1)

To a solution of 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-ol (200mg, 0.89mmol, 1 eq) and tert-butyl N- (2-chloroethyl) carbamate (162.5mg, 0.89mmol, 1 eq) in DMF (8mL) was added K ₂CO₃(612.7mg, 2.66mmol, 3 equiv.). The resulting mixture was stirred at 120 ℃ for 2 h. The mixture was filtered and concentrated under reduced pressure to give the title compound (400mg, 49.0%). LCMS (M + H)⁺＝365.1

Step 2: n- [2- (5- [2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -2-oxo-1, 2-dihydropyridin-1-yl) ethyl ] carbamic acid tert-butyl ester (compound 131-2)

Prepared in a similar manner to that described in step 6 of example 106 from N- [2- [ 2-oxo-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-dihydropyridin-1-yl]Ethyl radical]Tert-butyl carbamate the title compound (230mg, 95.6%) was prepared. LCMS (M + H)⁺＝530.5。

And step 3: 1- (2-aminoethyl) -5- [2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -1, 2-dihydropyridin-2-one (compound 131)

To N- [2- (5- [2- [4- (4-methylpiperazin-1-yl) phenyl)]-5H-pyrrolo [2,3-b]Pyrazin-7-yl]-2-oxo-1, 2-dihydropyridin-1-yl) ethyl]To a solution of tert-butyl carbamate (200mg, 0.15mmol, 1 equiv.) in dioxane (5mL) was added HCl solution (1M, 0.6mL, 0.6mmol, 4 equiv.). The resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC to give compound 131(9mg, 13.7%). ¹H NMR(400MHz,DMSO-d6)δ8.74(s,1H),8.63(s,1H),8.16-7.98(m,4H),7.05(d,J＝8.9Hz,2H),6.49(d,J＝9.4Hz,1H),4.04-3.93(m,2H),3.30-3.13(m,4H),3.02-2.92(m,4H),2.55-2.47(m,2H),2.25(s,3H)。LCMS(M+H)⁺＝430.1。

Example 132: n, N-dimethyl-2- (5- [2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -2-oxo-1, 2-dihydropyridin-1-yl) acetamide (compound 132)

Step 1: n, N-dimethyl-2- [ 2-oxo-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-dihydropyridin-1-yl ] acetamide (Compound 132-1)

The title compound (400mg, 81.9%) was prepared from 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-ol and 2-chloro-N, N-dimethylacetamide in a similar manner to the one described in example 131, step 1. LCMS (M + H)⁺＝307.1。

Step 2: n, N-dimethyl-2- (5- [2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -2-oxo-1, 2-dihydropyridin-1-yl) acetamide (compound 132)

Prepared from 7-iodo-2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] in a similar manner to that described in example 106 step 6]Pyrazine preparation compound 132(16mg, 12.1%).¹H NMR(400MHz,DMSO-d6)δ12.07(s,1H),8.79(s,1H),8.55-8.48(m,1H),8.26-8.17(m,1H),8.15(s,1H),8.04(d,J＝8.7Hz,2H),7.03(d,J＝8.7Hz,2H),6.52(d,J＝9.4Hz,1H),4.89(s,2H),3.25-3.17(m,4H),3.10(s,3H),2.87(s,3H),2.48-2.41(m,4H),2.22(s,3H)。LCMS(M+H)⁺＝472.1。

Example 133: n, N-dimethyl-3- (5- [2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -2-oxo-1, 2-dihydropyridin-1-yl) propanamide (compound 133)

Step 1: n, N-dimethyl-3- [ 2-oxo-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-dihydropyridin-1-yl ] acrylamide (Compound 133-1)

To a solution of 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-ol (400mg, 1.72mmol, 1 eq) in DMF (25mL) at 0 deg.C was added sodium hydride (60% in oil, 82.5mg, 2.02mmol, 1.17 eq). The mixture was stirred for 15 min. 3-chloro-N, N-dimethylpropionamide (245.3mg, 1.72mmol, 1.00 eq.) was added to the mixture. The resulting mixture was allowed to heat to 80 ℃ and stirred for 16 h. The reaction mixture was quenched with water and extracted with dichloromethane (3 × 25 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with dichloromethane: MeOH ═ 5: 1) to give the title compound (200mg, 25.5%). LCMS (M + H)⁺＝321.1。

Step 2: n, N-dimethyl-3- (5- [2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -2-oxo-1, 2-dihydropyridin-1-yl) propanamide (compound 133)

Prepared from 7-iodo-2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] in a similar manner to that described in example 106 step 6]Pyrazine preparation compound 133(23.4mg, 15.9%).¹H NMR(300MHz,DMSO-d6)δ8.80(d,J＝3.4Hz,2H),8.26-8.16(m,2H),8.12(d,J＝8.6Hz,2H),7.03(d,J＝8.6Hz,2H),6.55(d,J＝9.4Hz,1H),4.21(t,J＝6.8Hz,2H),3.25-3.16(m,4H),2.95-2.76(m,8H),2.48-2.39(m,4H),2.21(s,3H)。LCMS(M+H)⁺＝486.4。HPLC:254nm,99.4％。

Example 134: n, N-dimethyl-2- ((5- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) pyridin-2-yl) oxy) acetamide (Compound 134)

Step 1: methyl 2- ((5-bromopyridin-2-yl) oxy) acetate (Compound 134-1)

The title compound (6g, 66.2%) was prepared from methyl 2-glycolate and 5-bromo-2-fluoropyridine in a similar manner to that described in example 130, step 1.

Step 2: 2- ((5-Bromopyridin-2-yl) oxy) acetic acid (Compound 134-2)

To a solution of methyl 2- ((5-bromopyridin-2-yl) oxy) acetate (6g, 18.53mmol) in THF (100mL) was added NaOH (0.9g, 22.23mmol) in H₂Solution in O (50 mL). The resulting mixture was stirred at room temperature for 3 h. The mixture was washed with ethyl acetate (2 × 50 mL). The inorganic layer was neutralized with HCl (1M) and extracted with ethyl acetate (3 × 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (4g, 87.8%). LCMS (M + H)⁺＝231.9。

And step 3: 2- ((5-Bromopyridin-2-yl) oxy) -N, N-dimethylacetamide (Compound 134-3)

To a solution of 2- ((5-bromopyridin-2-yl) oxy) acetic acid (3.9g, 15.80mmol), dimethylamine (1.6g, 34.76mmol) and N, N-diisopropyl-ethylamine (5.3mL, 40.41mmol) in dichloromethane (100mL) at 0 deg.C was added HATU (9.2g, 23.71 mmol). The mixture was stirred at room temperature for 30 min. The reaction was then quenched with water (200mL) and extracted with dichloromethane (3 × 150 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column on silica gel (elution with ethyl acetate: petroleum ether ═ 4: 1) to give the title compound (3.73g, 86.6%). LCMS (M + H) ⁺＝259.0。

And 4, step 4: n, N-dimethyl-2- ((5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) oxy) acetamide (Compound 134-4)

In the same manner as in example 109 step 1 from 2- [ (5-bromopyridin-2-yl) oxy]-N, N-Dimethylacetamide the title compound (1g, crude) was prepared. LCMS (M + H)⁺＝307.1。

And 5: n, N-dimethyl-2- ((5- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) pyridin-2-yl) oxy) acetamide (Compound 134)

Prepared from 7-iodo-2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] in a similar manner to that described in example 106 step 6]Pyrazine preparation compound 134(21.3mg, 5.9%).¹H NMR(400MHz,DMSO-d6)δ12.24(s,1H),9.09(d,J＝2.4Hz,1H),8.83(s,1H),8.58-8.49(m,1H),8.37(s,1H),8.06(d,J＝8.4Hz,2H),7.17-6.88(m,3H),5.09(s,2H),3.28-3.19(m,4H),3.03(s,3H),2.85(s,3H),2.51-2.42(m,4H),2.23(s,3H)。LCMS(M+H)⁺＝472.2。

Example 135: 2- ((5- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) pyridin-2-yl) oxy) ethylamine (compound 135)

Step 1: (2- ((5-Bromopyridin-2-yl) oxy) ethyl) carbamic acid tert-butyl ester (Compound 135-1)

The title compound (7.84g, 71.7%) was prepared from 5-bromo-2-fluoropyridine in a similar manner to that described in example 130, step 1. LCMS (M + H)⁺＝317.1。

Step 2: (tert-butyl 2- ((5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) oxy) ethyl) carbamate (Compound 135-2)

The title compound (1g, crude) was prepared from tert-butyl (2- ((5-bromopyridin-2-yl) oxy) ethyl) carbamate in a similar manner to that described in example 109, step 1. LCMS (M + H)⁺＝365.2。

And step 3: (tert-butyl 2- ((5- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) pyridin-2-yl) oxy) ethyl) carbamate (Compound 135-3)

Prepared from 7-iodo-2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] in a similar manner to that described in example 106 step 6]Pyrazine prepared the title compound (300mg, 58.2%). LCMS (M + H)⁺＝530.1。

And 4, step 4: 2- ((5- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) pyridin-2-yl) oxy) ethylamine (compound 135)

Prepared from (2- ((5- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2, 3-b) in a similar manner to that described in example 131, step 3]Pyrazin-7-yl) pyridin-2-yl) oxy) ethyl) carbamic acid tert-butyl ester compound 135(100mg, 84.1%) was prepared.¹H NMR(400MHz,DMSO-d6)δ9.17(d,J＝2.4Hz,1H),8.82(s,1H),8.56-8.46(m,1H),8.37(s,1H),8.06(d,J＝8.4Hz,2H),7.07(d,J＝8.5Hz,2H),6.93(d,J＝8.7Hz,1H),4.31-4.21(m,2H),3.27-3.18(m,4H),2.99-2.87(m,2H),2.50-2.41(m,4H),2.22(s,3H)。LCMS(M+H)⁺＝430.1。HPLC:254nm,98.1％。

Example 136: 1-methyl-4- [4- [7- (1-methylpiperidin-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl ] phenyl ] piperazine (compound 136)

Step 1: 1-methyl-4- [4- [7- (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl ] phenyl ] piperazine (compound 136-1)

Prepared from 7-iodo-2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] in a similar manner to that described in example 106 step 6]Pyrazine the title compound was prepared (200mg, 53.1%). LCMS (M + H)⁺＝389.2。

Step 2: 1-methyl-4- [4- [7- (1-methylpiperidin-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl ] phenyl ] piperazine (compound 136)

To 1-methyl-4- [4- [7- (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) -5H-pyrrolo [2,3-b ]]Pyrazin-2-yl radicals]Phenyl radical]To a solution of piperazine (100mg, 0.23mmol, 1 eq) in MeOH (10.0mL) was added Pd/C (77.2mg,0.69mmol, 3.00 equiv). Mixing the obtained mixture in

The mixture was stirred overnight under a hydrogen atmosphere (5 atm). The mixture was filtered and concentrated. The residue was purified by preparative HPLC to give compound 136(80mg, 83.9%).¹H NMR(400MHz,DMSO-d6)δ11.65(s,1H),8.70(s,1H),8.01-7.93(m,2H),7.57(s,1H),7.10-7.03(m,2H),3.26-3.19(m,4H),2.95-2.85(m,3H),2.51-2.44(m,4H),2.26-2.19(m,6H),2.09-1.99(m,4H),1.94-1.80(m,2H)。LCMS(M+H)⁺＝391.2。

Example 137: 1- (4- [7- [4- (cyclopropanesulfonyl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-2-yl ] phenyl) -4-methylpiperazine (compound 137)

Step 1: 1-bromo-4- (cyclopropylsulfanyl) benzene (compound 137-1)

(Cyclopropylsulfanyl) benzene (1.5g, 9.98mmol, 1 eq, 100%) in CHCl at 25 deg.C₃(50mL) to a stirred solution of Br added dropwise₂(1.6g, 10.01mmol, 1.00 equiv.). The resulting mixture was stirred at 25 ℃ for 3 h. The reaction was performed with 30% NaHCO at 0 deg.C ₃The solution was quenched and extracted with dichloromethane (3 × 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with ethyl acetate: petroleum ether ═ 10: 90) to give the title compound (800mg, 33.2%).

Step 2: 1-bromo-4- (cyclopropanesulfonyl) benzene (compound 137-2)

A mixture of 1-bromo-4- (cyclopropylsulfanyl) benzene (600mg, 2.49mmol, 1 eq.) and m-CPBA (1807.4mg, 9.95mmol, 4 eq.) in dichloromethane (100mL) was stirred at 25 ℃ overnight. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with ethyl acetate: petroleum ether ═ 8: 92) to give the title compound (650mg, 95.0%).

And step 3: 2- [4- (Cyclopropanesulfonyl) phenyl ] -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (compound 137-3)

The title compound (300mg, 35.3%) was prepared from 1-bromo-4- (cyclopropanesulfonyl) benzene in a similar manner to that described in example 109, step 1. LCMS (M + H)⁺＝308.9。

And 4, step 4: 1- (4- [7- [4- (cyclopropanesulfonyl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-2-yl ] phenyl) -4-methylpiperazine (compound 137)

Prepared from 7-iodo-2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] in a similar manner to that described in example 106 step 6 ]Pyrazine preparation compound 137(15mg, 5.0%).¹H NMR(400MHz,DMSO-d6)δ12.50(s,1H),8.87(s,1H),8.61(s,3H),8.29-7.75(m,4H),7.09(s,2H),3.43-3.13(m,4H),2.90-2.85(m,1H),2.50-2.37(m,4H),2.24(s,3H),1.29-0.92(m,4H)。LCMS(M+H)⁺＝474.0。

Example 138: 4- (2- (3-chloro-4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -N, N-dimethylbenzamide (compound 138)

To compound 73(114mg, 0.26mmol, 1 eq) in CHCl at room temperature was added₃To the solution in (4mL) was added benzoyl peroxide (13.3mg, 0.05mmol, 0.20 equiv.) and NCS (51.8mg, 0.39mmol, 1.50 equiv.) in that order. The resulting mixture was stirred at 25 ℃ for 16 h. Will react with H₂Quench O (2mL) and extract with dichloromethane (3 × 10 mL). The combined organic layers were dried over MgSO₄Dried and concentrated under reduced pressure. The residue was purified by preparative HPLC to give compound 138(13mg, 10.5%).¹H NMR(300MHz,DMSO-d6)δ12.41(s,1H),8.90(s,1H),8.51(s,1H),8.34(d,J＝8.0Hz,2H),8.25-8.06(m,2H),7.49(d,J＝8.0Hz,2H),7.29(d,J＝8.4Hz,1H),3.11-2.98(m,10H),2.56-2.49(m,4H),2.24(s,3H)。LCMS(M+H)⁺＝475.1。

Example 139: 3, 5-difluoro-N, N-dimethyl-4- [2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] benzamide (compound 139)

Step 1: 3, 5-difluoro-4- [2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] benzoic acid (compound 139-1)

Prepared from 7-iodo-2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] in a similar manner to that described in example 106 step 6]Pyrazine prepared the title compound (250mg, 78%). LCMS (M + H) ⁺＝450.1。

Step 2: 3, 5-difluoro-N, N-dimethyl-4- [2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] benzamide (compound 139)

To 3, 5-difluoro-4- [2- [4- (4-methylpiperazin-1-yl) phenyl ] at 0 DEG C]-5H-pyrrolo [2,3-b]Pyrazin-7-yl]To a solution of benzoic acid (250mg, 0.56mmol, 1 eq), dimethylamine (75.2mg, 1.67mmol, 3.00 eq), N-diisopropyl-ethylamine (215.7mg, 1.67mmol, 3.0 eq) in DMF (15mL) was added HATU (317.2mg, 0.83mmol, 1.5 eq). The resulting solution was warmed to room temperature and stirred for 16 h. The reaction mixture was quenched with water (20mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with dichloromethane: methanol ═ 85: 15) and further purified by preparative HPLC to give compound 139(12.4mg, 4.5%).¹H NMR(300MHz,DMSO-d6)δ12.48(s,1H),8.82(s,1H),8.10(s,1H),7.99-7.90(m,2H),7.32(d,J＝7.3Hz,2H),7.02(d,J＝9.0Hz,2H),3.24-3.15(m,4H),3.06-2.96(m,6H),2.48-2.39(m,4H),2.20(s,3H)。LCMS(M+H)⁺＝477.2。

Example 140: n, N-dimethyl-4- [2- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] benzamide (compound 140)

Step 1: 1-methyl-4- (2-methyl-4-nitrophenyl) piperazine (Compound 140-1)

In a 100mL round bottom flask, 1-fluoro-2-methyl-4-nitrobenzene (3g, 18.952mmol, 1 equivalent), 1-methylpiperazine (3.87g, 37.864mmol, 2.00 equivalents), K ₂CO₃A mixture of (8.02g, 56.856mmol, 3 equiv.) in DMF (30mL) was stirred at 90 ℃ for 5 h. After cooling, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with ethyl acetate: MeOH ═ 95: 5) to give the title compound (4g, 88%). LCMS (M + H)⁺＝236.4。

Step 2: 3-methyl-4- (4-methylpiperazin-1-yl) aniline (compound 140-2)

To a solution of 1-methyl-4- (2-methyl-4-nitrophenyl) piperazine (720mg, 2.91mmol, 1 eq) in MeOH (100mL) was added Pd/C (10%, 154.7 mg). The resulting mixture was hydrogenated at room temperature under 30psi of hydrogen pressure for 5 h. The mixture was filtered through a pad of celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with ethyl acetate) to give the title compound (600mg, 40.2%). LCMS (M + H)⁺＝206.4。

And step 3: 1- (4-bromo-2-methylphenyl) -4-methylpiperazine (compound 140-3)

To a 100mL round bottom flask purged and maintained with a nitrogen inert atmosphere was placed 3-methylbutyl nitrite (159.3mg, 1.33mmol, 1.2 equiv.), CuBr₂(379.7mg, 1.67mmol, 1.5 equiv.) in MeCN (20 mL). The resulting mixture was stirred at 0 ℃ for 5 min. To the mixture was added 3-methyl-4- (4-methylpiperazin-1-yl) aniline (570mg, 1.11mmol, 1 eq) at 0 ℃. The resulting mixture was stirred at room temperature for 2 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with dichloromethane: methanol ═ 30: 70) to give the title compound (250mg, 76.5%). LCMS (M + H) ⁺＝269.0。

And 4, step 4: 1-methyl-4- [ 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] piperazine (compound 140-4)

The title compound (200mg, 80.5%) was prepared from 1- (4-bromo-2-methylphenyl) -4-methylpiperazine in a similar manner to the one described in example 109, step 1. LCMS (M + H)⁺＝317.0。

And 5: 1-methyl-4- (2-methyl-4- [ 5H-pyrrolo [2,3-b ] pyrazin-2-yl ] phenyl) piperazine (compound 140-5)

Prepared in a similar manner to that described in step 4 of example 106 from 1-methyl-4- [ 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Piperazine prepared the title compound (180mg, 96.6%). LCMS (M + H)⁺＝308.2。

Step 6: 1- (4- [ 7-iodo-5H-pyrrolo [2,3-b ] pyrazin-2-yl ] -2-methylphenyl) -4-methylpiperazine (compound 140-6)

Prepared from 1-methyl-4- (2-methyl-4- [ 5H-pyrrolo [2,3-b ] in a similar manner to that described in step 5 of example 106]Pyrazin-2-yl radicals]Phenyl) piperazine the title compound (150mg, 78.7%) was prepared. LCMS (M + H)⁺＝432.1。

And 7: n, N-dimethyl-4- [2- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] benzamide (compound 140)

Prepared from 1- (4- [ 7-iodo-5H-pyrrolo [2,3-b ] in a similar manner to that described in step 6 of example 106 ]Pyrazin-2-yl radicals]-2-methylphenyl) -4-methylpiperazine preparation compound 140(9mg, 6.1%).¹H NMR(300MHz,DMSO-d6)δ12.35(s,1H),8.86(s,1H),8.51(s,1H),8.39(d,J＝8.0Hz,2H),8.00(d,J＝6.8Hz,2H),7.52(d,J＝8.1Hz,2H),7.18(d,J＝8.5Hz,1H),3.02(s,6H),2.96-2.90(m,4H),2.62-2.51(m,4H),2.38(s,3H),2.27(s,3H)。LCMS(M+H)⁺＝455.5。

Example 141: 4- [2- [3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -N, N-dimethylbenzamide (compound 141)

Step 1: 1- (4-bromo-2, 6-dimethylphenyl) -4-methylpiperazine (compound 141-1) to a 10mL vial was placed 4-bromo-2, 6-dimethylaniline (1.038g, 4.93mmol, 1 equivalent), bis (2-chloroethyl) (methyl) amine hydrochloride (1.0g, 4.93mmol, 1.00 equivalent) in 2- (2-methoxyethoxy) ethan-1-ol (5 mL). The resulting solution was stirred at 130 ℃ for 16 h. After cooling the reaction to room temperature, the solid was collected by filtration and purified by silica gel column chromatography (eluting with chloroform: methanol 80: 20) to give the title compound (1.3g, 76.3%). LCMS (M + H)⁺＝282.9。

Step 2: 1- [2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] -4-methylpiperazine (compound 141-2)

The title compound (223mg, 33.9%) was prepared from 1- (4-bromo-2, 6-dimethylphenyl) -4-methylpiperazine in a similar manner to the one described in example 109, step 1. LCMS (M + H)⁺＝331.3。

And step 3: 1- (2, 6-dimethyl-4- [ 5H-pyrrolo [2,3-b ] pyrazin-2-yl ] phenyl) -4-methylpiperazine (compound 141-3)

Prepared in a similar manner to that described in step 4 of example 106 from 1- [2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-4-methylpiperazine the title compound (180mg, 94.0%) was prepared. LCMS (M + H)⁺＝322.1。

And 4, step 4: 1- (4- [ 7-iodo-5H-pyrrolo [2,3-b ] pyrazin-2-yl ] -2, 6-dimethylphenyl) -4-methylpiperazine (compound 141-4)

Prepared from 1- (2, 6-dimethyl-4- [ 5H-pyrrolo [2,3-b ] in a similar manner to that described in step 5 of example 106]Pyrazin-2-yl radicals]Phenyl) -4-methylpiperazine the title compound (212mg, 76.0%) was prepared. LCMS (M + H)⁺＝447.9。

And 5: 4- [2- [3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -N, N-dimethylbenzamide (compound 141)

Prepared from 1- (4- [ 7-iodo-5H-pyrrolo [2,3-b ] in a similar manner to that described in step 6 of example 106]Pyrazin-2-yl radicals]-2, 6-dimethylphenyl) -4-methylpiperazine prepared compound 141(2.9mg, 1.6%).¹H NMR(300MHz,DMSO-d6)δ8.79(s,1H),8.47(s,1H),8.35(d,J＝8.3Hz,2H),7.78(s,2H),7.48(d,J＝8.3Hz,2H),3.09-3.03(m,4H),2.99(s,6H),2.48-2.41(m,4H),2.39(s,6H),2.23(s,3H)。LCMS(M+H)⁺＝469.2。

Example 142: 4- [2- [3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] benzoic acid (compound 142)

Prepared from 1- (4- [ 7-iodo-5H-pyrrolo [2,3-b ] in a similar manner to that described in step 6 of example 106 ]Pyrazin-2-yl radicals]-2, 6-dimethylphenyl) -4-methylpiperazine prepared compound 142(3mg, 3.1%).¹H NMR(400MHz,DMSO-d6)δ12.5-12.4(m,1H),8.85(s,1H),8.42(d,J＝8.0Hz,2H),8.02(d,J＝7.2Hz,2H),7.82(s,2H),3.14-3.09(m,4H),2.61-2.41(m,10H),2.08(s,3H)。LCMS(M+H)⁺＝442.2。

Example 143: 4- [2- [3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -N-ethyl-N-methylbenzamide (compound 143)

Step 1: 4- (Ethyl (methyl) carbamoyl) phenylboronic acid (Compound 143-1)

The title compound (5g, 84%) was prepared from 4- (dihydroxyboryl) benzoic acid and ethyl (methyl) amine in a similar manner as described in example 112, step 1. LC-MS (M + H)⁺＝208.1。

Step 2: 4- [2- [3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -N-ethyl-N-methylbenzamide (compound 143)

Compound 143(3.5mg, 3.1%) was prepared in a similar manner to that described in example 141, step 5.¹H NMR(400MHz,DMSO-d6)δ12.37(s,1H),8.84(s,1H),8.50(s,1H),8.38(d,J＝8.0Hz,2H),7.81(s,2H),7.49(d,J＝7.9Hz,2H),3.49-3.44(m,2H),3.12-3.06(m,4H),2.98(s,3H),2.53-2.44(m,4H),2.41(s,6H),2.27(s,3H),1.21-1.00(m,3H)。LCMS(M+H)⁺＝483.4。

Example 144: 4- (2- [4- [4- (cyclopropylmethyl) piperazin-1-yl ] phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -N, N-dimethylbenzamide (compound 144)

Step 1: 1- (4-bromophenyl) -4- (cyclopropylmethyl) piperazine (compound 144-1)

To a solution of 1- (4-bromophenyl) piperazine (2.38g, 9.38mol, 1 eq) in dichloromethane (60mL) was added cyclopropanecarboxaldehyde (1.4g, 18.75mol, 2.00 eq). The resulting mixture was stirred at room temperature for 2 h. Add NaBH (AcO) to the mixture in portions ₃(318mg, 1.43mmol, 1.45 equiv.). The resulting mixture was stirred at room temperature for an additional 12 h. Then the reaction is applied to H₂Quench O (50mL) and extract with dichloromethane (3 × 40 mL). The combined organic layers were dried over MgSO₄Dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with ethyl acetate: petroleum ether ═ 3: 7) to give the title compound (2.4g, 84.9%). LCMS (M + H)⁺＝295.3。

Step 2: 1- (cyclopropylmethyl) -4- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] piperazine (compound 144-2)

The title compound (3g, 76.6%) was prepared from 1- (4-bromophenyl) -4- (cyclopropylmethyl) piperazine in a similar manner to that described in example 109, step 1. LCMS (M + H)⁺＝343.0。

And step 3: 1- (cyclopropylmethyl) -4- (4- [ 5H-pyrrolo [2,3-b ] pyrazin-2-yl ] phenyl) piperazine (compound 144-3)

Prepared in a similar manner to that described in step 4 of example 106 from 1- (cyclopropylmethyl) -4- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Piperazine prepared the title compound (2.5g, 91.7%). LCMS (M + H)⁺＝334.1。

And 4, step 4: 1- (cyclopropylmethyl) -4- (4- [ 7-iodo-5H-pyrrolo [2,3-b ] pyrazin-2-yl ] phenyl) piperazine (compound 144-4)

Prepared from 1- (cyclopropylmethyl) -4- (4- [ 5H-pyrrolo [2, 3-b) in a similar manner to that described in step 5 of example 106 ]Pyrazin-2-yl radicals]Phenyl) piperazine the title compound (600mg, 91.4%) was prepared. LCMS (M + H)⁺＝460.0。

And 5: 4- (2- [4- [4- (cyclopropylmethyl) piperazin-1-yl ] phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -N, N-dimethylbenzamide (compound 144)

Prepared from 1- (cyclopropylmethyl) -4- (4- [ 7-iodo-5H-pyrrolo [2, 3-b) in a similar manner to that described in step 6 of example 106]Pyrazin-2-yl radicals]Phenyl) piperazine prepared compound 144(59mg, 41.4%).¹H NMR(300MHz,DMSO-d6)δ12.34(s,1H),8.85(s,1H),8.52-8.45(m,1H),8.44-8.36(m,2H),8.10(d,J＝8.4Hz,2H),7.56-7.47(m,2H),7.12(d,J＝8.6Hz,2H),3.05-2.99(m,4H),2.96(s,6H),2.69-2.63(m,4H),2.32-2.26(m,2H),0.95-0.89(m,1H),0.57-0.49(m,2H),0.19-0.13(m,2H)。LCMS(M+H)⁺＝418.2。

Example 145: 4- (2- [4- [ (2R,6S) -2, 6-Dimethylmorpholin-4-yl ] phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -N, N-dimethylbenzamide (Compound 145)

Step 1: (2R,6S) -4- (4-bromophenyl) -2, 6-dimethylmorpholine (Compound 145-1)

In a 30mL sealed tube, 1, 4-dibromobenzene (1.8g, 7.25mmol, 1.10 equiv), (2R,6S) -2, 6-dimethylmorpholine (800mg, 6.60mmol, 1 equiv), BINAP (865.0mg, 1.32mmol, 0.20 equiv), Pd₂(dba)₃.CHCl₃A mixture of (719.0mg, 0.66mmol, 0.10 equiv.), t-BuONa (1.35g, 13.35mmol, 2.02 equiv.) in toluene (13mL) was stirred at 80 ℃ under a nitrogen atmosphere for 16 h. The mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (using petroleum ether: ethyl acetate) 10:1 elution) to give the title compound (750mg, 39.9%). LCMS (M + H)⁺＝270.0。

Step 2: (2R,6S) -2, 6-dimethyl-4- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] morpholine (Compound 145-2)

The title compound (700mg, 72.2%) was prepared from (2R,6S) -4- (4-bromophenyl) -2, 6-dimethylmorpholine in a similar manner to that described in example 109, step 1. LCMS (M + H)⁺＝318.3。

And step 3: (2R,6S) -2, 6-dimethyl-4- (4- [ 5H-pyrrolo [2,3-b ] pyrazin-2-yl ] phenyl) morpholine (Compound 145-3)

Prepared in a similar manner to that described in step 4 of example 106 from (2R,6S) -2, 6-dimethyl-4- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Morpholine prepared the title compound (200mg, 59%). LCMS (M + H)⁺＝309.2。

And 4, step 4: (2R,6S) -4- (4- [ 7-iodo-5H-pyrrolo [2,3-b ] pyrazin-2-yl ] phenyl) -2, 6-dimethylmorpholine (compound 145-4)

Prepared from (2R,6S) -2, 6-dimethyl-4- (4- [ 5H-pyrrolo [2,3-b ] in a similar manner to that described in step 5 of example 106]Pyrazin-2-yl radicals]Phenyl) morpholine the title compound (180mg, 61.5%) was prepared. LCMS (M + H)⁺＝435.1。

And 5: 4- (2- [4- [ (2R,6S) -2, 6-Dimethylmorpholin-4-yl ] phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -N, N-dimethylbenzamide (Compound 145)

Prepared from (2R,6S) -4- (4- [ 7-iodo-5H-pyrrolo [2,3-b ] in a similar manner to that described in step 6 of example 106]Pyrazin-2-yl radicals]Phenyl) -2, 6-dimethylmorpholine preparation compound 145(32.3mg, 23.7%).¹H NMR(400MHz,DMSO-d6)δ12.27(s,1H),8.85(s,1H),8.47(s,1H),8.39(d,J＝8.0Hz,2H),8.10(d,J＝8.5Hz,2H),7.51(d,J＝8.0Hz,2H),7.11(d,J＝8.8Hz,2H),3.73(d,J＝10.7Hz,4H),3.02(s,6H),2.40-2.31(m,2H),1.20(d,J＝6.1Hz,6H)。LCMS(M+H)⁺＝456.1。

Example 146: 4- (2- [4- [ (2R,6R) -2, 6-Dimethylmorpholin-4-yl ] phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -N, N-dimethylbenzamide (Compound 146)

Step 1: (2S,6S) -4- (4-bromophenyl) -2, 6-dimethylmorpholine (Compound 146-1)

The title compound (470mg, 39.3%) was prepared from (2S,6S) -2, 6-dimethylmorpholine in a similar manner to that described in example 145, step 1. LCMS (M + H)⁺＝270.2。

Step 2: (2R,6R) -2, 6-dimethyl-4- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] morpholine (Compound 146-2)

The title compound (300mg, 83.1%) was prepared from (2S,6S) -4- (4-bromophenyl) -2, 6-dimethylmorpholine in a similar manner to that described in example 109, step 1. LCMS (M + H)⁺＝318.4。

And step 3: (2R,6R) -2, 6-dimethyl-4- (4- [ 5H-pyrrolo [2,3-b ] pyrazin-2-yl ] phenyl) morpholine (Compound 146-3)

Prepared in a similar manner to that described in step 4 of example 106 from (2R,6R) -2, 6-dimethyl-4- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ]Morpholine prepared the title compound (20mg, 73.0%). LCMS (M + H)⁺＝309.2。

And 4, step 4: (2R,6R) -4- (4- [ 7-iodo-5H-pyrrolo [2,3-b ] pyrazin-2-yl ] phenyl) -2, 6-dimethylmorpholine (compound 146-4)

Prepared from (2R,6R) -2, 6-dimethyl-4- (4- [ 5H-pyrrolo [2,3-b ] in a similar manner to that described in step 5 of example 106]Pyrazin-2-yl radicals]Phenyl) morpholine the title compound (134mg, 36.4%) was prepared. LCMS (M + H)⁺＝434.1。

And 5: 4- (2- [4- [ (2R,6R) -2, 6-Dimethylmorpholin-4-yl ] phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -N, N-dimethylbenzamide (Compound 146)

Prepared from (2R,6R) -4- (4- [ 7-iodo-5H-pyrrolo [2,3-b ] in a similar manner to that described in step 6 of example 106]Pyrazin-2-yl radicals]Phenyl) -2, 6-dimethylmorpholine preparation of compound 146(28.1mg, 25).7％)。¹H NMR(400MHz,DMSO-d6)δ12.29(s,1H),8.83(s,1H),8.46(s,1H),8.42-8.35(m,2H),8.12-8.04(m,2H),7.53-7.46(m,2H),7.08(d,J＝8.9Hz,2H),4.13-4.03(m,2H),3.36-3.27(m,2H),3.03-2.89(m,8H),1.23(d,J＝6.4Hz,6H)。LCMS(M+H)⁺＝456.1。

Example 147: n, N-dimethyl-4- (2- (4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) benzamide (compound 147)

Step 1: 1- (4-bromophenyl) -4- (1-methylpiperidin-4-yl) piperazine (compound 147-1)

A solution of 1- (4-bromophenyl) piperazine (2g, 7.88mmol, 1 eq) and 1-methylpiperidin-4-one (1.4g, 11.75mmol, 1.49 eq) in MeCN (10mL) was stirred at 50 ℃ for 5 min. To the above mixture was added NaBH (OAc) in order at 50 deg.C ₃(5.3g, 23.76mmol, 3.01 equiv.) and CH₃COOH (0.1 mL). The resulting mixture was stirred at 50 ℃ for another 3 h. The reaction mixture was slowly quenched with water (50mL) and extracted with dichloromethane (3 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with dichloromethane: MeOH ═ 10: 1) to give the title compound (2.5g, 90%). LCMS (M + H)⁺＝338.1。

Step 2: 1- (1-methylpiperidin-4-yl) -4- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] piperazine (compound 147-2)

The title compound (1.1g, 44.0%) was prepared from 1- (4-bromophenyl) -4- (1-methylpiperidin-4-yl) piperazine in a similar manner to that described in example 109, step 1. LCMS (M + H)⁺＝386.3。

And step 3: 1- (1-methylpiperidin-4-yl) -4- (4- [ 5H-pyrrolo [2,3-b ] pyrazin-2-yl ] phenyl) piperazine (compound 147-3)

Prepared from 1- (1-methylpiperidin-4-yl) in a similar manner to that described in step 4 of example 106) -4- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Piperazine prepared the title compound (520mg, 43.0%). LCMS (M + H)⁺＝377.2。

And 4, step 4: 1- (4- [ 7-iodo-5H-pyrrolo [2,3-b ] pyrazin-2-yl ] phenyl) -4- (1-methylpiperidin-4-yl) piperazine (compound 147-4)

Prepared in a similar manner to that described in step 5 of example 106 from 1- (1-methylpiperidin-4-yl) -4- (4- [ 5H-pyrrolo [2, 3-b)]Pyrazin-2-yl radicals]Phenyl) piperazine the title compound (320mg, 61.0%) was prepared. LCMS (M + H)⁺＝442.2。

And 5: n, N-dimethyl-4- (2- (4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) benzamide (compound 147)

Prepared from 1- (4- [ 7-iodo-5H-pyrrolo [2,3-b ] in a similar manner to that described in step 6 of example 106]Pyrazin-2-yl radicals]Phenyl) -4- (1-methylpiperidin-4-yl) piperazine compound 147(20mg, 15.6%) was prepared.¹H NMR(300MHz,DMSO-d6)δ12.29(s,1H),8.82(s,1H),8.45(s,1H),8.42-8.33(m,2H),8.07(d,J＝8.7Hz,2H),7.49(d,J＝8.3Hz,2H),7.07(d,J＝8.7Hz,2H),3.28-3.15(m,4H),3.00(s,6H),2.84-2.74(m,2H),2.67-2.59(m,4H),2.19-2.10(m,4H),1.91-1.70(m,4H),1.52-1.34(m,2H)。LCMS(M+H)⁺＝442.2；HPLC:254nm,97.5％。

Example 148: 4- (2- [4- [4- (2-hydroxyethyl) piperazin-1-yl ] phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -N, N-dimethylbenzamide (compound 148)

Step 1: 1- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] piperazine (compound 148-1)

The title compound (4g, 68.4%) was prepared from 1- (4-bromophenyl) piperazine in a similar manner to that described in example 109, step 1. LCMS (M + H)⁺＝289.0。

Step 2: 2- [4- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] piperazin-1-yl ] ethan-1-ol (Compound 148-2)

To 1- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ]Piperazine (1.3g, 4.18mmol, 1 eq.) and 2-bromoethan-1-ol (2.9g, 22.05mmol, 5.27 eq.) in CH₃CN (20.0mL) solution was added with K₂CO₃(3.2g, 21.99mmol, 5.26 equiv.). The resulting mixture was stirred at 60 ℃ under a nitrogen atmosphere for 48 h. After cooling, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with dichloromethane: methanol ═ 10: 90) to give the title compound (1g, 47.6%). LCMS (M + H)⁺＝333.1。

And step 3: 2- [4- (4- [ 5H-pyrrolo [2,3-b ] pyrazin-2-yl ] phenyl) piperazin-1-yl ] ethan-1-ol (compound 148-3)

Prepared from 2- [4- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl in a similar manner to that described in step 4 of example 106]Piperazin-1-yl]Ethan-1-ol the title compound (640mg, 93.9%) was prepared. LCMS (M + H)⁺＝324.0。

And 4, step 4: 2- [4- (4- [ 7-iodo-5H-pyrrolo [2,3-b ] pyrazin-2-yl ] phenyl) piperazin-1-yl ] ethan-1-ol (compound 148-4)

Prepared from 2- [4- (4- [ 5H-pyrrolo [2,3-b ] in a similar manner to that described in step 5 of example 106]Pyrazin-2-yl radicals]Phenyl) piperazin-1-yl]Ethan-1-ol the title compound (110mg, 62.2%) was prepared. LCMS (M + H)⁺＝449.9。

And 5: 4- (2- [4- [4- (2-hydroxyethyl) piperazin-1-yl ] phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -N, N-dimethylbenzamide (compound 148)

Prepared from 2- [4- (4- [ 7-iodo-5H-pyrrolo [2,3-b ] in a similar manner to that described in step 6 of example 106]Pyrazin-2-yl radicals]Phenyl) piperazin-1-yl]Ethan-1-ol preparation of compound 148(25mg, 14.8%).¹H NMR(400MHz,DMSO-d6)δ12.30(s,1H),8.83(s,1H),8.46(d,J＝2.6Hz,1H),8.41-8.35(m,2H),8.08(d,J＝8.8Hz,2H),7.50(d,J＝8.3Hz,2H),7.09(d,J＝8.7Hz,2H),4.43(s,1H),3.60-3.51(m,2H),3.29-3.22(m,4H),3.01(s,6H),2.62-2.56(m,4H),2.48-2.42(m,2H)。LCMS(M+H)⁺＝471.1。

Example 149: n, N-dimethyl-4- (2- [4- [ (4-methylpiperazin-1-yl) methyl ] phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl) benzamide (compound 149)

Step 1: 1-methyl-4- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) piperazine (compound 149-1)

Prepared from 1- [ (4-bromophenyl) methyl group in a similar manner to that described in step 1 of example 109]-4-methylpiperazine the title compound (700mg, 56.4%) was prepared. LCMS (M + H)⁺＝317.2。

Step 2: 1-methyl-4- [ (4- [ 5H-pyrrolo [2,3-b ] pyrazin-2-yl ] phenyl) methyl ] piperazine (compound 149-2)

Prepared from 2-bromo-5H-pyrrolo [2,3-b ] in a similar manner to that described in step 4 of example 106]Pyrazine prepared the title compound (110mg, 92.8%). LCMS (M + H)⁺＝308.1。

And step 3: 1- [ (4- [ 7-iodo-5H-pyrrolo [2,3-b ] pyrazin-2-yl ] phenyl) methyl ] -4-methylpiperazine (compound 149-3)

Prepared from 1-methyl-4- [ (4- [ 5H-pyrrolo [2,3-b ] in a similar manner to that described in step 5 of example 106]Pyrazin-2-yl radicals ]Phenyl) methyl]Piperazine prepared the title compound (140mg, 85.4%). LCMS (M + H)⁺＝434.2。

And 4, step 4: n, N-dimethyl-4- (2- [4- [ (4-methylpiperazin-1-yl) methyl ] phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl) benzamide (compound 149)

Prepared from 1- [ (4- [ 7-iodo-5H-pyrrolo [2,3-b ] in a similar manner to that described in step 6 of example 106]Pyrazin-2-yl radicals]Phenyl) methyl]-4-methylpiperazine preparation compound 149(17.3mg, 11.7%).¹H NMR(400MHz,DMSO-d6)δ12.43(s,1H),8.91(s,1H),8.53(s,1H),8.43-8.35(m,2H),8.19-8.12(m,2H),7.54-7.43(m,4H),3.54(s,2H),3.01(s,6H),2.47-2.26(m,8H),2.16(s,3H)。LCMS(M+H)⁺＝455.1。

Example 150: 4- (2- (4- (4-methoxyphenylethyl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -N, N-dimethylbenzamide (Compound 150)

Step 1: 1-bromo-4- [2- (4-methoxyphenyl) vinyl ] benzene (Compound 150-1)

To [ (4-methoxyphenyl) methyl group at room temperature]To a solution of diethyl phosphonate (200mg, 0.736mmol, 1 eq) in DMF (5mL) was added NaH (37.2mg, 0.930mmol, 1.26 eq in oil, 60%). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 30 min. To the above mixture was added 4-bromobenzaldehyde (143.2mg, 0.735mmol, 1.00 equiv.) at room temperature and the resulting mixture was stirred for an additional 16 h. Reacting with saturated NH₄The Cl solution was quenched and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (150mg, 52.1%). LCMS (M + H) ⁺＝⁺289.9。

Step 2: 2- [4- [2- (4-methoxyphenyl) vinyl ] phenyl ] -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (Compound 150-2)

Prepared in a similar manner to that described in step 1 of example 109 from 1-bromo-4- [2- (4-methoxyphenyl) vinyl]Benzene the title compound (90mg, 39.2%) was prepared. LCMS (M + H)⁺＝337.0。

And step 3: 2- [4- [2- (4-methoxyphenyl) ethyl ] phenyl ] -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (compound 150-3)

To 2- [4- [2- (4-methoxyphenyl) vinyl at room temperature under nitrogen atmosphere]Phenyl radical]To a solution of-4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (1g, 2.790mmol, 1 eq) in EtOH (50mL) was added Pd/C (350mg, 0.329mmol, 0.12 eq). The reaction flask was degassed and refilled with hydrogen. The resulting mixture was hydrogenated at 30 ℃ under a hydrogen atmosphere using a hydrogen balloon for 16 h. The solid was filtered off and washed with EtOH (2 × 30 mL). The filtrate was concentrated under reduced pressure to give the title compound (800mg, 80.5%).LCMS(M+H)⁺＝⁺339.2。

And 4, step 4: 2- [4- [2- (4-methoxyphenyl) ethyl ] phenyl ] -5H-pyrrolo [2,3-b ] pyrazine (compound 150-4)

Prepared from 2- [4- [2- (4-methoxyphenyl) ethyl group in a similar manner to that described in step 4 of example 106 ]Phenyl radical]-4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan the title compound (450mg, 97.2%) was prepared. LCMS (M + H)⁺＝⁺330.1。

And 5: 7-iodo-2- [4- [2- (4-methoxyphenyl) ethyl ] phenyl ] -5H-pyrrolo [2,3-b ] pyrazine (compound 150-5)

Prepared from 2- [4- [2- (4-methoxyphenyl) ethyl group in a similar manner to that described in step 5 of example 106]Phenyl radical]-5H-pyrrolo [2,3-b]Pyrazine prepared the title compound (380mg, 65.9%). LCMS (M + H)⁺＝⁺456.0。

Step 6: 4- (2- (4- (4-methoxyphenylethyl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -N, N-dimethylbenzamide (Compound 150)

Prepared from [4- (dimethylcarbamoyl) phenyl in a similar manner to that described in step 6 of example 106]Boronic acid preparation compound 150(35mg, 39.8%).¹H NMR(300MHz,DMSO-d6)δ12.37(s,1H),8.90(s,1H),8.52(s,1H),8.42-8.35(m,2H),8.15-8.08(m,2H),7.55-7.47(m,2H),7.42-7.36(m,2H),7.21-7.14(m,2H),6.89-6.81(m,2H),3.72(s,3H),3.01(s,6H),2.98-2.84(m,4H)。LCMS(M+H)⁺＝477.1。

Example 151: n, N-dimethyl-4- ([2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] methyl) benzamide (compound 151)

Step 1: 4- [ hydroxy ([2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl) methyl ] -N, N-dimethylbenzamide (compound 151-1)

In a 30mL sealed tube, 1-methyl-4- (4- [ 5H-pyrrolo [2,3-b ]]Pyrazin-2-yl radicals]A mixture of phenyl) piperazine (500mg, 1.53mmol, 1 eq), 4-formyl-N, N-dimethylbenzamide (360mg, 1.93mmol, 1.26 eq), and KOH (656mg, 11.69mmol, 7.62 eq) in MeOH (27mL) was stirred at 30 ℃ under a nitrogen atmosphere for 24 h. The resulting mixture was concentrated under reduced pressure and the residue was purified by reverse phase flash chromatography (eluting with a gradient of acetonitrile 1% to 95% in water) to give the title compound (107mg, 14.6%). LCMS (M + H) ⁺＝471.2。

Step 2: n, N-dimethyl-4- ([2- [4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] methyl) benzamide (compound 151)

4- [ hydroxy ([2- [4- (4-methylpiperazin-1-yl) phenyl) was added to a 25mL sealed tube at room temperature]-5H-pyrrolo [2,3-b]Pyrazin-7-yl]) Methyl radical]To a solution of (E) -N, N-dimethylbenzamide (25.2mg, 0.05mmol, 1 eq) in dichloromethane (4mL) was added TFA (57.4mg, 0.50mmol, 9.50 eq) and Et₃SiH (57mg, 0.49mmol, 9.25 equiv.). The resulting mixture was stirred in an oil bath at 85 ℃ for 3 h. The mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (eluting with a gradient of acetonitrile 1% to 80% in water) to give compound 151(21.1mg, 87.0%).¹H NMR(300MHz,DMSO-d6)δ11.75(d,J＝2.4Hz,1H),8.73(s,1H),8.03-7.95(m,2H),7.64(d,J＝2.3Hz,1H),7.47-7.41(m,2H),7.34-7.27(m,2H),7.09-7.01(m,2H),4.16(s,2H),3.29-3.17(m,4H),2.96-2.87(m,6H),2.50-2.43(m,4H),2.23(s,3H)。LCMS(M+H)⁺＝455.1。

Example 152: n, N-dimethyl-4- (1- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) ethyl) benzamide (compound 152)

In a 50mL round-bottom flask, 4- [ hydroxy ([2- [4- (4-methylpiperazin-1-yl) phenyl) at 0 deg.C]-5H-pyrrolo [2,3-b]Pyrazin-7-yl]) Methyl radical]-N, N-Dimethylbenzamide (43.5mg, 0.092mmol, 1 equiv.) was added to SOCl₂(5mL, 65.479mmol, 712 equivalents). The resulting mixture was stirred at 0 ℃ for 2h, and then concentrated under reduced pressure. The residue was dissolved in dichloromethane (15mL) and cooled to-40 ℃. Dropwise addition of AlMe to the mixture ₃Solution (2M in toluene, 0.18ml, 0.36 mmol). The resulting mixture was stirred at 0 ℃ for 3 h. The reaction was performed with saturated NH at 0 deg.C₄The Cl solution was quenched and extracted with dichloromethane (3 × 30 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (eluting within 40min with a gradient of acetonitrile 1% to 95% in water) to afford compound 152(17.5mg, 40%).¹H NMR(300MHz,DMSO-d6)δ11.73(d,J＝2.7Hz,1H),8.70(s,1H),7.99-7.91(m,2H),7.63(d,J＝2.7Hz,1H),7.52-7.46(m,2H),7.35-7.27(m,2H),7.08-7.00(m,2H),4.58-4.48(m,1H),3.25-3.14(m,4H),2.95-2.87(m,6H),2.50-2.43(m,4H),2.23(s,3H),1.77(d,J＝7.3Hz,3H)。LCMS(M+H)⁺＝469.2。

Example 153: 3- (2 '-methoxy- [1, 1' -biphenyl ] -4-yl) -5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (compound 153)

Compound 153(27.5mg, 5.9%) was prepared from compounds 1-3 in a similar manner to that described in example 106, step 6.¹H NMR(400MHz,DMSO-d6,ppm)δ11.94(d,J＝2.7Hz,1H),8.52(d,J＝2.1Hz,1H),8.39(d,J＝2.1Hz,1H),7.92(d,J＝2.5Hz,1H),7.85-7.79(m,2H),7.66-7.60(m,2H),7.60-7.53(m,2H),7.40-7.31(m,2H),7.13(dd,J＝8.8,1.1Hz,1H),7.10-7.01(m,3H),3.80(s,3H),3.25-3.09(m,4H),2.51-2.44(m,4H),2.24(s,3H)。LCMS(M+H)⁺＝475.2。

Example 154: 3- (2 '-methyl- [1, 1' -biphenyl ] -4-yl) -5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (compound 154)

Compound 154(43mg, 21.2%) was prepared in a similar manner to that in example 153.¹H NMR(300MHz,DMSO-d6)δ11.97(d,J＝2.7Hz,1H),8.53(d,J＝2.0Hz,1H),8.41(d,J＝2.1Hz,1H),7.96(d,J＝2.6Hz,1H),7.86(d,J＝7.9Hz,2H),7.64(d,J＝8.4Hz,2H),7.43(d,J＝8.0Hz,2H),7.36-7.25(m,4H),7.06(d,J＝8.5Hz,2H),3.23-3.16(m,4H),2.54-2.45(m,4H),2.32(s,3H),2.24(s,3H)。LCMS(M+H)⁺＝459.3。

Example 155: 5- (4- (4-Methylpiperazin-1-yl) phenyl) -3- (4- (piperidin-2-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (Compound 155)

Step 1: 2- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) piperidine (compound 155-1)

The title compound (150mg, 37.4%) was prepared from 2- (4-bromophenyl) piperidine in a similar manner to that described in example 109, step 1.

Step 2: 5- (4- (4-Methylpiperazin-1-yl) phenyl) -3- (4- (piperidin-2-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (Compound 155)

Prepared from 3-iodo-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that described in example 106, step 6]Pyridine preparation compound 155(14mg, 6.2%).¹H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.51(s,1H),8.32(s,1H),7.83(s,1H),7.70(d,J＝7.8Hz,2H),7.61(d,J＝8.4Hz,2H),7.43(d,J＝7.9Hz,2H),7.06(d,J＝8.4Hz,2H),3.60-3.53(m,1H),3.22-3.16(m,4H),3.12-3.04(m,1H),2.74-2.64(m,1H),2.51-2.45(m,4H),2.25(s,3H),1.84-1.80(m,1H),1.77-1.70(m,1H),1.62-1.55(m,1H),1.52-1.32(m,3H)。LCMS(M+H)⁺＝452.1。HPLC:254nm,97.0％。

Example 156: n, N-diethyl-4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 156)

Compound 156(4mg, 9%) was prepared from compounds 1-3 in a similar manner to that described in example 106, step 6.¹H NMR(400MHz,DMSO-d6)δ11.99(s,1H),8.50(d,J＝2.1Hz,1H),8.37(d,J＝2.1Hz,1H),7.96(d,J＝2.5Hz,1H),7.83(d,J＝8.2Hz,2H),7.61(d,J＝8.7Hz,2H),7.40(d,J＝8.1Hz,2H),7.03(d,J＝8.7Hz,2H),3.22-3.13(m,8H),2.49-2.42(m,4H),2.22(s,3H),1.17-1.07(m,6H)。LC-MS(M+H)⁺＝468.1。HPLC:254nm,98.3％。

Example 157: N-cyclopropyl-N-methyl-4- [5- [4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide (compound 157)

Compound 157(26.4mg, 16.5%) was prepared from N-cyclopropyl-N-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide in a similar manner to that described in example 106, step 6.¹H NMR(400MHz,DMSO-d6)δ12.01(s,1H),8.52(s,1H),8.39(s,1H),7.99(s,1H),7.87-7.80(m,2H),7.66-7.55(m,4H),7.09-7.01(m,2H),3.12-3.20(m,4H),3.03-2.97(m,4H),2.49-2.42(m,4H),2.24(s,3H),0.64-0.60(m,2H),0.44-0.50(m,2H)。LCMS(M+H)⁺＝466.2。

Example 158: n- (3-methoxypropyl) -N-methyl-4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 158)

Compound 158(12mg, 4.6%) was prepared from N- (3-methoxypropyl) -N-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide in a similar manner to that described in example 106, step 6.¹H NMR(300MHz,DMSO-d6)δ11.99(s,1H),8.51(d,J＝2.1Hz,1H),8.37(d,J＝2.1Hz,1H),7.96(d,J＝2.5Hz,1H),7.83(d,J＝8.2Hz,2H),7.61(d,J＝8.7Hz,2H),7.44(d,J＝7.8Hz,2H),7.04(d,J＝8.7Hz,2H),3.48-3.28(m,5H),3.26-3.13(m,6H),2.95(s,3H),2.50-2.41(m,4H),2.22(s,3H),1.83-1.77(m,2H)。LCMS(M+H)⁺＝498.3。

Example 159: n- (2-methoxyethyl) -N-methyl-4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 159)

Compound 159(50mg, 30.3%) was prepared from N- (2-methoxyethyl) -N-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide in a similar manner to that described in example 106, step 6.¹H NMR(300MHz,DMSO-d6)δ12.01(s,1H),8.53(d,J＝2.0Hz,1H),8.40(d,J＝2.1Hz,1H),7.99(s,1H),7.86(d,J＝8.0Hz,2H),7.68-7.60(m,2H),7.47(d,J＝8.2Hz,2H),7.03(d,J＝8.7Hz,2H),3.70-3.40(m,4H),3.22-3.19(m,7H),3.02(s,3H),2.50-2.46(m,4H),2.24(s,3H)。LCMS(M+H)⁺＝484.5。

Example 160: 3, 5-difluoro-N, N-dimethyl-4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 160)

Compound 160(9mg, 6.0%) was prepared from 3, 5-difluoro-N, N-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide in a similar manner to that described in example 106, step 6.¹H NMR(300MHz,DMSO-d6)δ12.22(s,1H),8.53(d,J＝2.1Hz,1H),7.97(d,J＝2.2Hz,1H),7.81(s,1H),7.54(d,J＝8.6Hz,2H),7.31(d,J＝7.8Hz,2H),7.01(d,J＝8.7Hz,2H),3.20-3.11(m,4H),3.03-2.93(m,6H),2.49-2.40(m,4H),2.21(s,3H)。LCMS(M+H)⁺＝476.5。

Example 161: n, N, 3-trimethyl-4- [5- [4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide (compound 161)

Step 1: n, N, 3-trimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide (compound 161-1)

To a solution of 3-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoic acid (385mg, 1.395mmol, 1.20 equivalents), N-diisopropyl-ethylamine (325mg, 2.389mmol, 2.05 equivalents), HATU (700mg, 1.749mmol, 1.50 equivalents) in DMF (10mL) was added dimethylamine hydrochloride (100mg, 1.165mmol, 1 equivalent). The resulting mixture was stirred at room temperature for 5 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with ethyl acetate: MeOH ═ 1: 1) to give the title compound (120mg, 34.2%). LC-MS (M + H)⁺＝290.0。

Step 2: n, N, 3-trimethyl-4- [5- [4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide (compound 161)

Prepared from 3-iodo-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that described in example 106, step 6]Pyridine preparation compound 161(18.5mg, 12.1%).¹H NMR(400MHz,DMSO-d6)δ11.96(d,J＝2.6Hz,1H),8.52(d,J＝2.1Hz,1H),7.95(d,J＝2.1Hz,1H),7.67(d,J＝2.4Hz,1H),7.55(d,J＝8.4Hz,2H),7.51(d,J＝7.8Hz,1H),7.39(s,1H),7.33-7.29(m,1H),7.01(d,J＝8.4Hz,2H),3.21-3.13(m,4H),3.01(s,6H),2.49-2.44(m,4H),2.38(s,3H),2.23(s,3H)。LC-MS(M+H)⁺＝454.4。

Example 162: n, N-dimethyl-5- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) picolinamide (compound 162)

Compound 162(18.5mg, 12.5%) was prepared from compound 106-3 and compound 1-3 in a similar manner to that described in example 106, step 6. ¹H NMR(300MHz,DMSO-d6)δ12.18(d,J＝2.8Hz,1H),9.04(d,J＝2.2Hz,1H),8.56(d,J＝2.1Hz,1H),8.44(d,J＝2.1Hz,1H),8.36-8.33(m,1H),8.15(d,J＝2.5Hz,1H),7.68-7.63(m,3H),7.05(d,J＝8.5Hz,2H),3.22-3.16(m,4H),3.09(s,3H),3.06(s,3H),2.49-2.45(m,4H),2.24(s,3H)。LCMS(M+H)⁺＝441.3。

Example 163: n, N-dimethyl-5- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidine-2-carboxamide (Compound 163)

Compound 163(48.1mg, 20.1%) was prepared from N, N-dimethyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine-2-carboxamide in a similar manner to that described in example 106, step 6.¹H NMR(400MHz,DMSO-d6)δ12.30(s,1H),9.35(s,2H),8.59(d,J＝2.1Hz,1H),8.52(d,J＝2.1Hz,1H),8.26(s,1H),7.70(d,J＝8.7Hz,2H),7.06(d,J＝8.8Hz,2H),3.36-3.16(m,4H),3.06(s,3H),2.90(s,3H),2.51-2.44(m,4H),2.25(s,3H)。LCMS(M+H)⁺＝442.3。

Example 164: 2- (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) oxazole (compound 164)

Prepared from 1- (4- [ 3-iodo-1H-pyrrolo [2,3-b ] in a manner similar to that described in step 6 of example 106]Pyridin-5-yl]Phenyl) -4-methylpiperazine prepared compound 164(30mg, 20%).¹H NMR(300MHz,DMSO-d6)δ12.06(s,1H),8.57-8.50(m,1H),8.47-8.41(m,1H),8.22(s,1H),8.10-8.01(m,3H),8.01-7.93(m,2H),7.64(d,J＝8.6Hz,2H),7.39(s,1H),7.06(d,J＝8.6Hz,2H),3.24-3.13(m,4H),2.50-2.44(m,4H),2.24(s,3H)。LCMS(M+H)⁺＝436.2。

Example 165: 2- (dimethylamino) -N-methyl-N- (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) acetamide (compound 165)

Prepared from 1- (4- [ 3-iodo-1H-pyrrolo [2,3-b ] in a manner similar to that described in step 6 of example 106]Pyridin-5-yl]Phenyl) -4-methylpiperazine prepared compound 165(21.9mg, 16.9%).¹H NMR(300MHz,DMSO-d6)δ11.95(s,1H),8.50(d,J＝2.1Hz,1H),8.35(d,J＝2.1Hz,1H),7.92(s,1H),7.82(d,J＝8.0Hz,2H),7.60(d,J＝8.2Hz,2H),7.35(d,J＝8.0Hz,2H),7.02(d,J＝8.5Hz,2H),3.23-3.12(m,7H),2.97-2.85(m,2H),2.47-2.39(m,4H),2.21(s,3H),2.14-2.04(m,6H)。LCMS(M+H)⁺＝483.2。

Example 166: 2- (dimethylamino) -N- (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) acetamide (Compound 166)

Compound 166(39.1mg, 28.6%) was prepared from example 13 and 2- (dimethylamino) acetic acid.¹H NMR(300MHz,DMSO-d6)δ11.86(d,J＝2.6Hz,1H),9.75(s,1H),8.50(d,J＝2.1Hz,1H),8.34(d,J＝2.2Hz,1H),7.86-7.58(m,6H),7.05(d,J＝8.8Hz,2H),3.24-3.15(m,4H),3.09(s,2H),2.51-2.44(m,4H),2.30(s,6H),2.24(s,3H)。LCMS(M+H)⁺＝469.3。

Example 167: 3-methyl-1- (4- [5- [4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] phenyl) urea (compound 167)

Preparation of compound from example 13Object 167(2.7mg, 8.1%).¹H NMR(400MHz,DMSO-d6)δ11.79(s,1H),8.54-8.44(m,2H),8.30(d,J＝2.1Hz,1H),7.75(d,J＝2.6Hz,1H),7.67-7.56(m,4H),7.53-7.43(m,2H),7.04(d,J＝8.8Hz,2H),5.99(d,J＝4.8Hz,1H),3.19(t,J＝5.1Hz,4H),2.65(d,J＝4.6Hz,3H),2.52-2.40(m,4H),2.23(s,3H)。LCMS(M+H)⁺＝441.3。

Example 168: 1, 3-dimethyl-1- (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) urea (compound 168)

Prepared in a similar manner to that described in step 6 of example 106 from 1, 3-dimethyl-1- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Urea preparation compound 168(2.8mg, 29.4%).¹H NMR(300MHz,DMSO-d6)δ11.95(d,J＝2.7Hz,1H),8.52(d,J＝2.1Hz,1H),8.36(d,J＝2.1Hz,1H),7.89(d,J＝2.6Hz,1H),7.82-7.76(m,2H),7.65-7.59(m,2H),7.36-7.29(m,2H),7.09-7.02(m,2H),5.96-5.89(m,1H),3.23-3.16(m,7H),2.58(d,J＝4.4Hz,3H),2.50-2.45(m,4H),2.24(s,3H)。LCMS(M+H)⁺＝455.4。

Example 169: 1, 1-dimethyl-3- (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) urea (Compound 169)

Prepared in a similar manner to that described in step 6 of example 106 from 3, 3-dimethyl-1- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Urea preparation compound 169(13.9mg, 5.1%).¹H NMR(300MHz,DMSO-d6)δ11.80(s,1H),8.48(d,J＝2.1Hz,1H),8.35-8.27(m,2H),7.77(d,J＝2.6Hz,1H),7.68-7.50(m,6H),7.04(d,J＝8.9Hz,2H),3.19(t,J＝5.0Hz,4H),2.95(s,6H),2.46(s,4H),2.23(s,3H)。LCMS(M+H)⁺＝455.1。

Example 170: 3- [2- (dimethylamino) ethyl ] -1- (4- [5- [4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] phenyl) urea (compound 170)

Prepared from 3- [2- (dimethylamino) ethyl group in a similar manner to that described in step 6 of example 106 ]-1- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Urea preparation compound 170(26.8mg, 9.2%).¹H NMR(300MHz,DMSO-d6)δ11.80(s,1H),8.68(s,1H),8.49(d,J＝2.1Hz,1H),8.31(d,J＝2.1Hz,1H),7.75(d,J＝2.4Hz,1H),7.63(s,1H),7.67-7.57(m,3H),7.47(d,J＝8.6Hz,2H),7.05(d,J＝8.8Hz,2H),6.13-6.03(m,1H),3.26-3.14(m,6H),2.50-2.45(m,4H),2.39-2.29(m,2H),2.24(s,3H),2.19(s,6H)。LCMS(M+H)⁺＝498.2。

Example 171: n- (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanesulfonamide (compound 171)

Prepared from N- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl in a similar manner to that described in step 6 of example 106]Methanesulfonamide preparation compound 171(45mg, 28.8%).¹H NMR(400MHz,DMSO-d6)δ11.88(d,J＝2.7Hz,1H),9.69(s,1H),8.50(d,J＝2.1Hz,1H),8.34(d,J＝2.1Hz,1H),7.83(d,J＝2.6Hz,1H),7.79-7.72(m,2H),7.66-7.59(m,2H),7.34-7.27(m,2H),7.08-7.01(m,2H),3.31(s,3H),3.22-3.15(m,4H),2.50-2.44(m,4H),2.24(s,3H)。LCMS(M+H)⁺＝462.1。

Example 172: n- (4- [5- [4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] phenyl) cyclopropanesulfonamide (compound 172)

Step 1: n- (4-bromophenyl) cyclopropanesulfonamide (Compound 172-1)

To a stirred solution of 4-bromoaniline (240mg, 1.40mmol, 0.33 equiv.) and pyridine (1.02g, 12.90mmol, 3.02 equiv.) in dichloromethane (20mL) was added cyclopropanesulfonyl chloride (600mg, 4.27mmol, 1 equiv.) dropwise at room temperature. The resulting mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with petroleum ether: ethyl acetate ═ 1: 1) to give the title compound (400mg, 28.2%).

Step 2: n- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] cyclopropanesulfonamide (Compound 172-2)

The title compound (320mg, 77.6%) was prepared from N- (4-bromophenyl) cyclopropanesulfonamide in a similar manner to that described in example 109, step 1. LCMS (M + H)⁺＝322.0。

And step 3: n- (4- [5- [4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] phenyl) cyclopropanesulfonamide (compound 172)

Prepared from 3-iodo-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that described in example 106, step 6]Pyridine preparation compound 172(31.6mg, 20.0%).¹H NMR(400MHz,DMSO-d6)δ11.89(d,J＝2.6Hz,1H),9.70(s,1H),8.51(d,J＝2.1Hz,1H),8.35(d,J＝2.1Hz,1H),7.84(d,J＝2.6Hz,1H),7.79-7.72(m,2H),7.66-7.58(m,2H),7.37-7.30(m,2H),7.09-7.01(m,2H),3.25-3.11(m,4H),2.69-2.58(m,1H),2.50-2.45(m,4H),2.24(s,3H),0.99-0.92(m,4H)。LCMS(M+H)⁺＝488.3。

Example 173: n- (4- [5- [4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] phenyl) propane-1-sulfonamide (compound 173)

Step 1: n- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] propane-1-sulfonamide (Compound 173-1)

The title compound (350mg, 61.4%) was prepared in a similar manner to that in example 172, step 1 and step 2.

Step 2: n- (4- [5- [4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] phenyl) propane-1-sulfonamide (compound 173)

Prepared from 3-iodo-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that described in example 106, step 6 ]Pyridine preparation compound 173(57.3mg, 24.9%).¹H NMR(400MHz,DMSO-d6)δ11.89(d,J＝2.8Hz,1H),9.77(s,1H),8.51(d,J＝2.2Hz,1H),8.35(d,J＝2.2Hz,1H),7.83(d,J＝2.6Hz,1H),7.75(d,J＝8.4Hz,2H),7.63(d,J＝8.4Hz,2H),7.34-7.27(m,2H),7.05(d,J＝8.7Hz,2H),3.23-3.16(m,4H),3.13-3.04(m,2H),2.50-2.45(m,4H),2.24(s,3H),1.79-1.65(m,2H),0.96(t,J＝7.5Hz,3H)。LCMS(M+H)⁺＝409.3。

Example 174: n- (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) butane-1-sulfonamide (compound 174)

Step 1: n- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) butane-1-sulfonamide (compound 174-1)

The title compound (360.0mg, 54.7%) was prepared in a similar manner to that in example 172, step 1 and step 2. LC-MS (M + H)₂O)⁺＝357.1。

Step 2: n- (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) butane-1-sulfonamide (compound 174)

Prepared from 3-iodo-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that described in example 106, step 6]Pyridine preparation compound 174(58.4mg, 68%).¹H NMR(300MHz,DMSO-d6)δ11.89(d,J＝2.7Hz,1H),9.76(s,1H),8.51(d,J＝2.2Hz,1H),8.35(d,J＝2.2Hz,1H),7.83(d,J＝2.6Hz,1H),7.79-7.71(m,2H),7.66-7.60(m,2H),7.34-7.27(m,2H),7.08-7.01(m,2H),3.23-3.16(m,4H),3.14-3.06(m,2H),2.50-2.45(m,4H),2.24(s,3H),1.74-1.62(m,2H),1.44-1.30(m,2H),0.89-0.81(m,3H)。LC-MS(M+H)⁺＝504.2。

Example 175: n- (4- [5- [4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] phenyl) cyclopentanesulfonamide (compound 175)

Step 1: n- (4-bromophenyl) cyclopentane sulfonamide (compound 175-1)

The title compound (110mg, 24.5%) was prepared from 4-bromoaniline and cyclopentanesulfonyl chloride in a similar manner to that described in example 172, step 1. LC-MS (M + H) ⁺＝304.0。

Step 2: n- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] cyclopentanesulfonamide (Compound 175-2)

The title compound (70mg, 73.4%) was prepared from N- (4-bromophenyl) cyclopentane sulfonamide in a similar manner to that described in example 109, step 1. LC-MS (M + H)⁺＝350.3。

And step 3: n- (4- [5- [4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] phenyl) cyclopentanesulfonamide (compound 175)

Prepared from 3-iodo-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that described in example 106, step 6]Pyridine preparation compound 175(15.7mg, 19.5%).¹H NMR(300MHz,DMSO-d6)δ8.50(d,J＝2.1Hz,1H),8.34(d,J＝2.1Hz,1H),7.82(s,1H),7.77-7.71(m,2H),7.61(d,J＝8.7Hz,2H),7.34-7.30(m,2H),7.06-7.01(m,2H),3.60-3.52(m,1H),3.21-3.14(m,4H),2.49-2.44(m,4H),2.22(s,3H),1.98-1.81(m,4H),1.71-1.61(m,2H),1.59-1.47(m,2H)。LC-MS(M+H)⁺＝516.3。

Example 176: 4-methoxy-N- (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) benzenesulfonamide (compound 176)

Step 1: n- (4-bromophenyl) -4-methoxybenzenesulfonamide (compound 176-1)

The title compound (1.3g, 68.1%) was prepared from 4-bromoaniline and 4-methoxybenzene-1-sulfonyl chloride in a similar manner to that described in example 172, step 1. LC-MS (M + H)⁺＝341.9。

Step 2: 4-methoxy-N- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) benzenesulfonamide (compound 176-2)

The title compound (1.25g, 95.4%) was prepared from N- (4-bromophenyl) -4-methoxybenzene-1-sulfonamide in a similar manner to that described in example 109, step 1. LC-MS (M + H) ⁺＝389.9。

And step 3: 4-methoxy-N- (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) benzenesulfonamide (compound 176)

Prepared from 3-iodo-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that described in example 106, step 6]Pyridine preparation compound 176(12mg, 9.9%).¹H NMR(300MHz,DMSO-d6)δ11.87(d,J＝4.3Hz,1H),10.25(d,J＝1.9Hz,1H),8.52(s,1H),8.40(d,J＝4.2Hz,1H),7.6-7.8(m,7H),7.05-7.22(m,6H),3.80(s,3H),3.26-3.23(m,4H),2.52-2.48(m,4H),2.22-2.18(m,3H)。LC-MS(M+H)⁺＝554.2。

Example 177: n- [1- (4- [5- [4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] phenyl) ethyl ] ethane-1-sulfonamide (Compound 177)

Step 1: n- [1- (4-bromophenyl) ethyl ] ethane-1-sulfonamide (Compound 177-1)

Prepared from 1- (4-bromophenyl) ethan-1-amine and ethanesulfonyl chloride in a similar manner to that described in example 172, step 1The title compound (1.1g, 48.4%) was prepared. LC-MS (M + H)⁺＝291.0。

Step 2: n- [1- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] ethyl ] ethane-1-sulfonamide (Compound 177-2)

Prepared by reacting N- [1- (4-bromophenyl) ethyl group in a similar manner to that described in step 1 of example 109]Ethane-1-sulfonamide prepared the title compound (600mg, 53.8%). LC-MS (M + H)⁺＝296.0。

And step 3: n- [1- (4- [5- [4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] phenyl) ethyl ] ethane-1-sulfonamide (Compound 177)

Prepared from 3-iodo-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that described in example 106, step 6]Pyridine preparation compound 177(19.7mg, 13.2%).¹H NMR(400MHz,DMSO-d6)δ11.92(d,J＝2.7Hz,1H),8.51(d,J＝2.1Hz,1H),8.35(d,J＝2.1Hz,1H),7.88(d,J＝2.6Hz,1H),7.77-7.71(m,3H),7.66-7.59(m,2H),7.46(d,J＝8.1Hz,2H),7.09-7.02(m,2H),4.55-4.43(m,1H),3.23-3.16(m,4H),2.91-2.77(m,1H),2.76-2.63(m,1H),2.52-2.45(m,4H),2.24(s,3H),1.45(d,J＝6.9Hz,3H),1.10(t,J＝7.3Hz,3H)。LC-MS(M+H)⁺＝504.2。

Example 178: 5- (4- (4-Methylpiperazin-1-yl) phenyl) -3- (1-methylpiperidin-4-yl) -1H-pyrrolo [2,3-b ] pyridine (compound 178)

Step 1: 3- (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) -5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (compound 178-1)

Prepared from 3-iodo-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that described in example 106, step 6]Pyridine preparation the title compound (800mg, 53.2%). LCMS (M + H)⁺＝388.2。

Step 2: 5- (4- (4-Methylpiperazin-1-yl) phenyl) -3- (1-methylpiperidin-4-yl) -1H-pyrrolo [2,3-b ] pyridine (compound 178)

Prepared in a similar manner to that described in example 136, step 2 from 1-methyl-4- [4- [3- (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) -1H-pyrrolo [2,3-b ]]Pyridin-5-yl]Phenyl radical]Piperazine prepared compound 178(75mg, 60.2%).¹H NMR(400MHz,DMSO-d6)δ11.32(s,1H),8.41(d,J＝2.1Hz,1H),8.09(d,J＝2.1Hz,1H),7.57(d,J＝8.4Hz,2H),7.22(d,J＝2.3Hz,1H),7.04(d,J＝8.5Hz,2H),3.23-3.14(m,4H),2.91-2.83(m,2H),2.83-2.72(m,1H),2.50-2.44(m,4H),2.26-2.20(m,6H),2.10-2.00(m,2H),1.99-1.91(m,2H),1.79-1.68(m,2H)。LCMS(M+H)⁺＝390.2。

Example 179: 3- (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenoxy) propan-1-amine (Compound 179)

Step 1: 2- (3- (4-bromophenoxy) propyl) isoindoline-1, 3-dione (Compound 179-1)

To 2- (3-hydroxypropyl) -2, 3-dihydro-1H-isoindole-1, 3-dione (2.052g, 9.499mmol, 1 equiv.), 4-bromophenol (1.73g, 9.999mmol, 1.05 equiv.), PPh₃(3.94g, 15.009mmol, 1.58 equiv.) to a solution in THF (25mL) was added DEAD (2.35mL, 13.494mmol, 1.42 equiv., 95%). The mixture was stirred at room temperature under a nitrogen atmosphere for 16 h. The reaction mixture was quenched with water (10mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with petroleum ether: ethyl acetate ═ 1: 1) to give the title compound (1.5g, 27.3%). LCMS (M + H)⁺＝360.1。

Step 2: 2- (3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy) propyl) isoindoline-1, 3-dione (Compound 179-2)

Prepared in a similar manner to that described in step 1 of example 109 from 2- [3- (4-bromophenoxy) propyl]Preparation of (E) -2, 3-dihydro-1H-isoindole-1, 3-dione (520mg, 93.9%))。LCMS(M+H)⁺＝⁺408.2。

And step 3: 2- (3- (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenoxy) propyl) isoindoline-1, 3-dione (Compound 179-3)

Prepared from 3-iodo-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that in example 106 step 6]Pyridine preparation the title compound (50mg, 10.8%). LCMS (M + H)⁺＝572.4。

And 4, step 4: 3- (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenoxy) propan-1-amine (Compound 179)

To the 2- [3- (4- [5- [4- (4-methylpiperazin-1-yl) phenyl group]-1H-pyrrolo [2,3-b]Pyridin-3-yl]Phenoxy) propyl group]To a solution of-2, 3-dihydro-1H-isoindole-1, 3-dione (38mg, 0.06mmol, 1 equiv.) in EtOH (9mL) was added hydrazine hydrate (66.6mg, 1.13mmol, 17.72 equiv.). The mixture was stirred at 80 ℃ under nitrogen atmosphere for 3 h. The mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC to give compound 179(10mg, 35.2%).¹H NMR(300MHz,DMSO-d6)δ11.81(s,1H),8.49(d,J＝2.1Hz,1H),8.28(d,J＝2.1Hz,1H),7.76(s,1H),7.67(d,J＝8.8Hz,2H),7.60(d,J＝8.8Hz,2H),7.06-7.02(m,4H),4.11-3.99(m,2H),3.23-3.08(m,4H),2.74-2.71(m,2H),2.54-2.45(m,4H),2.24(s,3H),1.91-1.76(m,2H)。LCMS(M+H)⁺＝442.4。

Example 180: dimethyl [2- (4- [5- [4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] phenoxy) ethyl ] amine (compound 180)

Prepared in a similar manner to that described in step 6 of example 106 from dimethyl ([2- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy)]Ethyl radical]) Amine preparation compound 180(26.8mg, 15.6%). ¹HNMR(400MHz,DMSO-d6)δ11.81(s,1H),8.49(d,J＝2.1Hz,1H),8.28(d,J＝2.1Hz,1H),7.75(d,J＝2.5Hz,1H),7.72-7.55(m,4H),7.09-6.98(m,4H),4.10-4.07(t,J＝5.8Hz,2H),3.20-3.16(m,4H),2.64(t,J＝5.8Hz,2H),2.48-2.44(m,4H),2.23(s,9H)。LCMS(M+H)⁺＝456.3。

Example 181: n, N-dimethyl-2- (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenoxy) acetamide (Compound 181)

Prepared from N, N-dimethyl-2- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy]Acetamide preparation compound 181(20mg, 7.1%).¹H NMR(400MHz,DMSO-d6)δ11.80(d,J＝2.6Hz,1H),8.49(d,J＝2.1Hz,1H),8.28(d,J＝2.1Hz,1H),7.75(d,J＝2.6Hz,1H),7.71-7.63(m,2H),7.67-7.56(m,2H),7.08-6.97(m,4H),4.83(s,2H),3.22-3.15(m,4H),3.03(s,3H),2.87(s,3H),2.51-2.44(m,4H),2.23(s,3H)。LCMS(M+H)⁺＝470.0。

Example 182: n, N-dimethyl-3- (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenoxy) propionamide (Compound 182)

Prepared from N, N-dimethyl-3- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy]Propionamide preparation of compound 182(22.9mg, 5.0%).¹H NMR(400MHz,DMSO-d6)δ11.81(s,1H),8.49(s,1H),8.29(s,1H),7.76(d,J＝2.4Hz,1H),7.68(d,J＝8.2Hz,2H),7.60(d,J＝8.3Hz,2H),7.03(t,J＝9.4Hz,4H),4.28-4.20(m,2H),3.22-3.15(m,4H),3.02(s,3H),2.88-2.78(m,5H),2.51-2.44(m,4H),2.24(s,3H)。LCMS(M+H)⁺＝484.3。HPLC:254nm,98.4％。

Example 183: 2- (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenoxy) ethylamine (compound 183)

Step 1: (tert-butyl 2- (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenoxy) ethyl) carbamate (Compound 183-1)

Prepared from 1- (4- [ 3-iodo-1H-pyrrolo [2,3-b ] in a manner similar to that described in step 6 of example 106]Pyridin-5-yl]Phenyl) -4-methylpiperazine the title compound (180mg, 39.3%) was prepared. LCMS (M + H) ⁺＝528.4。

Step 2: 2- (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenoxy) ethylamine (compound 183)

Prepared from N- [2- (4- [5- [4- (4-methylpiperazin-1-yl) phenyl ] in a similar manner to that described in step 3 of example 121]-1H-pyrrolo [2,3-b]Pyridin-3-yl]Phenoxy) ethyl]Tert-butyl carbamate compound 183(42.2mg, 27.9%) was prepared.¹H NMR(400MHz,DMSO-d6)δ11.82(s,1H),8.49(d,J＝2.1Hz,1H),8.29(d,J＝2.2Hz,1H),7.77(s,1H),7.70(d,J＝8.4Hz,2H),7.60(d,J＝8.4Hz,2H),7.12-7.00(m,4H),5.71-5.21(m,2H),4.11-3.99(m,2H),3.22-3.15(m,4H),3.09-3.03(m,2H),2.50-2.44(m,4H),2.24(s,3H)。LCMS(M+H)⁺＝428.3。

Example 184: n, N-dimethyl-2- (5- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) pyridin-2-yloxy) ethylamine (Compound 184)

Prepared from 1- (4- [ 3-iodo-1H-pyrrolo [2,3-b ] in a manner similar to that described in step 6 of example 106]Pyridin-5-yl]Phenyl) -4-methylpiperazine and dimethyl (2- [ [5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl]Oxy radical]Ethyl) amine preparation of compound 184(44.5mg, 32.9%).¹H NMR(300MHz,DMSO-d6)δ11.94(d,J＝2.7Hz,1H),8.60-8.51(m,2H),8.31(d,J＝2.1Hz,1H),8.15-8.09(m,1H),7.88(d,J＝2.6Hz,1H),7.65(d,J＝8.7Hz,2H),7.05(d,J＝8.6Hz,2H),6.91(d,J＝8.5Hz,1H),4.38(t,J＝7.8Hz,2H),3.23-3.17(m,4H),2.64(t,J＝8.0Hz,2H),2.50-2.44(m,4H),2.22(s,9H)。LCMS(M+H)⁺＝457.2。

Example 185: 3- (4- (ethylsulfonyl) phenyl) -5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (compound 185)

Prepared from 1- (4- [ 3-iodo-1H-pyrrolo [2,3-b ] in a manner similar to that described in step 6 of example 106]Pyridin-5-yl]Phenyl) -4-methylpiperazine compound 185(4.5mg, 2.0%) was prepared. ¹H NMR(300MHz,DMSO-d6)δ12.21(s,1H),8.56(s,1H),8.47(s,1H),8.15(s,1H),8.10(d,J＝8.0Hz,2H),7.91(d,J＝8.1Hz,2H),7.65(d,J＝8.3Hz,2H),7.06(d,J＝8.4Hz,2H),3.33-3.28(q,J＝7.3Hz,2H),3.24-3.17(m,4H),2.52-2.45(m,4H),2.24(s,3H),1.15(t,J＝7.3Hz,3H)。LCMS(M+H)⁺＝461.2。

Example 186: 5- (4- (4-Methylpiperazin-1-yl) phenyl) -3- (4- (methylsulfonyl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (Compound 186)

Compound 186(21.2mg, 21.2%) was prepared from 2- (4-methanesulfonylphenyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan in a similar manner to that described in example 106, step 6.¹H NMR(400MHz,DMSO-d6)δ12.18(s,1H),8.55(d,J＝2.1Hz,1H),8.45(d,J＝2.1Hz,1H),8.13(s,1H),8.11-8.04(m,2H),7.99-7.92(m,2H),7.68-7.61(m,2H),7.06(d,J＝8.8Hz,2H),3.31(s,3H),3.22-3.16(m,4H),2.50-2.44(m,4H),2.24(s,3H)。

Example 187: 3- (4- (cyclopropylsulfonyl) phenyl) -5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (compound 187)

Prepared from 2- [4- (cyclopropanesulfonyl) phenyl in a similar manner to that described in example 106, step 6]-4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan preparation compound 187(15mg, 7.0%).¹H NMR(400MHz,DMSO-d6)δ12.19(s,1H),8.55(d,J＝2.0Hz,1H),8.46(d,J＝2.1Hz,1H),8.13(s,1H),8.11-8.04(m,2H),7.96-7.88(m,2H),7.69-7.61(m,2H),7.10-7.01(m,2H),3.24-3.15(m,4H),2.93-2.82(m,1H),2.51-2.44(m,4H),2.23(s,3H),1.20-1.03(m,4H)。LCMS(M+H)⁺＝473.0。

Example 188: n, N-dimethyl-4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzenesulfonamide (compound 188)

Compound 188(52.9mg, 23.6%) was prepared from N, N-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzenesulfonamide in a similar manner to that described in example 106, step 6.¹H NMR(400MHz,DMSO-d6)δ12.20(s,1H),8.59-8.46(m,2H),8.19-8.06(m,3H),7.84-7.75(m,2H),7.66(d,J＝8.7Hz,2H),7.07(d,J＝8.7Hz,2H),3.25-3.16(m,4H),2.67(s,6H),2.52-2.44(m,4H),2.25(s,3H)。LCMS(M+H)⁺＝476.1。

Example 189: n, N-dimethyl-4- ((5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) benzamide (compound 189)

Step 1: 4- (hydroxy (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) -N, N-dimethylbenzamide (compound 189-1)

In a similar manner to that described in step 1 of example 151By reacting 4-formyl-N, N-dimethylbenzamide with 1-methyl-4- (4- [ 1H-pyrrolo [2,3-b ]]Pyridin-5-yl]Phenyl) piperazine the title compound (680mg, 84.8%) was prepared. LCMS (M + H)⁺＝470.2。

Step 2: n, N-dimethyl-4- ((5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) benzamide (compound 189)

Prepared from 4- [ hydroxy ([5- [4- (4-methylpiperazin-1-yl) phenyl) in a similar manner to that described in step 2 of example 151]-1H-pyrrolo [2,3-b]Pyridin-3-yl]) Methyl radical]Preparation of-N, N-dimethylbenzamide compound 189(15mg, 26.2%).¹H NMR(300MHz,DMSO-d6)δ11.43(s,1H),8.45-8.39(m,1H),8.00-7.95(m,1H),7.53-7.46(m,2H),7.42-7.34(m,2H),7.35-7.26(m,3H),7.05-6.98(m,2H),4.13(s,2H),3.21-3.14(m,4H),3.00-2.79(m,6H),2.54-2.43(m,4H),2.23(s,3H)。LCMS(M+H)⁺＝454.4。

Example 190: n, N-dimethyl-4- (1- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) ethyl) benzamide (compound 190)

Prepared from 4- [ hydroxy ([2- [4- (4-methylpiperazin-1-yl) phenyl) in a similar manner to that described in example 152, step 1]-5H-pyrrolo [2,3-b]Pyrazin-7-yl]) Methyl radical]-N, N-dimethylbenzamide preparation of compound 190(4mg, 5.7%). ¹H NMR(300MHz,DMSO-d6,ppm)δ11.45(s,1H),8.38(d,J＝2.2Hz,1H),7.74(d,J＝2.2Hz,1H),7.45-7.36(m,5H),7.31(d,J＝8.1Hz,2H),7.02-6.96(m,2H),4.48-4.38(m,1H),3.19-3.12(m,4H),3.00-2.81(m,6H),2.50-2.43(m,4H),2.23(s,3H),1.67(d,J＝7.2Hz,3H)。LCMS(M+H)⁺＝468.5。

Example 191: n, N-dimethyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide (compound 191)

Step 1: 5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (compound 191-1)

Prepared from 1-methyl-4- (2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) piperazine and 5-bromo-1H-pyrrolo [2,3-b ] in a similar manner to that described in example 106, step 4]Pyridine preparation the title compound (1.0g, 67.7%). LCMS (M + H)⁺＝307.0。

Step 2: 3-iodo-5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (compound 191-2)

Prepared from 5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that described in step 5 of example 106]Pyridine preparation the title compound (600mg, 54.2%). LCMS (M + H)⁺＝433.1。

And step 3: n, N-dimethyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide (compound 191)

Prepared from 3-iodo-5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that described in example 106, step 6]Pyridine preparation compound 191(18.6mg, 14.8%). ¹H NMR(400MHz,DMSO-d6)δ12.07(s,1H),8.53(s,1H),8.41(s,1H),8.00(s,1H),7.85(d,J＝7.8Hz,2H),7.60-7.44(m,4H),7.12(d,J＝8.2Hz,1H),3.03-2.98(m,6H),2.92-2.85(m,4H),2.53-2.45(m,4H),2.34(s,3H),2.25(s,3H)。LCMS(M+H)⁺＝454.5。

Example 192: (4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (2-oxa-6-azaspiro [3.3] hept-6-yl) methanone (Compound 192)

Step 1: (4- (2-oxa-6-azaspiro [3.3] heptane-6-carbonyl) phenyl) boronic acid (compound 192-1)

In step 1 and step 112In a similar manner to that described in step 2, starting from 2-oxa-6-azaspiro [3.3]Heptane the title compound was prepared (550mg, 75.4%). LC-MS (M + H)⁺＝248.1。

Step 2: (4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (2-oxa-6-azaspiro [3.3] hept-6-yl) methanone (Compound 192)

Prepared from 3-iodo-5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that described in example 106, step 6]Pyridine preparation compound 192(47.3mg, 40.8%).¹H NMR(400MHz,DMSO-d6)δ12.11(s,1H),8.54(s,1H),8.42(s,1H),8.04(s,1H),7.88(d,J＝8.0Hz,2H),7.70(d,J＝8.0Hz,2H),7.60-7.51(m,2H),7.13(d,J＝8.3Hz,1H),4.70(s,4H),4.55(brs,2H),4.24(s,2H),3.37-3.33(m,4H),2.91-2.86(m,4H),2.34(s,3H),2.26(s,3H)。LC-MS(M+H)⁺＝508.3。

Example 193: n- (3-methoxypropyl) -N-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide (compound 193)

Step 1: [4- [ (3-methoxypropyl) (methyl) carbamoyl ] phenyl ] boronic acid (compound 193-1)

The title compound (50mg, 81.3%) was prepared from 3-methoxypropyl-methylamine hydrochloride in a similar manner to that described in example 112, step 1 and step 2. LC-MS (M + H) ⁺＝252.2。

Step 2: n- (3-methoxypropyl) -N-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide (compound 193)

Prepared from 3-iodo-5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that described in example 106, step 6]Pyridine preparation compound 193(15.9mg, 10.9%).¹H NMR(400MHz,DMSO-d6)δ12.06(d,J＝2.7Hz,1H),8.53(d,J＝2.1Hz,1H),8.41(d,J＝2.1Hz,1H),8.00(d,J＝2.7Hz,1H),7.88-7.82(m,2H),7.60-7.50(m,2H),7.47-7.44(m,2H),7.13(d,J＝8.3Hz,1H),3.66-3.35(m,5H),3.31-3.07(m,4H),2.98(s,3H),2.91-2.88(m,4H),2.56-2.53(m,2H),2.34(s,3H),2.26(s,3H),1.82-1.79(m,2H)。LC-MS(M+H)⁺＝512.7。

Example 194: 4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (Compound 194)

Step 1: 5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (compound 194-1)

Prepared in a similar manner to that described in step 4 of example 106 from 1- [2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-4-methylpiperazine and 5-bromo-1H-pyrrolo [2,3-b]Pyridine preparation the title compound (4.8g, 58.8%). LCMS (M + H)⁺＝321.3。

Step 2: 5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -3-iodo-1H-pyrrolo [2,3-b ] pyridine (compound 194-2)

Prepared from 1- (2, 6-dimethyl-4- [ 1H-pyrrolo [2,3-b ] in a similar manner to that described in step 5 of example 106]Pyridin-5-yl ]Phenyl) -4-methylpiperazine the title compound (992mg, 17.4%) was prepared. LCMS (M + H)⁺＝447.3

And step 3: 4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (Compound 194)

Prepared from 1- (4- [ 3-iodo-1H-pyrrolo [2,3-b ] in a manner similar to that described in step 6 of example 106]Pyridin-5-yl]-2, 6-dimethylphenyl) -4-methylpiperazine prepared compound 194(14.6mg, 24%).¹H NMR(400MHz,DMSO-d6)δ12.05(s,1H),8.52(s,1H),8.40(s,1H),7.99(d,J＝2.6Hz,1H),7.85(d,J＝7.9Hz,2H),7.49(d,J＝7.8Hz,2H),7.37(s,2H),3.09-3.04(m,4H),3.01(s,6H),2.49-2.44(m,4H),2.37(s,6H),2.27(s,3H)。LCMS(M+H)⁺＝468.5。

Example 195: 4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (3-methoxypropyl) -N-methylbenzamide (Compound 195)

Prepared from 5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -3-iodo-1H-pyrrolo [2,3-b ] in a similar manner to that described in example 106, step 6]Pyridine preparation compound 195(16.6mg, 8.3%).¹H NMR(400MHz,DMSO-d6)δ12.05(s,1H),8.52(s,1H),8.40(s,1H),7.99(s,1H),7.84(d,J＝7.9Hz,2H),7.46(d,J＝7.7Hz,2H),7.37(s,2H),3.54-3.16(m,7H),3.09-3.02(m,4H),2.98(s,3H),2.47-2.40(m,4H),2.37(s,6H),2.25(s,3H),1.84-1.79(m,2H)。LC-MS(M+H)⁺＝526.1。

Example 196: 4- [5- [3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N- [2- (dimethylamino) ethyl ] -N-methylbenzamide (compound 196)

Prepared from 5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -3-iodo-1H-pyrrolo [2,3-b ] in a similar manner to that described in example 106, step 6 ]Pyridine preparation compound 196(9.6mg, 3.5%).¹H NMR(400MHz,DMSO-d6)δ12.06(d,J＝2.6Hz,1H),8.52(s,1H),8.40(s,1H),8.00(s,1H),7.85(d,J＝8.0Hz,2H),7.47(d,J＝7.9Hz,2H),7.37(s,2H),3.33-3.28(m,4H),3.10-3.05(m,4H),3.00(s,3H),2.39-2.35(m,8H),2.32-2.27(m,8H),2.04-2.00(m,3H)。LC-MS(M+H)⁺＝525.4。

Example 197: 4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N-ethyl-N-methylbenzamide (Compound 197)

Prepared from 5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -3-iodo-1H-pyrrolo [2,3-b ] in a similar manner to that described in example 106, step 6]Pyridine preparation compound 197(20mg, 8.9%).¹H NMR(400MHz,DMSO-d6)δ12.05(s,1H),8.51(s,1H),8.40(s,1H),7.99(s,1H),7.84(d,J＝8.0Hz,2H),7.46(d,J＝7.8Hz,2H),7.37(s,2H),3.46-3.30(m,2H),3.07-3.04(m,4H),2.97(s,3H),2.45-2.43(m,4H),2.26(s,6H),2.21(s,3H),1.23(s,3H)。LC-MS(M+H)⁺＝482.4；HPLC:254nm,98.7％。

Example 198: 1- (2, 6-dimethyl-4- [3- [4- (pyridin-2-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-5-yl ] phenyl) -4-methylpiperazine (compound 198)

Step 1: 2- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] pyridine (Compound 198-1)

The title compound (317mg, 90.5%) was prepared from 2- (4-bromophenyl) pyridine (250mg, 1.015mmol, 1 eq) in a similar manner to that described in example 109, step 1. LC-MS (M + H)⁺＝282.1。

Step 2: 1- (2, 6-dimethyl-4- [3- [4- (pyridin-2-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-5-yl ] phenyl) -4-methylpiperazine (compound 198)

Prepared from 5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -3-iodo-1H-pyrrolo [2,3-b ] in a similar manner to that described in example 106, step 6 ]Pyridine preparation compound 198(18.6mg, 11.0%).¹H NMR(400MHz,DMSO-d6)δ12.05(s,1H),8.69(d,J＝4.7Hz,1H),8.53(d,J＝2.3Hz,1H),8.43(d,J＝2.5Hz,1H),8.20(d,J＝7.9Hz,2H),8.01(d,J＝6.9Hz,2H),7.95-7.85(m,3H),7.39-7.36(m,3H),3.10-3.03(m,4H),2.47-2.43(m,4H),2.40-2.35(m,6H),2.26(s,3H)。LC-MS(M+H)⁺＝474.2。

Example 199: 5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -3- (4- (pyridin-3-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (compound 199)

Step 1: 3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) pyridine (compound 199-1)

The title compound (283mg, 74.4%) was prepared from 3- (4-bromophenyl) pyridine in a similar manner to that described in example 109, step 1. LC-MS (M + H)⁺＝282.2。

Step 2: 5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -3- (4- (pyridin-3-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (compound 199)

Prepared from 5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -3-iodo-1H-pyrrolo [2,3-b ] in a similar manner to that described in example 106, step 6]Pyridine preparation compound 199(26.7mg, 12%).¹H NMR(400MHz,DMSO-d6)δ12.05(s,1H),8.97(s,1H),8.58(d,J＝4.8Hz,1H),8.53(s,1H),8.42(s,1H),8.17-8.11(m,1H),8.01(d,J＝2.5Hz,1H),7.93(d,J＝8.0Hz,2H),7.83(d,J＝7.9Hz,2H),7.55-7.47(m,1H),7.38(s,2H),3.13-3.03(m,4H),2.47-2.40(m,4H),2.37(s,6H),2.25(s,3H)。LC-MS(M+H)⁺＝474.3。

Example 200: 1- (2, 6-dimethyl-4- [3- [4- (pyridin-4-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-5-yl ] phenyl) -4-methylpiperazine (compound 200)

Step 1: 4- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] pyridine (Compound 200-1)

The title compound (320mg, 77.6%) was prepared from 4- (4-bromophenyl) pyridine in a similar manner to that described in example 109, step 1. LC-MS (M + H) ⁺＝282.2。

Step 2: 1- (2, 6-dimethyl-4- [3- [4- (pyridin-4-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-5-yl ] phenyl) -4-methylpiperazine (compound 200)

Prepared from 5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -3-iodo-1H-pyrrolo [2,3-b ] in a similar manner to that described in example 106, step 6]Pyridine preparation compound 200(15.3mg, 8.9%).¹H NMR(400MHz,DMSO-d6)δ12.08(s,1H),8.68-8.62(m,2H),8.53(s,1H),8.43(s,1H),8.04(s,1H),7.99-7.88(m,4H),7.81-7.75(m,2H),7.39(s,2H),3.08-3.02(m,4H),2.46-2.42(m,4H),2.37(s,6H),2.25(s,3H)。LC-MS(M+H)⁺＝474.3。

Example 201: n- (4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) cyclopropanesulfonamide (Compound 201)

Prepared from 5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -3-iodo-1H-pyrrolo [2,3-b ] in a similar manner to that described in example 106, step 6]Pyridine preparation compound 201(12.9mg, 7.7%).¹H NMR(400MHz,DMSO-d6)δ11.94(d,J＝2.5Hz,1H),9.72(s,1H),8.50(s,1H),8.35(s,1H),7.85(s,1H),7.75(d,J＝8.2Hz,2H),7.39-7.31(m,4H),3.07(br s,4H),2.68-2.60(m,1H),2.51-2.45(m,4H),2.37(s,6H),2.30-2.26(m,3H),1.00-0.92(m,4H)。LC-MS(M+H)⁺＝516.2。

Example 202: 4- (5- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (Compound 202)

Step 1: 1- (4-bromo-2-methoxyphenyl) -4-methylpiperazine (compound 202-1)

The title compound (1.3g, 42.0%) was prepared from 4-bromo-2-methoxyaniline and bis (2-chloroethyl) (methyl) amine in a similar manner to that described in example 141, step 1. LC-MS (M + H)⁺＝285.0。

Step 2: 1- [ 2-methoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] -4-methylpiperazine (compound 202-2)

The title compound (400mg, 61.0%) was prepared from 1- (4-bromo-2-methoxyphenyl) -4-methylpiperazine in a similar manner to the one described in example 109, step 1. LC-MS (M + H)⁺＝333.3。

And step 3: 1- (2-methoxy-4- [ 1H-pyrrolo [2,3-b ] pyridin-5-yl ] phenyl) -4-methylpiperazine (compound 202-3)

Prepared from 1- [ 2-methoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl in a similar manner to that described in step 4 of example 106]-4-methylpiperazine and 5-bromo-1H-pyrrolo [2,3-b]Pyridine preparation the title compound (320.0mg, 76.0%). LC-MS (M + H)⁺＝323.2。

And 4, step 4: 3-iodo-5- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (compound 202-4)

Prepared from 1- (2-methoxy-4- [ 1H-pyrrolo [2,3-b ] in a similar manner to that described in step 5 of example 106]Pyridin-5-yl]Phenyl) -4-methylpiperazine the title compound (210.0mg, 57.0%) was prepared. LC-MS (M + H)⁺＝449.1。

And 5: 4- (5- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (Compound 202)

Prepared from 3-iodo-5- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that described in example 106, step 6 ]Pyridine and [4- (dimethylcarbamoyl) phenyl]Boronic acid preparation compound 202(26.0mg, 13.0%).¹H NMR(400MHz,DMSO-d6)δ12.07(s,1H),8.60-8.55(m,1H),8.46-8.41(m,1H),8.03-7.97(m,1H),7.86(d,J＝8.0Hz,2H),7.50(d,J＝8.0Hz,2H),7.31-7.23(m,2H),6.99(d,J＝8.0Hz,1H),3.91(s,3H),3.05-2.99(m,10H),2.51-2.45(m,4H),2.24(s,3H)。LC-MS(M+H)⁺＝470.3。

Example 203: 4- [5- [ 3-cyano-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N, N-dimethylbenzamide (Compound 203)

Step 1: 5-bromo-2- (4-methylpiperazin-1-yl) benzonitrile (Compound 203-1)

To a 20mL sealed tube were added 5-bromo-2-fluorobenzonitrile (200mg, 0.950mmol, 1 equivalent), 1-methylpiperazine (120.19mg, 1.140mmol, 1.20 equivalents), Cs₂CO₃(651.61mg, 1.900mmol, 2.00 equiv.) and DMSO (5 mL). The resulting mixture was stirred at 120 ℃ for 1 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluting with dichloromethane/MeOH ═ 5: 1) to give the title compound (220mg, 67.8%). LC-MS (M + H)⁺＝280.1。

Step 2: 2- (4-Methylpiperazin-1-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzonitrile (Compound 203-2)

The title compound (100mg, 43.6%) was prepared from 5-bromo-2- (4-methylpiperazin-1-yl) benzonitrile in a similar manner to the manner described in example 109, step 1. LC-MS (M + H)⁺＝328.2。

And step 3: 2- (4-Methylpiperazin-1-yl) -5- [ 1H-pyrrolo [2,3-b ] pyridin-5-yl ] benzonitrile (Compound 203-3)

Prepared in a similar manner to that described in example 106, step 4 from 2- (4-methylpiperazin-1-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzonitrile and 5-bromo-1H-pyrrolo [2,3-b ]]Pyridine preparation the title compound (30mg, 62.7%). LC-MS (M + H)⁺＝318.2。

And 4, step 4: 5- [ 3-iodo-1H-pyrrolo [2,3-b ] pyridin-5-yl ] -2- (4-methylpiperazin-1-yl) benzonitrile (compound 203-4)

Prepared from 2- (4-methylpiperazin-1-yl) -5- [ 1H-pyrrolo [2,3-b ] in a similar manner to that described in step 5 of example 106]Pyridin-5-yl]Benzonitrile the title compound (200mg, 46.6%) was prepared. LC-MS (M + H)⁺＝444.0。

And 5: 4- [5- [ 3-cyano-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N, N-dimethylbenzamide (Compound 203)

Prepared from [4- (dimethylcarbamoyl) phenyl in a similar manner to that described in step 6 of example 106]Boronic acids and 5- [ 3-iodo-1H-pyrrolo [2,3-b ]]Pyridin-5-yl]-2- (4-methylpiperazin-1-yl) benzonitrile compound 203(24.7mg, 7.1%) was prepared.¹H NMR(400MHz,DMSO-d6)δ12.12(s,1H),8.59(s,1H),8.52(s,1H),8.20(s,1H),8.03(d,J＝7.3Hz,2H),7.89(d,J＝7.8Hz,2H),7.49(d,J＝7.8Hz,2H),7.27(d,J＝8.6Hz,1H),3.25-3.18(m,4H),3.01(s,6H),2.58-2.52(m,4H),2.27(s,3H)。LC-MS(M+H)⁺＝465.2。

Example 204: 4- (5- (4- (4- (cyclopropylmethyl) piperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (compound 204)

Step 1: 5- (4- (4- (cyclopropylmethyl) piperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (compound 204-1)

Prepared from 1- (cyclopropylmethyl) -4- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) piperazine and 5-bromo-1H-pyrrolo [2,3-b ] in a similar manner to that described in example 106, step 4]Pyridine preparation the title compound (300mg, 58.2%). LCMS (M + H)⁺＝333.2。

Step 2: 5- (4- (4- (cyclopropylmethyl) piperazin-1-yl) phenyl) -3-iodo-1H-pyrrolo [2,3-b ] pyridine (compound 204-2)

Prepared from 5- (4- (4- (cyclopropylmethyl) piperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that described in step 5 of example 106]Pyridine preparation the title compound (200mg, 54.7%). LCMS (M + H)⁺＝459.1。

And step 3: 4- (5- (4- (4- (cyclopropylmethyl) piperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (compound 204)

Prepared in a similar manner to that described in step 6 of example 106 from 1- (cyclopropylmethyl) -4- (4- [ 3-iodo-1H-pyrrolo [2, 3-b)]Pyridin-5-yl]Phenyl) piperazine and [4- (dimethylcarbamoyl) phenyl]Boronic acid preparation compound 204(12mg, 8.0%).¹H NMR(400MHz,DMSO-d6)δ12.02(s,1H),8.53(d,J＝2.1Hz,1H),8.39(d,J＝2.2Hz,1H),7.98(s,1H),7.89-7.82(m,2H),7.66-7.58(m,2H),7.52-7.45(m,2H),7.05(d,J＝8.6Hz,2H),3.23-3.16(m,4H),3.00(s,6H),2.63-2.56(m,4H),2.23(d,J＝6.6Hz,2H),0.90-0.81(m,1H),0.53-0.44(m,2H),0.14-0.06(m,2H)。LCMS(M+H)⁺＝480.2。

Example 205: 4- (5- [4- [ (2R,6S) -2, 6-Dimethylmorpholin-4-yl ] phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (Compound 205)

Step 1: (2R,6S) -2, 6-dimethyl-4- (4- [ 1H-pyrrolo [2,3-b ] pyridin-5-yl ] phenyl) morpholine (Compound 205-1)

Prepared in a similar manner to that described in step 4 of example 106 from (2R,6S) -2, 6-dimethyl-4- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Morpholine and 5-bromo-1H-pyrrolo [2,3-b ]]Pyridine preparation the title compound (300mg, 52.6%). LCMS (M + H)⁺＝308.3。

Step 2: (2R,6S) -4- (4- [ 3-iodo-1H-pyrrolo [2,3-b ] pyridin-5-yl ] phenyl) -2, 6-dimethylmorpholine (Compound 205-2)

Prepared from (2R,6S) -2, 6-dimethyl-4- (4- [ 1H-pyrrolo [2,3-b ] in a similar manner to that described in step 5 of example 106]Pyridin-5-yl]Phenyl) morpholine the title compound (200mg, 43.7%) was prepared. LCMS (M + H)⁺＝433.8。

And step 3: 4- (5- [4- [ (2R,6S) -2, 6-Dimethylmorpholin-4-yl ] phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (Compound 205)

Prepared from (2R,6S) -4- (4- [ 3-iodo-1H-pyrrolo [2,3-b ] in a similar manner to that described in step 6 of example 106]Pyridin-5-yl]Phenyl) -2, 6-dimethylmorpholine prepared compound 205(21.1mg, 13.3%).¹H NMR(300MHz,DMSO-d6)δ12.02(s,1H),8.54(d,J＝2.0Hz,1H),8.41(d,J＝2.1Hz,1H),7.99(s,1H),7.86(d,J＝8.0Hz,2H),7.65(d,J＝8.61Hz,2H),7.50(d,J＝8.1Hz,2H),7.07(d,J＝8.6Hz,2H),3.80-3.59(m,4H),3.02(s,6H),2.36-2.25(m,2H),1.19(d,J＝6.2Hz,6H)。LCMS(M+H)⁺＝455.4。

Example 206: 4- (5- (4- ((2R,6R) -2, 6-Dimethylmorpholino) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-Dimethylbenzamide (Compound 206)

Step 1: (2R,6R) -4- (4- (1H-pyrrolo [2,3-b ] pyridin-5-yl) phenyl) -2, 6-dimethylmorpholine (Compound 206-1)

Prepared in a similar manner to that described in step 4 of example 106 from (2R,6R) -2, 6-dimethyl-4- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Morpholine and 5-bromo-1H-pyrrolo [2,3-b ]]Pyridine preparation the title compound (121.4mg, 26.9%). LCMS (M + H)⁺＝308.1。

Step 2: (2R,6R) -4- (4- (3-iodo-1H-pyrrolo [2,3-b ] pyridin-5-yl) phenyl) -2, 6-dimethylmorpholine (Compound 206-2)

Prepared from (2R,6R) -2, 6-dimethyl-4- (4- [ 1H-pyrrolo [2,3-b ] in a similar manner to that described in step 5 of example 106]Pyridin-5-yl]Phenyl) morpholine the title compound (180mg, 97.4%) was prepared. LCMS (M + H)⁺＝434.0。

And step 3: 4- (5- (4- ((2R,6R) -2, 6-Dimethylmorpholino) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-Dimethylbenzamide (Compound 206)

Prepared from (2R,6R) -4- (4- [ 3-iodo-1H-pyrrolo [2,3-b ] in a similar manner to that described in step 6 of example 106]Pyridin-5-yl]Phenyl) -2, 6-dimethylmorpholine (230mg, 0.53mmol, 1 eq) and [4- (dimethylcarbamoyl) phenyl]Boronic acid preparation compound 206(49.0mg, 20.2%).¹H NMR(400MHz,DMSO-d6)δ12.01(s,1H),8.52(d,J＝2.1Hz,1H),8.39(d,J＝2.1Hz,1H),7.98(d,J＝2.2Hz,1H),7.88-7.81(m,2H),7.66-7.60(m,2H),7.53-7.45(m,2H),7.08-7.00(m,2H),4.14-4.04(m,2H),3.28-3.20(m,2H),3.01(s,6H),2.95-2.86(m,2H),1.26-1.20(m,6H)。LCMS(M+H)⁺＝455.0。

Example 207: n, N-dimethyl-4- (5- (4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 207)

Step 1: 1- (1-methylpiperidin-4-yl) -4- (4- [ 1H-pyrrolo [2,3-b ] pyridin-5-yl ] phenyl) piperazine (compound 207-1)

Prepared in a similar manner to that described in step 4 of example 106 from 1- (1-methylpiperidin-4-yl) -4- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Piperazine and 5-bromo-1H-pyrrolo [2,3-b ]]Pyridine preparation the title compound (750mg, 80.6%). LCMS (M + H)⁺＝376.3。

Step 2: 1- (4- [ 3-iodo-1H-pyrrolo [2,3-b ] pyridin-5-yl ] phenyl) -4- (1-methylpiperidin-4-yl) piperazine (compound 207-2)

Prepared in a similar manner to that described in step 5 of example 106 from 1- (1-methylpiperidin-4-yl) -4- (4- [ 1H-pyrrolo [2, 3-b)]Pyridin-5-yl]Phenyl) piperazine the title compound (600mg, 90.4%) was prepared. LCMS (M + H)⁺＝502.2。

And step 3: n, N-dimethyl-4- (5- (4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 207)

Prepared from 1- (4- [ 3-iodo-1H-pyrrolo [2,3-b ] in a manner similar to that described in step 6 of example 106]Pyridin-5-yl]Phenyl) -4- (1-methylpiperidin-4-yl) piperazine and [4- (dimethylcarbamoyl) phenyl]Boronic acid preparation compound 207(20.0mg, 12.6%).¹H NMR(400MHz,DMSO-d6)δ12.00(s,1H),8.53(d,J＝2.1Hz,1H),8.39(d,J＝2.2Hz,1H),7.98(s,1H),7.85(d,J＝8.2Hz,2H),7.62(d,J＝8.6Hz,2H),7.49(d,J＝8.1Hz,2H),7.04(d,J＝8.5Hz,2H),3.21-3.14(m,4H),3.00(s,6H),2.83-2.76(m,2H),2.67-2.60(m,4H),2.16-2.12(m,4H),1.90-1.80(m,2H),1.80-1.72(m,2H),1.51-1.37(m,2H)。LCMS(M+H)⁺＝523.5。

Example 208: n, N-dimethyl-4- (5- (4- (2- (4-methylpiperazin-1-yl) ethyl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 208)

Step 1: 4-Methylbenzenesulfonic acid 4-bromobenzyl ethyl ester (Compound 208-1)

To a stirred solution of 2- (4-bromophenyl) ethan-1-ol (4g, 18.90mmol, 1 eq) and pyridine (4.7g, 56.70mmol, 3 eq) in dichloromethane (100mL) was added TsCl (5.7g, 28.35mmol, 1.5 eq) portionwise. The mixture was stirred at room temperature under a nitrogen atmosphere for 12 h. The mixture was concentrated and the residue was purified by silica gel column chromatography (eluting with petroleum ether: ethyl acetate ═ 10: 1) to give the title compound (5.0g, 63.3%).¹H NMR(300MHz,DMSO-d6)δ7.66(d,J＝7.9Hz,2H),7.42-7.38(dd,J＝8.1,4.1Hz,4H),7.09(d,J＝8.0Hz,2H),4.24(t,J＝6.2Hz,2H),2.87(t,J＝6.2Hz,2H),2.41(s,3H)。

Step 2: 1- (4-bromophenylethyl) -4-methylpiperazine (compound 208-2)

In a 20mL sealed tube, a mixture of 4-methylbenzene-1-sulfonic acid 2- (4-bromophenyl) ethyl ester (1.6g, 3.83mmol, 1 eq.) and 1-methylpiperazine (1.6g, 15.31mmol, 4 eq.) in THF (15mL) was stirred at 90 ℃ for 6 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with petroleum ether: ethyl acetate ═ 5: 1) to give the title compound (0.8g, 69.3%). LCMS (M + H)⁺＝283.3。

And step 3: 1-methyl-4- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenethyl) piperazine (compound 208-3)

Prepared by reacting 1- [2- (4-bromophenyl) ethyl group in a similar manner to that described in step 1 of example 109 ]-4-methylpiperazine the title compound (1.2g, 67.8%) was prepared. LCMS (M + H)⁺＝331.3。

And 4, step 4: 5- (4- (2- (4-methylpiperazin-1-yl) ethyl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (compound 208-4)

Prepared from 1-methyl-4- [2- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl in a similar manner to that described in step 4 of example 106]Ethyl radical]Piperazine and 5-bromo-1H-pyrrolo [2,3-b ]]Pyridine preparation the title compound (900mg, 95.7%). LCMS (M + H)⁺＝321.0。

And 5: 3-iodo-5- (4- (2- (4-methylpiperazin-1-yl) ethyl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (compound 208-5)

Prepared from 1-methyl-4- [2- (4- [ 1H-pyrrolo [2,3-b ] in a similar manner to that described in step 5 of example 106]Pyridin-5-yl]Phenyl) ethyl]Piperazine prepared the title compound (700mg, 63.4%). LCMS (M + H)⁺＝447.0。

Step 6: n, N-dimethyl-4- (5- (4- (2- (4-methylpiperazin-1-yl) ethyl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 208)

Prepared from 3-iodo-5- (4- (2- (4-methylpiperazin-1-yl) ethyl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that described in example 106, step 6]Pyridine preparation compound 208(20mg, 9.4%).¹H NMR(300MHz,DMSO-d6)δ12.06(s,1H),8.59-8.52(m,1H),8.48-8.41(m,1H),8.03-7.96(m,1H),7.90-7.81(m,2H),7.67(d,J＝8.1Hz,2H),7.52-7.43(m,2H),7.33(d,J＝8.1Hz,2H),3.01-2.94(m,6H),2.82-2.71(m,2H),2.59-2.50(m,2H),2.48-2.42(m,4H),2.35-2.29(m,4H),2.15(s,3H)。LCMS(M+H)⁺＝468.1。

Example 209: 4- (5- (4- (4- (2-hydroxyethyl) piperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (Compound 209)

Step 1: 2- (4- (4- (1H-pyrrolo [2,3-b ] pyridin-5-yl) phenyl) piperazin-1-yl) ethanol (compound 209-1)

Prepared from 2- [4- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl in a similar manner to that described in step 4 of example 106]Piperazin-1-yl]Ethan-1-ol and 5-bromo-1H-pyrrolo [2,3-b ]]Pyridine preparation the title compound (450mg, 69.9%). LCMS (M + H)⁺＝323.0。

Step 2: 2- (4- (4- (3-iodo-1H-pyrrolo [2,3-b ] pyridin-5-yl) phenyl) piperazin-1-yl) ethanol (compound 209-2)

Prepared from 2- [4- (4- [ 1H-pyrrolo [2,3-b ] in a similar manner to that described in step 5 of example 106]Pyridin-5-yl]Phenyl) piperazin-1-yl]Ethan-1-ol the title compound (100mg, 28.8%) was prepared. LCMS (M + H)⁺＝450.0。

And step 3: 4- (5- (4- (4- (2-hydroxyethyl) piperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (Compound 209)

Prepared from [4- (dimethylcarbamoyl) phenyl in a similar manner to that described in step 6 of example 106]Boronic acids and 2- [4- (4- [ 3-iodo-1H-pyrrolo [2,3-b ]]Pyridin-5-yl]Phenyl) piperazin-1-yl]Ethan-1-ol preparation of compound 209(14mg, 11.9%).¹H NMR(400MHz,DMSO-d6)δ12.03(s,1H),8.53(d,J＝2.1Hz,1H),8.40(d,J＝2.1Hz,1H),7.99(s,1H),7.89-7.82(m,2H),7.67-7.59(m,2H),7.53-7.46(m,2H),7.10-7.01(m,2H),4.45(t,J＝5.0Hz,1H),3.60-3.51(m,2H),3.23-3.16(m,4H),3.01(s,6H),2.62-2.55(m,4H),2.49-2.42(m,2H)。LCMS(M+H)⁺＝470.5。

Example 210: n, N-dimethyl-4- (5- [4- [ (4-methylpiperazin-1-yl) methyl ] phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 210)

Step 1: 1-methyl-4- [ (4- [ 1H-pyrrolo [2,3-b ] pyridin-5-yl ] phenyl) methyl ] piperazine (compound 210-1)

Prepared from 5-bromo-1H-pyrrolo [2,3-b ] in a similar manner to that described in step 4 of example 106]Pyridine and 1-methyl-4- [ [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Methyl radical]Piperazine prepared the title compound (320mg, 95.8%). LCMS (M + H)⁺＝308.1。

Step 2: 1- [ (4- [ 3-iodo-1H-pyrrolo [2,3-b ] pyridin-5-yl ] phenyl) methyl ] -4-methylpiperazine (compound 210-2)

Prepared from 1-methyl-4- [ (4- [ 1H-pyrrolo [2,3-b ] in a similar manner to that described in step 5 of example 106]Pyridin-5-yl]Phenyl) methyl]Piperazine prepared the title compound (350mg, 78.4%). LCMS (M + H)⁺＝434.2。

And step 3: n, N-dimethyl-4- (5- [4- [ (4-methylpiperazin-1-yl) methyl ] phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 210)

Prepared from 1- [ (4- [ 3-iodo-1H-pyrrolo [2,3-b ] in a similar manner to that described in step 6 of example 106]Pyridin-5-yl]Phenyl) methyl]-4-methylpiperazine preparation compound 210(38mg, 18.3%).¹H NMR(400MHz,DMSO-d6,ppm)δ12.08(s,1H),8.57(d,J＝2.1Hz,1H),8.47(d,J＝2.1Hz,1H),8.01(d,J＝2.4Hz,1H),7.90-.82(m,2H),7.76-7.69(m,2H),7.52-7.45(m,2H),7.44-7.37(m,2H),3.50(s,2H),3.01(s,6H),2.42-2.37(m,8H),2.16(s,3H)。LCMS(M+H)⁺＝455.1。

Example 211: 4- (5- (3, 5-dimethyl-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (Compound 211)

Step 1: (4-bromo-2, 6-dimethylphenyl) (4-methylpiperazin-1-yl) methanone (Compound 211-1)

To a solution of 4-bromo-2, 6-dimethylbenzoic acid (200mg, 0.83mmol, 1 eq) in dichloromethane (5mL) was slowly added oxalyl chloride (553.9mg, 4.36mmol, 5.26 eq) at room temperature. DMF (10mg, 0.14mmol, 0.16 eq, 100%) was then added to the mixture and the resulting mixture was stirred for 1 h. The mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (5mL), to which was added 1-methylpiperazine (96.2mg, 0.91mmol, 1.10 equivalents) and N, N-diisopropyl-ethylamine (321.6mg, 2.49mmol, 3.00 equivalents) in that order at room temperature. The mixture was stirred for 16 h. The mixture was diluted with water (10mL) and dichloromethane(3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (120mg, 40.4%). LC-MS (M + H)⁺＝311.1。

Step 2: (2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) (4-methylpiperazin-1-yl) methanone (Compound 211-2)

The title compound (520mg, 69.4%) was prepared from 1- (4-bromo-2, 6-dimethylbenzoyl) -4-methylpiperazine in a similar manner to the one described in example 109, step 1. LC-MS (M + H) ⁺＝359.3。

And step 3: (2, 6-dimethyl-4- (1H-pyrrolo [2,3-b ] pyridin-5-yl) phenyl) (4-methylpiperazin-1-yl) methanone (Compound 211-3)

Prepared from 5-bromo-1H-pyrrolo [2,3-b ] in a similar manner to that described in step 4 of example 106]Pyridine and 1- [2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoyl]-4-Methylpiperazine the title compound (630mg, crude) was prepared. LC-MS (M + H)⁺＝349.3。

And 4, step 4: 5- (3, 5-dimethyl-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (compound 211-4)

To 1- (2, 6-dimethyl-4- [ 1H-pyrrolo [2,3-b ] at room temperature]Pyridin-5-yl]To a solution of benzoyl) -4-methylpiperazine (200mg, 0.514mmol, 1 eq, 89.6%) in THF (15mL) was added LiAlH₄(65mg, 1.627mmol, 3.16 equiv.). The resulting mixture was then stirred at 80 ℃ for 16 h. The mixture was cooled to room temperature and slowly quenched with water (5 mL). The mixture was extracted with dichloromethane (3 × 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (140mg, 40.2%). LC-MS (M + H)⁺＝335.3。

And 5: 5- (3, 5-dimethyl-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -3-iodo-1H-pyrrolo [2,3-b ] pyridine (compound 211-5)

Prepared from 1- [ (2, 6-dimethyl-4- [ 1H-pyrrolo [2,3-b ] in a similar manner to that described in step 5 of example 106]Pyridin-5-yl]Phenyl radical) Methyl radical]-4-methylpiperazine the title compound (132.4mg, 95.4%) was prepared. LC-MS (M + H)⁺＝461.4。

Step 6: 4- (5- (3, 5-dimethyl-4- ((4-methylpiperazin-1-yl) methyl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (Compound 211)

Prepared from [4- (dimethylcarbamoyl) phenyl in a similar manner to that described in step 6 of example 106]Boronic acids and 1- [ (4- [ 3-iodo-1H-pyrrolo [2,3-b ]]Pyridin-5-yl]-2, 6-dimethylphenyl) methyl]-4-methylpiperazine preparation compound 211(26mg, 16.3%).¹H NMR(300MHz,DMSO-d6)δ12.07(d,J＝2.7Hz,1H),8.55(d,J＝2.0Hz,1H),8.44(d,J＝2.1Hz,1H),8.00(d,J＝2.6Hz,1H),7.90-7.83(m,2H),7.54-7.46(m,2H),7.40(s,2H),3.48(s,2H),3.01(s,6H),2.54-2.42(m,10H),2.30-2.25(m,4H),2.14(s,3H)。LC-MS(M+H)⁺＝482.3。

Example 212: 4- (5- (4- (4-methoxyphenylethyl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (Compound 212)

Step 1: 5- (4- (4-methoxyphenylethyl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (Compound 212-1)

Prepared from 2- [4- [2- (4-methoxyphenyl) ethyl group in a similar manner to that described in step 4 of example 106]Phenyl radical]4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan and 5-bromo-1H-pyrrolo [2,3-b ]]Pyridine preparation the title compound (200mg, 94.4%). LCMS (M + H) ⁺＝329.1。

Step 2: 3-iodo-5- (4- (4-methoxyphenethyl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (compound 212-2)

Prepared from 5- [4- [2- (4-methoxyphenyl) ethyl group in a similar manner to that described in step 5 of example 106]Phenyl radical]-1H-pyrrolo [2,3-b]Pyridine preparation the title compound (210mg, 67.9%). LCMS (M + H)⁺＝455.0。

And step 3: 4- (5- (4- (4-methoxyphenylethyl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (Compound 212)

Prepared from 3-iodo-5- (4- (4-methoxyphenethyl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that described in step 6 of example 106]Pyridine preparation compound 212(19mg, 10.2%).¹H NMR(300MHz,DMSO-d6)δ12.07(s,1H),8.56(d,J＝2.1Hz,1H),8.45(d,J＝2.2Hz,1H),8.01(d,J＝2.4Hz,1H),7.89-7.83(m,2H),7.72-7.65(m,2H),7.53-7.45(m,2H),7.34(d,J＝8.1Hz,2H),7.22-7.14(m,2H),6.89-6.81(m,2H),3.72(s,3H),3.01(s,6H),2.96-2.82(m,4H)。LCMS(M+H)⁺＝476.1。

Example 213: n, N-dimethyl-4- [5- [2- (4-methylpiperazin-1-yl) pyrimidin-5-yl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide (compound 213)

Step 1: 2- (4-Methylpiperazin-1-yl) -5- [ 1H-pyrrolo [2,3-b ] pyridin-5-yl ] pyrimidine (Compound 213-1)

Prepared from 2- (4-methylpiperazin-1-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine and 5-bromo-1H-pyrrolo [2,3-b ] in a similar manner to that described in example 106, step 4]Pyridine preparation the title compound (180mg, 52.5%). LC-MS (M + H) ⁺＝295.2。

Step 2: 5- [ 3-iodo-1H-pyrrolo [2,3-b ] pyridin-5-yl ] -2- (4-methylpiperazin-1-yl) pyrimidine (Compound 213-2)

Prepared from 2- (4-methylpiperazin-1-yl) -5- [ 1H-pyrrolo [2,3-b ] in a similar manner to that described in step 5 of example 106]Pyridin-5-yl]Pyrimidine the title compound was prepared (170mg, 76.0%). LC-MS (M + H)⁺＝421.0。

And step 3: n, N-dimethyl-4- [5- [2- (4-methylpiperazin-1-yl) pyrimidin-5-yl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide (compound 213)

Prepared from 5- [ 3-iodo-1H-pyrrolo [2,3-b ] in a similar manner to that described in step 6 of example 106]Pyridin-5-yl]-2- (4-methylpiperazin-1-yl) pyrimidine and [4- (dimethylamino)Formyl) phenyl]Boronic acid preparation compound 213(10.2mg, 8.4%).¹H NMR(400MHz,DMSO-d6)δ12.11(s,1H),8.82(s,2H),8.55(d,J＝2.1Hz,1H),8.50(d,J＝2.1Hz,1H),8.03(s,1H),7.89(d,J＝8.0Hz,2H),7.48(d,J＝7.9Hz,2H),3.83-3.76(m,4H),3.01(s,6H),2.41-2.36(m,4H),2.23(s,3H)。LC-MS(M+H)⁺＝442.2。

Example 214: n, N-dimethyl-4- (5- [4- [ N-methyl-2- (4-methylpiperazin-1-yl) acetamido ] phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 214)

Step 1: n- (4-bromophenyl) -N-methyl-2- (4-methylpiperazin-1-yl) acetamide (compound 214-1)

To a 25mL round bottom flask at room temperature were added 4-bromo-N-methylaniline (50mg, 0.26mmol, 1 eq.), 2- (4-methylpiperazin-1-yl) acetic acid (63.8mg, 0.38mmol, 1.50 eq.), N-diisopropyl-ethylamine (138.9mg, 1.02mmol, 4.00 eq.) and T in dichloromethane (3mL) ₃P (487.4mg, 0.77mmol, 3.00 equiv.). The resulting mixture was stirred at 30 ℃ under a nitrogen atmosphere for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with dichloromethane: MeOH ═ 2: 1) to give the title compound (550mg, 61.2%). LCMS (M + H)⁺＝326.2。

Step 2: n-methyl-2- (4-methylpiperazin-1-yl) -N- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) acetamide (compound 214-2)

The title compound (704mg, 85.1%) was prepared from N- (4-bromophenyl) -N-methyl-2- (4-methylpiperazin-1-yl) acetamide in a similar manner to that described in example 109, step 1. LCMS (M + H)⁺＝374.4。

And step 3: n-methyl-2- (4-methylpiperazin-1-yl) -N- (4- [ 1H-pyrrolo [2,3-b ] pyridin-5-yl ] phenyl) acetamide (compound 214-3)

5-bromo-1H-pyrrolo [2,3-b ] is added to a 100mL sealed tube at room temperature]Pyridine (250mg, 1.205mmol,1 equivalent), N-methyl-2- (4-methylpiperazin-1-yl) -N- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Acetamide (703.07mg, 1.205mmol, 1.00 equiv.), Pd (dppf) Cl₂.CH₂Cl₂(164.06mg, 0.181mmol, 0.15 equiv.), Cs₂CO₃(826.81mg, 2.411mmol, 2.00 equiv.), dioxane (15.00mL) and H ₂O (1.50 mL). The resulting mixture was stirred at 80 ℃ under an argon atmosphere for 16 h. The mixture was concentrated under reduced pressure. The residue was chromatographed on silica gel (using CHCl)₃MeOH ═ 8:1 elution) to give the title compound (200mg, 38.0%). LCMS (M + H)⁺＝364.3。

And 4, step 4: n- (4- [ 3-iodo-1H-pyrrolo [2,3-b ] pyridin-5-yl ] phenyl) -N-methyl-2- (4-methylpiperazin-1-yl) acetamide (compound 214-4)

Prepared from N-methyl-2- (4-methylpiperazin-1-yl) -N- (4- [ 1H-pyrrolo [2, 3-b) in a similar manner to that described in step 5 of example 106]Pyridin-5-yl]Phenyl) acetamide the title compound (230mg, 94.1%) was prepared. LCMS (M + H)⁺＝490.1。

And 5: n, N-dimethyl-4- (5- [4- [ N-methyl-2- (4-methylpiperazin-1-yl) acetamido ] phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 214)

Prepared from N- (4- [ 3-iodo-1H-pyrrolo [2,3-b ] in a similar manner to that described in step 6 of example 106]Pyridin-5-yl]Phenyl) -N-methyl-2- (4-methylpiperazin-1-yl) acetamide and [4- (dimethylcarbamoyl) phenyl]Boronic acid preparation compound 214(3mg, 2.3%).¹H NMR(400MHz,DMSO-d6,ppm)δ12.13(s,1H),8.62(s,1H),8.53(s,1H),8.04(s,1H),7.92-7.82(m,4H),7.50(d,J＝7.9Hz,2H),7.45(d,J＝8.1Hz,2H),3.28-3.17(m,3H),3.02-2.99(m,8H),2.39-2.35(m,4H),2.27-2.22(m,4H),2.12(s,3H)。LCMS(M+H)⁺＝511.2。

Example 215: n-methyl-2- (4-methylpiperazin-1-yl) -N- [4- [3- (4- [ 2-oxa-6-azaspiro [3.3] heptane-6-carbonyl ] phenyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl ] phenyl ] acetamide (compound 215)

Compound 215(11mg, 9.2%) was prepared from compound 214-4 in a similar manner to that in example 214.¹H NMR(400MHz,DMSO-d6)δ12.19(s,1H),8.62(d,J＝2.0Hz,1H),8.53(d,J＝2.1Hz,1H),8.09(s,1H),7.92(d,J＝8.0Hz,2H),7.85(d,J＝7.9Hz,2H),7.70(d,J＝8.0Hz,2H),7.45(d,J＝8.0Hz,2H),4.73-4.68(m,4H),4.58-4.53(m,2H),4.26-4.22(m,2H),3.24-3.20(m,3H),3.00-2.95(m,2H),2.39-2.34(m,4H),2.26-2.22(m,4H),2.11(s,3H)。LCMS(M+H)⁺＝565.3。

Example 216: (2- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) oxazol-4-yl) (3- (dimethylamino) azetidin-1-yl) methanone (compound 216)

Step 1: 1- (4-bromo-2, 6-dimethylphenyl) -4-methylpiperazine

To a mixture of 4-bromo-2, 6-dimethylaniline (15g, 75mmol) and 2-chloro-N- (2-chloroethyl) -N-methylethyl-1-amine hydrochloride (21.6g, 112mmol) in xylene (80mL) was added TsOH (0.2g, 1.2 mmol). The mixture was refluxed for 17h under a nitrogen atmosphere. The mixture was cooled to room temperature. The solid was collected by filtration and dissolved in MeOH (100 mL). The solution was saturated with NaHCO₃The solution was basified and extracted with ethyl acetate (3 × 200 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, and then filtered. To the resulting solution was added activated carbon (10 g). The mixture was stirred for 1h and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluting with dichloromethane: MeOH ═ 10: 1) to give the title compound (12g, 56%). LC-MS (M + H)⁺＝282.8,284.9。

Step 2: 1- (2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -4-methylpiperazine

To a mixture of 1- (4-bromo-2, 6-dimethylphenyl) -4-methylpiperazine (4.0g, 14mmol) and 4,4,4 ', 4 ', 5,5 ', 5 ' -octamethyl-2, 2 ' -bis (1,3, 2-dioxaborolan) (5.3g, 21mmol) in 1, 4-dioxane (50mL) were added AcOK (4.1g, 42mmol) and Pd (dppf) Cl₂(500mg，0.7mmol). The mixture was stirred at 90 ℃ under a nitrogen atmosphere overnight. The mixture was cooled and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with dichloromethane: MeOH ═ 15: 1) to give the title compound (3.5g, 76%). LC-MS (M + H)⁺＝331.0。

And step 3: 5-bromo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridine-3-carbaldehyde

To 5-bromo-1H-pyrrolo [2,3-b ] at 0 DEG C]Pyridine-3-carbaldehyde (10.0g, 44.4mmol) was added in portions to a solution in DMF (60mL) with NaH (60% in oil, 2.4g, 60 mmol). The mixture was stirred at 0 ℃ for 30 min. To the mixture was added (2- (chloromethoxy) ethyl) trimethylsilane (11.1g, 66.5mmol) dropwise at 0 ℃. The mixture was stirred at 0 ℃ for 3 hours. The mixture was quenched with water (150 mL). The resulting mixture was extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with water (3 × 200mL), brine (200mL), dried over anhydrous sodium sulfate, then filtered and concentrated. The residue was purified by silica gel column chromatography (eluting with petroleum ether: ethyl acetate ═ 5: 1) to give the title compound (13.6g, 75%). LC-MS (M + H) ⁺＝354.8,356.7。

And 4, step 4: 2- (5-bromo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) oxazole-4-carboxylic acid methyl ester

To 5-bromo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b]To a solution of pyridine-3-carbaldehyde (5.0g, 14mmol) and serine methyl ester hydrochloride (2.6g, 17mmol) in N, N-dimethylacetamide (30mL) was added K₂CO₃(2.4g, 17 mmol). The mixture was stirred at room temperature overnight. The mixture was cooled to 0 ℃ and then CCl was added to the mixture₃Br (8.3g, 42mmol) and DBU (6.4g, 42 mmol). The mixture was stirred at 0 ℃ for 5 hours. The mixture was diluted with water (100mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (3 × 200mL), dried over anhydrous sodium sulfate, then filtered and concentrated. The residue was purified by silica gel column chromatography (eluting with petroleum ether: ethyl acetate ═ 5: 1) to give the title compound (1) as a yellow solid.8g，25％)。LC-MS(M+H)⁺＝451.7,453.7。

And 5: 2- (5-bromo-1H-pyrrolo [2,3-b ] pyridin-3-yl) oxazole-4-carboxylic acid methyl ester

To 2- (5-bromo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) oxazole-4-carboxylic acid methyl ester (1.8g, 4.0mmol) was added to a solution of TFA (10mL) in dichloromethane (10mL) dropwise. The mixture was stirred at room temperature overnight. The mixture was concentrated under vacuum. The residue was taken up in saturated NaHCO ₃The solution was basified and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluting with petroleum ether: ethyl acetate ═ 1: 1) to give the title compound (1.1g, 85%). LC-MS (M + H)⁺＝321.7,323.7。

Step 6: 2- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) oxazole-4-carboxylic acid hydrochloride

To 2- (5-bromo-1H-pyrrolo [2,3-b ]]Pyridin-3-yl) oxazole-4-carboxylic acid methyl ester (700mg, 2.2mmol) and 1- (2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -4-methylpiperazine (870mg, 2.6mmol) were added to a mixture of 1, 4-dioxane (30mL) and water (10mL)₂CO₃(900mg, 6.6mmol) and Pd (dppf) Cl₂(150mg, 0.20 mmol). The mixture was stirred at 90 ℃ under a nitrogen atmosphere overnight. The mixture was cooled and diluted with water (30mL) and washed with ethyl acetate (30 mL). The inorganic layer was separated and acidified to pH 2 with HCl (2M). The aqueous layer was concentrated in vacuo and the residue diluted with a mixture of dichloromethane (50mL) and methanol (5 mL). The resulting mixture was stirred for 10 minutes and then filtered. The filtrate was concentrated to give the title compound (800mg, 70%). LC-MS (M + H) ⁺＝431.9。

And 7: (2- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) oxazol-4-yl) (3- (dimethylamino) azetidin-1-yl) methanone

To 2- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]Pyridin-3-yl) oxazole-4-carboxylic acid hydrochloride (100mg, 0.21mmol), N-dimethylazetidin-3-amine dihydrochloride (70mg, 0.40mmol) and Et₃To a solution of N (120mg, 1.2mmol) in DMF (10mL) was added HATU (150mg, 0.40 mmol). The mixture was stirred for 3 hours. The mixture was diluted with NaOH solution (1M, 30mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with brine (3 × 30mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluting with dichloromethane: methanol: 25% ammonium hydroxide ═ 200:20: 0.5) to give the title compound (40mg, 36%).¹H NMR(400MHz,DMSO-d6)δ12.52(s,1H),8.64-8.58(m,3H),8.30(d,J＝2.6Hz,1H),7.37(s,2H),4.78-4.70(m,1H),4.51-4.43(m,1H),4.11-4.03(m,1H),3.88-3.79(m,1H),3.23-3.09(m,5H),3.03-2.74(m,4H),2.58(s,3H),2.36(s,6H),2.14(s,6H)。LC-MS(M+H)⁺514.0. HPLC 99.7% at 214nm and 98.4% at 254 nm.

Example 217: 2- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethyloxazole-4-carboxamide hydrochloride (compound 217)

Prepared in a similar manner to that in example 216, step 7 from 2- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2, 3-b) ]Pyridin-3-yl) oxazole-4-carboxylic acid hydrochloride and dimethylamine hydrochloride preparation example 217 gave the title compound (30mg, 29%).¹H NMR(400MHz,DMSO-d6)δ12.53(s,1H),10.39(brs,1H),8.61(d,J＝2.2Hz,1H),8.56(d,J＝2.0Hz,1H),8.53(s,1H),8.29(d,J＝2.8Hz,1H),7.37(s,2H),3.39(s,3H),3.28-2.88(m,11H),2.71(brs,3H),2.39(s,6H)。LC-MS(M+H)⁺458.9. HPLC 96.3% at 214nm and 98.0% at 254 nm.

Example 218: (2- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) oxazol-4-yl) (3-hydroxyazetidin-1-yl) methanone (compound 218)

Prepared in a similar manner to that in example 216, step 7 from 2- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) oxazole-4-carboxylic acid hydrochloride and azetidin-3-ol preparation example 218 was prepared to give the title compound (25mg, 30%).¹H NMR(400MHz,DMSO-d6)δ12.49(s,1H),8.66-8.63(m,2H),8.61(s,1H),8.27(s,1H),7.36(s,2H),5.79(d,J＝6.7Hz,1H),4.96-4.88(m,1H),4.61-4.51(m,1H),4.47-4.39(m,1H),4.30-4.23(m,1H),3.83-3.75(m,1H),3.12-3.03(m,4H),2.47-2.40(m,4H),2.37(s,6H),2.25(s,3H)。LC-MS(M+H)⁺486.9. HPLC 100% at 214nm and 98.9% at 254 nm.

Example 219: (2- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) oxazol-4-yl) (2-oxa-6-azaspiro [3.3] hept-6-yl) methanone (compound 219)

Prepared in a similar manner to that in example 216, step 7 from 2- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) oxazole-4-carboxylic acid hydrochloride and 2-oxa-6-azaspiro [3.3]Heptane preparation example 219(15mg, 29%). ¹H NMR(400MHz,DMSO-d6)δ12.50(s,1H),8.69(s,1H),8.67(s,1H),8.61(s,1H),8.27(s,1H),7.42(s,2H),4.94(s,2H),4.74(brs,4H),4.23(s,2H),3.10-3.02(m,4H),2.46-2.41(m,4H),2.39(s,6H),2.24(s,3H)。LC-MS(M+H)⁺512.9. HPLC 90.0% at 214nm and 94.9% at 254 nm.

Example 220: 2- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (2- (dimethylamino) ethyl) -N-methyloxazole-4-carboxamide (compound 220)

Prepared in a similar manner to that in example 216, step 7 from 2- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) oxazole-4-carboxylic acid hydrochloride and N1, N1, N2-trimethylethane-1, 2-diamine preparation example 220(30mg, 34%).¹H NMR(400MHz,DMSO-d6)δ12.51(s,1H),8.59(s,1H),8.57(s,1H),8.53(s,1H),8.28(s,1H),7.33(s,2H),3.95(brs,1H),3.56(brs,1H),3.40(brs,1H),3.11-3.03(m,4H),3.01(brs,2H),2.65-2.56(m,1H),2.49-2.43(m,5H),2.37(s,6H),2.27(s,3H),2.23(brs,2H),2.06(brs,4H)。LC-MS(M+H)⁺515.9. HPLC 97.8% at 214nm and 98.0% at 254 nm.

Example 221: (3- (dimethylamino) azetidin-1-yl) (2- (5- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) oxazol-4-yl) methanone (compound 221)

Step 1: 1- (4-bromo-2-methoxyphenyl) -4-methylpiperazine

The title compound of step 1 (4.9g, 86%) was prepared from 4-bromo-2-methoxyaniline and 2-chloro-N- (2-chloroethyl) -N-methylethyl-1-amine hydrochloride in a similar manner to that in example 216, step 1. LC-MS (M + H)⁺＝285.0,287.0。

Step 2: 1- (2-methoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -4-methylpiperazine

The title compound of step 2 (2.5g, 56%) was prepared from 1- (4-bromo-2-methoxyphenyl) -4-methylpiperazine and 4,4,4 ', 4 ', 5,5,5 ', 5 ' -octamethyl-2, 2 ' -bis (1,3, 2-dioxaborolan) in a similar manner to that in step 2 of example 216. LC-MS (M + H)⁺＝333.0。

And step 3: 2- (5- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) oxazole-4-carboxylic acid hydrochloride

In a manner similar to that in step 6 of example 216In a similar manner from 2- (5-bromo-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) oxazole-4-carboxylic acid methyl ester (700mg, 2.2mmol) and 1- (2-methoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -4-methylpiperazine the title compound of step 3 (crude, 550mg) was prepared. LC-MS (M + H)⁺＝433.8。

And 4, step 4: (3- (dimethylamino) azetidin-1-yl) (2- (5- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) oxazol-4-yl) methanone

Prepared from 2- (5- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that in example 216 step 7]Pyridin-3-yl) oxazole-4-carboxylic acid hydrochloride and N, N-dimethyl azetidin-3-amine dihydrochloride preparation example 221(20mg, 18%). ¹H NMR(400MHz,DMSO-d6)δ12.50(s,1H),8.70-8.60(m,3H),8.28(d,J＝2.5Hz,1H),7.28(s,1H),7.23(d,J＝8.1Hz,1H),6.96(d,J＝8.1Hz,1H),4.81-4.72(m,1H),4.51-4.44(m,1H),4.11-4.02(m,1H),3.90(s,3H),3.86-3.79(m,1H),3.19-3.09(m,1H),3.01(brs,4H),2.51(brs,4H),2.26(s,3H),2.12(s,6H)。LC-MS(M+H)⁺516.0. HPLC 97.8% at 214nm and 98.6% at 254 nm.

Example 222: (R) -N- (2-hydroxypropyl) -N-methyl-4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (Compound 222)

Step 1: (R) -4-bromo-N- (2-hydroxypropyl) benzamide

4-Bromobenzoic acid (25g, 124mmol) was dissolved in DMF (30 ml). DIEA (32.2g, 249mmol) was added and stirred at room temperature. HATU (56.85g, 149mmol) and (R) -1-aminopropan-2-ol (10.28g, 137mmol) were added and stirred at room temperature overnight. DMF was removed in vacuo. Water (200ml) was added and extracted with ethyl acetate. The combined organic layers were washed with brine and over Na₂SO₄And (5) drying. The product was received by column chromatography on silica gel (32g, 99%). LC-MS (M + H)⁺＝258.0。

Step 2: (R) -4-bromo-N- (2- ((tert-butyldimethylsilyl) oxy) propyl) benzamide

(R) -4-bromo-N- (2-hydroxypropyl) benzamide (32g, 124mmol), TBDMSCl (22.42g, 149mmol) and TEA (25.05g, 247.94mmol) were dissolved in DCM (300mL) and stirred at room temperature overnight. Water (200ml) was added and extracted with DCM. The combined organic layers were washed with brine and over Na₂SO₄And (5) drying. The product was received by column chromatography on silica gel (44.7g, 100%). LC-MS (M + H) ⁺＝372.0。

And step 3: (R) -4-bromo-N- (2- ((tert-butyldimethylsilyl) oxy) propyl) -N-methylbenzamide

(R) -4-bromo-N- (2- ((tert-butyldimethylsilyl) oxy) propyl) benzamide (44.7g, 120mmol) was dissolved in DMF (300 ml). At 0 ℃ under N₂NaH (9.6g, 240mmol) was added and stirred at 0 ℃ for 1 h. MeI (25.6g, 180mmol) was added and stirred at room temperature overnight. Water (600mL) was added and extracted with ethyl acetate. The combined organic layers were washed with brine and over Na₂SO₄And (5) drying. The product was received after concentration (46.4g, 100%). LC-MS (M + H)⁺＝386.0。

And 4, step 4: (R) -4-bromo-N- (2-hydroxypropyl) -N-methylbenzamide

TBAF (32g, 122.4mmol) was dissolved in THF (400 mL). (R) -4-bromo-N- (2- ((tert-butyldimethylsilyl) oxy) propyl) -N-methylbenzamide (36.4g, 94.2mmol) was added at 0 ℃ and stirred at room temperature for 3 h. Water (400ml) was added and extracted with ethyl acetate. The combined organic layers were washed with brine and over Na₂SO₄And (5) drying. The product was received by column chromatography on silica gel (24.5g, 99.4%). LC-MS (M + H)⁺＝272.0。

And 5: (R) -N- (2-hydroxypropyl) -N-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide

Mixing (R) -4-bromo-N- (2-hydroxypropyl) -N-methylbenzamide (24.5g, 90mmol), 4,4,4 ', 4 ', 5,5,5 ', 5 ' -octamethyl-2, 2 ' -bis (1,3, 2-dioxaborole)Alkane) (45.7g, 180mmol), KOAc (26.5g, 270mmol) and Pd (dppf) Cl₂(3.3g, 4.502mmol) was dissolved in 1, 4-dioxane (300mL) and in N₂Heat to 95 ℃ overnight. The solvent was removed in vacuo. Water (200mL) was added and extracted with ethyl acetate. The combined organic layers were washed with brine and over Na₂SO₄And (5) drying. The product was received by column chromatography on silica gel (28.5g, 99%). LC-MS (M + H)⁺＝320.0。

Step 6: 5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine

Reacting 5-bromo-1H-pyrrolo [2,3-b ]]Pyridine (11.8g, 60mmol), 1-methyl-4- (2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) piperazine (19g, 60mmol), K₂CO₃(16.6g, 120mmol) and Pd (dppf) Cl₂(2.2g, 3.0mmol) was dissolved in 1, 4-dioxane (200mL) and H₂O (30mL) and in N₂Heat to 100 ℃ overnight. The solvent was removed in vacuo. The product was received by column chromatography on silica gel (11.6g, 63%). LC-MS (M + H)⁺＝307.0。

And 7: 3-iodo-5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine

Reacting 5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]Pyridine (11.6g, 37.9mmol) was dissolved in DMF (150 mL). NIS (11.1g, 49mmol) was added at 0 ℃ and stirred at room temperature overnight. Water (300mL) was added and the product was received by filtration (16.37g, 100%). LC-MS (M + H)⁺＝433.0。

And 8: 3-iodo-5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester

3-iodo-5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]Pyridine (16.37g, 37.87mmol), Boc₂O (9.92g, 45.44mmol) and TEA (7.65g, 75.74mmol) were dissolved in THF (200 mL). DMAP (92.53mg, 0.757mmol) was added and stirred at room temperature overnight. Water (100mL) was added and extracted with ethyl acetate. The combined organic layers were washed with brine and over Na₂SO₄And (5) drying. By using silica gelThe upper column receives the product (14g, 70%). LC-MS (M + H)⁺＝533.0。

And step 9: (R) -N- (2-hydroxypropyl) -N-methyl-4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

3-iodo-5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]Pyridine-1-carboxylic acid tert-butyl ester (4g, 7.5mmol), (R) -N- (2-hydroxypropyl) -N-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide (3.36g, 10.5mmol), K ₂CO₃(2.075g, 15.0mmol) and Pd (dppf) Cl₂(275mg, 0.376mmol) was dissolved in 1, 4-dioxane (60mL) and H₂O (6mL) and in N₂Heat to 95 ℃ overnight. The solvent was removed in vacuo. Water (20mL) was added and extracted with DCM. The combined organic layers were washed with brine and over Na₂SO₄And (5) drying. Example 222(300mg, 8%) was received through a chromatography column on silica gel.¹H NMR(400MHz,DMSO-d6)δ12.04(s,1H),8.52(d,J＝1.9Hz,1H),8.41(d,J＝1.8Hz,1H),7.99(d,J＝2.6Hz,1H),7.84(d,J＝8.0Hz,2H),7.68-7.39(m,4H),7.12(d,J＝8.3Hz,1H),4.87-4.82(m,1H),3.99-3.87(m,1H),3.49-3.46(m,1H),3.34-3.29(m,1H),3.03(s,3H),2.89(s,4H),2.51(s,2H),2.49-2.39(m,2H),2.34(s,3H),2.25(s,3H),1.11-0.89(m,3H)。LC-MS(M+H)⁺＝498.0。

Example 223: (S) -N- (2-hydroxypropyl) -N-methyl-4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (Compound 223)

Step 1: (S) -4-bromo-N- (2-hydroxypropyl) benzamide

The title compound (12.84g, 100%) was prepared from 4-bromobenzoic acid and (S) -1-aminopropan-2-ol in a similar manner to that described in example 222, step 1. LC-MS (M + H)⁺＝258.0。

Step 2: (S) -4-bromo-N- (2- ((tert-butyldimethylsilyl) oxy) propyl) benzeneThe title compound (16.4g, 88.5%) was prepared from (S) -4-bromo-N- (2-hydroxypropyl) benzamide in a similar manner to that in example 222, step 2. LC-MS (M + H)⁺＝372.0。

And step 3: (S) -4-bromo-N- (2- ((tert-butyldimethylsilyl) oxy) propyl) -N-methylbenzamide

The title compound (17g, 99.8%) was prepared from (S) -4-bromo-N- (2- ((tert-butyldimethylsilyl) oxy) propyl) benzamide and MeI in a similar manner to that in example 222, step 3. LC-MS (M + H) ⁺＝386.0。

And 4, step 4: (S) -4-bromo-N- (2-hydroxypropyl) -N-methylbenzamide

The title compound (12g, 100%) was prepared from (S) -4-bromo-N- (2- ((tert-butyldimethylsilyl) oxy) propyl) -N-methylbenzamide in a similar manner to that in example 222, step 4. LC-MS (M + H)⁺＝272.0。

And 5: (S) -N- (2-hydroxypropyl) -N-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide

The title compound (11.8g, 83.7%) was prepared from (S) -4-bromo-N- (2-hydroxypropyl) -N-methylbenzamide in a similar manner to that in example 222, step 5. LC-MS (M + H)⁺＝320.0。

Step 6: (S) -N- (2-hydroxypropyl) -N-methyl-4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Prepared in a similar manner to that in example 222, step 9 from (S) -N- (2-hydroxypropyl) -N-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide and 3-iodo-5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]Pyridine-1-carboxylic acid tert-butyl ester preparation example 223(495mg, 10.58%).¹H NMR(400MHz,DMSO-d6)δ12.05(s,1H),8.53(d,J＝1.9Hz,1H),8.41(d,J＝1.8Hz,1H),8.00(d,J＝2.6Hz,1H),7.85(d,J＝8.0Hz,2H),7.63-7.36(m,4H),7.13(d,J＝8.3Hz,1H),4.88-4.83(m,1H),3.99-3.87(m,1H),3.49-3.46(m,1H),3.35-3.30(m,1H),3.03(s,3H),2.89(s,4H),2.52(s,2H),2.49-2.37(m,2H),2.34(s,3H),2.26(s,3H),1.11-0.89(m,3H)。LC-MS(M+H)⁺＝498.0。

Example 224: n- (2- (dimethylamino) ethyl) -2- (5- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N-methyloxazole-4-carboxamide (Compound 224)

Prepared from 2- (5- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that in example 216 step 7]Pyridin-3-yl) oxazole-4-carboxylic acid hydrochloride and N1, N1, N2-trimethylethane-1, 2-diamine preparation example 224(20mg, 16%).¹H NMR(400MHz,DMSO-d6)δ12.51(s,1H),8.66(s,1H),8.60(s,1H),8.53(s,1H),8.27(s,1H),7.26-7.20(m,2H),7.01(d,J＝7.7Hz,1H),4.01-3.92(m,1H),3.90(s,3H),3.60-3.51(m,1H),3.43(brs,2H),3.01(s,6H),2.56br(s,2H),2.47(brs,4H),2.23(brs,2H),2.20(s,3H),2.04(s,3H)。LC-MS(M+H)⁺517.9. HPLC 97.1% at 214nm and 98.4% at 254 nm.

Example 225: 5- (3- (4- (3- (dimethylamino) azetidine-1-carbonyl) oxazol-2-yl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) -2- (4-methylpiperazin-1-yl) benzonitrile (compound 225)

Step 1: 2- (4-methylpiperazin-1-yl) benzonitrile

To a solution of 2-fluorobenzonitrile (10g, 82mmol) and 1-methylpiperazine (12g, 120mmol) in DMF (100mL) was added K₂CO₃(16.6g, 120 mmol). The mixture was stirred at 80 ℃ overnight. The mixture was cooled and diluted with water (300mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic phases were washed with brine (3 × 200mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluting with dichloromethane: methanol ═ 20: 1) to give the title compound (8.5g, 51%). LC-MS (M + H)⁺＝202.0。

Step 2: 5-bromo-2- (4-methylpiperazin-1-yl) benzonitrile

To a solution of 2- (4-methylpiperazin-1-yl) benzonitrile (4.5g, 22mmol) in EtOH (30mL) at 0 deg.C was added dropwise Br ₂(7.0g, 44 mmol). After the addition, the mixture was stirred at room temperature for 2 hours. The mixture was washed with saturated NaHCO₃The solution (50mL) was basified and extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (4.2g, 90%). LC-MS (M + H)⁺＝279.8,281.8。

And step 3: 2- (4-methylpiperazin-1-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzonitrile

The title compound of step 3 (2.4g, 49%) was prepared from 5-bromo-2- (4-methylpiperazin-1-yl) benzonitrile and 4,4,4 ', 4 ', 5,5,5 ', 5 ' -octamethyl-2, 2 ' -bis (1,3, 2-dioxaborolan) in a similar manner to that in step 2 of example 216. LC-MS (M + H)⁺＝328.0。

And 4, step 4: 2- (5- (3-cyano-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) oxazole-4-carboxylic acid hydrochloride

Prepared from 2- (5-bromo-1H-pyrrolo [2,3-b ] in a similar manner to that in step 6 of example 216]Pyridin-3-yl) oxazole-4-carboxylic acid methyl ester and 2- (4-methylpiperazin-1-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzonitrile the title compound (280mg, crude) was prepared. LC-MS (M + H)⁺＝428.8。

And 5: 5- (3- (4- (3- (dimethylamino) azetidine-1-carbonyl) oxazol-2-yl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) -2- (4-methylpiperazin-1-yl) benzonitrile

Prepared from 2- (5- (3-cyano-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that in example 216 step 7]Pyridin-3-yl) oxazole-4-carboxylic acid hydrochloride and N, N-dimethyl azetidin-3-amine dihydrochloride preparation example 225(30mg, 29%).¹H NMR(400MHz,DMSO-d6)δ12.57(s,1H),8.67(d,J＝2.2Hz,1H),8.65-8.60(m,2H),8.31(s,1H),8.09(d,J＝2.2Hz,1H),7.97(dd,J＝8.6,2.3Hz,1H),7.24(d,J＝8.7Hz,1H),4.77-4.69(m,1H),4.51-4.44(m,1H),4.11-4.03(m,1H),3.84-3.78(m,1H),3.25-3.16(m,4H),3.15-3.07(m,1H),2.57-2.52(m,4H),2.26(s,3H),2.13(s,6H)。LC-MS(M+H)⁺510.9. HPLC 98.5% at 214nm and 99.0% at 254 nm.

Example 226: n, N-dimethyl-2- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) oxazole-4-carboxamide (Compound 226)

Step 1: 1- (4-bromo-2-methylphenyl) -4-methylpiperazine

The title compound of step 1 (8.1g, 70%) was prepared from 4-bromo-2-methylaniline and 2-chloro-N- (2-chloroethyl) -N-methylethyl-1-amine hydrochloride in a similar manner to that in example 216, step 1. LC-MS (M + H)⁺＝268.8,270.8。

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

The title compound of step 2 (6.2g, 55%) was prepared from 1- (4-bromo-2-methylphenyl) -4-methylpiperazine and 4,4,4 ', 4 ', 5,5,5 ', 5 ' -octamethyl-2, 2 ' -bis (1,3, 2-dioxaborolan) in a similar manner to that in step 2 of example 216. LC-MS (M + H)⁺＝317.0。

And step 3: 2- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) oxazole-4-carboxylic acid hydrochloride

Prepared from 2- (5-bromo-1H-pyrrolo [2,3-b ] in a similar manner to that in step 6 of example 216]Pyridin-3-yl) oxazole-4-carboxylic acid methyl ester and 1-methyl-4- (2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) piperazine the title compound of step 3 (2.6g, crude) was prepared. LC-MS (M + H)⁺＝417.9。

And 4, step 4: n, N-dimethyl-2- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) oxazole-4-carboxamide

Prepared from 2- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that in example 216 step 7]Pyridin-3-yl) oxazole-4-carboxylic acid hydrochloride and dimethylamine hydrochloride preparation example 226(400mg, 40%).¹H NMR(400MHz,DMSO-d6)δ12.51(s,1H),8.61(d,J＝2.1Hz,1H),8.56(d,J＝2.0Hz,1H),8.52(s,1H),8.28(d,J＝2.4Hz,1H),7.53(s,1H),7.50(d,J＝8.2Hz,1H),7.15(d,J＝8.2Hz,1H),3.39(s,3H),3.01(s,3H),2.91(brs,4H),2.53(brs,4H),2.34(s,3H),2.28(s,3H)。LC-MS(M+H)⁺444.9. HPLC 96.2% at 214nm and 97.7% at 254 nm.

Example 227: 2- (5- (3, 5-dimethyl-4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethyloxazole-4-carboxamide (compound 227)

Step 1: 1- (4-bromo-2, 6-dimethylphenyl) piperazine

The title compound of step 1 (2.5g, 37%) was prepared from 4-bromo-2, 6-dimethylaniline and bis (2-chloroethyl) amine hydrochloride in a similar manner to that in example 216, step 1. LC-MS (M + H) ⁺＝268.8,270.8。

Step 2: 1- (4-bromo-2, 6-dimethylphenyl) -4- (1-methylpiperidin-4-yl) piperazine

To a mixture of 1- (4-bromo-2, 6-dimethylphenyl) piperazine (1.2g, 4.4mmol) and 1-methylpiperidin-4-one (0.75g, 6.6mmol) in dichloromethane (30mL) was added NaBH (AcO)₃(2.7g, 13 mmol). The mixture was stirred for 5 hours. The mixture is washed with NaHCO₃The solution was diluted and extracted with dichloromethane (3 × 30 mL). The organic layers were combined, washed with brine, and Na₂SO₄Dried, filtered and concentrated to give the title compound (1.8g, crude). LC-MS (M + H)⁺＝365.9,367.9。

And step 3: 1- (2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -4- (1-methylpiperidin-4-yl) piperazine

The title compound of step 3 (200mg, 10%) was prepared from 1- (4-bromo-2, 6-dimethylphenyl) -4- (1-methylpiperidin-4-yl) piperazine and 4,4,4 ', 4 ', 5,5,5 ', 5 ' -octamethyl-2, 2 ' -bis (1,3, 2-dioxaborolan) in a similar manner to that in step 2 of example 216. LC-MS (M + H)⁺＝414.0。

And 4, step 4: 2- (5- (3, 5-dimethyl-4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) oxazole-4-carboxylic acid hydrochloride

Prepared from 2- (5-bromo-1H-pyrrolo [2,3-b ] in a similar manner to that in step 6 of example 216 ]Pyridin-3-yl) oxazole-4-carboxylic acid methyl ester and 1- (2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -4- (1-methylpiperidin-4-yl) piperazine the title compound (200mg, crude) was prepared. LC-MS (M + H)⁺＝514.9。

And 5: 2- (5- (3, 5-dimethyl-4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethyloxazole-4-carboxamide

Prepared in a similar manner to that in example 216, step 7 from 2- (5- (3, 5-dimethyl-4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]Pyridin-3-yl) oxazole-4-carboxylic acid hydrochloride and dimethylamine hydrochloride preparation example 227(60mg, 31%).¹H NMR(400MHz,DMSO-d6)δ12.50(s,1H),8.60(d,J＝2.1Hz,1H),8.55(d,J＝2.1Hz,1H),8.52(s,1H),8.28(s,1H),7.33(s,2H),3.39(s,3H),3.05(brs,4H),3.01(s,3H),2.90-2.82(m,2H),2.60(brs,4H),2.37(s,6H),2.23-2.18(m,5H),1.96(brs,2H),1.81-1.74(m,2H),1.54-1.42(m,2H)。LC-MS(M+H)⁺541.9. HPLC 94.5% at 214nm and 96.7% at 254 nm.

Example 228: 2- (5- (3-methoxy-4- (1-methylpiperidin-4-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethyloxazole-4-carboxamide (compound 228)

Step 1: 4- (4-chloro-2-methoxyphenyl) -1-methyl-1, 2,3, 6-tetrahydropyridine

To a mixture of 1-bromo-4-chloro-2-methoxybenzene (3.5g, 15.8mmol) and 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,2,3, 6-tetrahydropyridine (3.5g, 15.8mmol) in DMF (30mL) was added K ₂CO₃(4.3g, 31.1mmol) and Pd (dppf) Cl₂(500mg, 0.68 mmol). The mixture was stirred at 90 ℃ under a nitrogen atmosphere overnight. The mixture was cooled to room temperature, diluted with water (80mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with water (950mL) and brine (50mL) over anhydrous Na₂SO₄Dried, filtered and concentrated. The residue was purified by silica gel column chromatography (eluting with dichloromethane: MeOH ═ 20: 1) to give the title compound (2.2g, 61%). LC-MS (M + H)⁺＝237.9,239.9。

Step 2: 4- (4-chloro-2-methoxyphenyl) -1-methylpiperidine

To a solution of 4- (4-chloro-2-methoxyphenyl) -1-methyl-1, 2,3, 6-tetrahydropyridine (2.2g, 7.8mmol) in EtOH (20mL) were added AcOH (5mL) and PtO₂(50mg, 0.22 mmol). The mixture was stirred under a hydrogen atmosphere (1atm) for 3 hours. The mixture was filtered and concentrated. The residue was taken up in saturated NaHCO₃The solution (20mL) was basified and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄Dried, filtered and concentrated. The residue was purified by silica gel column chromatography (eluting with dichloromethane: MeOH ═ 15: 1) to give the title compound (1.3g, 69%). LC-MS (M + H)⁺＝239.9,241.9。

And step 3: 4- (2-methoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -1-methylpiperidine

To a mixture of 4- (4-chloro-2-methoxyphenyl) -1-methylpiperidine (1.3g, 4.6mmol) and 4,4,4 ', 4 ', 5,5,5 ', 5 ' -octamethyl-2, 2 ' -bis (1,3, 2-dioxaborolan) (1.5g, 5.9mmol) in dioxane (30mL) was added K₂CO₃(1.2G, 8.7mmol), Pd (X-Phos) G2(180mg, 0.23mmol), and X-Phos (220mg, 0.46 mmol). The mixture was stirred at 90 ℃ under a nitrogen atmosphere overnight. The mixture was cooled to room temperature, filtered and concentrated.The residue was purified by silica gel column chromatography (eluting with dichloromethane: MeOH ═ 20: 1) to give the title compound (0.8g, 52%). LC-MS (M + H)⁺＝332.0。

And 4, step 4: 2- (5- (3-methoxy-4- (1-methylpiperidin-4-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) oxazole-4-carboxylic acid hydrochloride

Prepared from 2- (5-bromo-1H-pyrrolo [2,3-b ] in a similar manner to that in step 6 of example 216]Pyridin-3-yl) oxazole-4-carboxylic acid methyl ester and 4- (2-methoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -1-methylpiperidine the title compound of step 4 (300mg, crude) was prepared. LC-MS (M + H)⁺＝432.9。

And 5: 2- (5- (3-methoxy-4- (1-methylpiperidin-4-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethyloxazole-4-carboxamide

Prepared from 2- (5- (3-methoxy-4- (1-methylpiperidin-4-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that in example 216 step 7]Pyridin-3-yl) oxazole-4-carboxylic acid hydrochloride and dimethylamine hydrochloride preparation example 228(20mg, 21%).¹H NMR(400MHz,DMSO-d6)δ12.54(s,1H),8.69(d,J＝1.9Hz,1H),8.62(d,J＝1.8Hz,1H),8.53(s,1H),8.30(d,J＝1.9Hz,1H),7.31(d,J＝7.7Hz,1H),7.27-7.23(m,2H),3.91(s,3H),3.42(s,3H),3.01(s,3H),2.94-2.86(m,3H),2.22(s,3H),2.01(brs,2H),1.75-1.62(m,4H)。LC-MS(M+H)⁺459.9. HPLC 94.6% at 214nm and 98.6% at 254 nm.

Example 229: n- (2- (dimethylamino) ethyl) -2- (5- (3-methoxy-4- (1-methylpiperidin-4-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N-methyloxazole-4-carboxamide (compound 229)

Prepared from 2- (5- (3-methoxy-4- (1-methylpiperidin-4-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that in example 216 step 7]Pyridin-3-yl) oxazole-4-carboxylic acid hydrochloride and N1, N1, N2-trimethylethane-1, 2-diamine preparation example 229(15mg, 14%).¹H NMR(400MHz,DMSO-d6)δ12.59(s,1H),8.70(s,1H),8.63(s,1H),8.58(s,1H),8.32(s,1H),7.33-7.27(m,3H),3.94(s,3H),3.75(brs,1H),3.50-3.40(m,4H),3.21-3.12(m,2H),3.12-2.99(m,5H),2.74(s,3H),2.65(brs,3H),2.27(brs,2H),2.06-1.90(m,5H)。LC-MS(M+H)⁺517.0. HPLC 95.8% at 214nm and 98.8% at 254 nm.

Example 230: n- (2- (dimethylamino) ethyl) -2- (5- (3-fluoro-4- (1-methylpiperidin-4-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N-methyloxazole-4-carboxamide (Compound 230)

Prepared from 2- (5- (3-fluoro-4- (1-methylpiperidin-4-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that in example 216 step 7]Pyridin-3-yl) oxazole-4-carboxylic acid hydrochloride and N1, N1, N2-trimethylethane-1, 2-diamine preparation example 230(30mg, 13%). ¹H NMR(400MHz,DMSO-d6)δ12.58(s,1H),8.68-8.58(m,2H),8.53(s,1H),8.30(s,1H),7.56-7.50(m,2H),7.49-7.42(m,1H),3.95(brs,1H),3.56(brs,1H),3.39(brs,1H),3.02(brs,2H),2.93-2.86(m,2H),2.84-2.73(m,1H),2.62-2.56(m,1H),2.49-2.43(m,1H),2.23-2.18(m,5H),2.10-1.94(m,6H),1.84-1.69(m,4H)。LC-MS(M+H)⁺504.9. HPLC 95.5% at 214nm and 96.8% at 254 nm.

Example 231: 2- (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenoxy) ethan-1-amine dihydrochloride (Compound 231)

Step 1: (2- (4-bromophenoxy) ethyl) carbamic acid tert-butyl ester

To a solution of 2- (4-bromophenoxy) ethan-1-amine (580mg, 4.6mmol, 1.0 eq.) in THF (30mL) was added (Boc)₂O (60mg, 49mmol, 1.05 eq.) and Et₃N (2.0mL, 13.9mmol, 3.0 equiv.). The reaction mixture was stirred at room temperature for 3 hours, thenThen diluted with ethyl acetate (30 mL). The organic layer was washed with brine (40mL) and Na₂SO₄Dried and evaporated in vacuo to afford the title compound (880mg, quantitative).

Step 2: (2- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy) ethyl) carbamic acid tert-butyl ester

To a solution of tert-butyl (2- (4-bromophenoxy) ethyl) carbamate (880mg, 2.8mmol, 1.0 equiv.) in 1, 4-dioxane (30mL) under nitrogen was added 4,4,4 ', 4 ', 5,5,5 ', 5 ' -octamethyl-2, 2 ' -bis (1,3, 2-dioxaborolan) (480mg, 3.1mmol, 1.1 equiv.), Pd (dppf) Cl₂(120mg, 0.21mmol, 0.07 equiv.) and AcOK (410mg, 4.2mmol, 1.5 equiv.). The reaction mixture was refluxed overnight and then cooled to room temperature. The reaction mixture was diluted with ethyl acetate (30mL), washed with brine (30mL), and taken over Na ₂SO₄Dried, filtered and evaporated in vacuo to afford the title compound (600mg, 60%).

And step 3: 5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine

To 5-bromo-1H-pyrrolo [2,3-b ] under nitrogen]To a solution of pyridine (501mg, 2.5mmol, 1.0 equiv.) in dioxane (25ml) and water (2ml) was added (4- (4-methylpiperazin-1-yl) phenyl) boronic acid (560mg, 2.5mmol, 1.0 equiv.), K₂CO₃(527mg, 3.8mmol, 1.5 equiv.) and Pd (dppf) Cl₂(93mg, 0.13mmol, 0.05 equiv.). The reaction mixture was heated to 100 ℃ for 4 hours. It was cooled to room temperature and diluted with ethyl acetate (50ml), washed with brine (30ml), over Na₂SO₄Dried, filtered and evaporated to give the crude product as a white solid (560mg, 75%), which was used in the next step without further purification.

And 4, step 4: 3-bromo-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine

Reacting 5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]Pyridine (0.56g, 1.9mmol, 1.0 equiv.) and NBS (376mg, 2.1mmol, 1.1 equiv.) were added to THF (40 ml). The reaction mixture was stirred at room temperature overnight. Removal of solvent in vacuoAnd purified by column chromatography (dichloromethane/MeOH ═ 20/1) to give the title compound (360mg, 51%). ¹H NMR(400MHz,DMSO-d6))δ12.10(s,1H),8.56(d,J＝2.1Hz,1H),7.94(d,J＝1.9Hz,1H),7.74(d,J＝2.6Hz,1H),7.65(d,J＝8.7Hz,2H),7.10(d,J＝8.7Hz,2H),3.35(bs,4H),3.03(bs,4H),2.62(s,3H)。LC-MS(M+H)⁺＝371.0,373.0。

And 5: 3-bromo-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester

Reacting 3-bromo-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]Pyridine (100mg, 0.27mmol, 1.0 equiv.), di-tert-butyl dicarbonate (65mg, 0.30mmol, 1.1 equiv.) and triethylamine (0.11ml, 0.81mmol, 3.0 equiv.) were added to THF (10 ml). The reaction mixture was stirred at room temperature overnight. 20ml of ethyl acetate were added and washed with brine (20ml), over Na₂SO₄Dried and evaporated in vacuo to afford the title compound (110mg, 87%). LC-MS (M + H)⁺＝471.1,473.1。

Step 6: 3- (4- (2- ((tert-butoxycarbonyl) amino) ethoxy) phenyl) -5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester

To 3-bromo-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] under nitrogen]To a solution of pyridine-1-carboxylic acid tert-butyl ester (200mg, 0.42mmol, 1.0 eq) in 1, 4-dioxane (30mL) and water (5mL) was added tert-butyl (2- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy) ethyl) carbamate (154mg, 0.42mmol, 1.0 eq), K₃PO₄(225mg, 1.06mmol, 2.5 equiv.) and XPhos Pd G2(33mg, 0.04mmol, 0.1 equiv.). The reaction mixture was refluxed overnight. Ethyl acetate (40mL) was added and washed with brine (40mL), which was purified by preparative TLC (dichloromethane/MeOH ═ 6:1) to give the title compound (200mg, 62%). LC-MS (M + H) ⁺＝628.4。

And 7: 2- (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenoxy) ethan-1-amine

Reacting 3- (4- (2- ((tert-butoxycarbonyl) amino) ethoxy) phenyl) -5- (4- (4-methylpiperazine-1-yl) phenyl) -1H-pyrrolo [2,3-b]Pyridine-1-carboxylic acid tert-butyl ester (200mg, 0.031mmol, 1.0 equiv.) was suspended in HCl/dioxane (10 mL). It was stirred at room temperature for 3 hours. The reaction mixture was filtered and washed with MTBE (10mL) and dried in vacuo to afford the title compound (24mg, 15%).¹H NMR(400MHz,DMSO-d6)¹H NMR(400MHz,DMSO)δ12.03(s,1H),10.96(s,1H),8.55(s,1H),8.38(s,1H),8.23(s,3H),7.84(s,1H),7.74(d,J＝8.1Hz,2H),7.69(d,J＝7.7Hz,2H),7.14-7.08(m,4H),4.23(t,J＝4.7Hz,2H),3.90(d,J＝9.6Hz,2H),3.51(d,J＝8.2Hz,2H),3.30-3.20(m,2H),3.23-3.15(m,4H),2.83-2.82(m,3H)。LC-MS(M+H)⁺＝428.4。

Example 232: 5- (3- (4- (2-oxa-6-azaspiro [3.3] heptane-6-carbonyl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) -2- (4-methyl-1, 4-diazepan-1-yl) benzonitrile (Compound 232)

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

Reacting 5-bromo-1H-pyrrolo [2,3-b ]]Pyridine (8.38g, 42.53mmol), 4,4,4 ', 4 ', 5,5,5 ', 5 ' -octamethyl-2, 2 ' -bis (1,3, 2-dioxaborolan) (21.6g, 85.06mmol), Pd (dppf) Cl₂(1.55g, 2.13mmol) and KOAc (12.56g, 127.60mmol) were dissolved in 1, 4-dioxane (120mL) and under N₂Heat to 100 ℃ overnight. The solvent was removed in vacuo. Water (100mL) was added and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine and over Na ₂SO₄And (5) drying. The crude product was purified by silica gel chromatography to provide the title compound (9.5g, 91%). LC-MS (M + H)⁺＝244.0。

Step 2: 2- (4-methyl-1, 4-diazepan-1-yl) -5- (1H-pyrrolo [2,3-b ] pyridin-5-yl) benzonitrile

Reacting 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ]]Pyridine (2.83g, 11.59mmol), 5-bromo-2- (4-methyl-1, 4-dinitrogenHeteroheptan-1-yl) benzonitrile (3.1g, 10.54mmol), Pd (dppf) Cl₂(385mg, 0.53mmol) and K₂CO₃(2.91g, 21.08mmol) was dissolved in 1, 4-dioxane (25mL) and H₂In O (15mL) and in N₂Heat to 90 ℃ overnight. The solvent was removed in vacuo and the crude product was purified by silica gel chromatography to provide the title compound (2.5g, 65%). LC-MS (M + H)⁺＝331.0。

And step 3: 5- (3-iodo-1H-pyrrolo [2,3-b ] pyridin-5-yl) -2- (4-methyl-1, 4-diazepan-1-yl) benzonitrile

2- (4-methyl-1, 4-diazepan-1-yl) -5- (1H-pyrrolo [2, 3-b)]Pyridin-5-yl) benzonitrile (2.5g, 7.54mmol) was dissolved in DMF (20 mL). NIS (2.04g, 9.05mmol) was added and stirred at room temperature overnight. The solvent was removed in vacuo. Water (20mL) was added and the mixture was filtered to give the title compound (2.5g, 72%). LC-MS (M + H) ⁺＝457.0。

And 4, step 4: tert-butyl-5- (3-cyano-4- (4-methyl-1, 4-diazepan-1-yl) phenyl) -3-iodo-1H-pyrrolo [2,3-b ] pyridine-1-carboxylate

Reacting 5- (3-iodo-1H-pyrrolo [2,3-b ]]Pyridin-5-yl) -2- (4-methyl-1, 4-diazepan-1-yl) benzonitrile (2.5g, 5.47mmol), Boc₂O (1.55g, 7.11mmol), DIPEA (1.41g, 10.94mmol) and DMAP (25mg, 0.205mmol) were dissolved in DMF (30mL) and stirred at room temperature overnight. Water (50mL) was added and extracted with dichloromethane (2 × 50 mL). The combined organic layers were washed with brine and over Na₂SO₄And (5) drying. The crude product was purified by silica gel chromatography to give the title compound (2.4g, 79%). LC-MS (M + H)⁺＝557.0。

And 5: (2-oxa-6-azaspiro [3.3] hept-6-yl) (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) methanone

4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoic acid (1.5g, 6.03mmol), 2-oxa-6-azaspiro [3.3]Heptane (896.7mg, 9.045mmol), HATU (2.52g, 6.633mmol) and NMM (2.44g, 24.12mmol) were dissolved in DMF (10mL) and stirred at room temperature overnight. Water (50mL) was added and ethyl acetate was used(2 × 30 mL). The combined organic layers were washed with brine and over Na ₂SO₄And (5) drying. The solvent was removed in vacuo to provide the title compound (750mg, 38%). LC-MS (M + H)⁺＝330.0。

Step 6: 5- (3- (4- (2-oxa-6-azaspiro [3.3] heptane-6-carbonyl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) -2- (4-methyl-1, 4-diazepan-1-yl) benzonitrile

Reacting 5- (3-cyano-4- (4-methyl-1, 4-diazepan-1-yl) phenyl) -3-iodo-1H-pyrrolo [2,3-b]Pyridine-1-carboxylic acid tert-butyl ester (500mg, 0.897mmol), (2-oxa-6-azaspiro [3.3]]Hept-6-yl) (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) methanone (443mg, 1.35mmol), Na₂CO₃(332.8mg, 3.14mmol) and Pd (dppf) Cl₂(32.8mg,0.045mmol) was dissolved in 1, 4-dioxane (15mL) and H₂O (10mL) and in N₂Heat to 90 ℃ overnight. The solvent was removed in vacuo and the crude product was purified by silica gel chromatography to provide the title compound (220mg, 49%).¹H NMR(400MHz,DMSO-d6)δ12.13(d,J＝2.5Hz,1H),8.56(d,J＝2.1Hz,1H),8.47(d,J＝2.1Hz,1H),8.06(d,J＝2.6Hz,1H),8.01(d,J＝2.4Hz,1H),7.90(m,3H),7.76-7.63(m,2H),7.11(d,J＝9.1Hz,1H),4.70(brs,4H),4.55(s,2H),4.24(s,2H),3.74-3.66(m,2H),3.63(t,J＝6.0Hz,2H),2.78-2.70(m,2H),2.59-2.53(m,2H),2.29(s,3H),2.04-1.90(m,2H)。LC-MS(M+H)⁺＝533.0。

Example 233: 5- (3- (4- (3-hydroxyazetidine-1-carbonyl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) -2- (4-methyl-1, 4-diazepan-1-yl) benzonitrile (Compound 233)

Prepared in a similar manner to that described in example 232, step 6 from 5- (3-cyano-4- (4-methyl-1, 4-diazepan-1-yl) phenyl) -3-iodo-1H-pyrrolo [2,3-b ]Preparation of pyridine-1-carboxylic acid tert-butyl ester and (3-hydroxyazetidin-1-yl) (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) methanone233(60mg，22％)。¹H NMR(400MHz,DMSO-d6)δ12.13(d,J＝2.4Hz,1H),8.56(d,J＝2.1Hz,1H),8.48(d,J＝2.0Hz,1H),8.05(d,J＝2.7Hz,1H),8.01(d,J＝2.4Hz,1H),7.96-7.79(m,3H),7.70(d,J＝8.5Hz,2H),7.11(d,J＝9.1Hz,1H),5.77(d,J＝6.0Hz,1H),4.53(brs,2H),4.27(brs,1H),4.10(brs,1H),3.82(brs,1H),3.74-3.67(m,2H),3.63(t,J＝6.0Hz,2H),2.74(d,J＝4.4Hz,2H),2.61-2.53(m,2H),2.30(s,3H),2.04-1.92(m,2H)。LC-MS(M+H)⁺＝507.0。

Example 234: 5- (3- (4- (3- (dimethylamino) azetidine-1-carbonyl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) -2- (4-methyl-1, 4-diazepan-1-yl) benzonitrile (compound 234)

Prepared in a similar manner to that described in example 232, step 6 from (3- (dimethylamino) azetidin-1-yl) (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) methanone and 5- (3-cyano-4- (4-methyl-1, 4-diazepan-1-yl) phenyl) -3-iodo-1H-pyrrolo [2,3-b]Pyridine-1-carboxylic acid tert-butyl ester preparation example 234(60mg, 22%).¹H NMR(400MHz,DMSO-d6)δ12.14(d,J＝2.4Hz,1H),8.57(d,J＝2.1Hz,1H),8.48(d,J＝2.1Hz,1H),8.06(d,J＝2.7Hz,1H),8.02(d,J＝2.4Hz,1H),7.95-7.87(m,3H),7.73(d,J＝8.5Hz,2H),7.12(d,J＝9.1Hz,1H),4.38(s,1H),4.15(s,1H),4.12-4.01(m,1H),3.86(s,1H),3.74-3.66(m,2H),3.64(t,J＝6.0Hz,2H),3.16-3.05(m,1H),2.79-2.70(m,2H),2.61-2.54(m,2H),2.30(s,3H),2.11(s,6H),2.03-1.92(m,2H)。LC-MS(M+H)⁺＝534.0。

Example 235: 4- (5- (3-cyano-4- (4-methyl-1, 4-diazepan-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (2- (dimethylamino) ethyl) -N-methylbenzamide (compound 235)

To the same as in step 6 of example 232In a similar manner to (1) from N- (2- (dimethylamino) ethyl) -N-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide and 5- (3-cyano-4- (4-methyl-1, 4-diazepan-1-yl) phenyl) -3-iodo-1H-pyrrolo [2,3-b ]Pyridine-1-carboxylic acid tert-butyl ester preparation example 235(125mg, 26%).¹H NMR(400MHz,CDCl₃)δ10.06(s,1H),8.53(s,1H),8.29(s,1H),7.77(d,J＝1.9Hz,1H),7.72-7.62(m,3H),7.61-7.47(m,3H),6.98(d,J＝8.9Hz,1H),3.86-3.75(m,2H),3.75-3.65(m,2H),3.12(s,3H),2.91(d,J＝4.0Hz,2H),2.81-2.69(m,2H),2.46-2.42(m,2H),2.37(s,3H),2.14(s,6H),1.93(s,4H)。LC-MS(M+H)⁺＝536.0。

Example 236: 5- (3, 5-dimethoxy-4- (4-methylpiperazin-1-yl) phenyl) -3- (4- (5-methyl-1H-1, 2, 3-triazol-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (compound 236)

Step 1: 4-bromo-2, 6-dimethoxyaniline

To a solution of 2, 6-dimethoxyaniline (5g, 32.6mmol, 1.0 equiv) in DMF (100ml) was added NBS (6.1g, 34.3mmol, 1.05 equiv) portionwise. The reaction mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: MeOH ═ 50:1) to give the title compound (6.96g, 92%). LC-MS (M + H)⁺＝231.9,233.9。

Step 2: 1- (4-bromo-2, 6-dimethoxyphenyl) -4-methylpiperazine

A mixture of 4-bromo-2, 6-dimethoxyaniline (6.96g, 30mmol, 1.0 equiv.) and nitrogen mustard hydrochloride (5.78g, 30mmol, 1.0 equiv.) in xylene (50mL) was stirred under N₂Stirring was continued overnight at 140 ℃. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: MeOH ═ 50:1) to give the title compound (2.2g, 23%). LC-MS (M + H)⁺＝314.9,316.9。

And step 3: 5- (3, 5-dimethoxy-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine

To 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ]]Pyridine (272mg, 1.1mmol, 1.0 equiv.) and 1- (4-bromo-2, 6-dimethoxyphenyl) -4-methylpiperazine (350mg, 1.1mmol, 1.0 equiv.) to a mixture of dioxane (30mL) and water (5mL) was added K₂CO₃(306mg, 2.2mmol, 2 equiv.) and Pd (dppf) Cl₂(80mg, 0.11mmol, 0.1 equiv.). The reaction mixture was stirred at 100 ℃ under nitrogen for 4 h. The mixture was cooled to room temperature and diluted with ethyl acetate (50mL), washed with brine (30mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: MeOH ═ 50:1) to give the title compound (180mg, 34%). LC-MS (M + H)⁺＝352.9。

And 4, step 4: 5- (3, 5-dimethoxy-4- (4-methylpiperazin-1-yl) phenyl) -3-iodo-1H-pyrrolo [2,3-b ] pyridine

To 5- (3, 5-dimethoxy-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]To a solution of pyridine (180mg, 0.51mmol, 1.0 equiv) in THF (40ml) was added NIS (127mg, 0.56mmol, 1.1 equiv) in portions. The reaction mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: MeOH ═ 20:1) to give the title compound (160mg, 65%). LC-MS (M + H) ⁺＝478.9。

And 5: 5- (3, 5-dimethoxy-4- (4-methylpiperazin-1-yl) phenyl) -3-iodo-1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester

To 5- (3, 5-dimethoxy-4- (4-methylpiperazin-1-yl) phenyl) -3-iodo-1H-pyrrolo [2,3-b]To a mixture of pyridine (160mg, 0.34mmol, 1.0 equiv.) and di-tert-butyl dicarbonate (87mg, 0.41mmol, 1.2 equiv.) in THF (20mL) was added triethylamine (68mg, 0.67mmol, 2.0 equiv.). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (20mL), washed with brine (20mL), dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (120mg, 62%). LC-MS (M + H)⁺＝578.9。

Step 6: 1- (4-bromophenyl) -5-methyl-1H-1, 2, 3-triazole

A mixture of 4-bromophenyl azide (5mmol, 1.0 equiv.), tetramethylguanidine (1.725g, 15mmol, 3.0 equiv.), and acetonylphosphonate (0.83g, 5mmol, 1.0 equiv.) was stirred at 80 ℃ for 16 h. The reaction was monitored by TLC until the reaction was complete. The crude product was partitioned between water (100mL) and ethyl acetate (100mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 10:1) to give the title compound (240mg, 20%). LC-MS (M + H) ⁺＝237.9,239.9。

And 7: 5-methyl-1- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -1H-1,2, 3-triazole

To a solution of 1- (4-bromophenyl) -5-methyl-1H-1, 2, 3-triazole (240mg, 1mmol, 1.0 equiv.) and 4,4,4 ', 4 ', 5,5,5 ', 5 ' -octamethyl-2, 2 ' -bis (1,3, 2-dioxaborolan (381mg, 1.5mmol, 1.5 equiv.) in dioxane (20mL) was added Pd (dppf) Cl₂(73mg, 0.1mmol, 0.1 equiv.) and AcOK (295mg, 3mmol, 3.0 equiv.). The mixture was refluxed under nitrogen for 5 h. The mixture was cooled to room temperature and diluted with ethyl acetate (30mL), washed with brine (20mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: MeOH ═ 20:1) to give the title compound (210mg, 74%). LC-MS (M + H)⁺＝285.9。

And 8: 5- (3, 5-dimethoxy-4- (4-methylpiperazin-1-yl) phenyl) -3- (4- (5-methyl-1H-1, 2, 3-triazol-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine

Prepared in a similar manner to that in step 4 of example 285 from 5-methyl-1- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -1H-1,2, 3-triazole and 5- (3, 5-dimethoxy-4- (4-methylpiperazin-1-yl) phenyl) -3-iodo-1H-pyrrolo [2,3-b ]Pyridine-1-carboxylic acid tert-butyl ester preparation example 236(25mg, 23%).¹H NMR(400MHz,DMSO-d6)δ12.17(s,1H),8.60(d,J＝2.0Hz,1H),8.50(d,J＝1.9Hz,1H),8.08(d,J＝2.0Hz,1H),8.04(d,J＝8.5Hz,2H),7.72(d,J＝0.5Hz,1H),7.66(d,J＝8.5Hz,2H),6.94(s,2H),3.86(s,6H),3.06(brs,4H),2.39(brs,7H),2.21(s,3H)。LC-MS(M+H)⁺＝509.9。

Example 237: 5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -3- (4- (pyridin-2-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (Compound 237)

Step 1: 1- (2, 6-dimethylphenyl) -4-methylpiperazine

To 2-chloro-N- (2-chloroethyl) -N-methylethyl-1-amine hydrochloride (1g, 5.2mmol, 1.0 equiv.), 2, 6-dimethylaniline (630mg, 5.2mmol, 1.0 equiv.), and p-TsOH (90mg, 0.052mmol, 0.1 equiv.) was added o-xylene (30 mL). It was refluxed for 4 hours. The reaction mixture was cooled to room temperature and water (30mL) was added, extracted with dichloromethane (30mL), over Na₂SO₄Dry, it was purified by preparative TLC (dichloromethane/MeOH ═ 8:1) to give the title compound (200mg, 20%). LC-MS (M + H)⁺＝205.1。

Step 2: 1- (4-bromo-2, 6-dimethylphenyl) -4-methylpiperazine

To a solution of 1- (2, 6-dimethylphenyl) -4-methylpiperazine (200mg, 1.0mmol, 1.0 equiv.) in ethanol (10mL) was added dropwise Br₂(0.06mL, 1.1mmol, 1.1 equiv.). The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo and the residue was diluted with water (10mL), filtered and washed with water, dried in vacuo to give the title compound (400mg, quantitative crude). LC-MS (M + H) ⁺＝283.0,285.0。

And step 3: 5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine

The title compound (116mg, 28%) was prepared from 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ] pyridine in a similar manner to that in example 236, step 3.

And 4, step 4: 3-bromo-5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine

The title compound (110mg, 75%) was prepared from 5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine and NBS in a similar manner to that in example 236 step 4.

And 5: tert-butyl-3-bromo-5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine-1-carboxylate

3-bromo-5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]Pyridine (110mg, 0.28mmol, 1.0 eq), (Boc)₂O (73mg, 0.33mmol, 1.2 equiv.) and Et₃N (0.15mL, 0.83mmol, 3.0 equiv.) was added to THF (20 mL). It was stirred at room temperature for 2 hours. Ethyl acetate (30mL) was added and the mixture was washed with brine (30mL) over Na₂SO₄Dried and evaporated in vacuo to afford the compound (135mg, 100%).

Step 6: 5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -3- (4- (pyridin-2-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine

Prepared from (4- (pyridin-2-yl) phenyl) boronic acid and 3-bromo-5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that in step 4 of example 285]Pyridine-1-carboxylic acid tert-butyl ester preparation example 237(2mg, 3%).¹H NMR(400MHz,DMSO-d6)δ12.05(s,1H),8.68(d,J＝5.0Hz,1H),8.53(s,1H),8.43(s,1H),8.19(d,J＝8.3Hz,2H),8.01(d,J＝7.2Hz,2H),7.93-7.87(m,3H),7.38(s,2H),7.36-7.31(m,1H),3.07(brs,4H),2.46(brs,4H),2.37(s,6H),2.27(s,3H)。LC-MS(M+H)⁺＝474.2。

Example 238: 4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -2-fluoro-N, N-dimethylbenzamide (Compound 238)

Prepared from 5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -3-iodo-1H-pyrrolo [2,3-b ] in a similar manner to that in step 4 of example 285]Pyridine-1-carboxylic acid tert-butyl ester and (4- (dimethylcarbamoyl) -3-fluorophenyl) boronic acid preparation example 238(60mg, 30.9%).¹H NMR(400MHz,DMSO-d6)δ12.15(s,1H),8.52(d,J＝1.8Hz,1H),8.37(d,J＝1.9Hz,1H),8.09(d,J＝2.6Hz,1H),7.81-7.62(m,2H),7.47-7.36(m,3H),3.34-3.32(m,4H),3.16-3.12(m,4H),3.03(s,3H),2.92(s,3H),2.51(s,3H),2.37(s,6H)。LCMS(M+H)⁺＝486.2。HPLC:254nm,97.7％。

Example 239: 2-chloro-4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (compound 239)

Prepared from 5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -3-iodo-1H-pyrrolo [2,3-b ] in a similar manner to that in step 4 of example 285]Pyridine-1-carboxylic acid tert-butyl ester and (3-chloro-4- (dimethylcarbamoyl) phenyl) boronic acid preparation example 239(34mg, 17%). ¹H NMR(400MHz,DMSO-d6)δ12.14(s,1H),8.52(d,J＝1.9Hz,1H),8.37(d,J＝1.9Hz,1H),8.09(d,J＝2.6Hz,1H),7.88-7.83(m,2H),7.43-7.37(m,3H),3.34-3.32(m,4H),3.16-3.12(m,4H),3.03(s,3H),2.85(s,3H),2.51(s,3H),2.37(s,6H)。LCMS(M+H)⁺＝502.1。HPLC:254nm,93.1％。

Example 240: 4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N, 2-trimethylbenzamide (Compound 240)

Prepared from 5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -3-iodo-1H-pyrrolo [2,3-b ] in a similar manner to that in step 4 of example 285]Pyridine-1-carboxylic acid tert-butyl ester and (4- (dimethylcarbamoyl) -3-methylphenyl) boronic acid preparation 240(42mg, 21.8%).¹H NMR(400MHz,CDCl₃)δ9.60(s,1H),8.56(d,J＝1.8Hz,1H),8.31(d,J＝1.8Hz,1H),7.57-7.44(m,3H),7.29-7.26(m,3H),3.30-3.26(m,4H),3.17(s,3H),2.94(s,3H),2.76-2.62(m,4H),2.49(s,3H),2.43(s,6H),2.37(s,3H)。LCMS(M+H)⁺＝482.1。HPLC:254nm,99.8％。

Example 241: 3- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (Compound 241)

Prepared from 5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -3-iodo-1H-pyrrolo [2,3-b ] in a similar manner to that in step 4 of example 285]Pyridine-1-carboxylic acid tert-butyl ester and (3- (dimethylcarbamoyl) phenyl) boronic acid preparation example 241(7mg, 10.9%).¹H NMR(400MHz,DMSO-d6)δ12.03(s,1H),8.50(d,J＝2.0Hz,1H),8.33(d,J＝2.0Hz,1H),7.97(s,1H),7.86(d,J＝8.2Hz,1H),7.72(s,1H),7.52(t,J＝7.7Hz,1H),7.34(s,2H),7.27(d,J＝7.6Hz,1H),3.09-3.03(m,4H),3.02-3.27(m,6H),2.46-2.40(m,4H),2.36(s,6H),2.24(s,3H)。LCMS(M+H)⁺＝467.9。HPLC:254nm,99.8％。

Example 242: (4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (piperazin-1-yl) methanone (Compound 242)

Step 1: 4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzoic acid methyl ester

To 3-bromo-5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] under a nitrogen atmosphere ]To a solution of pyridine-1-carboxylic acid tert-butyl ester (501mg, 1.0mmol, 1 equiv.) and (4- (methoxycarbonyl) phenyl) boronic acid (200mg, 1.1mmol, 1.1 equiv.) in dioxane (20mL) and water (4mL) was added K₃PO₄(318mg, 1.5mmol, 1.5 equiv.) and chlorine (2-dicyclohexylphosphino-2 ', 4', 6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl ]]Palladium (II) (79mg, 0.1mmol, 0.1 equiv.). After stirring at 90 ℃ for 15h under a nitrogen atmosphere, the reaction mixture is filteredThe mixture should be concentrated under reduced pressure. The crude product was applied to a silica gel column with dichloromethane/methanol (10/1) to give the title compound (200mg, 44%). LCMS (M + H)⁺＝454.9。

Step 2: 4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzoic acid

4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2, 3-b)]A solution of pyridin-3-yl) benzoic acid methyl ester (200mg, 0.44mmol, 1 equiv), NaOH (74mg,1.32mmol, 3 equiv) in MeOH (20mL) and water (10mL) was stirred at 50 ℃ for 4 h. The reaction mixture was concentrated under reduced pressure. The residue was acidified with HCl (4M) to pH 2-3 and the precipitate was collected by filtration to give the title compound (180mg, 93%). LCMS (M + H)⁺＝440.9。

And step 3: (4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (piperazin-1-yl) methanone

To 4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] under nitrogen]Pyridin-3-yl) benzoic acid (130mg, 0.295mmol, 1.0 equiv.) and piperazine (51mg, 0.59mmol, 2.0 equiv.) were added to a solution of HATU (168mg, 0.44mmol, 1.5 equiv.) in DMF (20 mL). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with water (30mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (3 × 30mL), 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 (20mg, 13.3%).¹H NMR(400MHz,DMSO-d6)δ12.16(s,1H),10.12(s,1H),8.52(d,J＝1.9Hz,1H),8.41(s,1H),8.02(d,J＝2.5Hz,1H),7.88(d,J＝8.0Hz,2H),7.55(d,J＝8.0Hz,2H),7.48-7.35(m,2H),3.91-3.70(m 4H),3.32-3.22(m,4H),3.20-2.98(m,8H),2.68(s,3H),2.38(s,6H)。LC-MS(M+H)⁺＝509。HPLC:254nm,96.7％。

Example 243: n-cyclopropyl-4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N-methylbenzamide (compound 243)

Step 1: (4- (cyclopropyl (methyl) carbamoyl) phenyl) boronic acid

To a solution of 4-dihydroxyborobenzoic acid (1.0g, 6mmol, 1.0 equiv.), N-methylcyclopropylamine hydrochloride (0.78g, 7.2mmol, 1.2 equiv.), and TEA (1.8g, 18mmol, 3 equiv.) in DMF (20ml) under nitrogen was added HATU (2.18g, 6mmol, 1.0 equiv.). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with water (30mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (3 × 30mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: MeOH ═ 20:1) to give the title compound (0.92g, 70%).

Step 2: n-cyclopropyl-4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N-methylbenzamide

Prepared in a similar manner to that in step 4 of example 285 from 3-bromo-5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]Pyridine-1-carboxylic acid tert-butyl ester and (4- (cyclopropyl (methyl) carbamoyl) phenyl) boronic acid preparation example 243(10mg, 10%).¹H NMR(400MHz,DMSO-d6)δ12.06(s,1H),8.51(d,J＝1.7Hz,1H),8.40(d,J＝1.7Hz,1H),8.01(s,1H),7.83(d,J＝8.2Hz,2H),7.59(d,J＝8.0Hz,2H),7.37(s,2H),3.05(brs,4H),2.99-2.97(m,4H),2.43(brs,4H),2.36(s,6H),2.24(s,3H),0.60(brs,2H),0.48(brs,2H)。LC-MS(M+H)⁺＝494.0。

Example 244: 5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -3- (4- ((tetrahydrofuran-3-yl) oxy) phenyl) -1H-pyrrolo [2,3-b ] pyridine (compound 244)

Step 1: 4-Methylbenzenesulfonic acid tetrahydrofuran-3-yl ester

4-Methylbenzenesulfonyl chloride (2.37g, 12.5mmol, 1.1 eq.) is added portionwise to the solutionA stirred solution of tetrahydrofuran-3-ol (1.0g, 11.36mmol, 1.0 equiv.) and TEA (2.3g, 22.73mmol, 2.0 equiv.) in dichloromethane (40mL) at 0 deg.C. The mixture was then stirred at room temperature for 4 h. The reaction mixture was washed with water (40mL), NaHCO₃(sat, 40mL), brine (40mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1) to give the title compound (0.9g, 42%).

Step 2: 4,4,5, 5-tetramethyl-2- (4- ((tetrahydrofuran-3-yl) oxy) phenyl) -1,3, 2-dioxaborolan

Tetrahydrofuran-3-yl 4-methylbenzenesulfonate (0.9g, 3.72mmol, 1.0 eq.), 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol (0.818g, 3.72mmol, 1.0 eq.) and K₂CO₃(1.03g, 7.44mmol, 2.0 equiv.) of a mixture in DMF (30mL) in N₂Stirring was continued for 6h at 60 deg.C (LC-MS monitoring the reaction). The mixture was then cooled to room temperature, ethyl acetate (100mL) was added, washed with brine (100mL), and Na₂SO₄Dried, concentrated and purified by silica gel column chromatography to give the title compound (0.8g, 74%). LC-MS (M + H)⁺＝290.9。

And step 3: 5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -3- (4- ((tetrahydrofuran-3-yl) oxy) phenyl) -1H-pyrrolo [2,3-b ] pyridine

Prepared in a similar manner to that in step 4 of example 285 from 3-bromo-5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]Pyridine-1-carboxylic acid tert-butyl ester and 4,4,5, 5-tetramethyl-2- (4- ((tetrahydrofuran-3-yl) oxy) phenyl) -1,3, 2-dioxaborolan preparation example 244(12mg, 17%).¹H NMR(400MHz,DMSO-d6)δ11.89(s,1H),8.49(d,J＝1.9Hz,1H),8.31(d,J＝1.7Hz,1H),7.79(d,J＝2.5Hz,1H),7.68(d,J＝8.7Hz,2H),7.44(s,1H),7.35(s,1H),7.01(d,J＝8.7Hz,2H),5.07(brs,1H),3.94-3.89(m,1H),3.87-3.81(m,2H),3.79-3.75(m,1H),3.63(brs,2H),3.42-3.39(m,2H),3.24-3.09(m,2H),3.06-3.03(m,2H),2.84(s,3H),2.38(s,6H),2.29-2.20(m,1H),2.04-1.99(m,1H)。LC-MS(M+H)⁺＝482.9。

Example 245: 5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -3- (4- (pyrrolidin-3-yloxy) phenyl) -1H-pyrrolo [2,3-b ] pyridine (compound 245)

Step 1: 3- (tosyloxy) pyrrolidine-1-carboxylic acid tert-butyl ester

The title compound (1.6g, 93%) was prepared from tert-butyl 3-hydroxypyrrolidine-1-carboxylate in a similar manner to that in example 244, step 1. LC-MS (M + H)⁺＝342.0。

Step 2: tert-butyl-3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy) pyrrolidine-1-carboxylate

The title compound (0.7g, 45%) was prepared from tert-butyl 3- (tosyloxy) pyrrolidine-1-carboxylate and 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol in a similar manner to that in example 244, step 2. LC-MS (M + H)⁺＝390.0。

And step 3: 3- (4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenoxy) pyrrolidine-1-carboxylic acid tert-butyl ester

Prepared in a similar manner to that in step 4 of example 285 from 3-bromo-5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]Pyridine-1-carboxylic acid tert-butyl ester and 3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy) pyrrolidine-1-carboxylic acid tert-butyl ester the title compound (60mg, 71%) was prepared. LC-MS (M + H)⁺＝582.0。

And 4, step 4: 5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -3- (4- (pyrrolidin-3-yloxy) phenyl) -1H-pyrrolo [2,3-b ] pyridine

3- (4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) phenoxy) pyrrolidine-1-carboxylic acid tert-butyl ester (60mg, 0.10mmol) was stirred in dichloromethane (20mL) and TFA (10mL) at room temperature for 2h and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the titleCompound (25mg, 52%).¹H NMR(400MHz,DMSO-d6)δ11.90(s,1H),8.49(d,J＝1.9Hz,1H),8.30(d,J＝1.8Hz,1H),7.80(d,J＝2.0Hz,1H),7.71(d,J＝8.7Hz,2H),7.35(s,2H),7.06(d,J＝8.7Hz,2H),5.15(brs,1H),3.53-3.16(m,5H),3.07(brs,4H),2.48(brs,4H),2.36(s,6H),2.28(s,3H),2.24-2.04(m,2H)。LC-MS(M+H)⁺＝481.9。

Example 246: 3- (4- (azetidin-3-yloxy) phenyl) -5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (compound 246)

Step 1: 3- (tosyloxy) azetidine-1-carboxylic acid tert-butyl ester

The title compound (1.8g, 100%) was prepared from tert-butyl 3-hydroxyazetidine-1-carboxylate in a similar manner to that in example 244, step 1. LC-MS (M + H)⁺＝328.0。

Step 2: 3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy) azetidine-1-carboxylic acid tert-butyl ester

The title compound (1.0g, 58%) was prepared from tert-butyl 3- (tosyloxy) azetidine-1-carboxylate and 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol in a similar manner to that in example 244, step 2. LC-MS (M + H)⁺＝376.0。

And step 3: 3- (4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenoxy) azetidine-1-carboxylic acid tert-butyl ester

Prepared in a similar manner to that in step 4 of example 285 from 3-bromo-5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]Pyridine-1-carboxylic acid tert-butyl ester and 3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy) azetidine-1-carboxylic acid tert-butyl ester the title compound (80mg, 48%) was prepared. LC-MS (M + H)⁺＝567.9。

And 4, step 4: 3- (4- (azetidin-3-yloxy) phenyl) -5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine

Prepared from 3- (4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that in example 245 step 4]Pyridin-3-yl) phenoxy) azetidine-1-carboxylic acid tert-butyl ester preparation example 246(25mg, 52%).¹H NMR(400MHz,DMSO-d6)δ11.99(s,1H),8.50(d,J＝1.7Hz,1H),8.30(s,1H),7.82(d,J＝2.4Hz,1H),7.71(d,J＝8.6Hz,2H),7.39(brs,2H),6.96(d,J＝8.6Hz,2H),5.14-5.10(m,1H),4.45-4.40(m,2H),4.00-3.96(m,2H),3.73(brs,2H),3.37(brs,2H),3.18-3.03(m,5H),2.80(s,3H),2.38(s,6H)。LC-MS(M+H)⁺＝467.9。

Example 247: 5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -3- (4- (piperidin-4-yloxy) phenyl) -1H-pyrrolo [2,3-b ] pyridine (Compound 247)

Step 1: 4- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy) piperidine-1-carboxylic acid tert-butyl ester

The title compound (200mg, 10%) was prepared from tert-butyl 4-bromopiperidine-1-carboxylate and 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol in a similar manner to that in example 244, step 2. LC-MS (M + H) ⁺＝403.9。

Step 2: tert-butyl-4- (4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenoxy) piperidine-1-carboxylate

Prepared in a similar manner to that in step 4 of example 285 from 3-bromo-5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]Pyridine-1-carboxylic acid tert-butyl ester and 4- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy) piperidine-1-carboxylic acid tert-butyl ester the title compound (50mg, 28%) was prepared. LC-MS (M + H)⁺＝596.0。

And step 3: 5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -3- (4- (piperidin-4-yloxy) phenyl) -1H-pyrrolo [2,3-b ] pyridine

Prepared from 4- (4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that in example 245 step 4]Pyridin-3-yl) phenoxy) piperidine-1-carboxylic acid tert-butyl ester preparation example 247(7mg, 11%).¹H NMR(400MHz,DMSO-d6)δ11.84(s,1H),8.48(d,J＝1.9Hz,1H),8.29(d,J＝1.8Hz,1H),7.76(s,1H),7.65(d,J＝8.6Hz,2H),7.34(s,2H),7.03(d,J＝8.6Hz,2H),4.41(brs,1H),3.05(brs,4H),2.97-2.94(m,2H),2.57-2.50(m,3H),2.43(brs,4H),2.36(s,6H),2.24(s,3H),1.95-1.93(m,2H),1.50-1.43(m,2H)。LC-MS(M+H)⁺＝496.0。

Example 248: (3- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (3- (dimethylamino) azetidin-1-yl) methanone (compound 248)

Step 1: 3- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzoic acid methyl ester

Prepared in a similar manner to that in step 4 of example 285 from 3-bromo-5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]Pyridine-1-carboxylic acid tert-butyl ester and methyl 3-dihydroxybenzoate the title compound (1.2g, 55%) was prepared. LC-MS (M + H)⁺＝455.2。

Step 2: 3- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzoic acid

3- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) benzoic acid methyl ester (1.2g, 2.6mmol, 1.0 equiv.) was dissolved in methanol (20mL) and LiOH. H was added₂A solution of O (560mg, 13.2mmol, 5.0 equiv.) in water (20 mL). The reaction mixture was heated to 70 ℃ overnight. Water (20mL) was added and the mixture was washed with MTBE (20mL), then the aqueous layer was acidified to pH 6-7, extracted with ethyl acetate (2 × 30mL), over Na₂SO₄Drying in vacuumEvaporation gave the title compound (900mg, 73%).

And step 3: (3- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (3- (dimethylamino) azetidin-1-yl) methanone

To 3- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2, 3-b) ]Pyridin-3-yl) benzoic acid (80mg, 0.18mmol, 1.0 equiv.), N-Dimethylazetidin-3-amine hydrochloride (38mg, 0.22mmol, 1.2 equiv.), HATU (76mg, 0.20mmol, 1.1 equiv.), and Et₃DMF (5mL) was added to N (0.08mL, 0.55mmol, 3.0 equiv). The mixture was stirred at room temperature for 2 hours. Water (30mL) was added and the mixture was extracted with ethyl acetate (3 × 20mL), the combined organic layers were washed with brine (30mL), over Na₂SO₄Dried and evaporated in vacuo. The crude product was purified by preparative TLC (dichloromethane/MeOH ═ 8:1) to give the title compound (20mg, 21%).¹H NMR(400MHz,DMSO-d6)δ12.08(s,1H),8.51(s,1H),8.34(s,1H),8.01(d,J＝2.3Hz,1H),7.93(s,1H),7.91(s,1H),7.57-7.51(m,2H),7.38(s,2H),4.43-4.35(m,1H),4.17-4.09(m,2H),3.95-3.80(m,1H),3.51-3.40(m,1H),3.28-2.94(m,8H),2.74(s,3H),2.37(s,6H),2.20-2.00(m,6H)。LC-MS(M+H)⁺＝523.3。

Example 249: (3- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (3-hydroxyazetidin-1-yl) methanone (Compound 249)

Prepared in a similar manner to that in example 248, step 3 from 3- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) benzoic acid and azetidin-3-ol preparation example 249(37mg, 41%).¹H NMR(400MHz,DMSO-d6)δ12.09(d,J＝1.8Hz,1H),10.71(s,1H),8.52(d,J＝1.7Hz,1H),8.34(d,J＝1.6Hz,1H),8.00(d,J＝2.5Hz,1H),7.92(d,J＝8.5Hz,2H),7.56-7.49(m,2H),7.39(s,2H),5.81(d,J＝5.9Hz,1H),7.56-7.49(m,2H),4.29(d,J＝8.9Hz,1H),4.13(d,J＝4.6Hz,1H),3.82(d,J＝8.3Hz,1H),3.52-3.38(m,1H),3.30-3.29(m,6H),2.78(s,3H),2.38(s,6H)。LC-MS(M+H)⁺＝496.2。

Example 250: 3- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (2- (dimethylamino) ethyl) -N-methylbenzamide (Compound 250)

Prepared in a similar manner to that in example 248, step 3 from 3- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) benzoic acid and N1, N1, N2-trimethylethane-1, 2-diamine preparation example 250(20mg, 21%).¹H NMR(400MHz,DMSO-d6)δ12.08(s,1H),8.52(d,J＝1.9Hz,1H),8.35(s,1H),8.00(s,1H),7.87(d,J＝7.4Hz,2H),7.53(t,J＝7.7Hz,1H),7.40-7.35(m,3H),3.83-3.70(m,2H),3.28-2.85(m,12H),2.78-2.55(m,8H),2.38(s,6H),2.20-2.00(m,2H)。LC-MS(M+H)⁺＝525.3。

Example 251: 5- (3- (4- (dimethylcarbamoyl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) -N, N-dimethyl-2- (4-methylpiperazin-1-yl) benzamide (compound 251)

Step 1: 5-bromo-2- (4-methylpiperazin-1-yl) benzoic acid

5-bromo-2- (4-methylpiperazin-1-yl) benzonitrile (700mg, 2.5mmol) in NaOH (5M, 5mL) and EtOH (5mL) was stirred at reflux for 24 h. The mixture was cooled and acidified with HCl to pH 5-6. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (550mg, 73.5%).

Step 2: 5-bromo-2- (4-methylpiperazin-1-yl) benzoic acid ethyl ester

To a solution of 5-bromo-2- (4-methylpiperazin-1-yl) benzoic acid (550mg, 1.84mmol) in EtOH (40mL) was added H₂SO₄(2 drops). The mixture was stirred at reflux overnight. The mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (100mL) and saturated NaHCO₃The solution (50mL), water (30mL), brine (50mL) was washed, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (275mg, 46%) as an oil.

And step 3: 2- (4-Methylpiperazin-1-yl) -5- (1H-pyrrolo [2,3-b ] pyridin-5-yl) benzoic acid ethyl ester

Prepared from ethyl 5-bromo-2- (4-methylpiperazin-1-yl) benzoate and 5-bromo-1H-pyrrolo [2,3-b ] in a similar manner to that in step 3 of example 236]Pyridine preparation the title compound (250mg, 82%). LC-MS (M + H)⁺＝365.1。

And 4, step 4: ethyl-5- (3-bromo-1H-pyrrolo [2,3-b ] pyridin-5-yl) -2- (4-methylpiperazin-1-yl) benzoate

Prepared in a similar manner to that in step 4 of example 236 from 2- (4-methylpiperazin-1-yl) -5- (1H-pyrrolo [2, 3-b)]Pyridin-5-yl) benzoic acid Ethyl ester and NBS preparation of the title compound (220mg, 72%). LC-MS (M + H)⁺＝443.1。

And 5: 3-bromo-5- (3- (ethoxycarbonyl) -4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester

Prepared from 5- (3-bromo-1H-pyrrolo [2,3-b ] in a similar manner to that in step 5 of example 236]Pyridin-5-yl) -2- (4-methylpiperazin-1-yl) benzoic acid ethyl ester the title compound (120mg, 44%) was prepared. LC-MS (M + H)⁺＝543.1。

Step 6: 5- (3- (4- (dimethylcarbamoyl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) -2- (4-methylpiperazin-1-yl) benzoic acid ethyl ester

Prepared in a similar manner to that in step 4 of example 285 from 3-bromo-5- (3- (ethoxycarbonyl) -4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ]Pyridine-1-carboxylic acid tert-butyl ester the title compound (630mg, 51%) was prepared.¹H NMR(400MHz,CDCl₃)δ8.50(s,1H),8.32(s,1H),8.12(s,1H),7.70-7.67(m,3H),7.63(s,1H),7.54(d,J＝8.1Hz,2H),7.15(d,J＝8.4Hz,1H),4.37(q,J＝7.1Hz,2H),3.54(brs,4H),3.12(s,6H),2.89(s,3H),1.84(brs,4H),1.40(t,J＝7.1Hz,3H)。LC-MS(M+H)⁺＝512.2。

And 7: 5- (3- (4- (dimethylcarbamoyl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) -2- (4-methylpiperazin-1-yl) benzoic acid

To 5- (3- (4- (dimethylcarbamoyl) phenyl) -1H-pyrrolo [2, 3-b)]To a solution of pyridin-5-yl) -2- (4-methylpiperazin-1-yl) benzoic acid ethyl ester (630mg, 1.23mmol, 1.0 equiv) in a mixture of methanol (15mL) and water (15mL) was added NaOH (148mg, 3.70mmol, 3.0 equiv). The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was acidified with HCl (4M) to pH 2-3 and the precipitate was collected by filtration to give the title compound as a white solid (500mg, 84%). LC-MS (M + H)⁺＝484.2。

And 8: 5- (3- (4- (dimethylcarbamoyl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) -N, N-dimethyl-2- (4-methylpiperazin-1-yl) benzamide

To 5- (3- (4- (dimethylcarbamoyl) phenyl) -1H-pyrrolo [2,3-b ] under nitrogen]Pyridin-5-yl) -2- (4-methylpiperazin-1-yl) benzoic acid (60mg, 0.124mmol, 1.0 eq), dimethylamine hydrochloride (20mg, 0.248mmol, 2.0 eq) and Et₃To a solution of N (38mg, 0.372mmol, 3.0 equiv.) in DMF (5mL) was added HATU (47mg, 0.124mmol, 1.0 equiv.). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with water (30mL) and extracted with ethyl acetate (30 mL). The organic layer was washed with brine (30mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane: MeOH ═ 8:1) to give the title compound (30mg, 48%). ¹H NMR(400MHz,DMSO-d6)δ12.09(s,1H),8.55(s,1H),8.43(s,1H),8.01(s,1H),7.86(d,J＝8.2Hz,2H),7.78(d,J＝8.4Hz,1H),7.57(s,1H),7.49(d,J＝8.2Hz,2H),7.20(d,J＝8.4Hz,1H),3.31-3.23(m,6H),3.04(s,3H),3.00-2.89(m,9H),2.83(s,3H),2.58(s,2H)。LC-MS(M+H)⁺＝511.2。

Example 252: 5- (3- (4- (dimethylcarbamoyl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) -N- (4-methoxyphenyl) -2- (4-methylpiperazin-1-yl) benzamide (compound 252)

Example 252(30mg, 41%) was prepared from 4-methoxyaniline in a similar manner to that in example 251, step 8.¹H NMR(400MHz,DMSO-d6)δ12.14(s,1H),11.14(s,1H),8.58(d,J＝1.9Hz,1H),8.48(d,J＝1.7Hz,1H),8.08(d,J＝2.1Hz,1H),8.03(d,J＝2.6Hz,1H),7.92-7.84(m,3H),7.73(d,J＝9.0Hz,2H),7.50(d,J＝8.2Hz,2H),7.40(d,J＝8.4Hz,1H),6.97(d,J＝9.0Hz,2H),3.76(s,3H),3.08(brs,4H),3.00(s,6H),2.56(brs,4H),2.27(s,3H)。LC-MS(M+H)⁺＝588.9。

Example 253: n, N-dimethyl-4- (5- (3- (methylamino) -4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 253)

Step 1: 5-bromo-N-methyl-2-nitroaniline

A solution of 4-bromo-2-fluoro-1-nitrobenzene (2.2g, 10mmol, 1.0 equiv.), methylamine hydrochloride (1.35mg, 20mmol, 2.0 equiv.), and DIPEA (3.87g, 30mmol, 3.0 equiv.) in THF (40mL) was stirred at 60 ℃ for 2 h. The mixture was cooled to room temperature and diluted with ethyl acetate (50mL), washed with HCl (50mL, 1M), brine (50mL), dried over sodium sulfate and concentrated under reduced pressure to give the title compound (2.4g, 100%) which was used in the next step without further purification. LC-MS (M + H)⁺＝230.9,232.9。

Step 2: 5-bromo-N1-methylbenzene-1, 2-diamine

To a solution of 5-bromo-N-methyl-2-nitroaniline (2.3g, 10.43mmol, 1.0 equiv.) in AcOH (40ml) was added Zn powder (3.39g, 52.2mmol, 5.0 equiv.) in portions. The reaction mixture was stirred at 60 ℃ for 1h and filtered, then the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 6:1) to give The title compound (2.0g, 99%). LC-MS (M + H)⁺＝200.9,202.9。

And step 3: 5-bromo-N-methyl-2- (4-methylpiperazin-1-yl) aniline

The title compound (570mg, 33%) was prepared from 5-bromo-N1-methylbenzene-1, 2-diamine and 2-chloro-N- (2-chloroethyl) -N-methylethyl-1-amine hydrochloride in a similar manner to that in example 236, step 2. LC-MS (M + H)⁺＝283.9,285.9。

And 4, step 4: n-methyl-2- (4-methylpiperazin-1-yl) -5- (1H-pyrrolo [2,3-b ] pyridin-5-yl) aniline

Prepared from 5-bromo-N-methyl-2- (4-methylpiperazin-1-yl) aniline and 5-bromo-1H-pyrrolo [2,3-b ] in a similar manner to that in example 236 step 3]Pyridine preparation the title compound (270mg, 42%). LC-MS (M + H)⁺＝321.9。

And 5: 5- (3-iodo-1H-pyrrolo [2,3-b ] pyridin-5-yl) -N-methyl-2- (4-methylpiperazin-1-yl) aniline

Prepared in a similar manner to that in step 4 of example 236 from N-methyl-2- (4-methylpiperazin-1-yl) -5- (1H-pyrrolo [2, 3-b)]Pyridin-5-yl) aniline the title compound (310mg, 83%) was prepared. LC-MS (M + H)⁺＝447.9。

Step 6: 3-iodo-5- (3- (methylamino) -4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester

Prepared from 5- (3-iodo-1H-pyrrolo [2,3-b ] in a similar manner to that in step 5 of example 236]Pyridin-5-yl) -N-methyl-2- (4-methylpiperazin-1-yl) aniline the title compound was prepared (260mg, 68%). LC-MS (M-Boc) ⁺＝447.9。

And 7: n, N-dimethyl-4- (5- (3- (methylamino) -4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Prepared from 3-iodo-5- (3- (methylamino) -4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that in example 285 step 4]Pyridine-1-carboxylic acid tert-butyl ester and (4- (dimethylcarbamoyl) phenyl) boronic acid preparation example 253(35mg, 26%).¹H NMR(400MHz,DMSO-d6)δ12.05(d,J＝2.2Hz,1H),8.53(d,J＝2.0Hz,1H),8.39(d,J＝1.8Hz,1H),7.99(d,J＝2.6Hz,1H),7.84(d,J＝8.2Hz,2H),7.49(d,J＝8.2Hz,2H),7.04(d,J＝8.0Hz,1H),6.94-6.91(m,1H),6.80(d,J＝1.8Hz,1H),5.19-4.99(m1H),3.00(s,6H),2.85-2.84(m,7H),2.55(br s,4H),2.27(s,3H)。LC-MS(M+H)⁺＝469.0。

Example 254: (4- (5- (3- (methylamino) -4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (2-oxa-6-azaspiro [3.3] hept-6-yl) methanone (Compound 254)

Step 1: (2-oxa-6-azaspiro [3.3] hept-6-yl) (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) methanone

4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoic acid (2.48g, 10mmol, 1.0 eq.), 2-oxa-6-azaspiro [3.3]A mixture of heptane (1.09g, 11mmol, 1.1 equiv.), HATU (3.8g, 10mmol, 1.0 equiv.), and TEA (3.03g, 30mmol, 3.0 equiv.) in DMF (40mL) was stirred at room temperature under nitrogen for 5 h. The mixture was diluted with ethyl acetate (50mL), washed with brine (50mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (1.6g, 50%). LC-MS (M + H) ⁺＝329.9。

Step 2: (4- (5- (3- (methylamino) -4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (2-oxa-6-azaspiro [3.3] hept-6-yl) methanone

Prepared from 3-iodo-5- (3- (methylamino) -4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that in example 285 step 4]Pyridine-1-carboxylic acid tert-butyl ester and (2-oxa-6-azaspiro [ 3.3)]Hept-6-yl) (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) methanone preparation example 254(8mg, 8.4%).¹H NMR(400MHz,DMSO-d6)δ12.10(s,1H),8.53(d,J＝1.9Hz,1H),8.40(d,J＝1.8Hz,1H),8.03(d,J＝2.7Hz,1H),7.87(d,J＝8.3Hz,2H),7.70(d,J＝8.3Hz,2H),7.05(d,J＝8.0Hz,1H),6.93(dd,J＝8.0,1.8Hz,1H),6.81(d,J＝1.7Hz,1H),5.04(brs,1H),4.70(s,4H),4.55(s,2H),4.23(s,2H),2.85-2.84(m,7H),2.59(brs,4H),2.30(s,3H)。LC-MS(M+H)⁺＝522.9。

Example 255: (S) -4- (5- (3- (3-hydroxypyrrolidin-1-yl) -4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (Compound 255)

Step 1: (S) -1- (5-bromo-2-nitrophenyl) pyrrolidin-3-ol

The title compound (2.85g, 100%) was prepared from (S) -pyrrolidin-3-ol and 4-bromo-2-fluoro-1-nitrobenzene in a similar manner to that in example 253, step 1. LC-MS (M + H)⁺＝286.9,288.9。

Step 2: (S) -1- (2-amino-5-bromophenyl) pyrrolidin-3-ol

The title compound (1.8g, 87%) was prepared from (S) -1- (5-bromo-2-nitrophenyl) pyrrolidin-3-ol in a similar manner as in example 253, step 2. LC-MS (M + H)⁺＝256.9,258.9。

And step 3: (S) -1- (5-bromo-2- (4-methylpiperazin-1-yl) phenyl) pyrrolidin-3-ol

The title compound (520mg, 25%) was prepared from (S) -1- (2-amino-5-bromophenyl) pyrrolidin-3-ol and nitrogen mustard hydrochloride in a similar manner to that in example 236 step 2. LC-MS (M + H)⁺＝339.9,341.9。

And 4, step 4: 5-bromo-3-iodo-1H-pyrrolo [2,3-b ] pyridines

To 5-bromo-1H-pyrrolo [2,3-b ] at room temperature]To a solution of pyridine (5g, 25.4mmol, 1 eq) in THF (80mL) was added NIS (6.85g, 30.4mmol, 1.2 eq). After stirring at room temperature for 2h, the reaction mixture was concentrated under reduced pressure. The crude product was applied to a silica gel column with petroleum ether/ethyl acetate (15/1) to give the title compound (8g, 97%). LCMS (M + H)⁺＝322.6。

And 5: 5-bromo-3-iodo-1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester

Reacting 5-bromo-3-iodo-1H-pyrrolo [2,3-b ]]Pyridine (8g, 24.7mmol, 1 eq.), Boc₂O (7.5g, 34.6mmol, 1.4 equiv.) and Et₃A solution of N (7.4g, 74mmol, 3 equiv.) in THF (80mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The crude product was applied to a silica gel column with petroleum ether/ethyl acetate (20/1) to give the title compound (10g, 95%). LCMS (M + H)⁺＝422.6。

Step 6: 4- (5-bromo-1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide

To 5-bromo-3-iodo-1H-pyrrolo [2,3-b ] in a nitrogen atmosphere ]To a solution of pyridine-1-carboxylic acid tert-butyl ester (2g, 4.71mmol, 1 eq) and (4- (dimethylcarbamoyl) phenyl) boronic acid (0.91g, 4.71mmol, 1 eq) in 50mL dioxane and 10mL water was added K₂CO₃(1.3g, 9.4mmol, 2 equiv.) and Pd (dppf) Cl₂ CH₂Cl₂(345mg, 0.47mmol, 0.1 equiv.). After stirring at 90 ℃ for 5h under a nitrogen atmosphere, the reaction mixture was concentrated under reduced pressure. The crude was loaded onto a silica gel column and eluted with dichloromethane/MeOH (30/1) to give the title compound (1.2g, 74%). LCMS (M + H)⁺＝343.8。

And 7: 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

In a 100mL sealed tube purged with and maintained under an inert atmosphere of nitrogen, 4- (5-bromo-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) -N, N-Dimethylbenzamide (200mg, 0.58mmol, 1 equiv.), BPD (221mg, 0.87mmol, 1.5 equiv.), Pd (dppf) Cl₂ CH₂Cl₂A mixture of (25mg, 0.035mmol, 0.06 equiv.), KOAc (170mg, 1.74mmol, 3.00 equiv.) in dioxane (30mL) was stirred in an oil bath at 90 deg.C overnight. The solid was filtered off and the residue was applied to a silica gel column with dichloromethane/MeOH (20/1) to give the title compound (120mg, 53%).

And 8: (S) -4- (5- (3- (3-hydroxypyrrolidin-1-yl) -4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide

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 (200mg, 0.51mmol, 1.0 equiv.) and (S) -1- (5-bromo-2- (4-methylpiperazin-1-yl) phenyl) pyrrolidin-3-ol (173mg, 0.51mmol, 1.0 equiv.) in dioxane (20mL) and H₂Pd (dppf) Cl was added to a solution in O (4mL)₂(37mg, 0.05mmol, 0.1 equiv.) and K₂CO₃(140mg, 1.02mmol, 2.0 equiv.). The mixture was refluxed under nitrogen for 5 h. The mixture was cooled to room temperature and diluted with ethyl acetate (30mL), washed with brine (20mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: MeOH ═ 20:1) to give the title compound (23mg, 18%).¹H NMR(400MHz,DMSO-d6)δ12.05(s,1H),8.51(d,J＝1.7Hz,1H),8.38(s,1H),7.99(d,J＝2.5Hz,1H),7.84(d,J＝8.1Hz,2H),7.48(d,J＝8.1Hz,2H),7.13(d,J＝8.1Hz,1H),7.07-6.95(m,2H),4.88-4.78(m,1H),4.35(s,1H),3.57-3.53(m,1H),3.51-3.45(m,1H),3.28-3.24(m,1H),3.17-3.15(m,1H),3.00-2.92(m,10H),2.58(brs,4H),2.29(s,3H),2.07-2.02(m,1H),1.78(brs,1H)。LC-MS(M+H)⁺＝524.9。

Example 256: n, N-dimethyl-4- (5- (4- (4-methylpiperazin-1-yl) -3- (((tetrahydrofuran-2-yl) methyl) amino) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 256)

Step 1: 5-bromo-2-nitro-N- ((tetrahydrofuran-2-yl) methyl) aniline

The title compound (2.8g, 93%) was prepared from (tetrahydrofuran-2-yl) methylamine and 4-bromo-2-fluoro-1-nitrobenzene in a similar manner to that in example 253, step 1. LC-MS (M + H) ⁺＝300.9,302.9。

Step 2: 5-bromo-N1- ((tetrahydrofuran-2-yl) methyl) benzene-1, 2-diamine

The title compound (2) was prepared from 5-bromo-2-nitro-N- ((tetrahydrofuran-2-yl) methyl) aniline in a similar manner to that in example 253, step 2.5g，99％)。LC-MS(M+H)⁺＝270.9,272.9。

And step 3: 5-bromo-2- (4-methylpiperazin-1-yl) -N- ((tetrahydrofuran-2-yl) methyl) aniline

The title compound (0.56g, 17%) was prepared from 5-bromo-N1- ((tetrahydrofuran-2-yl) methyl) benzene-1, 2-diamine and nitrogen mustard hydrochloride in a similar manner as in example 236 step 2. LC-MS (M + H)⁺＝353.9,355.9。

And 4, step 4: n, N-dimethyl-4- (5- (4- (4-methylpiperazin-1-yl) -3- (((tetrahydrofuran-2-yl) methyl) amino) phenyl) -1H-pyrrolo [2,3-b]Pyridin-3-yl) benzamide example 256(58mg, 27%) was prepared from 5-bromo-2- (4-methylpiperazin-1-yl) -N- ((tetrahydrofuran-2-yl) methyl) aniline and (4- (dimethylcarbamoyl) phenyl) boronic acid in a similar manner to that in example 255 step 8.¹H NMR(400MHz,DMSO-d6)δ12.08(s,1H),8.52(d,J＝1.9Hz,1H),8.38(d,J＝1.6Hz,1H),8.00(d,J＝2.6Hz,1H),7.84(d,J＝8.2Hz,2H),7.49(d,J＝8.2Hz,2H),7.33(d,J＝8.3Hz,1H),7.20(s,1H),7.02(d,J＝8.3Hz,1H),4.90(brs,1H),3.66(brs,3H),3.38-3.17(m,7H),3.00(s,6H),2.79(brs,4H),2.66-2.63(m,1H),2.44(brs,1H),1.91-1.89(m,1H),1.84-1.81(m,1H),1.60-1.57(m,1H),1.38-1.17(m,1H)。LC-MS(M+H)⁺＝539.0。

Example 257: (R) -4- (5- (3- (3-hydroxypyrrolidin-1-yl) -4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (Compound 257)

Step 1: (R) -1- (5-bromo-2-nitrophenyl) pyrrolidin-3-ol

The title compound (2.6g, 91%) was prepared from (R) -pyrrolidin-3-ol in a similar manner to that in example 253, step 1. LC-MS (M + H) ⁺＝286.9,288.9。

Step 2: (R) -1- (2-amino-5-bromophenyl) pyrrolidin-3-ol

Prepared from (R) -1- (5-bromo-2-nitrobenzene in a similar manner to that in step 2 of example 253Yl) pyrrolidin-3-ol the title compound (2.2g, 94%) was prepared. LC-MS (M + H)⁺＝256.9、258.9。

And step 3: (R) -1- (5-bromo-2- (4-methylpiperazin-1-yl) phenyl) pyrrolidin-3-ol

The title compound (0.48g, 13%) was prepared from (R) -1- (2-amino-5-bromophenyl) pyrrolidin-3-ol and nitrogen mustard hydrochloride in a similar manner as in example 236 step 2. LC-MS (M + H)⁺＝339.9,341.9。

And 4, step 4: (R) -4- (5- (3- (3-hydroxypyrrolidin-1-yl) -4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide

Example 257(13mg, 6%) was prepared from (R) -1- (5-bromo-2- (4-methylpiperazin-1-yl) phenyl) pyrrolidin-3-ol and (4- (dimethylcarbamoyl) phenyl) boronic acid in a similar manner to that in example 255 step 8.¹H NMR(400MHz,DMSO-d6)δ12.08(s,1H),8.53(d,J＝1.9Hz,1H),8.39(s,1H),8.00(d,J＝2.6Hz,1H),7.84(d,J＝8.2Hz,2H),7.49(d,J＝8.2Hz,2H),7.25-7.12(m,1H),7.08-7.06(m,2H),4.88(brs,1H),4.37(brs,1H),3.59-3.47(m,5H),3.39-3.21(m,5H),3.00(s,6H),2.97-2.85(m,5H),2.11-2.01(m,1H),1.80(brs,1H)。LC-MS(M+H)⁺＝525.0。

Example 258: n, N-dimethyl-6- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) nicotinamide (compound 258)

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

1-methyl-4- (2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) piperazine (13.0g, 41.0mmol), 5-bromo-1H-pyrrolo [2,3-b ] is added ]Pyridine (10.4g, 41.0mmol), Pd (dppf) Cl₂(1.81g, 2.46mmol) and Na₂CO₃(8.70g, 82.0mmol) in dioxane (150mL) and H₂The solution in O (50mL) was stirred at 80 ℃ for 16h under a nitrogen atmosphere. Allowing the mixture to cool to roomAnd (4) warming. Insoluble solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane/MeOH ═ 15/1) to give the title compound (7.2g, 57%). LCMS (M + H)⁺＝307.1

Step 2: 3-bromo-5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine

To 5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]NBS (4.1g, 23.13mmol) was added to a solution of pyridine (7.2g, 23.13mmol) in THF (100 mL). The reaction mixture was stirred at room temperature for 2 h. The solvent was concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane/MeOH ═ 20/1) to give the title compound (274mg, 72%). LCMS (M + H)⁺＝385.0,387.0

And step 3: 3-bromo-5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b ] pyridine

To 3-bromo-5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] at 0 DEG C]To a solution of pyridine (6.5g, 16.75mmol) in DMF (50mL) was added NaH (60%, 1.00g, 25.12 mmol). The reaction mixture was stirred at room temperature for 1h and benzenesulfonyl chloride (3.26g, 18.42mmol) was added. The reaction mixture was stirred at room temperature for 2H, dichloromethane (200mL) and H were added ₂O (200 mL). The aqueous layer was extracted with ethyl acetate (100mLx 2). The combined organic layers were washed with H₂O (50mLx4), brine (50mL) and Na over₂SO₄And (5) drying. The solvent was concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane/MeOH ═ 15/1) to give the title compound (4.3g, 49%). LCMS (M + H)⁺＝525.0,527.0。

And 4, step 4: (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) boronic acid

Reacting 3-bromo-5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b ]]Pyridine (4g, 7.63mmol), 4,4,4 ', 4 ', 5,5,5 ', 5 ' -octamethyl-2, 2 ' -bis (1,3, 2-dioxaborolan) (2.18g, 8.40mmol), Pd (dppf) Cl₂(235mg, 0.916mmol) and KOAc (1.46g, 15.27mmol) inThe solution in dioxane (300mL) was stirred under nitrogen at 80 ℃ for 16 h. The mixture was allowed to cool to room temperature. Insoluble solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane/MeOH ═ 15/1) to give the title compound (0.64g, 17%). LCMS (M + H)⁺＝491.1

And 5: n, N-dimethyl-6- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) nicotinamide

Reacting (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1- (phenylsulfonyl) -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) boronic acid (200mg, 0.404mmol), 6-bromo-N, N-dimethylnicotinamide (111mg, 0.484mmol), Pd (dppf) Cl₂(15mg, 0.02mmol) and Na₂CO₃(90mg, 0.848mmol) in dioxane (20mL) and H₂The solution in O (10mL) was stirred at 80 ℃ for 16h under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. Insoluble solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane/MeOH ═ 15/1) to give the title compound (120mg, 50%). LCMS (M + H)⁺＝595.2

Step 6: n, N-dimethyl-6- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) nicotinamide

To N, N-dimethyl-6- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1- (phenylsulfonyl) -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) nicotinamide (110mg, 0.186mmol) in MeOH (10mL) was added K₂CO₃(77mg, 0.557 mmol). The reaction mixture was stirred at room temperature for 2 h. The solvent was concentrated in vacuo. The residue was purified by preparative TLC (dichloromethane/MeOH ═ 15/1) to give the product (35mg, 42%).¹H NMR(400MHz,DMSO-d6)12.23(s,1H),8.93(d,J＝2.0Hz,1H),8.68(d,J＝1.7Hz,1H),8.54(d,J＝2.1Hz,1H),8.39(d,J＝2.8Hz,1H),7.99(d,J＝8.3Hz,1H),7.84(dd,J＝8.3,2.2Hz,1H),7.60-7.47(m,2H),7.17(d,J＝8.2Hz,1H),3.07-3.04(m,14H),2.69-2.59(m,3H),2.37(s,3H)。LCMS(M+H)⁺＝455.2。

Example 259: 6- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylnicotinamide (Compound 259)

Step 1: 3-bromo-5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b ] pyridine

Prepared in a similar manner to that in step 3 of example 258 from 3-bromo-5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]Pyridine preparation the title compound (4.5g, 55.5% yield). LCMS (M + H)⁺＝539.0,541.0。

Step 2: (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) boronic acid

Prepared in a similar manner to that in example 258 step 4 from 3-bromo-5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b]Pyridine preparation the title compound (240mg, 31.1% yield). LCMS (M + H)⁺＝505.2。

And step 3: 6- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylnicotinamide

Prepared in a similar manner to that described in step 5 of example 258 from 6-bromo-N, N-dimethylnicotinamide and (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b ] p]Pyridin-3-yl) boronic acid the title compound was prepared (50mg, 27.6% yield). LCMS (M + H)⁺＝609.2。

And 4, step 4: 6- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylnicotinamide.

Prepared in a similar manner to that in example 258 step 6 from 6- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1- (phenylsulfonyl) -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) -N, N-Dimethylnicotinamide preparation example 259(21mg, 55.3%).¹H NMR(400MHz,DMSO-d6)12.20(s,1H),8.90(d,J＝2.1Hz,1H),8.68(d,J＝1.9Hz,1H),8.51(d,J＝2.1Hz,1H),8.37(d,J＝2.8Hz,1H),7.99(d,J＝8.3Hz,1H),7.84(dd,J＝8.3,2.2Hz,1H),7.33(s,2H),3.10-3.03(m,10H),2.55-2.50(m,4H),2.37(s,6H),2.27(s,3H)。LCMS(M+H)⁺＝469.2。

Example 260: 5- (3-fluoro-4- (4-methylpiperazin-1-yl) phenyl) -3- (4- (5-methyl-1H-1, 2, 3-triazol-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (Compound 260)

Step 1: 5- (3-fluoro-4- (4-methylpiperazin-1-yl) phenyl) -3-iodo-1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester

Prepared from 5- (3-fluoro-4- (4-methylpiperazin-1-yl) phenyl) -3-iodo-1H-pyrrolo [2,3-b ] in a similar manner to that in example 236 step 5]Pyridine preparation the title compound (460mg, 45%). LC-MS (M + H)⁺＝536.9。

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

Prepared from 5- (3-fluoro-4- (4-methylpiperazin-1-yl) phenyl) -3-iodo-1H-pyrrolo [2,3-b ] in a similar manner to that in example 285 step 4]Pyridine-1-carboxylic acid tert-butyl ester and 5-methyl-1- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -1H-1,2, 3-triazole preparation example 260(4mg, 4%). ¹H NMR(400MHz,DMSO-d6)δ12.15(d,J＝1.8Hz,1H),8.59(d,J＝1.9Hz,1H),8.51(d,J＝1.7Hz,1H),8.09(d,J＝2.6Hz,1H),8.05(d,J＝8.5Hz,2H),7.72(s,1H),7.67-7.65(m,3H),7.57-7.51(m,1H),7.15-7.11(m,1H),3.07(brs,4H),2.51(brs,4H),2.39(s,3H),2.24(s,3H)。LC-MS(M+H)⁺＝467.9。

Example 261: 3- (4- (5-methyl-1H-1, 2, 3-triazol-1-yl) phenyl) -5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (compound 261)

Step 1: 3-bromo-5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester

Prepared in a similar manner to that in step 5 of example 236 from 3-bromo-5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]Pyridine preparation the title compound (450mg, 90%). LC-MS (M + H)⁺＝484.9。

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

Prepared from 3-bromo-5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that in example 285 step 4]Pyridine-1-carboxylic acid tert-butyl ester and 5-methyl-1- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -1H-1,2, 3-triazole preparation example 261(9mg, 6%).¹H NMR(400MHz,DMSO-d6)δ12.15(s,1H),8.56(d,J＝1.8Hz,1H),8.47(s,1H),8.08(d,J＝2.6Hz,1H),8.03(d,J＝8.5Hz,2H),7.72(s,1H),7.69-7.62(m,3H),7.60(d,J＝8.5Hz,1H),7.16(d,J＝8.2Hz,1H),3.11(brs,7H),2.75(brs,4H),2.39(s,3H),2.36(s,3H)。LC-MS(M+H)⁺＝463.9。

Example 262: 3- (4-methoxyphenyl) -5- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (compound 262)

Step 1: (4- ((4-methylpiperazin-1-yl) methyl) phenyl) boronic acid

To (4-bromophenyl) boronic acid (500mg, 2.3mmol, 1.0 equiv.), 1-methylpiperazine (232mg, 2.5mmol, 1.1 equiv.), and Et ₃THF (20mL) was added to N (0.5mL, 3.5mmol, 1.5 equiv). The mixture was stirred at room temperature for 3 hours. Water (30mL) was added and the mixture was extracted with ethyl acetate (30 mL). The combined organic layers were passed over Na₂SO₄Dried and evaporated in vacuo to afford the title compound (200mg, 37%). LC-MS (M + H)⁺＝235.1。

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

To 5-bromo-1H-pyrrolo [2,3-b ] under nitrogen]To a solution of pyridine (170mg, 0.85mmol, 1.0 eq) in 1, 4-dioxane (20mL) and water (5mL) was added (4- ((4-methylpiperazin-1-yl) methyl) phenyl) boronic acid (200mg, 0.85mmol, 1.0 eq), Pd (dppf) Cl₂(31mg, 0.04mmol, 0.05 eq.) and K₂CO₃(180mg, 1.27mmol, 1.5 equiv.). It was refluxed overnight. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (40mL) over Na₂SO₄Dried and evaporated in vacuo. The crude product was purified by preparative TLC (dichloromethane/MeOH ═ 8:1) to give the title compound (180mg, 68%). LC-MS (M + H)⁺＝307.1。

And step 3: 3-bromo-5- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) -1H-pyrrolo [2,3-b ] pyridine

To a solution of 5- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (180mg, 0.59mmol, 1.0 eq) in THF (20mL) was added NBS (115mg, 0.64mmol, 1.1 eq). The reaction mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo and purified by preparative TLC (dichloromethane/MeOH ═ 8:1) to give the title compound (185mg, 82%).

And 4, step 4: 3- (4-methoxyphenyl) -5- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) -1H-pyrrolo [2,3-b ] pyridine

To 3-bromo-5- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) -1H-pyrrolo [2,3-b ] under nitrogen]To a solution of pyridine (185mg, 0.50mmol, 1.0 equiv.) in 1, 4-dioxane (25mL) and water (5mL) were added (4-methoxyphenyl) boronic acid (83mg, 0.55mmol, 1.1 equiv.), XPhos Pd G2(39mg, 0.055mmol, 0.1 equiv.), and K₃PO₄(160mg, 0.75 mmol). The reaction mixture was refluxed overnight. It was cooled to room temperature and diluted with ethyl acetate (40mL), washed with brine (40mL), over Na₂SO₄Dried and purified by preparative TLC (dichloromethane/MeOH ═ 6:1) to give the title compound (3mg, 1.5%).¹H NMR(400MHz,DMSO-d6)δ11.90(s,1H),8.54(s,1H),8.37(s,1H),7.80(d,J＝1.9Hz,1H),7.76-7.66(m,4H),7.41(d,J＝7.8Hz,2H),7.03(d,J＝8.5Hz,2H),3.80(s,3H),3.53(s,2H),2.50-2.35(m,9H),2.29(s,3H)。LC-MS(M+H)⁺＝412.2。

Example 263: 4- (5- (3, 5-difluoro-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (Compound 263)

Step 1: 3, 5-difluoro-4- (4-methylpiperazin-1-yl) aniline

The title compound was prepared from 1- (2, 6-difluoro-4-nitrophenyl) -4-methylpiperazine in analogy to the procedure in example 320, step 3. LC-MS (M + H)⁺＝228.2。

Step 2: 1- (4-bromo-2, 6-difluorophenyl) -4-methylpiperazine

The title compound was prepared from 3, 5-difluoro-4- (4-methylpiperazin-1-yl) aniline in a similar manner to that in example 320, step 4. LC-MS (M + H) ⁺＝293.0。

And step 3: 1- (4-bromo-2, 6-difluorophenyl) -4-methylpiperazine

The title compound was prepared from 1- (4-bromo-2, 6-difluorophenyl) -4-methylpiperazine and BPD in a similar manner to that in example 109, step 1. LC-MS (M + H)⁺＝257.1。

And 4, step 4: 4- (5- (3, 5-difluoro-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide

Prepared from 1- (2, 6-difluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -4-methylpiperazine and 4- [ 5-chloro-1H-pyrrolo [2,3-b ] in a similar manner to that in step 4 of example 285]Pyridin-3-yl]-N, N-dimethylbenzamide preparation example 263.¹H NMR(400MHz,DMSO-d6)δ12.15(brs,1H),8.60(s,1H),8.51(s,1H),8.03(s,1H),7.93-7.86(m,2H),7.63-7.52(m,2H),7.52-7.46(m,2H),3.21-3.11(m,4H),3.01(s,6H),2.50-2.42(m,4H),2.24(s,3H)。LC-MS(M+H)⁺＝476.1。

Example 264: (R) -4- (5- (4- (2, 4-dimethylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (Compound 264)

Step 1: (R) -1- (4-bromophenyl) -2, 4-dimethylpiperazine

(4-bromophenyl) boronic acid (530mg, 2.6mmol, 1.0 equiv.), (R) -1, 3-dimethylpiperazine (300mg, 2.6mmol, 1.0 equiv.), Cu (OAc) under an air atmosphere₂(524mg, 2.9mmol, 1.1 equiv.) and Et₃N (1.8mL, 13.2mmol, 5.0 equiv.) was added to dichloromethane (30 mL). The mixture was stirred at room temperature overnight. Water (30mL) was added and the mixture was extracted with dichloromethane (2 x 40mL), over Na ₂SO₄Dried and evaporated in vacuo. It was purified by preparative TLC (dichloromethane/MeOH ═ 8:1) to give the title compound (50mg, 7%). LC-MS (M + H)⁺＝269.0,271.0。

Step 2: (R) -5- (4- (2, 4-dimethylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine

The title compound (50mg, 89%) was prepared from 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ] pyridine and (R) -1- (4-bromophenyl) -2, 4-dimethylpiperazine in a similar manner to that in example 262, step 2.

And step 3: (R) -3-bromo-5- (4- (2, 4-dimethylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester

Reacting (R) -5- (4- (2, 4-dimethylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]Pyridine (50mg, 0.16mmol, 1.0 equiv.) and NBS (35mg, 0.20mmol, 1.2 equiv.) were added to THF (20 mL). It was stirred at room temperature for 1h, then Et was added₃N (0.1mL, 0.64mmol, 4.0 equiv.) and di-tert-butyl dicarbonate (89mg, 0.4mmol, 2.5 equiv.). The mixture was refluxed overnight. The solvent was removed in vacuo and the mixture was purified by preparative TLC (dichloromethane/MeOH ═ 8:1) to give the title compound (70mg, 89%). LC-MS (M + H)⁺＝485.1,487.1。

And 4, step 4: (R) -4- (5- (4- (2, 4-dimethylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide

Example 264(12mg, 18%) was prepared from (4- (dimethylcarbamoyl) phenyl) boronic acid in a similar manner to that in example 262, step 4.¹H NMR(400MHz,DMSO-d6)δ12.06(s,1H),8.54(s,1H),8.41(s,1H),7.99(d,J＝2.4Hz,1H),7.86(d,J＝8.1Hz,2H),7.66(d,J＝7.9Hz,2H),7.49(d,J＝8.0Hz,2H),7.06(s,2H),3.45-3.40(m,3H),3.25-3.05(m,2H),3.00(s,6H),2.96-2.56(m,3H),2.45-2.00(m,2H),1.16(s,3H)。LC-MS(M+H)⁺＝454.2。

Example 265: (S) -4- (5- (4- (2, 4-dimethylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (Compound 265)

Step 1: (S) -1- (4-bromophenyl) -2, 4-dimethylpiperazine

Coupling (4-bromophenyl) boronic acid (880mg, 4.4mmol, 1.0 equiv.), (R) -1, 3-dimethylpiperazine (500mg, 4.4mmol, 1.0 equiv.), Cu (OAc)₂(873mg, 4.8mmol, 1.1 equiv.) and Et₃N (1.9mL, 13.2mmol, 3.0 equiv.) was added to dichloromethane (100 mL). The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the crude product was purified by column chromatography eluting with dichloromethane/MeOH ═ 20:1 to give the title compound (240mg, 20%). LC-MS (M + H)⁺＝269.0,271.0。

Step 2: (S) -5- (4- (2, 4-dimethylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine

Prepared in a similar manner to that in step 2, example 262 from 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ]]Pyridine and (S) -1- (4-bromophenyl) -2, 4-dimethylpiperazine the title compound was prepared (150mg, 55%). LC-MS (M + H) ⁺＝307.1。

And step 3: (S) -3-bromo-5- (4- (2, 4-dimethylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester

To (S) -5- (4- (2, 4-dimethylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]To pyridine (150mg, 0.49mmol, 1.0 equiv.) and NBS (105mg, 0.59mmol, 1.2 equiv.) was added THF (20 mL). The reaction mixture was stirred at room temperature for 2 hours, then (Boc) was added₂O (107mg, 0.49mmol, 1.0 equiv.) and Et₃N (0.2mL, 1.43mmol, 3.0 equiv.). The reaction was refluxed overnight. The solvent was removed in vacuo and the crude was purified by preparative TLC (dichloromethane/MeOH ═ 20:1) to give the title compound (160mg, 68%). LC-MS (M + H)⁺＝485.1,487.1。

And 4, step 4: (S) -4- (5- (4- (2, 4-dimethylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide

Prepared from (4- (dimethylcarbamoyl) phenyl) boronic acid and (S) -3-bromo-5- (4- (2, 4-dimethylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that in step 4 of example 262]Pyridine-1-carboxylic acid tert-butyl ester preparation example 265(56mg, 38%).¹H NMR(400MHz,DMSO-d6)δ12.07(s,1H),8.54(d,J＝1.9Hz,1H),8.41(s,1H),7.99(d,J＝2.6Hz,1H),7.86(d,J＝8.3Hz,2H),7.67(d,J＝8.1Hz,2H),7.49(d,J＝8.3Hz,2H),7.06(s,2H),3.65-3.40(m,3H),3.30-3.03(m,4H),3.01(s,6H),2.95-2.55(m,3H),1.27-0.94(m,3H)。LC-MS(M+H)⁺＝453.3。

Example 266: 4- (5- (4- (4- (dimethylamino) piperidin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (Compound 266)

Step 1: 1- (4-bromophenyl) -N, N-dimethylpiperidin-4-amine

1- (4-bromophenyl) piperidin-4-one (0.5g, 2.0mmol, 1.0 equiv.), dimethylamine (1.2mL, 2.4mmol, 1.2 equiv.), NaBH (OAc)₃(500mg, 2.4mmol, 1.2 equiv.) and AcOH (142mg, 2.4mmol, 1.2 equiv.) were added to dichloromethane (30 mL). Mixing the reactionThe mixture was stirred at room temperature overnight. Add 20mL NaHCO₃And the mixture was separated with ethyl acetate (20 mL). The organic layer was washed with brine (20mL) and Na₂SO₄Dried and evaporated in vacuo. The crude product was purified by preparative TLC (dichloromethane/MeOH ═ 8:1) to give the title compound (360mg, 65%). LC-MS (M + H)⁺＝283.0,285.0。

Step 2: 4- (5- (4- (4- (dimethylamino) piperidin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide

Prepared in a similar manner to that in example 255 step 8 from 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 and 1- (4-bromophenyl) -N, N-dimethylpiperidin-4-amine preparation example 266(10mg, 8%).¹H NMR(400MHz,DMSO-d6)δ12.05(s,1H),8.53(d,J＝1.9Hz,1H),8.39(d,J＝1.8Hz,1H),7.99(d,J＝2.6Hz,1H),7.85(d,J＝8.2Hz,2H),7.64(d,J＝8.7Hz,2H),7.49(d,J＝8.2Hz,2H),7.09(d,J＝8.8Hz,2H),3.92(d,J＝12.5Hz,2H),3.30-3.21(m,1H),3.01(s,6H),2.82-2.64(m,8H),2.12(d,J＝11.5Hz,2H),1.75(q,J＝11.7Hz,2H)。LC-MS(M+H)⁺＝468.2。

Example 267: n, N-dimethyl-4- (5- (4- (4- (methylamino) piperidin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 267)

Step 1: 1- (4-bromophenyl) -N-methylpiperidin-4-amine

The title compound (280mg, 56%) was prepared from 1- (4-bromophenyl) piperidin-4-one and methylamine in a similar manner to that in example 266 step 1.

Step 2: n, N-dimethyl-4- (5- (4- (4- (methylamino) piperidin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Prepared in a similar manner to that in example 255 step 8 from 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 and 1- (4-bromophenyl) -N-methylpiperidin-4-amine preparation example 267(16mg, 6%).¹H NMR(400MHz,DMSO-d6)δ12.05(s,1H),8.53(s,1H),8.39(s,1H),7.99(s,1H),7.85(d,J＝6.7Hz,2H),7.65(d,J＝7.2Hz,2H),7.49(d,J＝6.6Hz,2H),7.09(d,J＝7.6Hz,2H),3.90-3.86(m,2H),3.20-3.10(m,1H),3.01(s,6H),2.78(t,J＝12.3Hz,3H),2.57(s,3H),2.10-2.07(m,2H),1.66-1.64(m,2H)。LC-MS(M+H)⁺＝454.2。

Example 268: 4- (5- (3-cyano-4- (4-methyl-1, 4-diazepan-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (Compound 268)

Step 1: 5-bromo-3-iodo-1H-pyrrolo [2,3-b ] pyridines

Reacting 5-bromo-1H-pyrrolo [2,3-b ]]Pyridine (3g, 15.23mmol) was dissolved in DMF (30 mL). NIS (3.77g, 16.75mmol) was added and stirred at room temperature for 4 hours. The solvent was removed in vacuo. Water (50mL) was added. The title compound (4.77g, 97%) was received by filtration. LC-MS (M + H)⁺＝323.0。

Step 2: 5-bromo-3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridine

Reacting 5-bromo-3-iodo-1H-pyrrolo [2,3-b ]]Pyridine (4.77g, 14.77mmol) was dissolved in DMF (50 mL). NaH (60%, 886.4mg, 22.16mmol) was added at 0 ℃ and stirred at 0 ℃ for 30 min. SEMCl (3.694g, 22.16mmol) was added and stirred at room temperature for 4 hours. Water (20mL) was added and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine and Na₂SO₄And (5) drying. The crude product was purified by preparative TLC (dichloromethane/MeOH ═ 8:1) to give the title compound (5.2g, 78%). LC-MS (M + H)⁺＝453.0。

And step 3: 4- (5-bromo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide

Reacting 5-bromo-3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b]Pyridine (5.2g, 11.5mmol), (4- (dimethylcarbamoyl) phenyl) boronic acid (2.2g, 11.6mmol), Na₂CO₃(2.4g, 22.9mmol) and Pd (dppf) Cl₂(420mg, 0.574mmol) was dissolved in 1, 4-dioxane (50mL) and H₂In O (20mL) and then in N₂The reaction mixture was then heated to 90 ℃ overnight. The solvent was removed in vacuo. The title compound (5.45g, 100%) was received via a column on silica gel. LC-MS (M + H)⁺＝474.0。

And 4, step 4: n, N-dimethyl-4- (5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Reacting 4- (5-bromo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) -N, N-Dimethylbenzamide (2.68g, 5.65mmol), 4,4,4 ', 4 ', 5,5,5 ', 5 ' -octamethyl-2, 2 ' -bis (1,3, 2-Dioxolane) (2.87g, 11.30mmol), KOAc (1.661g, 16.95mmol), and Pd (dppf) Cl₂(207mg, 0.2825mmol) was dissolved in 1, 4-dioxane (30mL) and washed with N₂Heat to 90 ℃ overnight. The solvent was removed in vacuo. The title compound (3.05g, 100%) was received via a column on silica gel. LC-MS (M + H)⁺＝522.0。

And 5: 2- (1, 4-diazepan-1-yl) benzonitrile

2-fluorobenzonitrile (5g, 41.285mmol), 1, 4-diazepane (4.55g, 45.413mmol) and K₂CO₃(11.4g, 82.57mmol) was dissolved in DMF (50mL) and heated to 110 ℃ overnight. Water (200mL) was added and the reaction mixture was extracted with dichloromethane. The combined organic layers were washed with brine and Na₂SO₄And (5) drying. The title compound (6.5g, 78.3%) was received by column chromatography on silica gel. LC-MS (M + H)⁺＝202.0。

Step 6: 2- (4-methyl-1, 4-diazepan-1-yl) benzonitrile

2- (1, 4-Diazepan-1-yl) benzonitrile (3g, 14.91mmol) was dissolved in dichloromethane. Addition of AcOH (0.5 mL). 35% formalin solution (13mL) was added and stirred at 0 ℃ for 5 min. Addition of NaHB (AcO) at 0 deg.C₃(9.48g, 44.73mmol) and stirred at room temperature overnight. A saturated aqueous solution of sodium bicarbonate was added to pH 8-9 and extracted with dichloromethane. The combined organic layers were washed with brine and over Na₂SO₄And (5) drying. The title compound (3.21g, 100%) was received. LC-MS (M + H)⁺＝216.0。

And 7: 5-bromo-2- (4-methyl-1, 4-diazepan-1-yl) benzonitrile

2- (4-methyl-1, 4-diazepan-1-yl) benzonitrile (3.21g, 14.91mmol) was dissolved in EtOH (40 mL). Dropwise addition of Br at 0 deg.C₂(4.77g, 29.82mmol) and stirred at room temperature for 3 hours. The solvent was removed in vacuo. Water (50mL) was added and extracted with dichloromethane. The combined organic layers were saturated with Na₂S₂O₃And washed with brine and Na₂SO₄And (5) drying. The title compound (3.6g, 82%) was received via a column on silica gel. LC-MS (M + H)⁺＝294.0。

And 8: 4- (5- (3-cyano-4- (4-methyl-1, 4-diazepan-1-yl) phenyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide

Mixing N, N-dimethyl-4- (5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1- ((2- (trimethylsilyl) ethyoxyl) methyl) -1H-pyrrolo [2,3-b ] ]Pyridin-3-yl) benzamide (500mg, 0.959mmol), 5-bromo-2- (4-methyl-1, 4-diazepan-1-yl) benzonitrile (310mg, 1.055mmol), K₂CO₃(264.7mg, 1.918mmol) and Pd (dppf) Cl₂(35.1mg, 0.048mmol) was dissolved in 1, 4-dioxane (10mL) and H₂O (10mL) and in N₂Heat to 90 ℃ overnight. The solvent was removed in vacuo and the title compound (170mg, 29.12%) was received by column chromatography on silica gel. LC-MS (M + H)⁺＝609.0。

And step 9: 4- (5- (3-cyano-4- (4-methyl-1, 4-diazepan-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide

Reacting 4- (5- (3-cyano-4- (4-methyl-1, 4-diazepan-1-yl) phenyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ]]Pyridin-3-yl) -N, N-dimethylbenzamide (170mg, 0.2792mmol) was dissolved in dichloromethane (15 mL). TFA (15mL) was added and stirred at room temperature overnight. The solvent was removed in vacuo. MeOH (10mL) was added and dissolved with K₂CO₃The pH is adjusted to 11-12. MeOH was removed in vacuo. Water (10mL) was added and the mixture was extracted with dichloromethane. The combined organic layers were washed with Na₂S₂O₃Washed with brine and over Na₂SO₄And (5) drying. The title compound (45mg, 33.7%) was received by column chromatography on silica gel. ¹H NMR(400MHz,DMSO-d6)δ12.08(s,1H),8.56(s,1H),8.47(s,1H),8.01(s,2H),7.88(d,J＝7.7Hz,3H),7.49(d,J＝7.7Hz,2H),7.10(d,J＝9.0Hz,1H),3.68(s,2H),3.62(t,J＝5.5Hz,2H),3.01(s,6H),2.73(s,2H),2.55(d,J＝4.4Hz,2H),2.29(s,3H),1.97(s,2H)。LC-MS(M+H)⁺＝479.0。

Example 269: n, N-dimethyl-4- (5- (3-methyl-4- (4-methyl-1, 4-diazepan-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 269)

Step 1: 1- (2-methyl-4-nitrophenyl) -1, 4-diazepane

1-fluoro-2-methyl-4-nitrobenzene (5g, 32.23mmol) and 1, 4-diazepane (4.2g, 41.90mmol) were dissolved in DMF (50 mL). Addition of K₂CO₃(8.9g, 64mmol) and heated to 100 ℃ overnight. Water (100mL) was added and the mixture was extracted with dichloromethane. The combined organic layers were washed with brine and over Na₂SO₄And (5) drying. The title compound (7.58g, 100%) was received via a column on silica gel. LC-MS (M + H)⁺＝236.0。

Step 2: 1-methyl-4- (2-methyl-4-nitrophenyl) -1, 4-diazepane

Reacting 1- (2-methyl-4-Nitrophenyl) -1, 4-diazepane (7.58g, 32.224mmol) was dissolved in dichloromethane (200 mL). AcOH (1mL) was added. Formalin (35%, 27.65g, 322.24mmol) was added and stirred at room temperature for 5 min. Addition of NaHB (AcO) at 0 deg.C₃(20.49g, 96.672mmol) and stirred at room temperature overnight. The combined organic layers were washed with brine and over Na₂SO₄And (5) drying. The title compound (7.7g, 95.7%) was received by column chromatography on silica gel. LC-MS (M + H) ⁺＝250.0。

And step 3: 3-methyl-4- (4-methyl-1, 4-diazepan-1-yl) aniline

1-methyl-4- (2-methyl-4-nitrophenyl) -1, 4-diazepane (7.7g, 30.89mmol) was dissolved in MeOH (100 mL). Pd/C10% (500mg) and in H₂Stirring was continued at room temperature overnight. The catalyst was removed by filtration and the title compound (6g, 88.5%) was received after concentration. LC-MS (M + H)⁺＝220.0。

And 4, step 4: 1- (4-bromo-2-methylphenyl) -4-methyl-1, 4-diazepane

3-methyl-4- (4-methyl-1, 4-diazepan-1-yl) aniline (1g, 4.56mmol) was dissolved in CH₃CN (50 mL). T-BuONO (0.941g, 9.12mmol) and CuBr were added at room temperature₂(1.22g, 5.47mmol) and stirred at room temperature overnight. With NaHCO₃(saturation) the pH was adjusted to 8 and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and over Na₂SO₄And (5) drying. The product was received by column chromatography on silica gel (165mg, 12.8%). LC-MS (M + H)⁺＝283.0。

And 5: n, N-dimethyl-4- (5- (3-methyl-4- (4-methyl-1, 4-diazepan-1-yl) phenyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Prepared in a similar manner to that described in example 268, step 8 from N, N-dimethyl-4- (5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ]Pyridin-3-yl) benzamide and 1- (4-bromo-2-methylphenyl) -4-methyl-1, 4-dinitrogenHeteroheptane the title compound was prepared (77mg, 22.9%). LC-MS (M + H)⁺＝598.0。

Step 6: n, N-dimethyl-4- (5- (3-methyl-4- (4-methyl-1, 4-diazepan-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Prepared in a similar manner to that described in example 268, step 9 from N, N-dimethyl-4- (5- (3-methyl-4- (4-methyl-1, 4-diazepan-1-yl) phenyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b]Pyridin-3-yl) benzamide preparation example 269(12mg, 19.6%).¹H NMR(400MHz,DMSO-d6)δ12.04(s,1H),8.52(s,1H),8.39(s,1H),7.99(s,1H),7.85(d,J＝8.0Hz,2H),7.67-7.39(m,4H),7.15(d,J＝8.3Hz,1H),3.25-3.08(m,4H),3.00(s,6H),2.67(t,J＝5.5Hz,4H),2.34(s,3H),2.32(s,3H),1.96-1.76(m,2H)。LC-MS(M+H)⁺＝468.0。

Example 270: n, N-dimethyl-4- (5- (4- (4-methyl-1, 4-diazepan-1-yl) -3-nitrophenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 270)

Step 1: 1- (4-bromo-2-nitrophenyl) -4-methyl-1, 4-diazepane

4-bromo-1-fluoro-2-nitrobenzene (800mg, 3.64mmol) was dissolved in DMF (10 mL). 1-methyl-1, 4-diazepane (498.3mg, 4.364mmol) was added at room temperature and stirred at room temperature for 2 h. The solvent was removed in vacuo. Water (10mL) was added and Na was added₂CO₃The pH was adjusted to 9. The reaction mixture was extracted with dichloromethane. The combined organic layers were washed with brine and over Na ₂SO₄And (5) drying. The title compound (1.142g, 100%) was received via a column on silica gel. LC-MS (M + H)⁺＝314.0。

Step 2: n, N-dimethyl-4- (5- (4- (4-methyl-1, 4-diazepan-1-yl) -3-nitrophenyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Prepared in a similar manner to that described in example 268, step 8 from N, N-dimethyl-4- (5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b]Pyridin-3-yl) benzamide and 1- (4-bromo-2-nitrophenyl) -4-methyl-1, 4-diazepane the title compound was prepared (630mg, 100%). LC-MS (M + H)⁺＝629.0。

And step 3: n, N-dimethyl-4- (5- (4- (4-methyl-1, 4-diazepan-1-yl) -3-nitrophenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Prepared in a similar manner to that described in example 268, step 9 from N, N-dimethyl-4- (5- (4- (4-methyl-1, 4-diazepan-1-yl) -3-nitrophenyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b]Pyridin-3-yl) benzamide preparation example 270(60mg, 12%).¹H NMR(400MHz,DMSO-d6)δ12.11(s,1H),8.57(s,1H),8.48(s,1H),8.11(s,1H),8.02(s,1H),7.94-7.84(m,3H),7.49(d,J＝7.9Hz,2H),7.30(d,J＝8.9Hz,1H),3.40(d,J＝6.8Hz,2H),3.32-3.24(m,2H),3.01(s,6H),2.68(s,2H),2.51(s,2H),2.26(s,3H),1.90(s,2H)。LC-MS(M+H)⁺＝499.0。

Example 271: n, N-dimethyl-4- (5- (4- (4-methyl-1, 4-diazepan-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 271)

Step 1: 1-methyl-4- (4-nitrophenyl) -1, 4-diazepane

1-fluoro-4-nitrobenzene (3g, 21.3mmol) and 1-methyl-1, 4-diazepane (2.92g, 25.52mmol) were dissolved in DMF (30mL) and K was added₂CO₃(5.88g, 42.60 mmol). The reaction mixture was heated to 100 ℃ for 3 hours and cooled to room temperature. Water (100mL) was added and extracted with dichloromethane. The combined organic layers were washed with brine and over Na₂SO₄And (5) drying. The title compound (5g, 99.9%) was received. LC-MS (M + H)⁺＝236.0。

Step 2: 4- (4-methyl-1, 4-diazepan-1-yl) aniline

1-methyl-4- (4-nitrophenyl) -1, 4-diazepane (5g, 21.25mmol) was dissolved in MeOH (50 mL). Pd/C10% (100mg) and in H₂Stirring was continued overnight. The catalyst was removed by filtration. The title compound (4.3g, 98.5%) was received. LC-MS (M + H)⁺＝206.0。

And step 3: 1- (4-bromophenyl) -4-methyl-1, 4-diazepane

4- (4-methyl-1, 4-diazepan-1-yl) aniline (2g, 9.741mmol) was dissolved in CH₃CN (100 mL). T-BuONO (2.01g, 19.483mmol) was added at room temperature. Adding CuBr₂(2.01g, 19.48mmol) and stirred at room temperature overnight. Addition of NaHCO₃(saturated aqueous solution, 20mL) and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and over Na ₂SO₄And (5) drying. The title compound (5g, crude) was received by column chromatography on silica gel. LC-MS (M + H)⁺＝269.0。

And 4, step 4: n, N-dimethyl-4- (5- (4- (4-methyl-1, 4-diazepan-1-yl) phenyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Prepared in a similar manner to that described in example 268, step 8 from N, N-dimethyl-4- (5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b]Pyridin-3-yl) benzamide and 1- (4-bromophenyl) -4-methyl-1, 4-diazepan the title compound was prepared (508mg, 62.85%). LC-MS (M + H)⁺＝584.0。

And 5: n, N-dimethyl-4- (5- (4- (4-methyl-1, 4-diazepan-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Example 271(150mg, 38%) was prepared in a similar manner to that in example 268, step 9.¹H NMR(400MHz,DMSO-d6)δ11.99(s,1H),8.50(d,J＝2.0Hz,1H),8.36(d,J＝1.7Hz,1H),7.97(d,J＝2.6Hz,1H),7.84(d,J＝8.2Hz,2H),7.56(d,J＝8.7Hz,2H),7.48(d,J＝8.2Hz,2H),6.81(d,J＝8.8Hz,2H),3.62-3.52(m,2H),3.49(t,J＝6.2Hz,2H),3.00(s,6H),2.64(s,2H),2.49-2.39(m,2H),2.28(s,3H),1.98-1.82(m,2H)。LC-MS(M+H)⁺＝454.0。

Example 272: 4- (5- (3-methoxy-4- (4-methyl-1, 4-diazepan-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (Compound 272)

Step 1: 1- (2-methoxy-4-nitrophenyl) -4-methyl-1, 4-diazepane

The title compound (4.65g, 100%) was prepared from 1-fluoro-2-methoxy-4-nitrobenzene and 1-methyl-1, 4-diazepan in a similar manner to that in example 271, step 1. LC-MS (M + H) ⁺＝266.0。

Step 2: 3-methoxy-4- (4-methyl-1, 4-diazepan-1-yl) aniline

The title compound (4.1g, 99.3%) was prepared in a similar manner to that in example 271, step 2. LC-MS (M + H)⁺＝236.0。

And step 3: 1- (4-bromo-2-methoxyphenyl) -4-methyl-1, 4-diazepane

The title compound (311mg, 12.23%) was prepared in a similar manner to that in example 271, step 3. LC-MS (M + H)⁺＝299.0。

And 4, step 4: 4- (5- (3-methoxy-4- (4-methyl-1, 4-diazepan-1-yl) phenyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide

Prepared in a similar manner to that described in example 268, step 8 from N, N-dimethyl-4- (5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b]Pyridin-3-yl) benzamide and 1- (4-bromo-2-methoxyphenyl) -4-methyl-1, 4-diazepan the title compound was prepared (400mg, 69%). LC-MS (M + H)⁺＝614.0。

And 5: 4- (5- (3-methoxy-4- (4-methyl-1, 4-diazepan-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide

Prepared in a similar manner to that described in example 268, step 9 from 4- (5- (3-methoxy-4- (4-methyl-1, 4-diazepan-1-yl) phenyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ]Pyridin-3-yl) -N, N-Dimethylbenzamide preparation example 272(60mg, 19%).¹H NMR(400MHz,DMSO-d6)δ12.05(s,1H),8.56(d,J＝1.9Hz,1H),8.41(d,J＝1.8Hz,1H),7.99(d,J＝2.6Hz,1H),7.85(d,J＝8.1Hz,2H),7.49(d,J＝8.1Hz,2H),7.26(d,J＝1.6Hz,1H),7.25-7.16(m,1H),6.95(d,J＝8.2Hz,1H),3.88(s,3H),3.32-3.24(m,4H),3.00(s,6H),2.79(brs,2H),2.70(brs,2H),2.38(s,3H),1.95(brs,2H)。LC-MS(M+H)⁺＝484.0。

Example 273: 4- (5- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -3-methylphenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (Compound 273)

Step 1: n1, N1, N2-trimethyl-N2- (2-methyl-4-nitrophenyl) ethane-1, 2-diamine

The title compound (3.1g, 67.54%) was prepared from 1-fluoro-2-methyl-4-nitrobenzene and N1, N1, N2-trimethylethane-1, 2-diamine in a similar manner to that in example 271, step 1. LC-MS (M + H)⁺＝238.0。

Step 2: n1- (2- (dimethylamino) ethyl) -N1, 2-dimethylbenzene-1, 4-diamine

The title compound (2.69g, 99.2%) was prepared in a similar manner to that in example 271, step 2. LC-MS (M + H)⁺＝208.0。

And step 3: n1- (4-bromo-2-methylphenyl) -N1, N2, N2-trimethylethane-1, 2-diamine

The title compound (428mg, 12%) was prepared in a similar manner to that in example 271, step 3. LC-MS (M + H)⁺＝271.0。

And 4, step 4: 4- (5- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -3-methylphenyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide

Prepared in a similar manner to that described in example 268, step 8 from N, N-dimethyl-4- (5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ]Pyridin-3-yl) benzamide and N1- (4-bromo-2-methylphenyl) -N1, N2, N2-trimethylethane-1, 2-diamine the title compound was prepared (388mg, 42%). LC-MS (M + H)⁺＝586.0。

And 5: 4- (5- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -3-methylphenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide

Prepared in a similar manner as in step 9 of example 268 from 4- (5- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -3-methylphenyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] methyl]Pyridin-3-yl) -N, N-Dimethylbenzamide preparation example 273(85mg, 28%).¹H NMR(400MHz,DMSO-d6)δ12.05(d,J＝2.0Hz,1H),8.53(d,J＝1.9Hz,1H),8.41(d,J＝1.8Hz,1H),8.00(d,J＝2.6Hz,1H),7.85(d,J＝8.2Hz,2H),7.76-7.23(m,4H),7.17(d,J＝8.2Hz,1H),3.01(s,6H),2.97(s,2H),2.69(s,3H),2.47-2.37(m,2H),2.34(s,3H),2.16(s,6H)。LC-MS(M+H)⁺＝456.0。

Example 274: 4- (5- (3-fluoro-4- (4-methyl-1, 4-diazepan-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (Compound 274)

Step 1: 1- (2-fluoro-4-nitrophenyl) -4-methyl-1, 4-diazepane

The title compound (4.5g, 94%) was prepared from 1, 2-difluoro-4-nitrobenzene and 1-methyl-1, 4-diazepan in a similar manner to that in example 271, step 1. LC-MS (M + H)⁺＝254.0。

Step 2: 3-fluoro-4- (4-methyl-1, 4-diazepan-1-yl) aniline

The title compound (3.97g, 100%) was prepared from 1- (2-fluoro-4-nitrophenyl) -4-methyl-1, 4-diazepane in a similar manner as in example 271, step 2. LC-MS (M + H) ⁺＝224.0。

And step 3: 1- (4-bromo-2-fluorophenyl) -4-methyl-1, 4-diazepane

The title compound (220.3g, 8.54%) was prepared from 3-fluoro-4- (4-methyl-1, 4-diazepan-1-yl) aniline in a similar manner to that in example 271, step 3. LC-MS (M + H)⁺＝287.0。

And 4, step 4: 4- (5- (3-fluoro-4- (4-methyl-1, 4-diazepan-1-yl) phenyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide

Prepared in a similar manner to that described in example 268, step 8 from N, N-dimethyl-4- (5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b]Pyridin-3-yl) benzamide and 1- (4-bromo-2-fluorophenyl) -4-methyl-1, 4-diazepane the title compound was prepared (97mg, 20%). LC-MS (M + H)⁺＝602.0。

And 5: 4- (5- (3-fluoro-4- (4-methyl-1, 4-diazepan-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide

Prepared in a similar manner to that described in example 268, step 9 from 4- (5- (3-fluoro-4- (4-methyl-1, 4-diazepan-1-yl) phenyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ]Pyridin-3-yl) -N, N-Dimethylbenzamide preparation example 274(35mg, 46%).¹H NMR(400MHz,DMSO-d6)δ12.06(d,J＝1.9Hz,1H),8.55(d,J＝2.0Hz,1H),8.43(d,J＝1.8Hz,1H),8.00(d,J＝2.6Hz,1H),7.87(d,J＝8.3Hz,2H),7.57(dd,J＝15.4,2.0Hz,1H),7.52-7.42(m,3H),7.08-6.92(m,1H),3.49-3.38(m,4H),3.01(s,6H),2.74(brs,2H),2.62(brs,2H),2.34(s,3H),2.04-1.85(m,2H)。LC-MS(M+H)⁺＝472.0。

Example 275: 3- (3-methyl-4- (2H-1,2, 3-triazol-2-yl) phenyl) -5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (compound 275)

Step 1: (4-bromo-2-methylphenyl) hydrazine

4-bromo-2-methylaniline (3g, 16.13mmol) was dissolved in concentrated HCl (15 mL). NaNO in water (6mL) was added dropwise at 0 deg.C₂(1.23g, 16.13mmol) and stirred at 0 ℃ for 30 min. SnCl in concentrated HCl (12mL) was added dropwise at 0 deg.C₂(22.93g, 120.94mmol) and stirred at room temperature overnight. The reaction mixture was made basic with 40% NaOH solution and extracted with ethyl acetate. The combined organic layers were washed with brine and over Na₂SO₄And (5) drying. The title compound (1.143g, 35.3%) was received by column chromatography on silica gel. LC-MS (M + H)⁺＝201.0。

Step 2: 1, 2-bis (2- (4-bromo-2-methylphenyl) hydrazono) ethane

(4-bromo-2-methylphenyl) hydrazine (1.143g, 5.69mmol) was dissolved in toluene (30 mL). Glyoxal (0.423g, 39%, 2.85mmol) was added dropwise and stirred at room temperature overnight. The title compound (768mg, 31.85%) was received by filtration.¹HNMR(400MHz,DMSO-d6)δ9.73(s,2H),7.95(s,2H),7.40-6.97(m,6H),2.20(s,6H)。LC-MS(M+H)⁺＝425.0。

And step 3: 2- (4-bromo-2-methylphenyl) -2H-1,2, 3-triazole

1, 2-bis (2- (4-bromo-2-methylphenyl) hydrazono) ethane (768mg, 1.811mmol) was dissolved in toluene (30 mL). Addition of Cu (CF)₃SO₃)₂(65.5mg, 0.1811mmol) and heated to reflux overnight. The reaction mixture was allowed to cool and filtered through celite and the filter pad was washed with ethyl acetate. The combined organic layers were washed with brine and over Na₂SO₄And (5) drying. The title compound (320mg, 74.2%) was received by column chromatography on silica gel. LC-MS (M + H)⁺＝238.0。

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

2- (4-bromo-2-methylphenyl) -2H-1,2, 3-triazole (320mg, 1.344mmol), bis (pinacolato) diboron (682.61mg, 2.688mmol), Pd (dppf) Cl₂(98.3mg, 0.1344mmol) and KOAc (395mg, 4.032mmol) were dissolved in 1, 4-dioxane (15mL) and in N₂Heat to 90 ℃ overnight. The solvent was removed under reduced pressure, and the title compound (465mg, 100%) was received through a chromatography column on silica gel. LC-MS (M + H)⁺＝286.0。

And 5: 3-iodo-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine

Reacting 5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]Pyridine (4.36g, 14.92mmol) was dissolved in DMF (50 ml). NIS (4.03g, 17.894mmol) was added and stirred at room temperature overnight. Water (100ml) was added and the title compound (6.24g, 69.9%) was received by filtration. LC-MS (M + H) ⁺＝419.0。

Step 6: 3-iodo-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester

3-iodine-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]Pyridine (6.24g, 14.92mmol), Boc₂O (4.23g, 19.39mmol), DIPEA (3.86g, 29.84mmol) and DMAP (150mg, 1.228mmol) were dissolved in THF (100ml) and stirred at room temperature overnight. Water (50ml) was added and the reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and over Na₂SO₄And (5) drying. The title compound (5.78g, 74.7%) was received via a column on silica gel. LC-MS (M + H)⁺＝519.0。

And 7: 3- (3-methyl-4- (2H-1,2, 3-triazol-2-yl) phenyl) -5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine

3-iodine-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]Pyridine-1-carboxylic acid tert-butyl ester (500mg, 0.965mmol), 2- (2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -2H-1,2, 3-triazole (289mg,1.013mmol), Na₂CO₃(204.5mg, 1.929mmol) and Pd (dppf) Cl₂(35.3mg, 0.0483mmol) was dissolved in 1, 4-dioxane/H₂O (15ml/10ml) and in N₂Heat to 90 ℃ overnight. The solvent was removed in vacuo and the title compound (140mg, 31.56%) (140mg, 32%) was received by chromatography on silica gel. ¹H NMR(400MHz,DMSO-d6)δ12.05(d,J＝2.1Hz,1H),8.53(d,J＝1.9Hz,1H),8.42(d,J＝1.8Hz,1H),8.12(brs,2H),8.01(d,J＝2.6Hz,1H),7.89-7.77(m,2H),7.67-7.57(m,3H),7.06(d,J＝8.8Hz,2H),3.26-3.10(m,4H),2.49-2.42(m,4H),2.37(s,3H),2.24(s,3H)。LC-MS(M+H)⁺＝450.0。

Example 276: 4- (4-chloro-5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (Compound 276)

Step 1: 4-chloro-5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine

To 5-bromo-4-chloro-1H-pyrrolo [2,3-b ] in a nitrogen atmosphere]Pyridine (0.7g, 3mmol, 1 equiv.) and 1- (2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -4-methylpiperazine (1.5g, 4.5mmol, 1.5 equiv.) in dioxane (40mL) and water (10mL) were added K₂CO₃(1.25g, 9mmol, 3 equiv.) and Pd (dppf) Cl₂ CH₂Cl₂(220mg, 0.3mmol, 0.1 equiv.). After stirring at 90 ℃ for 15h under a nitrogen atmosphere, the reaction mixture was concentrated under reduced pressure. The crude product was applied to a silica gel column with dichloromethane/methanol (50/1) to give the title compound (0.8g, 74.7%). LCMS (M + H)⁺＝355.1。

Step 2: 4-chloro-5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -3-iodo-1H-pyrrolo [2,3-b ] pyridine

To 4-chloro-5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] at room temperature]Pyridine (100mg, 0.28mmol, 1 equiv.) in THF (10mL) was added NIS (7) 0mg, 0.3mmol, 1.1 equiv), after stirring at room temperature for 2h, the reaction mixture is concentrated under reduced pressure. The crude product was applied to a silica gel column with dichloromethane/methanol (50/1) to give the title compound (60mg, 44.4%). LCMS (M + H)⁺＝480.7。

And step 3: 4-chloro-5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -3-iodo-1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester

4-chloro-5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -3-iodo-1H-pyrrolo [2, 3-b)]Pyridine (60mg, 0.124mmol, 1 equiv.), Boc₂O (35.2mg, 0.161mmol, 1.3 equiv.) and Et₃A solution of N (38mg, 0.372mmol, 3 equiv.) in THF (15mL) was stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure. The crude product was applied to a silica gel column with dichloromethane/methanol (50/1) to give the title compound (70mg, 97.3%). LCMS (M + H)⁺＝580.7。

And 4, step 4: 4- (4-chloro-5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide

To 4-chloro-5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -3-iodo-1H-pyrrolo [2,3-b ] under a nitrogen atmosphere]To a solution of pyridine-1-carboxylic acid tert-butyl ester (80mg, 0.14mmol, 1 eq) and (4- (dimethylcarbamoyl) phenyl) boronic acid (27mg, 0.16mmol, 1.2 eq) in dioxane (20mL) and water (5mL) was added K ₃PO₄(53mg, 0.25mmol, 1.8 equiv.) and chlorine (2-dicyclohexylphosphino-2 ', 4', 6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl ]]Palladium (II) (11mg, 0.014mmol, 0.1 equiv.). After stirring at 90 ℃ for 15h under a nitrogen atmosphere, the reaction mixture was concentrated under reduced pressure. The crude product was applied to a silica gel column with dichloromethane/methanol (20/1) to give the title compound (30mg, 70%).¹H NMR(400MHz,DMSO-d6)δ12.33(s,1H),8.18(s,1H),7.72(s,1H),7.61-7.53(m,2H),7.45-7.39(m,2H),7.15-7.03(m,2H),3.11-3.03(m,4H),2.99(s,6H),2.45-2.38(m,4H),2.32(s,6H),2.24(s,3H)。LCMS(M+H)⁺＝501.9。HPLC:254nm,99.7％。

Example 277: 4- (5- (3- ((2-methoxyethyl) (methyl) amino) -4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (Compound 277)

Step 1: 5-bromo-N- (2-methoxyethyl) -N-methyl-2-nitroaniline

The title compound (2.5g, 86.5%) was prepared from 4-bromo-2-fluoro-1-nitrobenzene and 2-methoxy-N-methylethyl-1-amine in a similar manner to that in example 253, step 1. LC-MS (M + H)⁺＝288.9、290.9。

Step 2: 5-bromo-N1- (2-methoxyethyl) -N1-methylbenzene-1, 2-diamine

The title compound (2g, 89.3%) was prepared from 5-bromo-N- (2-methoxyethyl) -N-methyl-2-nitroaniline in a similar manner to that in example 253, step 2. LC-MS (M + H)⁺＝258.9,260.9。

And step 3: 5-bromo-N- (2-methoxyethyl) -N-methyl-2- (4-methylpiperazin-1-yl) aniline

The title compound (200mg, 9%) was prepared from 5-bromo-N1- (2-methoxyethyl) -N1-methylbenzene-1, 2-diamine and 2-chloro-N- (2-chloroethyl) -N-methylethyl-1-amine hydrochloride in a similar manner to that in example 236, step 2. LC-MS (M + H)⁺＝341.9、343.9。

And 4, step 4: 4- (5- (3- ((2-methoxyethyl) (methyl) amino) -4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide

Prepared in a similar manner to that in example 255 step 8 from 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 and 5-bromo-N- (2-methoxyethyl) -N-methyl-2- (4-methylpiperazin-1-yl) aniline preparation example 277(5mg, 2.5%).¹H NMR(400MHz,DMSO-d6)δ12.05(d,J＝2.0Hz,1H),8.51(d,J＝1.9Hz,1H),8.38(s,1H),7.99(d,J＝2.6Hz,1H),7.85(s,1H),7.83(s,1H),7.49(s,1H),7.47(s,1H),7.27-7.22(m,1H),7.19(s,1H),7.00(d,J＝8.2Hz,1H),3.51-3.42(m,4H),3.35-3.33(m,2H),3.33-3.31(m,2H),3.21(s,3H),3.25-3.01(m,4H),3.00(s,6H),2.88(s,3H),2.24(s,3H)。LCMS(M+H)⁺＝527。HPLC:254nm,98.4％。

Example 278: 4- (5- (3-acetamido-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (Compound 278)

Step 1: 1- (4-bromo-2-nitrophenyl) -4-methylpiperazine

4-bromo-1-fluoro-2-nitrobenzene (10g, 45.5mmol, 1 eq.), 1-methylpiperazine (6.8g, 68.2mmol, 1.52 eq.), and K₂CO₃(12.6g, 91mmol, 2 equiv.) in CH₃The mixture in CN (100mL) was stirred at 50 ℃ for 3 hours. The mixture was diluted with water (300mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with brine (2 × 100mL), dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (13.5g, 96.5%). LC-MS (M + H) ⁺＝299.8,301.8。

Step 2: 5- (4- (4-methylpiperazin-1-yl) -3-nitrophenyl) -1H-pyrrolo [2,3-b ] pyridine

To 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ] under a nitrogen atmosphere]To a solution of pyridine (6.7g, 27.3mmol, 1 eq) and 1- (4-bromo-2-nitrophenyl) -4-methylpiperazine (10.7g, 35.6mmol, 1.3 eq) in dioxane (120mL) and water (30mL) was added K₂CO₃(7.6g, 54.6mmol, 2 equiv.) and Pd (dppf) Cl₂ CH₂Cl₂(2g, 2.73mmol, 0.1 equiv.). After stirring at 90 ℃ for 15h under a nitrogen atmosphere, the reaction mixture was concentrated under reduced pressure. The crude product was applied to a silica gel column with dichloromethane/methanol (50/1) to give the title compound (8g, 87%). LCMS (M + H)⁺＝337.9。

And step 3: 3-iodo-5- (4- (4-methylpiperazin-1-yl) -3-nitrophenyl) -1H-pyrrolo [2,3-b ] pyridine

To 5- (4- (4-methylpiperazin-1-yl) -3-nitrophenyl group at room temperature) -1H-pyrrolo [2,3-b]To a solution of pyridine (8g, 23.7mmol, 1 eq) in THF (300mL) was added NIS (5.87g, 26mmol, 1.1 eq). After stirring for 3h, the reaction mixture was concentrated under reduced pressure. The crude product was applied to a silica gel column with dichloromethane/methanol (50/1 to 20/1) to give the title compound (10g, 99%). LCMS (M + H) ⁺＝463.7。

And 4, step 4: 3-iodo-5- (4- (4-methylpiperazin-1-yl) -3-nitrophenyl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b ] pyridine

To 3-iodo-5- (4- (4-methylpiperazin-1-yl) -3-nitrophenyl) -1H-pyrrolo [2,3-b ] at 0 DEG C]To a solution of pyridine (2.17g, 4.56mmol, 1 eq) in DMF (100mL) was added NaH (1.72g, 43.2mmol, 60%) in portions. The mixture was stirred at room temperature for 1 h. A solution of benzenesulfonyl chloride (5.7g, 32.3mmol, 1.5 equiv.) in DMF (30mL) was added at 0 ℃. The resulting mixture was stirred overnight. The reaction mixture was washed with EtOH (10mL) and H₂O (10mL) was diluted until no gas was produced and concentrated. The mixture was extracted with EtOAc (500mL), washed with water (300mLx2) and brine (300mL), over anhydrous Na₂SO₄Dried and concentrated under reduced pressure. The residue was applied to a silica gel column with dichloromethane/methanol (50/1 to 30/1) to give the title compound (8.0g, 61.4%). LCMS (M + H)⁺＝603.7。

And 5: n, N-dimethyl-4- (5- (4- (4-methylpiperazin-1-yl) -3-nitrophenyl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

To 3-iodo-5- (4- (4-methylpiperazin-1-yl) -3-nitrophenyl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b ] under a nitrogen atmosphere ]To a solution of pyridine (5.15g, 8.54mmol, 1 eq) and (4- (dimethylcarbamoyl) phenyl) boronic acid (1.73g, 8.97mmol, 1.05 eq) in dioxane (100mL) and water (25mL) was added K₂CO₃(1.18g, 17mmol, 2 equiv.) and Pd (dppf) Cl₂ CH₂Cl₂(625mg, 0.854mmol, 0.1 equiv.). After stirring at 90 ℃ for 15h under a nitrogen atmosphere, the reaction mixture was concentrated under reduced pressure. The crude product was applied to a silica gel column with dichloromethane/methanol (20/1) to give the title compound (4.5g, 84.4%). LCMS (M + H)⁺＝624.9。

Step 6: 4- (5- (3-amino-4- (4-methylpiperazin-1-yl) phenyl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide

To N, N-dimethyl-4- (5- (4- (4-methylpiperazin-1-yl) -3-nitrophenyl) -1- (phenylsulfonyl) -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) benzamide (3.5g, 5.6mmol, 1 eq) was added to a solution of Pd/C (10%, 350mg) in MeOH (100 mL). The reaction mixture is left at room temperature in H₂Stir overnight under pressure (1 atm). LCMS showed desired MS. The reaction mixture was filtered. The filtrate was concentrated in vacuo to give the title compound (3.15g, 95%). LCMS (M + H)⁺＝594.9。

And 7: 4- (5- (3-acetamido-4- (4-methylpiperazin-1-yl) phenyl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide

To 4- (5- (3-amino-4- (4-methylpiperazin-1-yl) phenyl) -1- (phenylsulfonyl) -1H-pyrrolo [2, 3-b)]To a mixture of pyridin-3-yl) -N, N-dimethylbenzamide (500mg, 0.84mmol, 1 eq), DIPEA (152mmol, 1.176mol, 1.4 eq) in dichloromethane (15mL) was added a solution of acetyl chloride (80mg, 1.01mmol, 1.2 eq) in dichloromethane (1 mL). The mixture was stirred at room temperature overnight. The mixture is treated with NH₄Cl (aq, 10mL) and brine (10 mL). Subjecting the organic layer to Na₂SO₄Dried and evaporated to dryness to give the title compound (500mg, 93.5%). LCMS (M + H)⁺＝636.9。

And 8: 4- (5- (3-acetamido-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide

Reacting 4- (5- (3-acetamido-4- (4-methylpiperazin-1-yl) phenyl) -1- (phenylsulfonyl) -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) -N, N-Dimethylbenzamide (500mg, 0.79mmol, 1 eq.) and K₂CO₃A mixture of (325mg, 2.36mmol, 3 equiv.) in MeOH (50mL) was stirred at room temperature for 5 h. The solvent was concentrated under reduced pressure. The crude product was applied to a silica gel column with dichloromethane/methanol (10/1) to give the title compound (250mg, 64.2%).¹H NMR(400MHz,DMSO-d6)δ12.10(s,1H),8.89(s,1H),8.48(d,J＝1.7Hz,1H),8.37(s,1H),8.22(s,1H),8.01(d,J＝2.6Hz,1H),7.83(d,J＝8.2Hz,2H),7.53-7.43(m,3H),7.25(d,J＝8.2Hz,1H),3.00(s,6H),2.92-2.82(m,4H),2.62-2.53(m,4H),2.27(s,3H),2.14(s,3H)。LCMS(M+H)⁺＝496.9。HPLC:254nm,100％。

Example 279: 4- (5- (3- (isopropylamino) -4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (compound 279)

Step 1: 4- (5- (3- (isopropylamino) -4- (4-methylpiperazin-1-yl) phenyl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide

To 4- (5- (3-amino-4- (4-methylpiperazin-1-yl) phenyl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b ] at room temperature]Pyridin-3-yl) -N, N-Dimethylbenzamide (150mg, 0.25mmol, 1 equiv.) to a solution in dichloromethane (10mL) and AcOH (5mL) CO (CH) was added₃)₂(88mg, 1.5mmol, 6 equiv.) and NaBH (OAc)₃(106mg, 0.5mmol, 2 equiv.). The mixture was stirred overnight. The reaction mixture was washed with NaHCO₃Aqueous solution (20mL) was quenched and extracted with dichloromethane (3 × 20 mL). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane/methanol ═ 10/1) to give the title compound (70mg, 44%). LCMS (M + H)⁺＝636.9。

Step 2: 4- (5- (3- (isopropylamino) -4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide

Prepared in a similar manner to that described in step 8 of example 278 from 4- (5- (3- (isopropylamino) -4- (4-methylpiperazin-1-yl) phenyl) -1- (phenylsulfonyl) -1H-pyrrolo [2, 3-b) ]Pyridin-3-yl) -N, N-dimethylbenzamide and K₂CO₃Example 279(20mg, 36.6%) was prepared.¹H NMR(400MHz,DMSO-d6)δ12.06(s,1H),8.50(d,J＝1.9Hz,1H),8.38(s,1H),7.99(d,J＝2.2Hz,1H),7.84(d,J＝8.2Hz,2H),7.48(d,J＝8.2Hz,2H),7.07(d,J＝8.0Hz,1H),6.95-6.84(m,2H),4.55(d,J＝8.6Hz,1H),3.84-3.72(m,1H),3.00(s,6H),2.85-2.80(m,4H),2.51-2.48(m,4H),2.25(s,3H),1.20(d,J＝6.2Hz,6H)。LCMS(M+H)⁺＝497。HPLC:254nm,97％。

Example 280: 3-chloro-4- (5- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (Compound 280)

Step 1: 3-bromo-5- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester

To 3-bromo-5- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]Pyridine (0.6g, 1.5mmol) and (Boc)₂DMAP (20mg, 0.16mmol) was added to a mixture of O (0.5g, 2.3mmol) in THF (30 mL). The mixture was stirred for 4 h. The mixture was then concentrated. The residue was purified by silica gel column chromatography (dichloromethane: MeOH ═ 15:1) to give the title compound (400mg, 53%). LC-MS (M + H)⁺＝501.0、503.0。

Step 2: 3-chloro-4- (5- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzoic acid methyl ester

Prepared from 3-bromo-5- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that in example 285 step 4]Pyridine-1-carboxylic acid tert-butyl ester and (2-chloro-4- (methoxycarbonyl) phenyl) boronic acid the title compound (70mg, 71%) was prepared. LC-MS (M + H) ⁺＝491.1。

And step 3: 3-chloro-4- (5- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzoic acid

To 3-chloro-4- (5- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) benzoic acid methyl ester (70mg, 0.15mmol) in MeOH (2mL)To the solution of (3), NaOH solution (6M, 2mL) was added. The mixture was stirred overnight and then neutralized with HCl (2M). The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were passed over Na₂SO₄Dried and concentrated to give the title compound as a yellow solid (70mg, crude). LC-MS (M + H)⁺＝477.1。

And 4, step 4: 3-chloro-4- (5- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide

Prepared in a similar manner to that in example 216, step 7 from 3-chloro-4- (5- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]Pyridin-3-yl) benzoic acid and dimethylamine hydrochloride preparation example 280(20mg, 26%).¹H NMR(400MHz,DMSO-d6)δ12.15(s,1H),8.58(d,J＝2.0Hz,1H),8.08(d,J＝1.8Hz,1H),7.83(d,J＝2.6Hz,1H),7.70(d,J＝7.9Hz,1H),7.63(d,J＝1.6Hz,1H),7.46(dd,J＝7.9,1.6Hz,1H),7.26-7.18(m,2H),6.98(d,J＝8.2Hz,1H),3.88(s,3H),3.07(brs,4H),3.01(s,6H),2.70(brs,4H),2.42(brs,3H)。LC-MS(M+H)⁺504.1. HPLC 96.3% at 214nm and 96.3% at 254 nm.

Example 281: 2, 6-difluoro-N, N-dimethyl-4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 281)

Step 1: 4-bromo-2, 6-difluoro-N, N-dimethylbenzamide

To a stirred solution of 4-bromo-2, 6-difluorobenzoic acid (0.53g, 2.2mmol) and dimethylamine hydrochloride (0.27g, 3.4mmol) in anhydrous DMF (1.0mL) was added HATU (1.06g, 2.8mmol) followed by DIPEA (1.20mL, 0.86g, 6.7 mmol). After 90min, the mixture was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (EtOAc: petroleum ether ═ 0:1 to 2:3) to give the title compound (0.45g, 76%). LC-MS (M + H)⁺＝263.8,265.8。

Step 2: 2, 6-difluoro-N, N-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide

In N₂Next, 4-bromo-2, 6-difluoro-N, N-dimethylbenzamide (0.45g, 1.7mmol), bis (pinacolato) diboron (0.65g, 2.5mmol) and KOAc (0.33g, 3.4mmol) were suspended in dioxane (5 mL). The mixture was degassed by freeze-pump-thaw for 1 cycle, followed by addition of Pd (dppf) Cl₂DCM complex (15mg, 18 mol). The contents were degassed again for 2 cycles by freeze-pump-thaw, then heated to 100 ℃ for 2h, to 80 ℃ for 14 h. The reaction mixture was cooled to room temperature, concentrated and purified by silica gel chromatography (eluting with EtOAc: petroleum ether ═ 0:1 to 2:3) to give the title compound (0.55g, 99%). LC-MS (M-pin) ⁺＝230.0。

And step 3: 2, 6-difluoro-N, N-dimethyl-4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

In N₂2, 6-difluoro-N, N-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide (100mg, 0.32mmol), 3-iodo-5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]Pyridine-1-carboxylic acid tert-butyl ester (188mg, 0.35mmol) and K₂CO₃(134mg, 0.97mmol) was suspended in dioxane (5.0 mL). The mixture was degassed by freeze-pump-thaw for 1 cycle, followed by addition of Pd (dppf) Cl₂(12mg, 16 mol). The contents were degassed again for 2 cycles by freeze-pump-thaw, then heated to 70 ℃ for 18 h. Adding another portion of Pd (dppf) Cl₂(24mg, 32mol) and the mixture was then heated for 48h while maintaining 70 ℃. The solution was cooled to 0 ℃ and concentrated HCl (1.0mL) was added. After 4h, solid Na was added₂CO₃(3.0 g). All volatiles were removed under reduced pressure and the crude product was purified by silica gel chromatography (eluting with MeOH: DCM ═ 0:1 to 1: 8). The material was further purified by preparative HPLC to provide the title compound as a TFA salt. The salt was neutralized with ammonium hydroxide (25% aqueous) and purified by silica gel chromatography (eluting with MeOH: DCM ═ 0:1 to 1: 8) to provide the title compound (5.5mg, 3%). ¹H NMR(400MHz,DMSO-d6)δ12.23(s,1H),8.54(s,1H),8.45(s,1H),8.16(s,1H),7.69-7.62(m,2H),7.60(s,1H),7.57(d,J＝8.5Hz,1H),7.13(d,J＝7.9Hz,1H),3.05(s,3H),2.94(s,3H),2.92-2.84(m,4H),2.37-2.19(m,7H)。¹⁹F NMR(376MHz,DMSO)δ-114.24(s,1H),-114.27(s,1H)。LC-MS(M+H)⁺489.9. HPLC 92.8% at 214nm and 93.2% at 254 nm.

Example 282: n, N-dimethyl-4- (5- (3- ((1-methyl-1H-pyrazol-4-yl) methyl) -4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide; formic acid (Compound 282)

Step 1: 5-bromo-2- (4-methylpiperazin-1-yl) benzaldehyde

5-bromo-2-fluorobenzaldehyde (4.0g, 20mmol) and K were charged in a sealed tube₂CO₃(8.2g, 60mmol) to a stirred solution in anhydrous DMF (15mL) was added N-methylpiperazine (3.0g, 30 mmol). The vessel was warmed to 80 ℃ for 1h, then to 100 ℃ for 18 h. The solution was cooled to room temperature and the filter cake was taken up in Et₂O (30mL) wash. The filtrate was washed with water (60mL) and the organic layer was separated. The aqueous layer was successively treated with Et₂O (2 × 30mL) wash. The organic layer was concentrated and triturated with petroleum ether (30 mL). The liquid was decanted and the solid was rinsed with petroleum ether (2x30 mL). The solid was dried under vacuum to give the title compound (2.7g, 48%). LC-MS (M + H)⁺＝282.8,284.8。¹H NMR(400MHz,CDCl₃)δ10.24(s,1H),7.90(s,1H),7.60(d,J＝8.6Hz,1H),7.01(d,J＝8.7Hz,1H),3.11(s,4H),2.63(s,4H),2.38(s,3H)。

Step 2: (5-bromo-2- (4-methylpiperazin-1-yl) phenyl) (1-methyl-1H-pyrazol-4-yl) methanol

At-78 ℃ under N₂To a stirred solution of the following 4-bromo-1-methyl-1H-pyrazole (1.36g, 8.48mmol) in anhydrous THF (7.0mL) was added n-BuLi (2.4M in hexanes, 3.30mL, 7.91mmol) dropwise. After 1h, a solution of 5-bromo-2- (4-methylpiperazin-1-yl) benzaldehyde (1.60g, 5.65mmol) in anhydrous THF (7.0mL) was added dropwise. After an additional 1h, water (15mL) was added and The solution was warmed to room temperature. The mixture was partitioned between EtOAc (30mL) and water (20 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (30 mL). The combined organic layers were concentrated and purified by silica gel chromatography (2% NH in MeOH)₄OH: DCM ═ 0:1 to 1:4 elution) to give the title compound (1.09g, 53%). LC-MS (M + H)⁺＝365.0,367.0。

And step 3: 1- (4-bromo-2- ((1-methyl-1H-pyrazol-4-yl) methyl) phenyl) -4-methylpiperazine

At 0 ℃ in N₂To a stirred solution of (5-bromo-2- (4-methylpiperazin-1-yl) phenyl) (1-methyl-1H-pyrazol-4-yl) methanol (520mg, 1.42mmol) in TFA (5.0mL) was added NaBH (OAc)₃(1.51g, 7.12 mmol). The reaction mixture was stirred at room temperature for 16h and then concentrated under reduced pressure. The crude product was purified in EtOAc (30mL) with saturated NaHCO₃(100 mL). The organic layer was separated and the aqueous layer was extracted sequentially with EtOAc (2 × 20 mL). The combined organic layers were dried (Na)₂SO₄) Filtered and concentrated under reduced pressure. The crude product was chromatographed on silica gel (2% NH in MeOH)₄OH: DCM ═ 0:1 to 1:10 elution) to give the title compound (357mg, 72%). LC-MS (M + H)⁺＝348.9,350.9。

And 4, step 4: n, N-dimethyl-4- (5- (3- ((1-methyl-1H-pyrazol-4-yl) methyl) -4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide; formic acid

In N₂1- (4-bromo-2- ((1-methyl-1H-pyrazol-4-yl) methyl) phenyl) -4-methylpiperazine (117mg, 0.34mmol), N-dimethyl-4- (5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) benzamide (136mg, 0.35mmol) and K₂CO₃(93mg, 670mmol) was suspended in dioxane (6.0mL) and water (1.0 mL). The mixture was degassed by freeze-pump-thaw for 1 cycle, followed by addition of Pd (dppf) Cl₂DCM complex (14mg, 17 mol). The contents were degassed again for 2 cycles by freeze-pump-thaw, then heated to 90 ℃ for 18 h. The solution was cooled to room temperature and water (30.0mL) was added. The precipitate was filtered off and purified by preparative HPLC. Using NH for the material₄OH was neutralized and then re-purified by C18 reverse phase chromatography (eluting with ACN: 0.1% HCOOH in water 1:10 to 1: 1) to give the title compound (2mg, 1.1%).¹H NMR (400MHz, DMSO-d6) δ 12.07(d, J ═ 2.0Hz,1H),8.48(d, J ═ 1.9Hz,1H),8.36(d, J ═ 1.9Hz,1H),8.24(s,1H),8.00(d, J ═ 2.5Hz,1H),7.83(d, J ═ 8.2Hz,2H),7.55(dd, J ═ 8.2,2.1Hz,1H),7.49(dd, J ═ 8.7,5.5Hz,4H),7.30(s,1H),7.22(d, J ═ 8.2Hz,1H),3.87(s,2H),3.75(s,3H),3.00(s,6H),2.87(t, J ═ 8.2Hz,1H), 26.26H). (Note: 4 protons under DMSO solvent peak). LC-MS (M + H) ⁺534.0. HPLC 98.1% at 214nm and 98.2% at 254 nm.

Example 283: 7- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -2, 3-dihydro-1H-pyrido [2,3-b ] [1,4] oxazine (Compound 283)

Step 1: 2- ((5-bromo-3-nitropyridin-2-yl) oxy) acetic acid methyl ester

5-bromo-2-chloro-3-nitropyridine (5g, 21mmol, 1.0 eq.) and methyl 2-hydroxyacetate (3.78g, 42mmol, 2.0 eq.) and K₂CO₃A solution of (11.59g, 84mmol, 4.0 equiv.) in DMF (100mL) was stirred at 80 ℃ for 4 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The mixture was diluted with water (50mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine (3 × 50mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with PE: EA ═ 10: 1) to give the title compound (3.53g, 58%). LC-MS (M + H)⁺＝290.9。

Step 2: 7-bromo-1H-pyrido [2,3-b ] [1,4] oxazin-2 (3H) -one

To a solution of methyl 2- ((5-bromo-3-nitropyridin-2-yl) oxy) acetate (3.53g, 12.13mmol, 1.0 eq) in AcOH (30mL) at 60 ℃ was added Zn powder (4.73g, 72.78mmol, 6.0 eq) portionwise. The reaction mixture was then stirred at 100 ℃ for 1h, and the cooled reaction was mixed The material was filtered and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluting with DCM: MeOH ═ 20: 1) to give the title compound (1.6g, 58%). LC-MS (M + H)⁺＝229.0。

And step 3: 7-bromo-2, 3-dihydro-1H-pyrido [2,3-b ] [1, 4-oxazines

To BH₃-THF (7mL, 7mmol, 4.0 equiv.) was added dropwise to 7-bromo-1H-pyrido [2,3-b ] stirred at 0 deg.C][1,4]Oxazin-2 (3H) -one (400mg, 1.747mmol, 1.0 equiv.) in THF (5mL) solution. The reaction mixture was then stirred at 80 ℃ overnight. MeOH (1mL) was added. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluting with DCM: MeOH ═ 20: 1) to give the title compound (170mg, 45%). LC-MS (M + H)⁺＝214.9。

And 4, step 4: 7-bromo-2, 3-dihydro-1H-pyrido [2,3-b ] [1,4] oxazine-1-carboxylic acid tert-butyl ester

To 7-bromo-2, 3-dihydro-1H-pyrido [2,3-b ] at 0 deg.C][1,4]To a solution of oxazine (130mg, 0.605mmol, 1.0 equiv) in THF (anhydrous) (10mL) was added LiHMDS (1.3mL, 1.3mmol, 2.0 equiv). Di-tert-butyl dicarbonate (395mg, 1.814mmol, 3.0 equiv.) is added to the mixture at 0 ℃. In N₂The mixture was stirred at room temperature for 2 h. The mixture was quenched with water at 0 ℃ and extracted with EtOAc. The organic layer was separated, washed with brine and Na ₂SO₄Dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with PE: EtOAc ═ 10: 1) to give the title compound (190mg, 100%). LC-MS (M + H)⁺＝314.9。

And 5: 7- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-pyrido [2,3-b ] [1,4] oxazine-1-carboxylic acid tert-butyl ester

To 7-bromo-2, 3-dihydro-1H-pyrido [2,3-b ]][1,4]Oxazine-1-carboxylic acid tert-butyl ester (230mg, 0.73mmol, 1.0 equiv.) and 4,4,4 ', 4 ', 5,5,5 ', 5 ' -octamethyl-2, 2 ' -bis (1,3, 2-dioxaborolan (927mg, 3.65mmol, 5.0 equiv.) in dioxane (15mL) was added Pd (dppf) Cl₂(107mg, 0.146mmol, 0.2 equiv.) and AcOK (215mg, 2.19mmol, 3.0 equiv.). The mixture was refluxed under nitrogen for 5 h. The mixture was cooled to room temperature and diluted with EtOAc (30mL), washed with brine (20mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EtOAc ═ 1:1) to give the title compound (160mg, 60%). LC-MS (M + H)⁺＝363.0。

Step 6: 7- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -2, 3-dihydro-1H-pyrido [2,3-b ] [1,4] oxazine-1-carboxylic acid tert-butyl ester

Prepared from 3-iodo-5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that in step 4 of example 285]Pyridine-1-carboxylic acid tert-butyl ester and 7- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-pyrido [2,3-b ]][1,4]Oxazine-1-carboxylic acid tert-butyl ester the title compound (60mg, 41%) was prepared. LC-MS (M + H)⁺＝541.0。

And 7: 7- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -2, 3-dihydro-1H-pyrido [2,3-b ] [1,4 oxazine

Reacting 7- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) -2, 3-dihydro-1H-pyrido [2,3-b][1,4]A solution of oxazine-1-carboxylate (60mg, 0.11mmol) in TFA (2mL) and DCM (4mL) was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure, diluted with DCM (20mL) and NaHCO₃(sat, 20mL), brine (20mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH ═ 15:1) to give the title compound (6mg, 12%).¹H NMR(400MHz,DMSO-d6)δ11.90(s,1H),8.50(s,1H),8.26(s,1H),7.76(s,2H),7.55-7.50(m,2H),7.28(s,1H),7.13(d,J＝8.0Hz,1H),6.08(s,1H),4.29(app s,2H),2.93(br s,5H),2.67(br s,4H),2.37-2.34(m,7H)。LC-MS(M+H)⁺＝441.0。

Example 284: 1-methyl-7- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -2, 3-dihydro-1H-pyrido [2,3-b ] [1,4] oxazine (compound 284)

Step 1: 7-bromo-1-methyl-2, 3-dihydro-1H-pyrido [2,3-b ] [1, 4-oxazines

To 7-bromo-2, 3-dihydro-1H-pyrido [2,3-b ] at 0 deg.C][1,4]To a solution of oxazine (230mg, 1.0mmol, 1.0 equiv) in DMF (15mL) was added NaH (60mg, 1.5mmol, 1.5 equiv). The mixture was stirred at room temperature for 0.5h, and iodomethane (212mg, 1.5mmol, 1.5 equiv.) was added to the mixture. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water at 0 ℃ and extracted with EtOAc. The organic layer was separated, washed with brine and Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with PE: EtOAc ═ 10: 1) to give the title compound (170mg, 69%). LC-MS (M + H)⁺＝229.0。

Step 2: 1-methyl-7- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-pyrido [2,3-b ] [1,4] oxazine

Prepared in a similar manner to that in example 283 step 5 from 7-bromo-1-methyl-2, 3-dihydro-1H-pyrido [2,3-b ]][1,4 oxazine preparation the title compound (60mg, 29%). LC-MS (M + H)⁺＝276.9。

And step 3: 1-methyl-7- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -2, 3-dihydro-1H-pyrido [2,3-b ] [1,4] oxazine

Prepared in a similar manner to that in step 4 of example 285 from 1-methyl-7- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-pyrido [2,3-b][1,4]Oxazine preparation example 284(8mg, 6%).¹H NMR(400MHz,DMSO-d6)δ11.91(s,1H),8.51(d,J＝2.0Hz,1H),8.28(d,J＝1.9Hz,1H),7.95-7.77(m,2H),7.56(s,1H),7.54-7.49(m,1H),7.27(d,J＝1.9Hz,1H),7.11(d,J＝8.3Hz,1H),4.51-4.20(m,2H),3.31-3.23(m,2H),2.94(s,3H),2.89(br s,4H),2.62-2.52(m,4H),2.33(s,3H),2.27(s,3H)。LC-MS(M+H)⁺＝454.9。

Example 285: n, N-dimethyl-5- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) - [1, 1' -biphenyl ] -2-carboxamide (Compound 285)

Step 1: 5-bromo- [1, 1' -biphenyl ] -2-carboxylic acid

To NMP (20mL) and H₂To 2, 4-dibromobenzoic acid (5g, 17.86mmol) and phenylboronic acid (2.18g, 17.86mmol) in O (20mL) was added Pd₂(dba)₃(818mg, 0.893mmol) and LiOH (943mg, 39.3 mmol). The resulting solution was heated at 65 ℃ under N₂Stirring was continued overnight. The reaction mixture was cooled to room temperature and washed with H₂O (50mL) and extracted with EtOAc (50mLx 3). The combined EtOAc phases were washed with aqueous HCl (0.1N, 20mL) over Na₂SO₄Dried, concentrated and purified by column chromatography (DCM: MeOH ═ 20:1) to give the title compound (0.9g, 18%). LC-MS (M-H)^-＝274.8,276.8。

Step 2: 5-bromo-N, N-dimethyl- [1, 1' -biphenyl ] -2-carboxamide

To 5-bromo- [1, 1' -biphenyl in THF (20mL)]To 2-carboxylic acid (0.9g, 3.24mmol) and dimethylamine hydrochloride (396mg, 4.86mmol) were added HATU (2.46g, 6.48mmol) and Et ₃N (982mg, 9.72mmol), and the resulting solution was stirred at room temperature for 2 hours. Upon completion, the reaction mixture was washed with water (20mL) and extracted with ethyl acetate (20mLx3), over Na₂SO₄Dried, filtered and evaporated in vacuo to give the crude product, which was purified by column chromatography (DCM: MeOH ═ 200:1) to give the title compound (440mg, 44.7%). LC-MS (M + H)⁺＝303.8,305.8

And step 3: n, N-dimethyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) - [1, 1' -biphenyl ] -2-carboxamide

To 5-bromo-N, N-dimethyl- [1, 1' -biphenyl in 1, 4-dioxane (10mL)]KOAc (268.5mg, 2.74mmol) and Pd (dppf) Cl were added to (440mg, 1.37mmol) of (E) -2-carboxamide and (4,4, 4 ', 4 ', 5,5,5 ', 5 ' -octamethyl-2, 2 ' -bis (1,3, 2-dioxaborolan) (418mg, 1.65mmol)₂(100mg, 0.137 mmol). Will be describedThe obtained solution is subjected to a temperature of 90 ℃ under N₂Stirring was continued overnight. Upon completion, the reaction mixture was washed with water (50mL) and extracted with ethyl acetate (50mLx3), over Na₂SO₄Dried, filtered and evaporated in vacuo. The residue was purified by column chromatography (DCM/MeOH ═ 40:1) to give the title compound (126mg, 26%).¹H NMR(400MHz,CDCl₃)δ7.88-7.80(m,2H),7.52-7.45(m,2H),7.45-7.29(m,4H),2.84(s,3H),2.39(s,3H),1.35(s,12H)。LC-MS(M+H)⁺＝351.9。

And 4, step 4: n, N-dimethyl-5- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) - [1, 1' -biphenyl ] -2-carboxamide

To 3-iodo-5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]Pyridine-1-carboxylic acid tert-butyl ester (191mg, 0.36mmol) and N, N-dimethyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) - [1, 1' -biphenyl]-2-carboxamide (126mg, 0.36mmol) in 1, 4-dioxane (5mL) and H₂To a stirred solution in O (5mL) were added XPhos Pd G2(28mg, 0.036mmol) and K₃PO₄(152mg, 0.72 mmol). The resulting solution was heated at 80 ℃ under N₂Stirring was continued overnight. After completion, the reaction mixture was cooled to room temperature and washed with H₂O (10mL) and extracted with EtOAc (10mLx 3). The combined EtOAc phases were taken over Na₂SO₄Dried, concentrated and purified by preparative HPLC to give the title compound (12mg, 6.3%).¹H NMR(400MHz,CDCl₃)δ9.79(s,1H),8.59(s,1H),8.36(s,1H),7.76-7.67(m,2H),7.60(s,1H),7.57-7.50(m,3H),7.49-7.34(m,5H),7.29-7.23(m,2H),7.15(d,J＝7.9Hz,1H),3.10-2.96(m,4H),2.88(s,3H),2.80-2.54(m,4H),2.48(s,3H),2.46-2.36(m,6H)。LC-MS(M+H)⁺＝530.0。

Example 286: 5- (3- (4- (5-methyl-1H-1, 2, 3-triazol-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) -2- (1-methylpiperidin-4-yl) benzonitrile (Compound 286)

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

Azido-4-bromobenzene (5.7g, 28.8mmol), 1,3, 3-tetramethylguanidine (9.95g, 86.36mmol) and dimethyl (2-oxopropyl) phosphonate (4.78g, 28.8mmol) in THF (80mL) at 70 ℃ under N₂Stirring was continued overnight. The reaction mixture was cooled to room temperature and washed with H ₂O (80mL) and extracted with EtOAc (80mLx 3). The combined EtOAc phases were taken over Na₂SO₄Dry, concentrate and purify by column chromatography (DCM/MeOH ═ 50:1) to give the title compound (1.1g, 16%).¹H NMR(400MHz,DMSO-d6)δ7.82(d,J＝8.6Hz,2H),7.71(s,1H),7.60(d,J＝8.6Hz,2H),2.34(s,2H)。LC-MS(M+H)⁺＝237.8,239.8。

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

To 1- (4-bromophenyl) -5-methyl-1H-1, 2, 3-triazole (1.1g, 4.62mmol) and 4,4,4 ', 4 ', 5,5,5 ', 5 ' -octamethyl-2, 2 ' -bis (1,3, 2-dioxaborolan) (1.76g, 6.93mmol) in 1, 4-dioxane (50mL) was added KOAc (906mg, 9.24mmol) and Pd (dppf) Cl₂(338mg, 0.462 mmol). The resulting solution was stirred at 90 ℃ under N2 overnight. Upon completion, the reaction mixture was washed with water (50mL) and extracted with ethyl acetate (50mLx3), over Na₂SO₄Dried, filtered and evaporated in vacuo. The residue was purified by column chromatography (DCM/MeOH ═ 50:1) to give the title compound (1.76g, 134%, crude).¹H NMR(400MHz,DMSO-d6)δ7.89(d,J＝8.0Hz,2H),7.71(s,1H),7.63(d,J＝8.0Hz,2H),2.35(s,3H),1.33(s,12H)。LC-MS(M+H)⁺＝285.9。

And step 3: 4- (4-chloro-2-cyanophenyl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester

To 2-bromo-5-chlorobenzonitrile (2g, 9.24mmol) and tert-butyl 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (2.86g, 9.24mmol) in DMF (100mL) was added K ₂CO₃(2.55g, 18.48mmol) and Pd (dppf) Cl₂(676mg, 0.924 mmol). The resulting solution was heated at 90 ℃ under N₂Stirred for 5 hours.Upon completion, the reaction mixture was washed with water (200mL) and extracted with ethyl acetate (100mLx3), over Na₂SO₄Dried, filtered and evaporated in vacuo. The residue was purified by column chromatography (EtOAc: petroleum ether ═ 10:1) to give the title compound (2.3g, 78%).¹H NMR(400MHz,DMSO-d6)δ8.02(d,J＝2.2Hz,1H),7.76(dd,J＝8.5,2.3Hz,1H),7.53(d,J＝8.5Hz,1H),6.04(s,1H),4.01(s,2H),3.55(t,J＝5.4Hz,2H),2.49-2.42(m,2H),1.44(s,9H)。LC-MS(M+H-56)+＝262.8。

And 4, step 4: 4- (4-chloro-2-cyanophenyl) piperidine-1-carboxylic acid tert-butyl ester

To tert-butyl 4- (4-chloro-2-cyanophenyl) -3, 6-dihydropyridine-1 (2H) -carboxylate (1.8g, 5.6mmol) in i-PrOH (30mL) was added Pd/C (10%, 100 mg). The resulting solution was taken at room temperature under H₂(1atm) for 48 hours. The Pd/C was filtered, the filtrate was concentrated to give the crude product (1.8g, 100%) and it was used without purification. LC-MS (M + H-56) + (264.9).

And 5: 5-chloro-2- (piperidin-4-yl) benzonitrile

Crude tert-butyl 4- (4-chloro-2-cyanophenyl) piperidine-1-carboxylate (1.8g, 5.6mmol) in a solution of HCl (g) in 1, 4-dioxane (4N, 20mL) was stirred at room temperature for 2 hours. The mixture was concentrated and diluted with saturated NaHCO₃Aqueous (20mL) wash and extract with EtOAc (20mLx3) over Na₂SO₄Dried, filtered and evaporated in vacuo to give the crude product (1g, 80%) and used directly without purification. LC-MS (M + H) ⁺＝220.9。

Step 6: 5-chloro-2- (1-methylpiperidin-4-yl) benzonitrile

To crude 5-chloro-2- (piperidin-4-yl) benzonitrile (1g, 4.56mmol) in DCM (20mL) was added H₂O (37%) (3.7g, 45.6mmol) and NaBH (AcO)₃(1.93g, 9.12mmol) of HCHO and the resulting solution was stirred at room temperature for 3 hours. Upon completion, the reaction mixture was washed with water (20mL) and extracted with DCM (20mLx3), over Na₂SO₄Dried, filtered and evaporated in vacuo, the residue was purified by column chromatography (DCM: MeOH ═ 30:1) to give the title compound (200mg, 18.7%).LC-MS(M+H)⁺＝234.9。

And 7: 2- (1-methylpiperidin-4-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzonitrile

To 5-chloro-2- (1-methylpiperidin-4-yl) benzonitrile (200mg, 0.85mmol) and 4,4,4 ', 4 ', 5,5,5 ', 5 ' -octamethyl-2, 2 ' -bis (1,3, 2-dioxaborolan) (649mg, 2.55mmol) in 1, 4-dioxane (10mL) was added KOAc (250mg, 2.55mmol) and Pd (PCy)₃)₂Cl₂(31.4mg, 0.043 mmol). The resulting solution was heated at 110 ℃ under N₂Stirring was continued overnight. Upon completion, the reaction mixture was washed with water (10mL) and extracted with ethyl acetate (10mLx3), over Na₂SO₄Dry, filter and evaporate in vacuo, the residue is purified by column chromatography (DCM/MeOH ═ 50:1) to give the title compound (98mg, 35%). LC-MS (M + H) ⁺＝327.0。

And 8: 5-bromo-3- (4- (5-methyl-1H-1, 2, 3-triazol-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine

To 5-bromo-3-iodo-1H-pyrrolo [2,3-b ]]Pyridine-1-carboxylic acid tert-butyl ester (831mg, 1.97mmol) and 5-methyl-1- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -1H-1,2, 3-triazole (800mg, 1.97mmol, 70% purity) in 1, 4-dioxane (10mL) and H₂To a stirred solution in O (10mL) were added XPhos Pd G2(155mg, 0.197mmol) and K₃PO₄(833mg, 3.93 mmol). The resulting solution was heated at 80 ℃ under N₂Stirring was continued overnight. After completion, the reaction mixture was cooled to room temperature and washed with H₂O (20mL) and extracted with EtOAc (20mLx 3). The combined EtOAc phases were taken over Na₂SO₄Dried, concentrated and purified by preparative TLC to give the title compound (60mg, 8.6%). LC-MS (M + H)⁺＝353.8,355.8。

And step 9: 5- (3- (4- (5-methyl-1H-1, 2, 3-triazol-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) -2- (1-methylpiperidin-4-yl) benzonitrile

To 5-bromo-3- (4- (5-methyl-1H-1, 2, 3-triazol-1-yl) phenyl) -1H-pyrrolo [2,3-b]Pyridine (60mg, 0.169mmol) and 2- (1-methylpiperidin-4-yl) -5- (4,4,5, 5-tetramethyl-13, 2-Dioxopentaborane-2-yl) benzonitrile (55mg, 0.169mmol) in 1, 4-dioxane (5mL) and H ₂To a stirred solution in O (5mL) were added XPhos Pd G2(13mg, 0.017mmol) and K₃PO₄(72mg, 0.338 mmol). The resulting solution was heated at 80 ℃ under N₂Stirring was continued overnight. After completion, the reaction mixture was cooled to room temperature and washed with H₂O (20mL) and extracted with EtOAc (20mLx 3). The combined EtOAc phases were taken over Na₂SO₄Dried, concentrated and purified by preparative HPLC to give the title compound (3.67mg, 4.6%).¹H NMR(400MHz,CDCl₃)δ9.74(s,1H),8.61(s,1H),8.38(s,1H),8.09(s,1H),7.91(s,1H),7.89-7.79(m,3H),7.68(s,1H),7.66-7.58(m,2H),7.58-7.50(m,1H),3.13-2.98(m,3H),2.44(s,3H),2.39(s,2H),2.30-2.15(m,2H),2.00-1.88(m,3H),1.80-1.55(m,2H)。LC-MS(M+H)⁺＝473.9。

Example 287: 8- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -3-phenyl-3, 4-dihydrobenzo [ f ] [1,4] oxazepin-5 (2H) -one (Compound 287)

Step 1: 4-bromo-2-hydroxybenzoic acid methyl ester

Concentrated H was added dropwise to 4-bromo-2-hydroxybenzoic acid (10g, 46.1mmol) in MeOH (50mL) at 0 deg.C₂SO₄(20mL), the resulting solution was stirred at 65 ℃ overnight. MeOH was removed by addition of saturated NaHCO₃The residue was adjusted to pH 6-7 with aqueous solution and extracted with EtOAc (100mLx 3). The combined EtOAc phases were taken over Na₂SO₄Dried, concentrated and purified by column chromatography (EtOAc: petroleum ether ═ 10:1) to give the title compound (10.1g, 95%). LC-MS (M + H)⁺＝230.9。

Step 2: 4-bromo-2- (2- ((tert-butoxycarbonyl) amino) -2-phenylethoxy) benzoic acid methyl ester

To methyl 4-bromo-2-hydroxybenzoate (2g, 8.66mmol) and tert-butyl (2-hydroxy-1-phenylethyl) carbamate in toluene (50mL)(2.05g, 8.66mmol) to which was added DTBAD (2.98g, 12.98mmol) and PPh₃(3.4g, 12.98mmol) and the resulting solution was stirred at 60 ℃ for 3 hours. Toluene was removed in vacuo, the residue was slurried in EtOAc-petroleum ether 10:1(100mL), and PPh was precipitated₃O and it was filtered off, the filtrate was concentrated and purified by column chromatography (EtOAc: petroleum ether ═ 10:1) to give the title compound (3.66g, 94%). LC-MS (M + H)⁺＝449.8,451.8。

And step 3: 2- (2-amino-2-phenylethoxy) -4-bromobenzoic acid methyl ester

Methyl 4-bromo-2- (2- ((tert-butoxycarbonyl) amino) -2-phenylethoxy) benzoate (3.66g, 8.13mmol) in a solution of HCl (g) in 1, 4-dioxane (4N, 30mL) was stirred at room temperature overnight, the white solid was collected by filtration and dried in vacuo to give the HCl salt product by addition of NaHCO₃Aqueous (50mL) was freed and extracted with EtOAc (50mLx 3). The combined EtOAc phases were taken over Na₂SO₄Dried and concentrated to give the title compound (1.5g, 53%). LC-MS (M + H)⁺＝349.8,351.8。

And 4, step 4: 8-bromo-3-phenyl-3, 4-dihydrobenzo [ f ] [1,4] oxazepin-5 (2H) -one

Methyl 2- (2-amino-2-phenylethoxy) -4-bromobenzoate (1.5g, 4.28mmol) in PhMe (100mL) was stirred at 110 ℃ for 48 h. PhMe was removed in vacuo and the residue was purified by column chromatography (EtOAc: petroleum ether-5: 1) to give the title compound (1g, 73%). ¹H NMR(400MHz,CDCl₃)δ8.08(d,J＝8.5Hz,1H),7.47-7.17(m,7H),6.45(s,1H),4.84-4.72(m,1H),4.43(d,J＝4.5Hz,2H)。LC-MS(M+H)⁺＝317.8,319.8。

And 5: 3-phenyl-8- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydrobenzo [ f ] [1,4] oxazepin-5 (2H) -one

To 8-bromo-3-phenyl-3, 4-dihydrobenzo [ f ] in 1, 4-dioxane (25mL)][1,4]Oxazepin-5 (2H) -one (500mg, 1.57mmol) and 4,4,4 ', 4 ', 5,5,5 ', 5 ' -octamethyl-2, 2 ' -bis (1,3, 2-dioxaborolan) (479mg, 1.89mmol) to which KOAc (308mg, 3.14mmol) and Pd (dppf) Cl were added₂(115mg，0.157mmol). The resulting solution was heated at 90 ℃ under N₂Stirring was continued overnight. Upon completion, the reaction mixture was washed with water (25mL) and extracted with ethyl acetate (25mLx3), over Na₂SO₄Dried, filtered and evaporated in vacuo. The residue was purified by column chromatography (DCM/MeOH ═ 50:1) to give the title compound (724mg, 126%, crude).¹H NMR(400MHz,CDCl₃)δ8.11(d,J＝7.7Hz,1H),7.59(d,J＝7.8Hz,1H),7.49(s,1H),7.44-7.29(m,5H),6.83(s,1H),4.81-4.68(m,1H),4.48-4.33(m,2H),1.35(s,12H)。LC-MS(M+H)⁺＝365.9。

Step 6: 8- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) -3-phenyl-3, 4-dihydrobenzo [ f][1,4]Oxazepine-5 (2H to 3-iodo-5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2, 3-b)]Pyridine-1-carboxylic acid tert-butyl ester (798mg, 1.5mmol) and 3-phenyl-8- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydrobenzo [ f][1,4]Oxazepin-5 (2H) -one (724mg, 1.5mmol) in 1, 4-dioxane (30mL) and H ₂To a stirred solution in O (30mL) were added XPhos Pd G2(118mg, 0.15mmol) and K₃PO₄(636mg, 3 mmol). The resulting solution was heated at 80 ℃ under N₂Stirring was continued overnight. After completion, the reaction mixture was cooled to room temperature and washed with H₂O (30mL) and extracted with EtOAc (30mLx 3). The combined EtOAc phases were taken over Na₂SO₄Dried, concentrated and purified by preparative TLC to give the title compound (17mg, 2.1%).¹H NMR(400MHz,CDCl₃)δ9.69(s,1H),8.47(s,1H),8.38(s,1H),8.33(d,J＝8.0Hz,1H),7.66(s,1H),7.56-7.30(m,8H),7.26(s,1H),7.18(d,J＝7.5Hz,1H),6.63(s,1H),4.88(s,1H),4.50(d,J＝3.6Hz,2H),3.60-2.68(m,8H),2.58(s,3H),2.40(s,3H)。LC-MS(M+H)⁺＝543.9。

Example 288: 2-isopropyl-N, N-dimethyl-4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 288)

Step 1: 4-bromo-2-isopropyl-N, N-dimethylbenzamide

Will be in SOCl₂4-bromo-2-isopropylbenzoic acid (0.5g, 2.06mmol) in (5mL) was stirred at 60 ℃ for 3 h, DCM was removed in vacuo, and N in vacuo₂Dry, add DCM (20mL), then dimethylamine hydrochloride (185mg, 2.26mmol), and add Et dropwise while stirring at room temperature₃N (1.4 mL). The resulting solution was at room temperature in N₂Stirred for 1 hour. After completion, the reaction mixture was washed with H₂O (20mL) and extracted with EtOAc (20mLx 3). The combined EtOAc phases were taken over Na₂SO₄Dried and concentrated to give the crude product (500mg, 85%), which was used without purification. ¹H NMR(400MHz,CDCl₃)δ7.47(s,1H),7.34(d,J＝8.0Hz,1H),7.00(d,J＝8.1Hz,1H),3.13(s,3H),2.97-2.86(m,1H),2.82(s,3H),1.23(d,J＝6.2Hz,6H)。LC-MS(M+H)⁺＝269.8,271.8。

Step 2: 2-isopropyl-N, N-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide

To 4-bromo-2-isopropyl-N, N-dimethylbenzamide (500mg, 1.75mmol) and 4,4,4 ', 4 ', 5,5,5 ', 5 ' -octamethyl-2, 2 ' -bis (1,3, 2-dioxaborolan) (533mg, 2.1mmol) in 1, 4-dioxane (20mL) were added KOAc (343mg, 3.5mmol) and Pd (dppf) Cl₂(128mg, 0.175 mmol). The resulting solution was heated at 90 ℃ under N₂Stirring was continued overnight. Upon completion, the reaction mixture was washed with water (20mL) and extracted with ethyl acetate (20mLx3), over Na₂SO₄Dried, filtered and evaporated in vacuo. The residue was purified by column chromatography (DCM/MeOH ═ 50:1) to give the title compound (690mg, 124%, crude). LC-MS (M + H)⁺＝318.0。

And step 3: 2-isopropyl-N, N-dimethyl-4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

To 3-iodo-5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]Pyridine-1-carboxylic acid tert-butyl ester (931mg, 1.75mmol) and 2-isopropyl-N, N-dimethylPhenyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide (690mg, 1.75mmol) in 1, 4-dioxane (30mL) and H ₂To a stirred solution in O (30mL) were added XPhos Pd G2(138mg, 0.175mmol) and K₃PO₄(742mg，3.5mmol)。

The resulting solution was heated at 80 ℃ under N₂Stirring was continued overnight. After completion, the reaction mixture was cooled to room temperature and washed with H₂O (30mL) and extracted with EtOAc (30mLx 3). The combined EtOAc phases were taken over Na₂SO₄Dried, concentrated and purified by preparative TLC to give the title compound (109mg, 12.6%).¹H NMR(400MHz,CDCl₃)δ9.50(s,1H),8.58(s,1H),8.31(s,1H),7.61(s,1H),7.57-7.40(m,4H),7.25-7.13(m,2H),3.54-3.08(m,8H),3.08-2.84(m,7H),2.65(s,3H),2.39(s,3H),1.32(d,J＝5.7Hz,6H)。LC-MS(M+H)⁺＝496.0。

Example 289: 2-cyano-N, N-dimethyl-4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 289)

Step 1: 4-bromo-2-cyano-N, N-dimethylbenzamide

To 4-bromo-2-cyanobenzoic acid (862mg, 3.81mmol) and dimethylamine hydrochloride (331mg, 4.08mmol) in THF (30mL) was added HATU (2.06g, 5.42mmol) and Et₃N (821mg, 8.13mmol), and the resulting solution was stirred at room temperature for 2 hours. Upon completion, the reaction mixture was washed with water (20mL) and extracted with ethyl acetate (20mLx3), over Na₂SO₄Dried, filtered and evaporated in vacuo to give the crude product, which was purified by column chromatography (DCM: MeOH ═ 200:1) to give the title compound (475mg, 49%). LC-MS (M + H)⁺＝252.8,254.8

Step 2: 2-cyano-N, N-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide

To 4-bromo-2-cyano in 1, 4-dioxane (20mL)To the mixture of methyl-N, N-dimethylbenzamide (475mg, 1.38mmol) and 4,4,4 ', 4 ', 5,5,5 ', 5 ' -octamethyl-2, 2 ' -bis (1,3, 2-dioxaborolan) (421mg, 1.66mmol) were added KOAc (270mg, 2.76mmol) and Pd (CCy)₃)₂Cl₂(101mg, 0.138 mmol). The resulting solution was heated at 110 ℃ under N₂Stirring was continued overnight. Upon completion, the reaction mixture was washed with water (20mL) and extracted with ethyl acetate (20mLx3), over Na₂SO₄Dried, filtered and evaporated in vacuo. The residue was purified by column chromatography (DCM/MeOH ═ 50:1) to give the title compound (416mg, 100%). LC-MS (M + H)⁺＝300.9。

And step 3: 2-cyano-N, N-dimethyl-4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

To 3-iodo-5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]Pyridine-1-carboxylic acid tert-butyl ester (738mg, 1.39mmol) and 2-cyano-N, N-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide (416mg, 1.39mmol) in 1, 4-dioxane (25mL) and H₂To a stirred solution in O (25mL) were added XPhos Pd G2(109mg, 0.139mmol) and K₃PO₄(589mg, 2.78 mmol). The resulting solution was heated at 80 ℃ under N ₂Stirring was continued overnight. After completion, the reaction mixture was cooled to room temperature and washed with H₂O (30mL) and extracted with EtOAc (30mLx 3). The combined EtOAc phases were taken over Na₂SO₄Dried, concentrated and purified by preparative TLC to give the title compound (64mg, 9.6%).¹H NMR(400MHz,CDCl₃)δ10.52(s,1H),8.63(s,1H),8.30(s,1H),8.01-7.90(m,2H),7.66(s,1H),7.58(d,J＝8.0Hz,1H),7.51-7.40(m,2H),7.17(d,J＝7.8Hz,1H),3.29-3.16(m,3H),3.15-3.00(m,7H),2.85-2.52(m,4H),2.51-2.36(m,6H)。LC-MS(M+H)⁺＝478.9。

Example 290: 4-methyl-8- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -3-phenyl-3, 4-dihydrobenzo [ f ] [1,4] oxazepin-5 (2H) -one (Compound 290)

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

8-bromo-3-phenyl-3, 4-dihydrobenzo [ f ] in DMF (5mL)][1,4]Oxazepin-5 (2H) -one (250mg, 0.786mmol) in N₂Cool to 0 deg.C, add NaH (47mg, 60%, 1.18mmol), stir at 0 deg.C for 10min, add MeI (134mg, 0.943mmol) dropwise in DMF (1mL), and dissolve in N₂Stirring was carried out at room temperature for 20 min. After completion, the reaction mixture was washed with H₂O (10mL) and extracted with EtOAc (10mLx 3). The combined EtOAc phases were taken over Na₂SO₄Dried and concentrated to give the crude product (250mg, 96%) without purification. LC-MS (M + H)⁺＝331.8,333.8。

Step 2: 4-methyl-3-phenyl-8- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydrobenzo [ f ] [1,4] oxazepin-5 (2H) -one

To 8-bromo-4-methyl-3-phenyl-3, 4-dihydrobenzo [ f ] in 1, 4-dioxane (10mL)][1,4]Oxazepin-5 (2H) -one (250mg, 0.75mmol) and 4,4,4 ', 4 ', 5,5,5 ', 5 ' -octamethyl-2, 2 ' -bis (1,3, 2-dioxaborolan) (229mg, 0.90mmol) to which KOAc (148mg, 1.51mmol) and Pd (dppf) Cl were added₂(55mg, 0.075 mmol). The resulting solution was heated at 90 ℃ under N₂Stirring was continued overnight. After cooling, the reaction mixture was washed with water (20mL) and extracted with ethyl acetate (20mLx3), over Na₂SO₄Dried, filtered and evaporated in vacuo. The residue was purified by column chromatography (DCM/MeOH ═ 50:1) to give the title compound (200mg, 70%). LC-MS (M + H)⁺＝379.9。

And step 3: 4-methyl-8- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -3-phenyl-3, 4-dihydrobenzo [ f ] [1,4] oxazepin-5 (2H) -one

To 3-iodo-5- (3-methyl-4- (4-methylpiperazin-1-ylphenyl) -1H-pyrrolo [2, 3-b)]Pyridine-1-carboxylic acid tert-butyl ester (320.5mg, 0.60mmol) and 4-methyl-3-phenyl-8- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaCyclopentaborane-2-yl) -3, 4-dihydrobenzo [ f][1,4]Oxazepin-5 (2H) -one (200mg, 0.60mmol) in 1, 4-dioxane (15mL) and H₂To a stirred solution in O (15mL) were added XPhos Pd G2(47mg, 0.06mmol) and K ₃PO₄(255mg, 1.20 mmol). The resulting solution was heated at 80 ℃ under N₂Stirring was continued overnight. After completion, the reaction mixture was cooled to room temperature and washed with H₂O (30mL) and extracted with EtOAc (30mLx 3). The combined EtOAc phases were taken over Na₂SO₄Dried, concentrated and purified by preparative HPLC to give the title compound (40mg, 12%).¹H NMR(400MHz,CDCl₃)δ9.79(s,1H),8.59-8.51(m,2H),8.36(s,1H),7.62(s,1H),7.48-7.40(m,3H),7.40-7.28(m,3H),7.24-7.19(m,3H),7.15(d,J＝7.8Hz,1H),4.84-4.77(m,1H),4.75-4.66(m,1H),4.55-4.66(m,1H),3.14(s,3H),3.12-3.01(m,4H),2.94-2.58(m,4H),2.49(s,3H),2.39(s,3H)。LC-MS(M+H)⁺＝558.0。

Example 291: n, N-dimethyl-4- (5- (4- (4-methylpiperazin-1-yl) -3- (propylamino) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 291)

Step 1: 5-bromo-2-nitro-n-propylaniline

To 4-bromo-2-fluoro-1-nitrobenzene (5.6g, 25.5mmol, 1.0 equiv.), propan-1-amine (1.6g, 28.0mmol, 1.1 equiv.) and TEA (7.1ml, 50.9mmol, 2.0 equiv.) was added THF (30 ml). The reaction mixture was heated to 40 ℃ overnight. Add 30mL EtOAc and wash with brine (30mL) over Na₂SO₄Dried and evaporated in vacuo to afford the title compound (6.4g, 97%).

Step 2: 5-bromo-N1-propylbenzene-1, 2-diamine

To 5-bromo-2-nitro-n-propylaniline (6.4g, 24.5mmol, 1.0 equiv.) and Zn (8.0g, 123.6mmol, 5.0 equiv.) was added AcOH (50 ml). It was heated to 60 ℃ for 30 min. The solid was removed and the solvent was removed in vacuo. It was purified by column chromatography eluting with PE/EtOAc ═ 4:1 to give the title compound (3.5g, 63%).

And step 3: 5-bromo-2- (4-methylpiperazin-1-yl) -n-propylaniline

5-bromo-N1-propylbenzene-1, 2-diamine (3.5g, 15.3mmol, 1.0 equiv.) and 2-chloro-N- (2-chloroethyl) -N-methylethyl-1-amine hydrochloride (4.4g, 22.9mmol, 1.5 equiv.) were added to xylene (30 ml). The reaction mixture was heated to 140 ℃ for 6 hours. The mixture was cooled to room temperature and the supernatant was decanted. The solid was purified by column chromatography eluting with DCM/MeOH ═ 20:1 to give the title compound (3.0g, 64%). LC-MS (M + H)⁺＝312.1,313.1。

And 4, step 4: n, N-dimethyl-4- (5- (4- (4-methylpiperazin-1-yl) -3- (propylamino) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

N, N-dimethyl-4- (5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ] under nitrogen]Pyridin-3-yl) benzamide (263mg, 0.67mmol, 1.5 equiv.), 5-bromo-2- (4-methylpiperazin-1-yl) -n-propylaniline (140mg, 0.45mmol, 1.0 equiv.), XPhos Pd G2(35mg, 0.05mmol, 0.1 equiv.), and K₃PO₄(240mg, 1.12mmol, 2.5 equiv.) to a mixture of dioxane (15ml) and water (5ml) was added. The reaction mixture was refluxed overnight. 30ml of water was added and extracted with EtOAc (3 × 20 ml). The combined organic layers were washed with brine (30ml) and Na ₂SO₄Dry, evaporate in vacuo and purify by preparative TLC (DCM/MeOH ═ 8:1) to give the title compound (3mg, 1%).¹H NMR(400MHz,CD3OD)δ8.65-8.61(m,1H),8.54(s,1H),7.89(d,J＝4.0Hz,1H),7.83(d,J＝7.8Hz,2H),7.55(d,J＝7.4Hz,2H),7.25(t,J＝8.3Hz,1H),7.15-7.05(m,2H),3.65-3.62(m,2H),3.43-3.37(m,2H),3.30-3.24(m,4H),3.13-3.09(m,8H),3.00(s,3H),1.77-1.71(m,2H),1.05(t,J＝7.4Hz,3H)。LC-MS(M+H)⁺＝497.3。

Example 292: 4- (5- (3-hydroxy-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (Compound 292)

Step 1: 2- (4-methylpiperazin-1-yl) phenol

The title compound (22g, crude) was prepared from 2-aminophenol and 2-chloro-N- (2-chloroethyl) -N-methylethyl-1-amine hydrochloride in a similar manner to that in example 291, step 3.

Step 2: acetic acid 2- (4-methylpiperazin-1-yl) phenyl ester

To a solution of 2- (4-methylpiperazin-1-yl) phenol (500mg, 2.6mmol, 1.0 eq) in THF (20mL) at room temperature was added Et₃N (0.73mL, 5.2mmol, 2.0 equiv.) and acetyl chloride (305mg, 3.9mmol, 1.5 equiv.). The mixture was stirred for 2 hours. 20ml NaHCO was added₃It was isolated with DCM (20 mL). The combined organic layers were washed with brine (20mL) and Na₂SO₄Dried and evaporated in vacuo. It was purified by preparative TLC (DCM/MeOH ═ 20:1) to give the title compound (480mg, 79%).

And step 3: acetic acid 5-bromo-2- (4-methylpiperazin-1-yl) phenyl ester

2- (4-methylpiperazin-1-yl) phenyl acetate (480mg, 2.1mmol, 1.0 equiv.) and NBS (438mg, 2.5mmol, 1.2 equiv.) were added to ethanol (20 mL). It was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the mixture was purified by preparative TLC (DCM/MeOH ═ 8:1) to give the title compound (460mg, 72%). LC-MS (M + H) ⁺＝313.0、315.0。

And 4, step 4: 4- (5- (3-hydroxy-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide

Prepared in a similar manner to that in example 291, step 4 from 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 and acetic acid 5-bromo-2- (4-methylpiperazin-1-yl) phenyl ester preparation example 292(30mg, 4%).¹H NMR(400MHz,DMSO-d6)δ12.07(s,1H),9.33(s,1H),8.48(s,1H),8.35(s,1H),8.01(s,1H),7.84(d,J＝7.6Hz,2H),7.49(d,J＝7.3Hz,2H),7.17-7.15(m,2H),6.99(d,J＝7.8Hz,1H),3.20-3.05(m,4H),3.00(s,6H),2.90-2.75(m,4H),2.47(s,3H)。LC-MS(M+H)⁺＝455.9。

Example 293: n, N-dimethyl-4- (5- (3-methyl-4- (piperidin-4-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 293)

Step 1: 4- (4-bromo-2-methylphenyl) -1,2,3, 6-tetrahydropyridine

4-bromo-1-iodo-2-methylbenzene (3.1g, 10.5mmol, 1.1 equiv.), hydrochloride (2g, 9.6mmol, 1.0 equiv.) of (1,2,3, 6-tetrahydropyridin-4-yl) boronic acid, Pd (dppf) Cl₂(350mg, 0.48mmol, 0.05 eq.) and K₂CO₃(4.6g, 33.5mmol, 3.0 equiv.) was added to a mixture of dioxane (80ml) and water (20 ml). It was refluxed overnight. 50ml of water was added and extracted with EtOAc (3X 40 ml). The combined organic layers were washed with brine (50ml) and Na₂SO₄Dried and evaporated in vacuo to give the title compound (3.7g, crude).

Step 2: 4- (4-bromo-2-methylphenyl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester

To the solution was added 4- (4-bromo-2-methylphenyl) -1,2,3, 6-tetrahydropyridine (3.7g, 14.7mmol, 1.0 eq), (Boc)₂O (3.8g, 17.6mmol, 1.2 equiv.) and Et₃THF (70ml) was added to N (6.2ml, 44.0mmol, 3.0 equiv). The reaction mixture was refluxed overnight. It was cooled to room temperature and diluted with EA (70ml), washed with brine (2 x 100ml), over Na₂SO₄Dried and evaporated in vacuo. It was purified by column chromatography eluting with PE/EA ═ 30:1 to give an off-white solid (2.8g, 55%). LC-MS (M + H)⁺＝352.0。

And step 3: 4- (2-methyl-4- (1H-pyrrolo [2,3-b ] pyridin-5-yl) phenyl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester

Prepared in a similar manner to that described in step 6 of example 222 from 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ]]Pyridine and 4- (4-bromo-2-methylphenyl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (270mg,49%) the title compound was prepared. LC-MS (M + H)⁺＝390.2。

And 4, step 4: 4- (4- (3-bromo-1H-pyrrolo [2,3-b ] pyridin-5-yl) -2-methylphenyl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester

Tert-butyl 4- (2-methyl-4- (1H-pyrrolo [2,3-b ] pyridin-5-yl) phenyl) -3, 6-dihydropyridine-1 (2H) -carboxylate (270mg, 0.69mmol, 1.0 equiv.) and NBS (136mg, 0.76mmol, 1.1 equiv.) were added to THF (20 ml). It was stirred at room temperature overnight. The solvent was removed in vacuo and the title compound (290mg 90%) was given and used directly in the next step.

And 5: 3-bromo-5- (4- (1- (tert-butoxycarbonyl) -1,2,3, 6-tetrahydropyridin-4-yl) -3-methylphenyl) -1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester

The title compound (210mg, 60% white solid) was prepared from di-tert-butyl dicarbonate in a similar manner to that in example 293, step 2.

Step 6: 4- (4- (3- (4- (dimethylcarbamoyl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) -2-methylphenyl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester

The title compound (120mg, 61%) was prepared from tert-butyl 3-bromo-5- (4- (1- (tert-butoxycarbonyl) -1,2,3, 6-tetrahydropyridin-4-yl) -3-methylphenyl) -1H-pyrrolo [2,3-b ] pyridine-1-carboxylate in a similar manner to that in example 141, step 5.

And 7: n, N-dimethyl-4- (5- (3-methyl-4- (1,2,3, 6-tetrahydropyridin-4-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Tert-butyl 4- (4- (3- (4- (dimethylcarbamoyl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) -2-methylphenyl) -3, 6-dihydropyridine-1 (2H) -carboxylate (120mg, 0.23mmol) was dissolved in HCl/dioxane (10 ml). The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo and the title compound (100mg, 95%) was given and used directly in the next step.

And 8: n, N-dimethyl-4- (5- (3-methyl-4- (piperidin-4-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Adding N, N-dimethyl-4- (5- (3-methyl-4- (1,2,3, 6-tetrahydropyridin-4-yl) phenyl) -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) benzamide (50mg, 0.11mmol) and Pd/C (20mg) were dissolved in AcOH (40 ml). It was heated to 50 ℃ under 60psi hydrogen for two days. The solid was removed and purified by preparative TLC (DCM/MeOH) to give the title compound (1mg, 2%).¹H NMR(400MHz,CD₃OD)δ8.51(s,2H),7.83(d,J＝8.1Hz,3H),7.55(d,J＝7.8Hz,4H),7.35(d,J＝8.5Hz,1H),3.57-3.52(m,2H),3.25-3.18(m,3H),3.15-3.05(m,6H),2.49(s,3H),2.10-1.90(m,4H)。LC-MS(M+H)⁺＝439.2。

Example 294: n, N-dimethyl-4- (5- (3-methyl-4- (4- (methylamino) piperidin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 294)

Step 1: 1- (4-bromo-2-methylphenyl) piperidin-4-one

1- (o-tolyl) piperidin-4-one (2.8g, 14.8mmol, 1.0 equiv.) and NBS (2.8g, 15.6mmol, 1.05 equiv.) were added to THF (90 ml). It was stirred at room temperature for 3 hours. The solvent was removed in vacuo and the residue was purified by column chromatography, eluting with PE/EtOAc ═ 10:1 to give the title compound (2.3g, 58%).

Step 2: 1- (4-bromo-2-methylphenyl) -N-methylpiperidin-4-amine

1- (4-bromo-2-methylphenyl) piperidin-4-one (2.5g, 9.3mmol, 1.0 eq.), methylamine hydrochloride (1.25g, 18.7mmol, 2.0 eq.), TEA (2.6ml, 8.7mmol, 2.0 eq.), NaBH (OAc) ₃(3.0g, 14.0mmol, 1.5 equiv.) and CH₃COOH (1.6ml, 28.0mmol, 3.0 equiv.) was added to DCM (50 ml). It was stirred at room temperature overnight. 50ml NaHCO was added₃Separated with DCM and the aqueous layer extracted with DCM (2 × 50 ml). Subjecting the organic layer to Na₂SO₄Dry and purify it by column chromatography eluting with DCM/MeOH ═ 20:1 to give the title compound (530mg, 20%).

And step 3: n, N-dimethyl-4- (5- (3-methyl-4- (4- (methylamino) piperidin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Prepared in a similar manner to that in example 291, step 4 from 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 and 1- (4-bromo-2-methylphenyl) -N-methylpiperidin-4-amine preparation example 294(200mg, 22%).¹H NMR (400MHz, DMSO-d6) δ 12.05(s,1H),8.52(d, J ═ 1.9Hz,1H),8.40(d, J ═ 1.9Hz,1H),7.99(s,1H),7.85(d, J ═ 8.1Hz,2H),7.60-7.46(m,4H),7.12(d, J ═ 8.3Hz,1H),3.15-3.05(m,2H),3.00(s,6H),2.70-2.60(m,2H),2.55-2.40(m,1H),2.33(s,6H),1.98-1.90(m,2H),1.50-1.35(m, 2H). (Note: amine N-H) LC-MS (M + H) is not shown⁺＝468.0。

Example 295: 4- (5- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylpyridinamide (compound 295)

Step 1: 4-bromo-N, N-dimethylpyridinamides

4-Bromopicolinic acid (1g, 5.0mmol, 1.0 equiv.), dimethylamine hydrochloride (812mg, 10.0mmol, 2.0 equiv.), HATU (2.0g, 5.4mmol, 1.1 equiv.) and TEA (3.5ml, 24.8mmol, 5.0 equiv.) were added to DMF (15 ml). The mixture was stirred at room temperature overnight. 60ml of water was added and extracted with EtOAc (3 x 40 ml). The combined organic layers were washed with brine (3 × 50ml) and Na₂SO₄Dried and evaporated in vacuo to afford the title compound (640mg, 57%). LC-MS (M + H)⁺＝228.9,230.9。

Step 2: n, N-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) picolinamide

4-bromo-N, N-dimethylpyridinamide (640mg, 2.8mmol, 1.0 eq), 4,4,4 ', 4 ', 5,5,5 ', 5 ' -octamethyl-2, 2 ' -bis (1,3, 2-dioxaborolan) (850mg, 3.4mmol, 1.2 eq), Pd (dppf) Cl were added under nitrogen to a flask containing a mixture of N, N-dimethylpyridinamide and water₂(143mg, 0.2mmol, 0.07 equiv.) and AcOK (550mg, 5.6mmol, 2.0 equiv.) dioxane (30ml) was added. The reaction mixture was refluxed overnight. 40ml EtOAc was added and washed with brine (2X 30ml) and the aqueous layer was extracted with EtOAc (30 ml). The combined organic layers were passed over Na₂SO₄Dry and purify by preparative TLC (DCM/MeOH ═ 15:1) to give the title compound (360mg, 47%).

And step 3: 4- (5- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylpyridinamide

Prepared in a similar manner to that in example 291, step 4 from 3-bromo-5- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]Pyridine and N, N-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) picolinamide preparation example 295(25mg, 9%).¹H NMR(400MHz,DMSO-d6)δ12.37(s,1H),8.62-8.50(m,3H),8.34(s,1H),7.94-7.92(m,2H),7.37-7.25(m,2H),7.05(d,J＝8.1Hz,1H),3.92(s,3H),3.25-2.90(m,13H),2.70-2.55(m,4H)。LC-MS(M+H)⁺＝471.2。

Example 296: N-cyclopropyl-N-methyl-4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 296)

Step 1: 4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzoic acid methyl ester

The title compound (3.7g,>100%, white solid). LC-MS (M + H)⁺＝441.2。

Step 2: 4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzoic acid

To 4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) benzoic acid methyl ester (3.7g, 8.4mmol, 1.0 equiv.) and LiOH₂O (1g, 25.2mmol, 3.0 equiv.) to which CH was added ₃OH(80ml) And water (50 ml). It was stirred at room temperature overnight. Removal of CH in vacuo₃OH and washed with MTBE (2 × 50 ml). The aqueous layer was acidified to pH 2-3 and dried in vacuo. It was purified by column chromatography, eluting with DCM/MeOH ═ 20:1, to give a yellow solid (3.9g,>100％)。

and step 3: N-cyclopropyl-N-methyl-4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Prepared from N-methylcyclopropylamine and 4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that in step 1 of example 295]Pyridin-3-yl) benzoic acid preparation example 296(3mg, 3%).¹H NMR(400MHz,DMSO-d6)δ12.08(s,1H),8.53(s,1H),8.42(s,1H),8.02(s,1H),7.84(d,J＝7.7Hz,2H),7.64-7.52(m,4H),7.15(d,J＝8.1Hz,1H),3.20-2.90(m,12H),2.36(s,3H),0.65-0.44(m,4H)。LC-MS(M+H)⁺＝480.2。

Example 297: n-methyl-4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (1-methylpyrrolidin-3-yl) benzamide (compound 297)

Prepared from N, 1-dimethylpyrrolidin-3-amine and 3-iodo-5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that in step 1 of example 295]Pyridine-1-carboxylic acid tert-butyl ester preparation example 297(2mg, 3%).¹H NMR(400MHz,DMSO-d6)δ12.12(s,1H),8.69(s,1H),8.54(s,1H),8.42(s,1H),8.04(s,1H),7.96(d,J＝7.4Hz,2H),7.89(d,J＝7.5Hz,2H),7.58(s,1H),7.55(d,J＝8.1Hz,1H),7.13(d,J＝8.3Hz,1H),3.32-3.25(m,2H),3.28-3.01(m,4H),3.00-2.85(m,5H),2.75-2.55(m,8H),2.34(s,6H),2.10-2.00(m,1H),1.80-1.65(m,1H)。LC-MS(M+H)⁺＝523.3。

Example 298: n, N, 2-trimethyl-4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 298)

Prepared from dimethylamine and 4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that in step 1 of example 295]Pyridin-3-yl) benzoic acid preparation example 298(1mg, 1%).¹H NMR(400MHz,DMSO-d6)δ12.00(s,1H),8.50(s,1H),8.37(s,1H),7.93(s,1H),7.70-7.60(m,2H),7.60-7.48(m,2H),7.21(d,J＝7.5Hz,1H),7.13(d,J＝7.9Hz,1H),3.02(s,3H),2.92-2.80(m,7H),2.47-2.42(m,2H),2.33(s,3H),2.26(d,J＝8.1Hz,6H)。LC-MS(M+H)⁺＝468.2。

Example 299: n-methyl-4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (tetrahydro-2H-pyran-4-yl) benzamide (compound 299)

Prepared from N-methyltetrahydro-2H-pyran-4-amine and 4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that in example 295, step 1]Pyridin-3-yl) benzoic acid preparation example 299(2mg, 1%).¹H NMR(400MHz,DMSO-d6)δ12.08(s,1H),8.54(s,1H),8.42(s,1H),8.02(s,1H),7.86(d,J＝7.5Hz,2H),7.62-7.52(m,2H),7.46(d,J＝7.2Hz,2H),7.15(d,J＝7.8Hz,1H),3.97-3.90(m,2H),3.25-2.27(m,12H),2.35(s,3H),1.91-1.83(m,2H),1.62-1.60(m,2H),1.7-1.20(m,2H)。LC-MS(M+H)⁺＝524.2。

Example 300: N-methyl-N- ((1-methyl-1H-pyrazol-3-yl) methyl) -4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 300)

From N-methyl-1- (2) in a similar manner to that in step 1 of example 2951-methyl-4, 5-dihydro-1H-pyrazol-3-yl) methylamine and 4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b [ -l]Pyridin-3-yl) benzoic acid preparation example 300(12mg, 6%).¹H NMR(400MHz,DMSO-d6)δ12.08(s,1H),8.53(s,1H),8.42(s,1H),8.00(s,1H),7.86(d,J＝7.6Hz,2H),7.66(s,1H),7.64-7.45(m,4H),7.14(d,J＝8.1Hz,1H),6.18(s,1H),4.63-4.35(m,2H),3.82(s,3H),3.25-2.80(m,12H),2.70-2.55(m,2H),2.35(s,3H)。LC-MS(M+H)⁺＝534.2。

Example 301: n-methyl-4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (2- (4-methylpiperazin-1-yl) ethyl) benzamide (compound 301)

Prepared in a similar manner to that in example 295, step 1 from N-methyl-1- (1-methyl-4, 5-dihydro-1H-pyrazol-3-yl) methylamine and 4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) benzoic acid preparation example 301(12mg, 6%).¹H NMR(400MHz,DMSO-d6)δ12.08(s,1H),8.53(s,1H),8.40(s,1H),8.00(s,1H),7.85(d,J＝7.6Hz,2H),7.61-7.50(m,2H),7.47(d,J＝7.6Hz,2H),7.13(d,J＝8.0Hz,1H),3.70-3.50(m,1H),3.50-3.30(m,3H),3.10-2.90(m,9H),2.80-2.58(m,10H),2.45-2.30(m,10H)。LC-MS(M+H)⁺＝566.3。

Example 302: n- ((R) -2-hydroxypropyl) -N-methyl-4- (5- (3-methyl-4- ((S) -3- (methylamino) pyrrolidin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (Compound 302)

Step 1: n- ((R) -2-hydroxypropyl) -N-methyl-4- (5- (3-methyl-4- ((S) -3- (methylamino) pyrrolidin-1-yl) phenyl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

In a similar manner as in step 2 of example 311The formula is (R) -N- (2-hydroxypropyl) -N-methyl-4- (5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) benzamide and (S) -1- (4-chloro-2-methylphenyl) -N-methylpyrrolidin-3-amine the title compound was prepared (88mg, 37%, yellow solid). LC-MS (M + H)⁺＝652.5。

Step 2: n- ((R) -2-hydroxypropyl) -N-methyl-4- (5- (3-methyl-4- ((S) -3- (methylamino) pyrrolidin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Prepared in a similar manner to that described in example 369, step 6 from N- ((R) -2-hydroxypropyl) -N-methyl-4- (5- (3-methyl-4- ((S) -3- (methylamino) pyrrolidin-1-yl) phenyl) -1-toluenesulfonyl-1H-pyrrolo [2,3-b]Pyridin-3-yl) benzamide preparation example 302(11mg, 40%).¹H NMR(400MHz,DMSO-d6)δ12.01(s,1H),8.52(s,1H),8.39(s,1H),7.98(s,1H),7.87-7.81(m,2H),7.53-7.43(m,4H),6.93(d,J＝8.3Hz,1H),4.88-4.83(m,1H),4.09-3.83(m,1H),3.51-3.46(m,1H),3.40-3.17(m,6H),3.08-2.96(m,4H),2.38-2.30(m,6H),2.15-2.02(m,1H),1.78-1.67(m,1H),1.17-0.90(m,3H)。LC-MS(M+H)⁺＝498.3。

Example 303: 6- (4- [2- [3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] benzoyl) -2-oxa-6-azaspiro [3.3] heptane (compound 303)

Step 1: (4- [ 2-oxa-6-azaspiro [3.3] heptane-6-carbonyl ] phenyl) boronic acid

To a solution of 4- (dihydroxyboryl) benzoic acid (1.67g) in DMF (18mL) at 0 deg.C were added HATU (5.74g, 15.096mmol, 1.50 equivalents) and DIEA (3.90g, 30.192mmol, 3.00 equivalents) in portions. After 30min, 2-oxa-6-azaspiro [3.3] heptane (1.00g) was added. The resulting mixture was stirred at room temperature for another 16 h. The resulting mixture was concentrated under vacuum. The resulting mixture was diluted with water (10 mL). The precipitated solid was collected by filtration and washed with water (10 mL). This gave (4- [ 2-oxa-6-azaspiro [3.3] heptane-6-carbonyl ] phenyl) boronic acid (1.8g, 71.60%). M + H248.1.

Step 2: 6- (4- [2- [3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] benzoyl) -2-oxa-6-azaspiro [3.3] heptane

Adding 2- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -7-iodo-5H-pyrrolo [2,3-b ] to the tube at room temperature]Pyrazine (150mg), (4- [ 2-oxa-6-azaspiro [3.3 ]]Heptane-6-carbonyl]Phenyl) boronic acid (143.2mg, 0.46mmol, 1.5 equivalents, 80%), PdAMPHOS (24.3mg, 0.03mmol, 0.1 equivalents, 90%), K₃PO (69.1mg), i-PrOH (12mL, 159.75mmol) and H₂O (2.0 mL). The resulting mixture was stirred at 55 ℃ under a nitrogen atmosphere for 16 h. The resulting mixture was concentrated under vacuum. Purifying the residue by silica gel column chromatography using CH₂Cl₂MeOH (10:1) to give the crude product. The crude product (80mg) was purified by preparative HPLC and yielded 6- (4- [2- [3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl]-5H-pyrrolo [2,3-b]Pyrazin-7-yl]Benzoyl) -2-oxa-6-azaspiro [3.3]Heptane (4.9mg, 2.95%).¹H NMR(400MHz,DMSO-d6)δ12.43(s,1H),8.85(s,1H),8.54(s,1H),8.44-8.37(m,2H),7.81(s,2H),7.76-7.69(m,2H),4.71(s,4H),4.60-4.54(m,2H),4.26-4.21(m,2H),3.14-3.02(m,4H),2.55-2.35(m,10H),2.26(s,3H)。LC-MS(M+H)⁺＝523.3。

Example 304: 4- [2- [3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -N- [3- (dimethylamino) propyl ] -N-methylbenzamide (compound 304)

Step 1: (4- [ [3- (dimethylamino) propyl ] (methyl) carbamoyl ] phenyl) boronic acid

To a solution of 4- (dihydroxyboryl) benzoic acid (1.1g, 6.629mmol) in DMF (40mL) at room temperature was added [3- (dimethylamino) propyl ] carbamate ](methyl) amine (1.08g, 9.294mmol), DIEA (6.0g, 46.424mmol), HATU (5.3g, 13.939 mmol). Mixing the obtained mixtureStirred at room temperature for 16 h. When the reaction was complete, it was quenched by addition of water (50 mL). The resulting mixture was extracted with ethyl acetate (200mLx 3). The organic phases were combined, washed with brine and over Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by preparative HPLC. This gives (4- [ [3- (dimethylamino) propyl ] group](methyl) carbamoyl group]Phenyl) boronic acid (900mg, 50%). LCMS (M + H)⁺＝265.3。

Step 2: 4- [2- [3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -N- [3- (dimethylamino) propyl ] -N-methylbenzamide

Prepared from (4- [ [3- (dimethylamino) propyl) in a similar manner to that in step 2 of example 303](methyl) carbamoyl group]Phenyl) boronic acid and 2- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -7-iodo-5H-pyrrolo [2,3-b]Pyrazine preparation example 304.¹H NMR(400MHz,DMSO-d6)δ12.39(s,1H),8.84(s,1H),8.50(s,1H),8.41-8.33(m,2H),7.81(s,2H),7.53-7.43(m,2H),3.51-3.21(m,2H),3.15-2.95(m,7H),2.60-1.90(m,21H),1.80-1.62(m,2H)。LC-MS(M+H)⁺＝540.5。

Example 305: 4- (2- (3, 5-dimethyl-4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) -5H-pyrrolo [2, 3-b)]Pyrazin-7-yl) -N- (2- (dimethylamino) ethyl) -N-methylbenzamide (compound 305)

Step 1: 1- (4-bromo-2, 6-dimethylphenyl) piperazine

To a solution of bis (2-chloroethyl) amine hydrochloride (3.42g, 19.18mmol) in 2- (2-methoxyethoxy) ethan-1-ol (20mL) was added 4-bromo-2, 6-dimethylaniline (3.80g, 18.99mmol) at room temperature. The resulting mixture was stirred at 130 ℃ for 36 h. When the reaction was complete, the mixture was poured into water (150 mL). The resulting mixture was adjusted to pH 11 with NaOH solution (2M). The precipitated solid was collected by filtration and dissolved with EtOAc (200 mL). The resulting solution was washed with brine (2 × 50mL) over anhydrous Na₂SO₄And (5) drying. The solvent was removed under reduced pressure and the residue was taken up inPurify by flash chromatography eluting with MeOH in DCM (0.1% TEA) (gradient 0% to 10%) to give the title compound (1.66g, 32%). LC-MS (M + H)⁺＝271.0。

Step 2: 1- (4-bromo-2, 6-dimethylphenyl) -4- (1-methylpiperidin-4-yl) piperazine

To a solution of 1- (4-bromo-2, 6-dimethylphenyl) piperazine (1.66g, 6.18mmol) in DCM (200mL) was added 1-methylpiperidin-4-one (705mg, 6.18mmol) and STAB (2.27g, 10.74mmol) at room temperature. The resulting mixture was stirred at room temperature for 12 h. When the reaction was complete, it was treated with saturated NaHCO₃The solution was quenched. The resulting mixture was extracted with ethyl acetate (150mLx 3). The organic phases were combined, washed with brine and over Na ₂SO₄And (5) drying. The solvent was removed under reduced pressure and the residue was purified by flash chromatography, eluting with MeOH (0.1% TEA) in DCM (gradient 0% to 20%) to give 1- (4-bromo-2, 6-dimethylphenyl) -4- (1-methylpiperidin-4-yl) piperazine (1.38g, 62%). LCMS (M + H)⁺＝367.3。

And step 3: 1- [2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] -4- (1-methylpiperidin-4-yl) piperazine

To a solution of 1- (4-bromo-2, 6-dimethylphenyl) -4- (1-methylpiperidin-4-yl) piperazine (1.60g, 4.363mmol) in 1, 4-dioxane (25mL) was added BPD (1.43g, 5.612mmol), KOAc (1.23g, 12.584mmol), Pd (dppf) Cl at room temperature₂.CH₂Cl₂(356mg, 0.436 mmol). The resulting mixture was stirred at 95 ℃ under a nitrogen atmosphere for 14 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with MeOH in DCM (0.1% TEA) (gradient 0% to 20%) to give 1- [2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] -amine]-4- (1-methylpiperidin-4-yl) piperazine (1.23g, 68%). LCMS (M + H)⁺＝414.3。

And 4, step 4: 1- (2, 6-dimethyl-4- [ 5H-pyrrolo [2,3-b ] pyrazin-2-yl ] phenyl) -4- (1-methylpiperidin-4-yl) piperazine

1- [2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3) in nitrogen atmosphere2-Dioxolane-2-yl) phenyl]To a solution of (E) -4- (1-methylpiperidin-4-yl) piperazine (186mg, 0.450mmol) in dioxane (8mL) was added 2-bromo-5H-pyrrolo [2,3-b ]]Pyrazine (99mg, 0.499mmol), Cs₂CO₃(309mg, 0.948mmol) in Water (2mL), Pd (dppf) Cl₂.CH₂Cl₂(41mg, 0.050 mmol). The resulting mixture was stirred at 100 ℃ under a nitrogen atmosphere for 15 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with MeOH in DCM (0.1% TEA) (gradient 0% to 20%) to give 1- (2, 6-dimethyl-4- [ 5H-pyrrolo [2, 3-b)]Pyrazin-2-yl radicals]Phenyl) -4- (1-methylpiperidin-4-yl) piperazine (149mg, 82%). LC-MS (M + H)⁺＝405.6。

And 5: 1- (4- [ 7-bromo-5H-pyrrolo [2,3-b ] pyrazin-2-yl ] -2, 6-dimethylphenyl) -4- (1-methylpiperidin-4-yl) piperazine

To 1- (2, 6-dimethyl-4- [ 5H-pyrrolo [2,3-b ] at room temperature]Pyrazin-2-yl radicals]To a solution of phenyl) -4- (1-methylpiperidin-4-yl) piperazine (125mg, 0.309mmol) in DMF (6mL) was added NBS (67mg, 0.374 mmol). The resulting mixture was stirred at room temperature for 2 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with MeOH in DCM (0.1% TEA) (gradient 0% to 15%) to give 1- (4- [ 7-bromo-5H-pyrrolo [2, 3-b) ]Pyrazin-2-yl radicals]-2, 6-dimethylphenyl) -4- (1-methylpiperidin-4-yl) piperazine (141mg, 95%). LCMS (M + H)⁺＝483.3。

Step 6: 4- (2- (3, 5-dimethyl-4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -N- (2- (dimethylamino) ethyl) -N-methylbenzamide

Prepared from 1- (4- [ 7-bromo-5H-pyrrolo [2,3-b ] in a similar manner to that described in step 5 of example 141]Pyrazin-2-yl radicals]Preparation of (E) -2, 6-dimethylphenyl) -4- (1-methylpiperidin-4-yl) piperazine and 4- ((2- (dimethylamino) ethyl) (methyl) carbamoyl) phenylboronic acid example 305.¹H NMR(400MHz,DMSO-d6)δ12.44-12.34(m,1H),8.84(s,1H),8.50(s,1H),8.38(d,J＝8.1Hz,2H),7.79(s,2H),7.48(d,J＝8.1Hz,2H),3.60-3.50(m,2H),3.07-2.97(m,7H),2.82-2.74(m,2H),2.65-2.31(m,12H),2.29-1.91(m,10H),1.87-1.79(m,2H),1.77-1.67(m,2H),1.48-1.38(m,2H)。LC-MS(M+H)⁺＝609.5。

Example 306: (4- (2- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -2-methylphenyl) (2-oxa-6-azaspiro [3.3] hept-6-yl) methanone hydrochloride (Compound 306)

Step 1: (4-bromo-2-methylphenyl) (2-oxa-6-azaspiro [3.3] hept-6-yl) methanone

To 4-bromo-2-methylbenzoic acid (1.8g, 8.4mmol) and 2-oxa-6-azaspiro [ 3.3%]Et was added to a solution of heptane (830mg, 8.4mmol) in DMF (30mL)₃N (1.7g, 16.8mmol) and HATU (4.8g, 12.6 mmol). The mixture was stirred at room temperature for 15 h. The mixture was diluted with water (100mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with water (100mL) and brine (100mL) and washed with Na ₂SO₄Dried, filtered and concentrated. The residue was purified by silica gel column chromatography (eluted with EtOAc) to give the title compound (1.1g, 44%). LC-MS (M + H)⁺＝295.9,297.9。

Step 2: (2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) (2-oxa-6-azaspiro [3.3] hept-6-yl) methanone

To (4-bromo-2-methylphenyl) (2-oxa-6-azaspiro [3.3]]Hept-6-yl) methanone (1.1g, 3.7mmol) and 4,4,4 ', 4 ', 5,5,5 ', 5 ' -octamethyl-2, 2 ' -bis (1,3, 2-dioxaborolan) (1.2g, 4.7mmol) in a mixture of 1, 4-dioxane (30mL) was added Pd (dppf) Cl₂(140mg, 0.19mmol) and AcOK (1.1g, 11.2 mmol). The mixture was stirred at 100 ℃ for 4 hours. The mixture was cooled and diluted with EtOAc (30mL) and water (30 mL). The mixture was stirred for 5min and then filtered. The organic layer was separated and washed with brine (30mL), Na₂SO₄Dried, filtered and concentrated. The residue was purified by silica gel column chromatography (eluting with EtOAc: petroleum ether ═ 1: 1) to give the title compoundSubstance (800mg, 63%). LC-MS (M + H)⁺＝344.1。

And step 3: (4- (2-bromo-5-tosyl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -2-methylphenyl) (2-oxa-6-azaspiro [3.3] hept-6-yl) methanone

To (2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) (2-oxa-6-azaspiro [3.3]Hept-6-yl) methanone (400mg, 1.2mmol), 2-bromo-7-iodo-5-tosyl-5H-pyrrolo [2,3-b ]]To a mixture of pyrazine (690mg, 1.4mmol) in 1, 4-dioxane (10mL) and water (5mL) was added Pd (dppf) Cl₂(70mg, 0.1mmol) and K₂CO₃(330mg, 2.4 mmol). The mixture was stirred at 50 ℃ for 6 hours. The mixture was cooled and diluted with water (30mL) and extracted with EtOAc (3 × 30 mL). The combined organic phases were washed with brine (50mL) and Na₂SO₄Dried, filtered and concentrated. The residue was purified by silica gel column chromatography (eluting with EtOAc: petroleum ether ═ 1: 1) to give the title compound (500mg, 73%). LC-MS (M + H)⁺＝566.8,568.8。

And 4, step 4: (4- (2- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -2-methylphenyl) (2-oxa-6-azaspiro [3.3] hept-6-yl) methanone hydrochloride

To (4- (2-bromo-5-tosyl-5H-pyrrolo [2, 3-b))]Pyrazin-7-yl) -2-methylphenyl) (2-oxa-6-azaspiro [3.3]Hept-6-yl) methanone (100mg, 0.18mmol), 1- (2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -4-methylpiperazine (60mg, 0.18mmol), 1, 4-dioxane (20mL) and water (10mL) to a mixture of Pd (dppf) Cl ₂(15mg, 0.02mmol) and K₂CO₃(75mg, 0.54 mmol). The mixture was stirred at 95 ℃ for 16 hours. The mixture was cooled and diluted with water (30mL) and extracted with EtOAc (3 × 30 mL). The combined organic phases were washed with brine (50mL) and Na₂SO₄Dried, filtered and concentrated. The residue was purified by preparative TLC (eluting with dichloromethane: methanol ═ 1: 1) to give the crude product. The crude product was suspended in 3:1MeCN and water (8mL), then aqueous HCl (1.0M, 1 drop) was added, then lyophilized to give the title compound (35)mg，34％)。¹H NMR(400MHz,dmso)δ12.41(d,J＝2.6Hz,1H),10.62(brs,1H),8.87(s,1H),8.49(d,J＝2.9Hz,1H),8.26(s,1H),8.19(d,J＝8.0Hz,1H),7.86(s,2H),7.37(d,J＝8.0Hz,1H),4.75-4.65(m,4H),4.22(s,2H),4.16(s,2H),3.50-3.00(brs,8H),2.83(s,3H),2.42(s,6H),2.39(s,3H)。LC-MS(M+H)⁺537.0. HPLC 95.6% at 214nm and 98.5% at 254 nm.

Example 307: n, N-dimethyl-5- [5- [4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] pyridine-2-carboxamide (Compound 307)

Step 1: n, N-dimethyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) picolinamide

5-bromo-N, N-dimethylpyridine-2-carboxamide (50mg, 0.21mmol, 1 eq, 95%) and BPD (83.1mg, 0.31mmol, 95%) and AcOK (42.8mg, 0.41mmol, 95%) and Pd (dppf) Cl₂ CH₂Cl₂(26.7mg, 0.03mmol, 0.15 eq, 95%) in dioxane (4mL, 95%) at 120 ℃ in N₂Stirred under atmosphere for 16 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with EA: MeOH (20:80) to give N, N-dimethyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine-2-carboxamide (10mg, 17%). LC-MS (M + H) ⁺＝277.3。

Step 2: n, N-dimethyl-5- [5- [4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] pyridine-2-carboxamide

Prepared in a similar manner to that in step 5 of example 141 from N, N-dimethyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) picolinamide and 3-iodo-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]Pyridine production example 307.¹H NMR(400MHz,DMSO-d6,ppm)δ12.22-12.14(m,1H),9.08-9.00(m,1H),8.61-8.51(m,1H),8.50-8.40(m,1H),8.39-8.29(m,1H),8.20-8.10(m,1H),7.62-7.50(m,3H),7.10-6.98(m,2H),3.26-3.12(m,4H),3.13-2.99(m,6H),2.54-2.40(m,4H),2.24(s,3H)。LC-MS(M+H)⁺＝441.3。

Example 308: 3- (4- [5- [4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] phenoxy) propionic acid (compound 308)

Step 1: 3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy) propanoic acid

To a solution of 3- (4-bromophenoxy) propionic acid (307mg, 1.25mmol) in dioxane (15mL) at room temperature under a nitrogen atmosphere was added BPD (380mg, 1.50mmol), KOAc (370mg, 3.78mmol), Pd (dppf) Cl₂.CH₂Cl₂(103mg, 0.13 mmol). The resulting mixture was stirred at 90 ℃ under a nitrogen atmosphere for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography, eluting with MeOH in DCM (gradient 0% to 65%) to give 3- [4- (3,3,4, 4-tetramethylcyclopentylboran-1-yl) phenoxy]Propionic acid (138mg, 73%).

Step 2: 3- (4- [5- [4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] phenoxy) propionic acid

From 3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy) propionic acid and 3-iodo-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that in step 5 of example 141]Pyridine preparative example 308.¹H NMR(400MHz,DMSO-d6,ppm)δ11.85-11.80(m,1H),8.54-8.46(m,1H),8.33-8.25(m,1H),7.80-7.74(m,1H),7.73-7.65(m,2H),7.64-7.58(m,2H),7.7.10-6.98(m,4H),4.26-4.18(m,2H),3.25-3.13(m,4H),2.77-2.67(m,2H),2.53-2.45(m,4H),2.25(s,3H)。LC-MS(M+H)⁺＝457.3。

Example 309: 3- (4- [5- [4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzenesulfonyl) propan-1-amine (compound 309)

Step 1: n- [3- [ (4-bromophenyl) sulfanyl ] propyl ] carbamic acid tert-butyl ester

To a solution of 4-bromobenzene-1-thiol (950mg, 5.03mmol) in DMF (10mL) at room temperature was added tert-butyl N- (3-bromopropyl) carbamate (1320mg, 5.53mmol) and K₂CO₃(2.08g, 15.07 mmol). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 h. The mixture was allowed to cool to room temperature. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography, eluting with MeOH in DCM (gradient 0% to 8%) to give N- [3- [ (4-bromophenyl) sulfanyl group]Propyl radical]Tert-butyl carbamate (1.43g, 82%). LCMS (M + H)⁺＝290.0。

Step 2: n- [3- (4-Bromobenzenesulfonyl) propyl ] carbamic acid tert-butyl ester

To N- [3- [ (4-bromophenyl) sulfanyl group) at room temperature ]Propyl radical]To a solution of tert-butyl carbamate (950mg, 2.743mmol) in DCM (8mL) was added MCPBA (1420mg, 8.230 mmol). The resulting mixture was stirred at room temperature for 16 h. When the reaction was complete, the solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with MeOH in DCM (gradient 0% to 12%) to give N- [3- (4-bromobenzenesulfonyl) propyl]Tert-butyl carbamate (653mg, 63%). LCMS (M + Na)⁺＝395.0。

And step 3: n- [3- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzenesulfonyl ] propyl ] carbamic acid tert-butyl ester

To the N- [3- (4-bromobenzenesulfonyl) propyl group at room temperature under a nitrogen atmosphere]To a solution of tert-butyl carbamate (46mg, 0.123mmol) in dioxane (2mL) were added BPD (47mg, 0.185mmol), KOAc (38mg, 0.370mmol), Pd (dppf) Cl₂.CH₂Cl₂(10mg, 0.012 mmol). The resulting mixture was stirred at 90 ℃ under a nitrogen atmosphere for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography, eluting with MeOH in DCM (gradient 0% to 20%) to give N- [3- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzenesulfonyl]Propyl radical]Tert-butyl carbamate (366mg, 54%). LCMS (M-Boc) ⁺＝326.2。

And 4, step 4: n- [3- (4- [5- [4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzenesulfonyl) propyl ] carbamic acid tert-butyl ester

From N- [3- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzenesulfonyl group in a similar manner to that in step 5 of example 141]Propyl radical]Carbamic acid tert-butyl ester and 3-iodo-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]Pyridine the title compound was prepared. LCMS (M + H)⁺＝590.5。

And 5: 3- (4- [5- [4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzenesulfonyl) propan-1-amine

To N- [3- (4- [5- [4- (4-methylpiperazin-1-yl) phenyl ] at room temperature]-1H-pyrrolo [2,3-b]Pyridin-3-yl]Benzenesulfonyl) propyl group]To a solution of tert-butyl carbamate (60mg, 0.104mmol) in MeOH (5mL) was added aqueous HCl (37%, 0.2 mL). The resulting mixture was stirred at room temperature overnight, and then concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XBridge prep C18 OBD column, 150x19mm, 5 um; mobile phase: acetonitrile in water (containing 10mmol/L NH)₄HCO₃) Gradient 15% to 55% over 7 min; a detector: UV 254 nm. Obtaining 3- (4- [5- [4- (4-methylpiperazin-1-yl) phenyl) ]-1H-pyrrolo [2,3-b]Pyridin-3-yl]Benzenesulfonyl) propan-1-amine (15mg, 17%).¹H NMR(400MHz,DMSO-d6)δ8.60-8.52(m,1H),8.50-8.42(m,1H),8.16(s,1H),8.14-8.06(m,2H),7.94-7.88(m,2H),7.70-7.60(m,2H),7.10-7.02(m,2H),3.40-3.30(m,4H),3.25-3.15(m,4H),2.66-5.58(m,2H),2.55-2.45(m,4H),2.24(s,3H)。LC-MS(M+H)⁺＝490.4。

Example 310: n- (4-Methoxybutyl) -N-methyl-4- [5- [4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide (Compound 310)

Step 1: [4- [ (4-Methoxybutyl) (methyl) carbamoyl ] phenyl ] boronic acid

To a solution of 4- (dihydroxyboryl) benzoic acid (190mg, 1.145mmol) in DMF (10mL) at room temperature were added DIPEA (445mg, 3.435mmol), HATU (653mg, 1.717mmol), (4-methoxybutyl) (methyl) amine (140mg, 1.145 mmol). The resulting mixture was stirred at room temperature for 16 h. When the reaction was complete, it was then quenched by addition of water (10 mL). The resulting mixture was extracted with ethyl acetate (30mLx 3). The organic phases were combined, washed with brine and over Na₂SO₄And (5) drying. The solvent was removed under reduced pressure and the residue was purified by flash chromatography, eluting with MeOH in DCM (gradient 0% to 35%) to give [4- [ (4-methoxybutyl) (methyl) carbamoyl]Phenyl radical]Boric acid (174mg, 57%). LCMS (M + H)⁺＝266.1

Step 2: n- (4-methoxybutyl) -N-methyl-4- [5- [4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

Prepared from [4- [ (4-methoxybutyl) (methyl) carbamoyl ] in a similar manner to that in step 5 of example 141]Phenyl radical]Boronic acid and 3-iodo-5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b]Pyridine preparative example 310.¹H NMR(400MHz,DMSO-d6)δ12.06-11.98(m,1H),8.53(s,1H),8.39(s,1H),7.98(s,1H),7.86(d,J＝7.9Hz,2H),7.63(d,J＝8.3Hz,2H),7.52-7.38(m,2H),7.06(d,J＝8.3Hz,2H),3.55-3.10(m,11H),2.97(s,3H),2.50-2.40(m,4H),2.24(s,3H),1.70-1.30(m,4H)。LC-MS(M+H)⁺＝512.7。

Example 311: n, N-dimethyl-4- [5- [6- (4-methylpiperazin-1-yl) pyridin-3-yl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide (compound 311)

Step 1: 4- [ 5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N, N-dimethylbenzamide

To 3-bromo-5-chloro-1H-pyrrolo [2,3-b ] in a nitrogen atmosphere]Pyridine (710mg, 3.068mmol) and [4-(dimethylcarbamoyl) phenyl]To a solution of boric acid (600mg, 3.109mmol) in 1, 4-dioxane (50mL) was added Cs₂CO₃(3.0g, 9.208mmol) in H₂Solution in O (5mL), Pd (dppf) Cl₂.CH₂Cl₂(300mg, 0.367 mmol). The resulting mixture was stirred at 100 ℃ under a nitrogen atmosphere for 16h, and then concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with MeOH in DCM (gradient 0% to 10%) to give 4- [ 5-chloro-1H-pyrrolo [2,3-b ]]Pyridin-3-yl]-N, N-dimethylbenzamide (268mg, 29%). LCMS (M + H)⁺＝300.2。

Step 2: n, N-dimethyl-4- [5- [6- (4-methylpiperazin-1-yl) pyridin-3-yl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

4- [ 5-chloro-1H-pyrrolo [2,3-b ] at room temperature under a nitrogen atmosphere]Pyridin-3-yl]To a solution of (E) -N, N-dimethylbenzamide (90mg, 0.300mmol) in dioxane (12mL) was added K₂CO₃(110mg, 0.796mmol) in H₂Solution in O (3mL), Pd (PCy)₃)₂Cl₂(40mg, 0.054mmol), 1-methyl-4- [5- (3,3,4, 4-tetramethylcyclopentylboran-1-yl) pyridin-2-yl]Piperazine (140mg, 0.468 mmol). The final reaction mixture was irradiated with microwaves at 140 ℃ for 1h under a nitrogen atmosphere. When the reaction was complete, it was quenched by addition of water (10 mL). The resulting mixture was extracted with ethyl acetate (30mL x 3). The organic phases were combined, washed with brine and over Na₂SO₄And (5) drying. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give N, N-dimethyl-4- [5- [6- (4-methylpiperazin-1-yl) pyridin-3-yl]-1H-pyrrolo [2,3-b]Pyridin-3-yl]Benzamide (19mg, 15%).¹H NMR(400MHz,DMSO-d6)δ12.12-12.04(m,1H),8.58-8.50(m,2H),8.49-8.41(m,1H),8.04-7.95(m,2H),7.88(d,J＝7.9Hz,2H),7.48(d,J＝7.9Hz,2H),6.95(d,J＝8.9Hz,1H),3.60-3.50(m,4H),3.01(s,6H),2.47-2.39(m,4H),2.24(s,3H)。LC-MS(M+H)⁺＝441.2。

Example 312: 4- (2- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -N- (2-hydroxy-2-methylpropyl) -N-methylbenzamide (compound 312)

Step 1: 4-bromo-N- (2-hydroxy-2-methylpropyl) -N-methylbenzamide

In a flask, a mixture of 4-bromobenzoic acid (1.93g, 9.61mmol), 2-methyl-1- (methylamino) propan-2-ol (1g, 9.61mmol), TEA (1.94g, 19.2mmol), HATU (4.75g, 12.5mmol) in DMF (30mL) was stirred at room temperature overnight. The mixture was taken up in 60mL of H ₂O was diluted and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was applied to a silica gel column with PE/EtOAc 2:1 to EtOAc. This gave 4-bromo-N- (2-hydroxy-2-methylpropyl) -N-methylbenzamide (2.5g, 90.5%) as a pale yellow solid. LCMS (M + H)⁺286. Step 2: n- (2-hydroxy-2-methylpropyl) -N-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide

In a tube purged with and maintained under an inert atmosphere of nitrogen, 4-bromo-N- (2-hydroxy-2-methylpropyl) -N-methylbenzamide (2.5g, 8.7mmol), BPD (2.2g, 13mmol), Pd (dppf) Cl₂A mixture of (382mg, 0.52mmol), KOAc (1.7g, 17.4mmol, 2 equivalents) in dioxane (30mL) was stirred in an oil bath at 90 deg.C overnight. The solid was filtered off and the residue was applied to a silica gel column with PE/EtOAc ═ 5:1 to EtOAc. This gave N- (2-hydroxy-2-methylpropyl) -N-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide (3g, 100%). LCMS (M + H)⁺＝334.2。

And step 3: 4- (2-bromo-5-tosyl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -N- (2-hydroxy-2-methylpropyl) -N-methylbenzamide

To 2-bromo-7-iodo-5-tosyl-5H-pyrrolo [2,3-b ] under a nitrogen atmosphere]Pyrazine (4.3g, 9mmol, 1 equiv.) and N- (2-hydroxy-2-methylpropyl) -N-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide (3g, 9mmol) in 50mL dioxane and 10mL waterAdding K to the solution₂CO₃(1.6g, 11.7mmol) and Pd (dppf) Cl₂(395mg, 0.54 mmol). After stirring at 50 ℃ for 5h under a nitrogen atmosphere, the reaction mixture was concentrated under reduced pressure. The crude product was applied to a silica gel column with EtOAc to give the title compound (2.5g, 50%). LCMS (M + H)⁺＝557。

And 4, step 4: 4- (2- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -N- (2-hydroxy-2-methylpropyl) -N-methylbenzamide

To 4- (2-bromo-5-tosyl-5H-pyrrolo [2,3-b ] under a nitrogen atmosphere]To a solution of pyrazin-7-yl) -N- (2-hydroxy-2-methylpropyl) -N-methylbenzamide (168mg, 0.3mmol), 1- (2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -4-methylpiperazine (100mg, 0.3mmol) in 20mL dioxane and 5mL water was added K₂CO₃(124mg, 0.9mmol) and Pd (dppf) Cl₂(22mg, 0.03 mmol). After stirring at 100 ℃ for 15h under a nitrogen atmosphere, the reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative TLC (dichloromethane/methanol ═ 8/1) to give the title compound (70mg, 44%). ¹H NMR(400MHz,DMSO-d6)δ12.38(s,1H),8.84(s,1H),8.50(s,1H),8.43-8.34(m,2H),7.81(s,2H),7.57-7.41(m,2H),4.68-4.51(m,1H),3.49(s,2H),3.16-3.05(m,7H),2.48-2.43(m,4H),2.40(s,6H),2.26(s,3H),1.27-0.90(m,6H)。LCMS(M+H)⁺＝527。HPLC:254nm,96.91％。

Example 313: 4- [5- [ 3-methoxy-5-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N, N-dimethylbenzamide (Compound 313)

Step 1: 1- (4-bromo-2-methoxy-6-methylphenyl) -4-methylpiperazine

To a solution of 4-bromo-2-methoxy-6-methylaniline (0.95g, 4.40mmol) in 2- (2-methoxyethoxy) ethan-1-ol (5mL) was added bis (2-chloroethyl) (methyl) amine hydrochloride (844mg, 4.38mmol) at room temperature.The resulting mixture was stirred at 130 ℃ overnight. When the reaction was complete, the reaction mixture was diluted with water (20 mL). The pH of the mixture was adjusted to 11 with NaOH solution (1M). The resulting mixture was extracted with ethyl acetate (50mLx 3). The organic phases were combined, washed with brine and over Na₂SO₄And (5) drying. The solvent was removed under reduced pressure and the residue was purified by flash chromatography, eluting with EtOAc in hexanes (gradient 0% to 10%) to give 1- (4-bromo-2-methoxy-6-methylphenyl) -4-methylpiperazine (426mg, 32%) LCMS (M + H)⁺＝299.0。

Step 2: 1- [ 2-methoxy-6-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] -4-methylpiperazine

To a solution of 1- (4-bromo-2-methoxy-6-methylphenyl) -4-methylpiperazine (426mg, 1.422mmol) in dioxane (15mL) was added BPD (469mg, 1.755mmol), KOAc (419mg, 4.269mmol), Pd (dppf) Cl at room temperature under a nitrogen atmosphere ₂.CH₂Cl₂(140mg, 0.171 mmol). The resulting mixture was stirred at 100 ℃ under a nitrogen atmosphere overnight. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography, eluting with MeOH in EtOAc (gradient 0% to 25%) to give 1- [ 2-methoxy-6-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-4-methylpiperazine (288mg, 58%). LCMS (M + H)⁺＝347.2。

And step 3: 5- (3-methoxy-5-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine

Prepared in a similar manner to that described in step 4 of example 106 from 1- [ 2-methoxy-6-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-4-methylpiperazine and 5-bromo-1H-pyrrolo [2,3-b]Pyridine the title compound was prepared. LCMS (M + H)⁺＝337.1。

And 4, step 4: 1- (4- [ 3-iodo-1H-pyrrolo [2,3-b ] pyridin-5-yl ] -2-methoxy-6-methylphenyl) -4-methylpiperazine

To 5- (3-methoxy-5-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] at room temperature under a nitrogen atmosphere]Pyridine (C)297mg, 0.883mmol) in DCM (15mL) was added NIS (300mg, 1.330 mmol). The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was concentrated under reduced pressure and the crude product was recrystallized from acetone to give 1- (4- [ 3-iodo-1H-pyrrolo [2, 3-b) ]Pyridin-5-yl]-2-methoxy-6-methylphenyl) -4-methylpiperazine (316mg, 77%). LCMS (M + H)⁺＝463.1。

And 5: 4- [5- [ 3-methoxy-5-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N, N-dimethylbenzamide

Prepared from 1- (4- [ 3-iodo-1H-pyrrolo [2,3-b ] in a similar manner to that described in step 6 of example 106]Pyridin-5-yl]-2-methoxy-6-methylphenyl) -4-methylpiperazine and 4- (dimethylcarbamoyl) phenylboronic acid preparation example 313.¹H NMR(400MHz,DMSO-d6)δ12.12-12.04(m,1H),8.56(s,1H),8.43(s,1H),8.04-7.96(m,1H),7.85(d,J＝7.8Hz,2H),7.49(d,J＝7.8Hz,2H),7.20-7.10(m,2H),3.88(s,3H),3.30-3.20(m,4H),3.01(s,6H),2.80-2.60(m,4H),2.33(s,3H),2.23(s,3H)。LC-MS(M+H)⁺＝484.3。

Example 314: 4- [5- [3, 5-dimethoxy-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N, N-dimethylbenzamide (Compound 314)

Step 1: 1- (4-bromo-2, 6-dimethoxyphenyl) -4-methylpiperazine

The title compound was prepared from 4-bromo-2, 6-dimethoxyaniline and 2-chloro-N- (2-chloroethyl) -N-methylethylamine in a similar manner to that in example 141, step 1. LCMS (M + H)⁺＝317.2。

Step 2: 1- [2, 6-dimethoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] -4-methylpiperazine

The title compound was prepared from BPD and 1- (4-bromo-2, 6-dimethoxyphenyl) -4-methylpiperazine in a similar manner to that in example 109, step 1. LCMS (M + H) ⁺＝363.3。

And step 3: 1- (2, 6-dimethoxy-4- [ 1H-pyrrolo [2,3-b ] pyridin-5-yl ] phenyl) -4-methylpiperazine

Prepared in a similar manner to that described in step 4 of example 106 from 1- [2, 6-dimethoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-4-methylpiperazine and 5-bromo-1H-pyrrolo [2,3-b]Pyridine the title compound was prepared. LCMS (M + H)⁺＝353.3。

And 4, step 4: 1- (4- [ 3-iodo-1H-pyrrolo [2,3-b ] pyridin-5-yl ] -2, 6-dimethoxyphenyl) -4-methylpiperazine

Prepared from 1- (2, 6-dimethoxy-4- [ 1H-pyrrolo [2,3-b ] in a similar manner to that described in step 4 of example 313]Pyridin-5-yl]Phenyl) -4-methylpiperazine and NIS the title compound was prepared. LCMS (M + H)⁺＝479.1。

And 5: 4- [5- [3, 5-dimethoxy-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N, N-dimethylbenzamide

Prepared in a similar manner to that described in step 6 of example 106 from 5- (3, 5-dimethoxy-4- (4-methylpiperazin-1-yl) phenyl) -3-iodo-1H-pyrrolo [2,3-b]Pyridine and 4- (dimethylcarbamoyl) phenylboronic acid preparation example 314.¹H NMR(400MHz,DMSO-d6)δ12.12-12.05(m,1H),8.63-8.55(m,1H),8.49-8.41(m,1H),8.05-7.97(m,1H),7.90-7.83(m,2H),7.53-7.46(m,2H),6.93(s,2H),3.86(s,6H),3.12-3.02(m,4H),3.01(s,6H),2.46-2.36(m,4H),2.23(s,3H)。LC-MS(M+H)⁺＝500.3。

Example 315: 6- (4- [5- [3, 5-dimethoxy-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) -2-oxa-6-azaspiro [3.3] heptane (compound 315)

Prepared in a similar manner to that described in step 6 of example 106 from 5- (3, 5-dimethoxy-4- (4-methylpiperazin-1-yl) phenyl) -3-iodo-1H-pyrrolo [2,3-b]Pyridines and (4- [ 2-oxa-6-azaspiro [3.3]]Heptane-6-carbonyl]Phenyl) boronic acid preparation example 315.¹H NMR(400MHz,DMSO-d6,ppm)δ12.18-12.10(m,1H),8.63-8.55(m,1H),8.50-8.42(m,1H),8.09-8.01(m,1H),7.93-7.86(m,2H),7.74-7.67(m,2H),6.94(s,2H),4.71(s,4H),4.60-4.50(s,2H),4.29-4.19(s,2H),3.87(s,6H),3.12-3.02(m,4H),2.45-2.35(m,4H),2.23(s,3H)。LC-MS(M+H)⁺＝554.3。

Example 316: 6- (4- [5- [ 3-methoxy-5-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) -2-oxa-6-azaspiro [3.3] heptane (compound 316)

Prepared from (4- [ 2-oxa-6-azaspiro [3.3] in a similar manner to that in step 6 of example 106]Heptane-6-carbonyl]Phenyl) boronic acids and 1- (4- [ 3-iodo-1H-pyrrolo [2,3-b ]]Pyridin-5-yl]-2-methoxy-6-methylphenyl) -4-methylpiperazine preparation example 316.¹H NMR(400MHz,DMSO-d6)δ12.16-12.10(m,1H),8.57(s,1H),8.44(s,1H),8.05(s,1H),7.89(d,J＝7.9Hz,2H),7.70(d,J＝7.9Hz,2H),7.20-7.10(m,2H),4.70(s,4H),4.59-4.51(m,2H),4.28-4.20(m,2H),3.88(s,3H),3.30-3.20(m,3H),2.72-2.60(m,3H),2.37-2.10(m,8H)。LC-MS(M+H)⁺＝538.3。

Example 317: 4- [5- [3- (benzyloxy) -5-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N, N-dimethylbenzamide (compound 317)

Step 1: 1- [2- (benzyloxy) -4-bromo-6-methylphenyl ] -4-methylpiperazine

The title compound was prepared from 2- (benzyloxy) -4-bromo-6-methylaniline and 2-chloro-N- (2-chloroethyl) -N-methylethylamine in a similar manner to that in example 141, step 1. LCMS (M + H)⁺＝375.1。

Step 2: 1- [2- (benzyloxy) -6-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] -4-methylpiperazine

Prepared from BPD and 1- [2- (benzyloxy) -4-bromo-6-methylphenyl ] in a similar manner to that described in step 1 of example 109]-4-methylpiperazine the title compound was prepared. LCMS (M + H)⁺＝423.3。

And step 3: 1- [2- (benzyloxy) -6-methyl-4- [ 1H-pyrrolo [2,3-b ] pyridin-5-yl ] phenyl ] -4-methylpiperazine

Prepared in a similar manner to that described in step 4 of example 106 from 1- [2- (benzyloxy) -6-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-4-methylpiperazine and 5-bromo-1H-pyrrolo [2,3-b]Pyridine the title compound was prepared. LCMS (M + H)⁺＝413.2。

And 4, step 4: 1- [2- (benzyloxy) -4- [ 3-iodo-1H-pyrrolo [2,3-b ] pyridin-5-yl ] -6-methylphenyl ] -4-methylpiperazine

Prepared from 1- [2- (benzyloxy) -6-methyl-4- [ 1H-pyrrolo [2,3-b ] in a similar manner to that described in step 4 of example 313]Pyridin-5-yl]Phenyl radical]-4-methylpiperazine and NIS. LCMS (M + H)⁺＝539.1。

And 5: 4- [5- [3- (benzyloxy) -5-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N, N-dimethylbenzamide

Prepared in a similar manner to that in example 106, step 6 from 5- (3- (benzyloxy) -5-methyl-4- (4-methylpiperazin-1-yl) phenyl) -3-iodo-1H-pyrrolo [2,3-b]Pyridine and 4- (dimethylcarbamoyl) phenylboronic acid preparation example 317. ¹H NMR(400MHz,DMSO-d6)δ12.13-12.07(m,1H),8.58-8.50(m,1H),8.43-8.35(m,1H),8.04-7.96(m,1H),7.90-7.80(m,2H),7.58-7.46(m,4H),7.44-7.38(m,2H),7.37-7.29(m,1H),7.28-7.22(m,1H),7.21-7.15(m,1H),5.25(s,2H),3.33-3.23(m,4H),3.01(s,6H),2.80-2.48(m,3H),2.34(s,3H),2.25-2.03(m,4H)。LC-MS(M+H)⁺＝560.3。

Example 318: 4- [5- (4- [ [4- (cyclopropylmethyl) piperazin-1-yl ] methyl ] -3, 5-dimethylphenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N, N-dimethylbenzamide (compound 318)

Step 1: 1- (4-bromo-2, 6-dimethylbenzoyl) -4- (cyclopropylmethyl) piperazine

To a solution of 4-bromo-2, 6-dimethylbenzoic acid (0.95g, 4.15mmol) in DCM (50mL) was added DMF (200mg, 2.74mmol) and oxalyl dichloride (4.75g, 0.04mmol) at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2h, and then concentrated under vacuum. The residue was dissolved in DCM (50mL), to which was added 1- (cyclopropylmethyl) piperazine (1.26g, 0.01mmol) and DIEA (1.02g, 0.01mmol) at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for an additional 4 h. When the reaction was complete, by addition of saturated NaHCO₃The solution quenches it. The resulting mixture was extracted with DCM (100mLx 3). The organic phases were combined, washed with brine and over Na₂SO₄And (5) drying. The solvent was removed under reduced pressure to give 1- (4-bromo-2, 6-dimethylbenzoyl) -4- (cyclopropylmethyl) piperazine (1.35g, 93%). LCMS (M + H)⁺＝351.2。

Step 2: 1- (cyclopropylmethyl) -4- [2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoyl ] piperazine

To a solution of 1- (4-bromo-2, 6-dimethylbenzoyl) -4- (cyclopropylmethyl) piperazine (1.25g, 3.564mmol) in 1, 4-dioxane (60mL) was added Pd (dppf) Cl at room temperature under a nitrogen atmosphere₂.CH₂Cl₂(327mg, 0.40mmol), KOAc (827mg, 8.34mmol), 4,5, 5-tetramethyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3, 2-dioxaborolan (1.22g, 0.005 mmol). The resulting mixture was stirred at 80 ℃ under nitrogen atmosphere for 3 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give 1- (cyclopropylmethyl) -4- [2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoyl]Piperazine (1.68g, crude). LCMS (M + H)⁺＝399.4。

And step 3: 1- (cyclopropylmethyl) -4- (2, 6-dimethyl-4- [ 1H-pyrrolo [2,3-b ] pyridin-5-yl ] benzoyl) piperazine

To 5-bromo-1H-pyrrolo [2,3-b ] at room temperature under a nitrogen atmosphere]Pyridine compound(788mg, 4.02mmol) in dioxane (60mL) was added 1- (cyclopropylmethyl) -4- [2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoyl]Piperazine (1.68g, crude), Pd (dppf) Cl₂.CH₂Cl₂(344mg，0.40mmol)、K₂CO₃(1.16g, 8.40mmol) in H₂Solution in O (12 mL). The resulting mixture was stirred at 100 ℃ under a nitrogen atmosphere for 3 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography, eluting with MeOH in EtOAc (gradient 0% to 10%) to give 1- (cyclopropylmethyl) -4- (2, 6-dimethyl-4- [ 1H-pyrrolo [2, 3-b) ]Pyridin-5-yl]Benzoyl) piperazine (0.76g, 55% for 2 steps). LCMS (M + H)⁺＝389.3。

And 4, step 4: 1- (cyclopropylmethyl) -4- [ (2, 6-dimethyl-4- [ 1H-pyrrolo [2,3-b ] pyridin-5-yl ] phenyl) methyl ] piperazine

To 1- (cyclopropylmethyl) -4- (2, 6-dimethyl-4- [ 1H-pyrrolo [2,3-b ] at room temperature]Pyridin-5-yl]To a solution of benzoyl) piperazine (0.76g, 1.96mmol) in THF (30mL) was added LiAlH₄(236mg, 6.22 mmol). The resulting mixture was stirred at 80 ℃ under a nitrogen atmosphere for 16 h. When the reaction was complete, it was quenched by the addition of water (50mL) at room temperature. The resulting mixture was extracted with DCM (100mLx 3). The organic phases were combined, washed with brine and over Na₂SO₄And (5) drying. The solvent was removed under reduced pressure and the residue was purified by flash chromatography, eluting with EtOAc in hexanes (gradient 0% to 10%) to give 1- (cyclopropylmethyl) -4- [ (2, 6-dimethyl-4- [ 1H-pyrrolo [2, 3-b)]Pyridin-5-yl]Phenyl) methyl]Piperazine (425mg, 58%). LCMS (M + H)⁺＝375.3。

And 5: 1- (cyclopropylmethyl) -4- [ (4- [ 3-iodo-1H-pyrrolo [2,3-b ] pyridin-5-yl ] -2, 6-dimethylphenyl) methyl ] piperazine

Prepared from 1- (cyclopropylmethyl) -4- [ (2, 6-dimethyl-4- [ 1H-pyrrolo [2,3-b ] in a similar manner to that described in step 4 of example 313 ]Pyridin-5-yl]Phenyl) methyl]Piperazine and NIS. LCMS (M + H)⁺＝501.2。

Step 6: 4- [5- (4- [ [4- (cyclopropylmethyl) piperazin-1-yl ] methyl ] -3, 5-dimethylphenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N, N-dimethylbenzamide

Prepared from 1- (cyclopropylmethyl) -4- [ (4- [ 3-iodo-1H-pyrrolo [2, 3-b) in a similar manner to that described in step 6 of example 106]Pyridin-5-yl]-2, 6-dimethylphenyl) methyl]Piperazine and [4- (dimethylcarbamoyl) phenyl]Boric acid preparation example 318.¹H NMR(400MHz,CDCl₃)δ10.02-9.92(m,1H),8.63(s,1H),8.40(s,1H),7.78-7.68(m,2H),7.63-7.54(m,3H),7.33-7.27(m,2H),3.60(s,2H),3.21-3.09(m,6H),2.80-2.55(m,6H),2.50(m,10H),1.03-0.93(m,1H),0.61-0.53(m,2H),0.21-0.13(m,2H)。LC-MS(M+H)⁺＝522.6。

Example 319: 6- [4- [5- (4- [ [4- (cyclopropylmethyl) piperazin-1-yl ] methyl ] -3, 5-dimethylphenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl ] -2-oxa-6-azaspiro [3.3] heptane (compound 319)

Prepared from 1- (cyclopropylmethyl) -4- [ (4- [ 3-iodo-1H-pyrrolo [2, 3-b) in a similar manner to that described in step 6 of example 106]Pyridin-5-yl]-2, 6-dimethylphenyl) methyl]Piperazine and (4- [ 2-oxa-6-azaspiro [3.3]]Heptane-6-carbonyl]Phenyl) boronic acid preparation example 319.¹H NMR(400MHz,CDCl-d3,ppm)δ9.59-9.51(m,1H),8.63(s,1H),8.40(s,1H),7.81-7.71(m,4H),7.63(s,1H),7.32-7.25(m,2H),4.92-4.80(m,4H),4.65-4.38(m,4H),3.60(s,2H),2.80-2.55(m,4H),2.51(s,6H),2.45-2.30(m,4H),1.80-1.68(m,1H),1.0-0.80(s,2H),0.61-0.51(m,2H),0.21-0.11(m,2H)。LC-MS(M+H)⁺＝576.3。

Example 320: 4- [5- [ 3-cyclopropyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N, N-dimethylbenzamide (Compound 320)

Step 1: 1- (2-bromo-4-nitrophenyl) -4-methylpiperazine

To a solution of 2-bromo-1-fluoro-4-nitrobenzene (2.19g, 9.932mmol) in DMF (12mL) at room temperature was added 1-methylpiperazine (1.05g, 10.433mmol), K₂CO₃(2.38g, 17.185 mmol). The resulting mixture was stirred at 80 ℃ for 3 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography, eluting with EtOAc in hexanes (gradient 0% to 100%) to give 1- (2-bromo-4-nitrophenyl) -4-methylpiperazine (2.60g, 86%). LCMS (M + H)⁺＝300.1。

Step 2: 1- (2-cyclopropyl-4-nitrophenyl) -4-methylpiperazine

To a solution of 1- (2-bromo-4-nitrophenyl) -4-methylpiperazine (2.42g, 8.071mmol) in dioxane (50mL) was added cyclopropylboronic acid (760mg, 8.847mmol), water (5mL), Cs at room temperature₂CO₃(5.32g，16.328mmol)、Pd(dppf)Cl₂.CH₂Cl₂(790mg, 0.968 mmol). The resulting mixture was stirred at 95 ℃ for 15 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with MeOH in EtOAc (gradient 0% to 15%) to give 1- (2-cyclopropyl-4-nitrophenyl) -4-methylpiperazine (1.87g, 89%). LCMS (M + H)⁺＝262.2。

And step 3: 3-cyclopropyl-4- (4-methylpiperazin-1-yl) aniline

To 1- (2-cyclopropyl-4-nitrophenyl) -4-methylpiperazine (1.78g, 6.805mmol) in EtOH (50mL) and H at room temperature ₂To a solution in O (10mL) were added Fe powder (1.43g, 25.517mmol) and NH₄Cl (1.05g, 19.536 mmol). The resulting mixture was stirred at 80 ℃ for 4 h. When the reaction was complete, the reaction mixture was filtered. The filter cake was rinsed with EtOAc (50mLx3) and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with MeOH in EtOAc (gradient 0% to 35%) to give 3-cyclopropyl-4- (4-methylpiperazin-1-yl) aniline (1.40g, 88%). LCMS (M + H)⁺＝232.2。

And 4, step 4: 1- (4-bromo-2-cyclopropylphenyl) -4-methylpiperazine

To a solution of 3-cyclopropyl-4- (4-methylpiperazin-1-yl) aniline (1.29g, 5.580mmol) in aqueous HBr (8.6M, 20mL) at 0 deg.C was added NaNO dropwise over a period of 5min at 0 deg.C₂(1.90g, 27.538mmol) in water (5 mL). The resulting mixture was stirred at 0 ℃ for 30min, and then CuBr (1.61g, 11.258mmol) was added at 0 ℃. The reaction mixture was stirred at 60 ℃ for 1 h. After the reaction was complete, the pH of the mixture was adjusted to 8-9 with NaOH solution (2M). The resulting mixture was extracted with ethyl acetate (150mLx 3). The organic phases were combined, washed with brine and over Na₂SO₄And (5) drying. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography, eluting with MeOH in EtOAc (gradient 0% to 75%) to give 1- (4-bromo-2-cyclopropylphenyl) -4-methylpiperazine (665mg, 40%). LCMS (M + H) ⁺＝297.0。

And 5: 1- [ 2-cyclopropyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] -4-methylpiperazine

The title compound was prepared from BPD and 1- (4-bromo-2-cyclopropylphenyl) -4-methylpiperazine in analogy to the procedure in example 109, step 1. LCMS (M + H)⁺＝343.2。

Step 6: 5- (3-cyclopropyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine

Prepared in a similar manner to that described in step 4 of example 106 from 1- [ 2-cyclopropyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-4-methylpiperazine and 5-bromo-1H-pyrrolo [2,3-b]Pyridine the title compound was prepared. LCMS (M + H)⁺＝333.2。

And 7: 5- (3-cyclopropyl-4- (4-methylpiperazin-1-yl) phenyl) -3-iodo-1H-pyrrolo [2,3-b ] pyridine

Prepared from 5- (3-cyclopropyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that in example 313, step 4]Pyridine and NIS. LCMS (M + H)⁺＝459.2。

And 8: 4- [5- [ 3-cyclopropyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N, N-dimethylbenzamide

Prepared from 4- (dimethylcarbamoyl) phenylboronic acid and 5- (3-cyclopropyl-4- (4-methylpiperazin-1-yl) phenyl) -3-iodo-1H-pyrrolo [2,3-b ] in a similar manner to that described in step 6 of example 106 ]Pyridine preparative example 320.¹H NMR(400MHz,DMSO-d6)δ12.11-12.03(m,1H),8.50(s,1H),8.37(s,1H),8.00(s,1H),7.90-7.80(m,2H),7.54-7.42(m,3H),7.16-6.95(m,2H),3.20-2.80(m,10H),2.70-2.50(m,4H),2.35-2.20(m,4H),1.05-0.92(m,2H),0.88-0.78(m,2H)。LC-MS(M+H)⁺＝480.5。

Example 321: 4- (5- [3, 5-dimethyl-4- [4- (1-methylpiperidin-4-yl) piperazin-1-yl ] phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (compound 321)

Step 1: 1- [2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] -4- (1-methylpiperidin-4-yl) piperazine

The title compound was prepared from BPD and 1- (4-bromo-2, 6-dimethylphenyl) -4- (1-methylpiperidin-4-yl) piperazine in a similar manner to that in example 109, step 1. LCMS (M + H)⁺＝414.3。

Step 2: 1- (2, 6-dimethyl-4- [ 1H-pyrrolo [2,3-b ] pyridin-5-yl ] phenyl) -4- (1-methylpiperidin-4-yl) piperazine

Prepared in a similar manner to that described in step 4 of example 106 from 1- [2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-4- (1-methylpiperidin-4-yl) piperazine and 5-bromo-1H-pyrrolo [2,3-b]Pyridine the title compound was prepared. LCMS (M + H)⁺＝404.3。

And step 3: 1- (4- [ 3-iodo-1H-pyrrolo [2,3-b ] pyridin-5-yl ] -2, 6-dimethylphenyl) -4- (1-methylpiperidin-4-yl) piperazine

Prepared in a similar manner to that described in step 4 of example 313 from 1- (2, 6-dimethyl-4- [ 1H-pyrrolo [2,3-b ]]Pyridin-5-yl]Phenyl) -4- (1-methylpiperidin-4-yl) piperazine and NIS. LCMS (M + H) ⁺＝530.2。

And 4, step 4: 4- (5- [3, 5-dimethyl-4- [4- (1-methylpiperidin-4-yl) piperazin-1-yl ] phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide

Prepared from 1- (4- [ 3-iodo-1H-pyrrolo [2,3-b ] in a similar manner to that described in step 6 of example 106]Pyridin-5-yl]-2, 6-dimethylphenyl) -4- (1-methylpiperidin-4-yl) piperazine and [4- (dimethylcarbamoyl) phenyl]Boric acid preparation example 321.¹H NMR(400MHz,DMSO-d6)δ12.11-12.03(m,1H),8.52(s,1H),8.40(s,1H),7.99(s,1H),7.85(d,J＝8.0Hz,2H),7.49(d,J＝8.0Hz,2H),7.36(s,2H),3.07-2.95(m,10H),2.85-2.75(m,2H),2.62-2.55(m,4H),2.36(s,6H),2.24-2.16(m,1H),2.14(s,3H),1.90-1.80(m,2H),1.78-1.69(m,2H),1.52-1.42(m,2H)。LC-MS(M+H)⁺＝551.5。

Example 322: 6- [4- (5- [3, 5-dimethyl-4- [4- (1-methylpiperidin-4-yl) piperazin-1-yl ] phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzoyl ] -2-oxa-6-azaspiro [3.3] heptane (compound 322)

Prepared from 1- (4- [ 3-iodo-1H-pyrrolo [2,3-b ] in a similar manner to that described in step 6 of example 106]Pyridin-5-yl]-2, 6-dimethylphenyl) -4- (1-methylpiperidin-4-yl) piperazine and (4- [ 2-oxa-6-azaspiro [ 3.3)]Heptane-6-carbonyl]Phenyl) boronic acid preparation example 322.¹H NMR(400MHz,DMSO-d6)δ12.15-12.07(m,1H),8.53(s,1H),8.41(s,1H),8.05(s,1H),7.88(d,J＝8.0Hz,2H),7.71(d,J＝8.0Hz,2H),7.37(s,2H),4.71(s,4H),4.61-4.51(m,2H),4.29-4.19(m,2H),3.11-3.01(m,4H),2.86-2.76(m,2H),2.65-2.57(m,4H),2.38(s,6H),2.24-2.16(m,1H),2.15(s,3H),1.91-1.81(m,2H),1.80-1.72(m,2H),1.52-1.42(m,2H)。LC-MS(M+H)⁺＝605.5。

Example 323: 4- (5- [3, 5-dimethyl-4- [4- (1-methylpiperidin-4-yl) piperazin-1-yl ] phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- [2- (dimethylamino) ethyl ] -N-methylbenzamide (compound 323)

Step 1: (4- [ [2- (dimethylamino) ethyl ] (methyl) carbamoyl ] phenyl) boronic acid

To a stirred solution of 4- (dihydroxyboryl) benzoic acid (332mg, 1.9mmol, 1 equiv., 95%) and DIEA (775mg, 5.7mmol, 95%) in DMF was added HATU (1140mg, 2.848mmol, 95%) in portions at room temperature. The resulting mixture was stirred at room temperature for 30 min. To the above mixture was added [2- (dimethylamino) ethyl group](methyl) amine (204mg, 1.897mmol, 1.00 eq, 95%). The resulting mixture was stirred at room temperature for another 3 h. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography. This gives (4- [ [2- (dimethylamino) ethyl ] methyl](methyl) carbamoyl group]Phenyl) boronic acid (280mg, 58%). LC-MS (M + H)⁺＝251.2

Step 2: 4- (5- [3, 5-dimethyl-4- [4- (1-methylpiperidin-4-yl) piperazin-1-yl ] phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- [2- (dimethylamino) ethyl ] -N-methylbenzamide

Prepared from 1- (4- [ 3-iodo-1H-pyrrolo [2,3-b ] in a similar manner to that described in step 6 of example 106]Pyridin-5-yl]-2, 6-dimethylphenyl) -4- (1-methylpiperidin-4-yl) piperazine and (4- [ [2- (dimethylamino) ethyl)](methyl) carbamoyl group]Phenyl) boronic acid preparation example 323.¹H NMR(400MHz,DMSO-d6)δ12.10-12.02(m,1H),8.52(s,1H),8.40(s,1H),8.00(s,1H),7.85(d,J＝7.8Hz,2H),7.46(d,J＝7.9Hz,2H),7.41-7.33(m,2H),3.65-3.35(m,2H),3.03-2.95(m,7H),2.86-2.76(m,2H),2.64-2.58(m,4H),2.43-2.31(m,7H),2.25-1.95(m,11H),1.91-1.81(m,2H),1.80-1.72(m,2H),1.52-1.42(m,2H)。LC-MS(M+H)⁺＝608.5。

Example 324: 2- ((5- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) pyridin-2-yl) oxy) ethan-1-amine (Compound 324)

Step 1: (2- ((5-Bromopyridin-2-yl) oxy) ethyl) carbamic acid tert-butyl ester

To a solution of tert-butyl (2-hydroxyethyl) carbamate (5.5g, 33.41mmol) in DMF (50mL) at 0 deg.C was added sodium hydride (60% in oil, 2.2g, 53.8 mmol). The mixture was stirred at 0 ℃ for 15min, then 5-bromo-2-fluoropyridine (5g, 27.84mmol) was added portionwise at 0 ℃. The reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with water (100mL) and the resulting mixture was extracted with DCM (3 × 250 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to give the title compound tert-butyl (2- ((5-bromopyridin-2-yl) oxy) ethyl) carbamate (7.84g, 71.73%). LCMS (M + H)⁺＝317.1。

Step 2: (tert-butyl 2- ((5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) oxy) ethyl) carbamate

To a solution of tert-butyl (2- ((5-bromopyridin-2-yl) oxy) ethyl) carbamate (1g, 2.55mmol) and BPD (792.1mg, 3.06mmol) in toluene (30mL) under a nitrogen atmosphere were added AcOK (765.3mg, 7.64mmol) and Pd (dppf) Cl₂ CH₂Cl₂(424.6mg, 0.51 mmol). After stirring at 100 ℃ under a nitrogen atmosphere for 20h, the reaction mixture was concentrated under reduced pressure to give the title compound (1g, crude). The crude product was used directly in the next step without further purification. LCMS (M + H) ⁺＝365.2。

And step 3: (2- ((5- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) pyridin-2-yl) oxy) ethyl) carbamic acid tert-butyl ester

To 7-iodo-2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] under a nitrogen atmosphere]Pyrazine (900mg, 0.93mmol) and tert-butyl (2- ((5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) oxy) ethyl) carbamate (455.8mg, 1.02mmol) in iPrOH (16mL) and H₂To a solution in O (4mL) was added K₃PO₄(201.2mg, 0.93mmol) and Pd-AMPHOS (67.1mg, 0.09 mmol). After stirring at 80 ℃ for 3h under a nitrogen atmosphere, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography,eluting with EtOAc/MeOH (1:4) to give (2- ((5- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2, 3-b)]Pyrazin-7-yl) pyridin-2-yl) oxy) ethyl) carbamic acid tert-butyl ester (300mg, 24.6%). LCMS (M + H)⁺＝530.1。

And 4, step 4: 2- ((5- (2- (4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) pyridin-2-yl) oxy) ethan-1-amine

To N- [2- [ (5- [2- [4- (4-methylpiperazin-1-yl) phenyl) at room temperature]-5H-pyrrolo [2,3-b]Pyrazin-7-yl]Pyridin-2-yl) oxy]Ethyl radical]To a solution of tert-butyl carbamate (150mg, 0.27mmol) in dioxane (10mL) was added HCl solution (4M in dioxane, 0.25mL, 1.08 mmol). The resulting mixture was stirred at room temperature for 2 h. When the reaction was complete, the solvent was concentrated under reduced pressure and the residue was purified by preparative HPLC to give 2- [ (5- [2- [4- (4-methylpiperazin-1-yl) phenyl ] amine ]-5H-pyrrolo [2,3-b]Pyrazin-7-yl]Pyridin-2-yl) oxy]Ethan-1-amine (100mg, 84.19%).¹H NMR(400MHz,DMSO-d6)δ9.17(d,J＝2.4Hz,1H),8.82(s,1H),8.56-8.46(m,1H),8.37(s,1H),8.06(d,J＝8.4Hz,2H),7.07(d,J＝8.5Hz,2H),6.93(d,J＝8.7Hz,1H),4.31-4.21(m,2H),3.27-3.18(m,4H),2.99-2.87(m,2H),2.50-2.41(m,4H),2.22(s,3H)。LCMS(M+H)⁺＝430.1。

Example 325: 2- [ (5- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] pyridin-2-yl) oxy ] ethan-1-amine (Compound 325)

Step 1: n- [2- [ (5- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] pyridin-2-yl) oxy ] ethyl ] carbamic acid tert-butyl ester

Prepared from 1- (4- [ 3-iodo-1H-pyrrolo [2,3-b ] in a similar manner to that described in step 6 of example 106]Pyridin-5-yl]-2-methylphenyl) -4-methylpiperazine and N- (2- [ [5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl]Oxy radical]Ethyl) carbamic acid tert-butyl ester the title compound is prepared. LCMS (M + H)⁺＝543.3。

Step 2: 2- [ (5- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] pyridin-2-yl) oxy ] ethan-1-amine

Prepared from N- [2- [ (5- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] N- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) in a similar manner to the process described in step 5 in example 309]-1H-pyrrolo [2,3-b]Pyridin-3-yl]Pyridin-2-yl) oxy]Ethyl radical]Tert-butyl carbamate and HCl preparation example 325.¹H NMR(400MHz,DMSO-d6)δ12.01-11.93(m,1H),8.58(s,1H),8.52(s,1H),8.32(s,1H),8.15-8.07(m,1H),7.89(s,1H),7.59(s,1H),7.58-7.51(m,1H),7.12(d,J＝8.2Hz,1H),6.91(d,J＝8.6Hz,1H),4.30-4.22(m,2H),3.40-3.25(m,4H),2.95-2.85(m,6H),2.60-2.52(m,2H),2.34(s,3H),2.26(s,3H)。LC-MS(M+H)⁺＝443.4。

Example 326: 4- [5- [3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N- [3- (dimethylamino) propyl ] -N-methylbenzamide (compound 326)

Prepared from 1- (4- [ 3-iodo-1H-pyrrolo [2,3-b ] in a similar manner to that described in step 6 of example 106]Pyridin-5-yl]-2, 6-dimethylphenyl) -4-methylpiperazine and 4- (dihydroxymethyl) -N- [3- (dimethylamino) propyl]-N-methylbenzamide preparation example 326.¹H NMR(400MHz,DMSO-d6)δ12.08-12.03(m,1H),8.52(s,1H),8.39(s,1H),7.99(s,1H),7.89-7.81(m,2H),7.50-7.42(m,2H),7.37(s,2H),3.50-3.35(m,2H),3.09-3.02(m,4H),2.98(s,3H),2.53-1.90(m,21H),1.80-1.60(m,2H)。LC-MS(M+H)⁺＝539.4。

Example 327, the following: 1- (4- [5- [3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] phenyl) pyrrolidin-2-one (compound 327)

Step 1: 1- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] pyrrolidin-2-one

The title compound was prepared from BPD and 1- (4-bromophenyl) pyrrolidin-2-one in a similar manner as in example 109, step 1. LCMS (M + H)⁺＝288.1。

Step 2: 1- (4- [5- [3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] phenyl) pyrrolidin-2-one

Prepared from 1- (4- [ 3-iodo-1H-pyrrolo [2,3-b ] in a similar manner to that described in step 6 of example 106]Pyridin-5-yl]-2, 6-dimethylphenyl) -4-methylpiperazine and 1- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Pyrrolidin-2-one preparation example 327.¹H NMR(400MHz,DMSO-d6)δ11.98-11.92(m,1H),8.50(s,1H),8.36(s,1H),7.88(s,1H),7.85-7.72(m,4H),7.37(s,2H),3.93-3.85(m,2H),3.10-3.02(m,4H),2.57-2.20(m,15H),2.14-2.06(m,2H)。LC-MS(M+H)⁺＝480.3。

Example 328: n- (3-methoxypropyl) -N-methyl-5- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] pyridine-2-carboxamide (Compound 328)

Step 1: 5-bromo-N- (3-methoxypropyl) -N-methylpyridine-2-carboxamide

To a solution of 5-bromopyridine-2-carboxylic acid (323mg, 1.599mmol) in DMF (15mL) was added DIEA (475mg, 3.675mmol), HATU (760mg, 1.999mmol), (3-methoxypropyl) (methyl) amine hydrochloride (190mg, 1.361mmol) at room temperature. The resulting mixture was stirred at room temperature for 15 h. When the reaction was complete, it was quenched by addition of water (20mL) and the resulting mixture was extracted with ethyl acetate (50mLx 3). The organic phases were combined, washed with brine and over Na₂SO₄And (5) drying. The solvent was removed under reduced pressure and the residue was purified by flash chromatography, eluting with EtOAc in hexanes (gradient 0% to 35%) to give 5-bromo-N- (3-methoxypropyl) -N-methylpyridine-2-carboxamide (241mg, 62%)。LCMS(M+H)⁺＝289.0。

Step 2: n- (3-methoxypropyl) -N-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine-2-carboxamide

The title compound was prepared from BPD and 5-bromo-N- (3-methoxypropyl) -N-methylpyridine-2-carboxamide in a similar manner to that in example 109, step 1. LCMS (M + H)⁺＝335.2。

And step 3: n- (3-methoxypropyl) -N-methyl-5- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] pyridine-2-carboxamide

Prepared in a similar manner to that described in step 6 of example 106 from N- (3-methoxypropyl) -N-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine-2-carboxamide and 1- (4- [ 3-iodo-1H-pyrrolo [2, 3-b)]Pyridin-5-yl]-2-methylphenyl) -4-methylpiperazine preparation example 328.¹H NMR(400MHz,DMSO-d6,ppm)δ12.22-11.96(m,1H),9.03(d,J＝9.2Hz,1H),8.56(s,1H),8.48-8.42(m,1H),8.33(d,J＝8.3Hz,1H),8.19-8.11(m,1H),7.67-7.50(m,3H),7.13(d,J＝8.2Hz,1H),3.60-3.40(m,3H),3.29-3.20(m,3H),3.11(s,2H),3.06-3.00(m,3H),2.93-2.85(m,4H),2.50-2.40(m,3H),2.34(s,3H),2.26(s,3H),1.89-1.81(m,2H)。LC-MS(M+H)⁺＝513.6。

Example 329: 6- (4- [5- [ 3-methoxy-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) -2-oxa-6-azaspiro [3.3] heptane (compound 329)

Step 1: 6- (4- [ 5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) -2-oxa-6-azaspiro [3.3] heptane

3-bromo-5-chloro-1H-pyrrolo [2,3-b ] at room temperature under a nitrogen atmosphere]To a solution of pyridine (190mg, 0.821mmol, 1 eq, 95%) in dioxane (10mL) was added (4- [ 2-oxa-6-azaspiro [3.3]]Heptane-6-carbonyl]Phenyl) boronic acid (243mg, 0.985mmol), 2 nd generation XPhos pre-catalyst (64mg, 0.082mmol), and in H₂K in O (1mL)₃PO₄(523mg, 2.462mmol) solution. The resulting mixture was stirred at 90 ℃ under a nitrogen atmosphere for 4 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography, eluting with MeOH in DCM (gradient 0% to 10%) to give 6- (4- [ 5-chloro-1H-pyrrolo [2, 3-b) ]Pyridin-3-yl]Benzoyl) -2-oxa-6-azaspiro [3.3]Heptane (270mg, 93%). LCMS (M + H)⁺＝354.2。

Step 2: 6- (4- [5- [ 3-methoxy-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) -2-oxa-6-azaspiro [3.3] heptane

To 6- (4- [ 5-chloro-1H-pyrrolo [2,3-b ] at room temperature under a nitrogen atmosphere]Pyridin-3-yl]Benzoyl) -2-oxa-6-azaspiro [3.3]To a solution of heptane (118mg, 0.334mmol) in dioxane (12mL) was added 1- [ 2-methoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-4-methylpiperazine (147mg, 0.445mmol), Pd (Cy)₃)₂Cl₂(28mg, 0.036mmol), and in H₂K in O (1mL)₂CO₃(85mg, 0.594mmol) solution. The resulting mixture was irradiated with microwaves at 140 ℃ for 1h under a nitrogen atmosphere. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC to give 6- (4- [5- [ 3-methoxy-4- (4-methylpiperazin-1-yl) phenyl)]-1H-pyrrolo [2,3-b]Pyridin-3-yl]Benzoyl) -2-oxa-6-azaspiro [3.3]Heptane (37mg, 21%).¹H NMR(400MHz,DMSO-d6)δ12.14-12.08(m,1H),8.58(s,1H),8.44(s,1H),8.04(s,1H),7.92-7.86(m,2H),7.74-7.67(m,2H),7.31-7.23(m,2H),7.04-6.96(m,1H),4.71(s,4H),4.55(s,2H),4.24(s,2H),3.91(s,3H),3.07-2.97(s,4H),2.55-2.43(m,4H),2.24(s,3H)。LC-MS(M+H)⁺＝524.4。

Example 330: (3- (dimethylamino) azetidin-1-yl) (4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone (Compound 330)

Step 1: [4- [3- (dimethylamino) azetidine-1-carbonyl ] phenyl ] boronic acid

To a solution of 4- (dihydroxyboryl) benzoic acid (1.42g, 8.587mmol) in DMF (10mL) was added DIEA (3.32g, 25.762mmol), N-dimethylazetidin-3-amine (855mg, 8.536mmol), HATU (4.90g, 12.881mmol) at room temperature. The resulting mixture was stirred at room temperature for 15 h. When the reaction was complete, it was quenched by addition of water (20 mL). The resulting mixture was extracted with ethyl acetate (50mLx 3). The organic phases were combined, washed with brine and over Na₂SO₄And (5) drying. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC. To obtain [4- [3- (dimethylamino) azetidine-1-carbonyl]Phenyl radical]Boric acid (890mg, 42%). LCMS (M + H)⁺＝249.2。

Step 2: (4- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (3- (dimethylamino) azetidin-1-yl) methanone

To [4- [3- (dimethylamino) azetidine-1-carbonyl ] at room temperature under a nitrogen atmosphere]Phenyl radical]To a solution of boric acid (200mg, 0.806mmol) in dioxane (40mL) was added 3-bromo-5-chloro-1H-pyrrolo [2,3-b ]]Pyridine (205mg, 0.887mmol), K₃PO₄(342mg, 1.612mmol) in H₂Solution in O (4mL), 2G XPhos pre-catalyst (65mg, 0.081 mmol). The resulting mixture was stirred at 90 ℃ under a nitrogen atmosphere for 3 h. When the reaction was complete, it was quenched by addition of water (20 mL). The resulting mixture was extracted with ethyl acetate (50mLx 3). The organic phases were combined, washed with brine and over Na ₂SO₄And (5) drying. The solvent was removed under reduced pressure and the residue was purified by flash chromatography, eluting with MeOH in DCM (gradient 0% to 15%) to give 1- (4- [ 5-chloro-1H-pyrrolo [2, 3-b)]Pyridin-3-yl]Benzoyl) -N, N-dimethylazetidin-3-amine (83mg, 29%). LCMS (M + H)⁺＝355.1。

And step 3: (3- (dimethylamino) azetidin-1-yl) (4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone

Prepared from 1-methyl-4- (2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) piperazine and (4- (5-chloro-1H-pyrrolo [2,3-b ] in a similar manner to that in step 2 of example 329]Pyridin-3-yl) phenyl) (3- (dimethylamino) azetidin-1-yl) methanone preparation example 330.¹H NMR(400MHz,DMSO-d6)δ12.15-12.09(m,1H),8.54(s,1H),8.42(s,1H),8.04(s,1H),7.88(d,J＝8.2Hz,2H),7.73(d,J＝8.2Hz,2H),7.60-7.50(m,2H),7.13(d,J＝8.2Hz,1H),4.41-4.33(m,1H),4.22-4.02(m,2H),3.90-3.80(m,1H),3.13-3.05(m,1H),2.94-2.84(m,4H),2.60-2.40(m,4H),2.34(s,3H),2.25(s,3H),2.10(s,6H)。LC-MS(M+H)⁺＝509.4。

Example 331: n- [2- (dimethylamino) ethyl ] -4- [5- [ 3-methoxy-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N-methylbenzamide (Compound 331)

Step 1: 4- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (2- (dimethylamino) ethyl) -N-methylbenzamide

Prepared from 3-bromo-5-chloro-1H-pyrrolo [2,3-b ] in a similar manner to that in step 2 of example 330 ]Pyridine and 4- ((2- (dimethylamino) ethyl) (methyl) carbamoyl) phenylboronic acid the title compound was prepared. LCMS (M + H)⁺＝357.1。

Step 2: n- [2- (dimethylamino) ethyl ] -4- [5- [ 3-methoxy-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N-methylbenzamide

Prepared from 4- (5-chloro-1H-pyrrolo [2,3-b ] in a similar manner to that in example 329, step 2]Pyridin-3-yl) -N- (2- (dimethylamino) ethyl) -N-methylbenzamide and 1- (2-methoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -4-methylpiperazine preparation example 331.¹H NMR(400MHz,DMSO-d6)δ12.11-12.05(m,1H),8.57(s,1H),8.43(s,1H),8.00(s,1H),7.86(d,J＝7.9Hz,2H),7.46(d,J＝7.9Hz,2H),7.30-7.22(m,2H),6.99(d,J＝8.0Hz,1H),3.90(s,3H),3.60-3.35(m,2H),3.10-2.90(m,7H),2.50-2.35(m,6H),2.35-1.95(m,9H)。LC-MS(M+H)⁺＝527.5。

Example 332: 2-amino-5- [3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl ] -N- [4- (dimethylcarbamoyl) phenyl ] pyridine-3-carboxamide (Compound 332)

Step 1: 4- (2-amino-5-bromopyridine-3-carboxamido) benzoic acid methyl ester

To a solution of methyl 4-aminobenzoate (68mg, 0.438mmol) in DMF (2mL) was added 2-amino-5-bromopyridine-3-carboxylic acid (95mg, 0.440mmol), HATU (200mg, 0.525mmol), DIEA (89mg, 0.691mmol) at room temperature. The resulting mixture was stirred at 50 ℃ under a nitrogen atmosphere for 4 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the residue was purified by reverse phase flash chromatography using MeCN (containing 10mmol/L NH) in water ₄HCO₃) (gradient 0% to 80% over 30 min) to give methyl 4- (2-amino-5-bromopyridine-3-amido) benzoate (69mg, 45%). LCMS (M + H)⁺＝350.1。

Step 2: 4- (2-amino-5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) nicotinamido) benzoic acid methyl ester

To a solution of methyl 4- (2-amino-5-bromopyridine-3-amido) benzoate (59mg, 0.169mmol) in dioxane (15mL) was added 1- [2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl at room temperature under a nitrogen atmosphere]-4-methylpiperazine (81mg, 0.245mmol), Pd (dppf) Cl₂.CH₂Cl₂(21mg, 0.025mmol), and in H₂K in O (3mL)₂CO₃(70mg, 0.501mmol) of the resulting solution. The resulting mixture was irradiated with microwaves at 80 ℃ for 2h under a nitrogen atmosphere. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give methyl 4- (2-amino-5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) nicotinamido) benzoate (120mg, crude). LCMS (M + H)⁺＝474.4。

And step 3: 2-amino-5- [3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl ] -N- [4- (dimethylcarbamoyl) phenyl ] pyridine-3-carboxamide

Example 332 was prepared from methyl 4- (2-amino-5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) nicotinamido) benzoate and dimethylamine in a similar manner to that in example B03, step 9. ¹H NMR(400MHz,CDCl₃)δ8.69-8.60(m,1H),8.48-8.40(m,1H),8.08-8.02(m,1H),7.60-7.50(m,2H),7.40-7.32(m,2H),7.20(s,2H),6.36(s,2H),3.25-3.15(m,4H),3.04-2.99(m,6H),2.66-2.56(m,4H),2.48-2.36(m,9H)。LC-MS(M+H)⁺＝487.5。

Example 333: 5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -N- (4- (dimethylcarbamoyl) phenyl) -1H-pyrrolo [2,3-b ] pyridine-3-carboxamide (Compound 333)

Step 1: 5-bromo-1H-pyrrolo [2,3-b ] pyridine-3-carbonyl chloride

To a solution of 5-bromo-1H-pyrrolo [2,3-b ] pyridine-3-carboxylic acid (1.00g, 4.149mmol) in DCM (50mL) was added oxalyl dichloride (1.92g, 15.261mmol) and DMF (0.1mL) at room temperature. The resulting mixture was stirred at 40 ℃ for 3 h. When the reaction was complete, the mixture was concentrated under reduced pressure to give 5-bromo-1H-pyrrolo [2,3-b ] pyridine-3-carbonyl chloride (600mg, crude).

Step 2: 5-bromo-N- [4- (dimethylcarbamoyl) phenyl ] -1H-pyrrolo [2,3-b ] pyridine-3-carboxamide

To a solution of 4-amino-N, N-dimethylbenzamide (230mg, 1.401mmol) in DCM (40mL) was added pyridine (1.24g, 15.676mmol), 5-bromo-1H-pyrrolo [2,3-b ] at room temperature]Pyridine-3-carbonyl chloride (450mg, crude). The resulting mixture was stirred at room temperature for 16 h. When the reaction was complete, the mixture was concentrated in vacuo and the residue was purified by flash chromatography, eluting with MeOH in DCM (gradient 0% to 10%) to give 5-bromo-N- [4- (dimethylcarbamoyl) phenyl ]-1H-pyrrolo [2,3-b]Pyridine-3-carboxamides(200mg，17％)。LCMS(M+H)⁺＝389.5。

And step 3: 5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -N- (4- (dimethylcarbamoyl) phenyl) -1H-pyrrolo [2,3-b ] pyridine-3-carboxamide

Prepared in a similar manner to that described in step 2 of example 311 from 5-bromo-N- (4- (dimethylcarbamoyl) phenyl) -1H-pyrrolo [2,3-b ]]Pyridine-3-carboxamide and 1-methyl-4- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) piperazine preparation example 333.¹H NMR(400MHz,DMSO-d6,ppm)δ12.37(s,1H),10.02(s,1H),8.65(s,1H),8.58(s,1H),8.49(s,1H),7.85(d,J＝8.2Hz,2H),7.42(d,J＝8.5Hz,2H),7.34(s,2H),3.09-3.03(m,4H),2.98(s,6H),2.47-2.40(m,4H),2.37(s,6H),2.25(s,3H)。LC-MS(M+H)⁺＝511.3。

Example 334: n-methyl-2- (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) ethylamine (compound 334)

Step 1: n- [2- (4-bromophenyl) ethyl ] -N-methylcarbamic acid tert-butyl ester

To [2- (4-bromophenyl) ethyl group at room temperature]Boc was added to a solution of (methyl) amine (627mg, 2.928mmol) in EtOH (30mL)₂O (959mg, 4.624mmol) and DMAP (71mg, 0.617 mmol). The resulting mixture was stirred at room temperature for 16 h. When the reaction was complete, the mixture was concentrated and the residue was purified by flash chromatography, eluting with DCM, to give N- [2- (4-bromophenyl) ethyl]-tert-butyl N-methylcarbamate (799mg, 87%). LCMS (M + H-56)⁺＝258.1。

Step 2: N-methyl-N- [2- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] ethyl ] carbamic acid tert-butyl ester

To N- [2- (4-bromophenyl) ethyl group at room temperature under nitrogen atmosphere]BPD (990mg, 4.105mmol), Pd (dppf) Cl and a solution of tert-butyl (799mg, 2.737mmol) N-methylcarbamate in dioxane (20mL) were added₂.CH₂Cl₂(200mg, 0.274mmol), KOAc (765mg, 8.211 mmol). The resulting mixture was stirred at 100 ℃ under a nitrogen atmosphere for 16 h. When the reaction was complete, the solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with EtOAc in hexanes (gradient 0% to 50%) to give N-methyl-N- [2- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Ethyl radical]Tert-butyl carbamate (534mg, 54%). LCMS (M + H)⁺＝306.3。

And step 3: n- [2- (4- [ 5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl ] phenyl) ethyl ] -N-methylcarbamic acid tert-butyl ester

Prepared in a similar manner to that described in step 1, example 329 from N-methyl-N- [2- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Ethyl radical]Carbamic acid tert-butyl ester and 3-bromo-5-chloro-1H-pyrrolo [2,3-b ]]Pyridine the title compound was prepared. LCMS (M + H)⁺＝386.2。

And 4, step 4: N-methyl-N- [2- (4- [5- [4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] phenyl) ethyl ] carbamic acid tert-butyl ester

Prepared in a similar manner to that described in step 2 of example 329 from N-methyl-N- [2- (4- [5- [4- (4-methylpiperazin-1-yl) phenyl]-1H-pyrrolo [2,3-b]Pyridin-3-yl]Phenyl) ethyl]The title compound is prepared from tert-butyl carbamate and 1-methyl-4- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) piperazine. LCMS (M + H)⁺＝526.5。

And 5: n-methyl-2- (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) ethylamine

To N-methyl-N- [2- (4- [5- [4- (4-methylpiperazin-1-yl) phenyl) at room temperature]-1H-pyrrolo [2,3-b]Pyridin-3-yl]Phenyl) ethyl]To a solution of tert-butyl carbamate (134mg, 0.256mmol) in MeOH (20mL) was added HCl (0.2mL, 1.2mmol, 6M). The resulting mixture was stirred at room temperature for 16 h. When the reaction was complete, the mixture was concentrated. The residue was purified by preparative HPLC. Obtaining N-methyl-2- (4- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) phenyl) ethylamine (44mg, 38%).¹H NMR(400MHz,DMSO-d6)δ11.89(s,1H),8.51(s,1H),8.32(s,1H),7.83(s,1H),7.68(d,J＝7.8Hz,2H),7.61(d,J＝8.3Hz,2H),7.29(d,J＝7.7Hz,2H),7.05(d,J＝8.4Hz,2H),3.23-3.16(m,4H),2.76-2.71(m,4H),2.54-2.44(m,4H),2.32(s,3H),2.24(s,3H)。LC-MS(M+H)⁺＝426.3。

Example 335: 6- (5- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] pyridine-2-carbonyl) -2-oxa-6-azaspiro [3.3] heptane (compound 335)

Step 1: 6- (5-bromopyridine-2-carbonyl) -2-oxa-6-azaspiro [3.3] heptane

Prepared from 2-oxa-6-azaspiro [3.3] in a similar manner to that in step 2 of example 333]Heptane and 5-bromopyridine-2-carbonyl chloride. LCMS (M + H)⁺＝283.1。

Step 2: 6- [5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine-2-carbonyl ] -2-oxa-6-azaspiro [3.3] heptane

Prepared from 6- (5-bromopyridine-2-carbonyl) -2-oxa-6-azaspiro [3.3] in a similar manner to that in example 308, step 1]Heptane and BPD the title compound was prepared. LCMS (M + H)⁺＝331。

And step 3: 6- (5- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] pyridine-2-carbonyl) -2-oxa-6-azaspiro [3.3] heptane

From 6- [5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine-2-carbonyl in a similar manner to that in step 8 of example B03]-2-oxa-6-azaspiro [3.3]Heptane and 1- (4- [ 3-iodo-1H-pyrrolo [2,3-b ]]Pyridin-5-yl]-2-methylphenyl) -4-methylpiperazine preparation example 335.¹H NMR(400MHz,DMSO-d6)δ12.28(s,1H),9.09(s,1H),8.57(s,1H),8.46(s,1H),8.39(d,J＝8.3Hz,1H),8.22(s,1H),8.01(d,J＝8.2Hz,1H),7.63-7.53(m,2H),7.13(d,J＝8.2Hz,1H),4.83(s,2H),4.75-4.70(m,4H),4.27(s,2H),2.93-2.86(m,4H),2.59-2.46(m,4H),2.35(s,3H),2.26(s,3H)。LC-MS(M+H)⁺＝509.3。

Example 336: n, N-dimethyl-4- [5- [4- (4-methylpiperazin-1-yl) -3- [2- (morpholin-4-yl) ethoxy ] phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide (compound 336)

Step 1: 4- [2- (5-bromo-2-nitrophenoxy) ethyl ] morpholine

To a solution of 2- (morpholin-4-yl) ethan-1-ol (1.14g, 8.691mmol) in THF (200mL) at room temperature under a nitrogen atmosphere was added DEAD (1.90g), PPh₃(3.43g, 13.073mmol) and 5-bromo-2-nitrophenol (1.90g, 8.715 mmol). The resulting mixture was stirred at room temperature for 3 h. When the reaction was complete, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography, eluting with EtOAc in hexanes (gradient 0% to 14%) to give 4- [2- (5-bromo-2-nitrophenoxy) ethyl]Morpholine (1.43g, 50%). LCMS (M + H)⁺＝332.9。

Step 2: 4-bromo-2- [2- (morpholin-4-yl) ethoxy ] aniline

Prepared from Fe powder and 4- [2- (5-bromo-2-nitrophenoxy) ethyl group in a similar manner to that in step 3 of example 320]Morpholine the title compound was prepared. LCMS (M + H)⁺＝301.0。

And step 3: 4- [2- [ 5-bromo-2- (4-methylpiperazin-1-yl) phenoxy ] ethyl ] morpholine

Prepared in a similar manner to that described in step 1 of example 141 from bis (2-chloroethyl) (methyl) amine hydrochloride and 4-bromo-2- [2- (morpholin-4-yl) ethoxy]Aniline the title compound was prepared. LCMS (M + H)⁺＝384.1。

And 4, step 4: 4- [2- [2- (4-methylpiperazin-1-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy ] ethyl ] morpholine

Prepared from 4- [2- [ 5-bromo-2- (4-methylpiperazin-1-yl) phenoxy ] in a similar manner to that in step 1 of example 308]Ethyl radical]Morpholine and BPD the title compound was prepared. LCMS (M + H)⁺＝432.3。

And 5: n, N-dimethyl-4- [5- [4- (4-methylpiperazin-1-yl) -3- [2- (morpholin-4-yl) ethoxy ] phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

4- [2- [2- (4-methylpiperazin-1-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy group at room temperature under a nitrogen atmosphere]Ethyl radical]To a solution of morpholine (29mg, 0.068mmol) in dioxane (6mL) was added 4- [ 5-chloro-1H-pyrrolo [2,3-b ]]Pyridin-3-yl]-N, N-Dimethylbenzamide (19mg, 0.068mmol), K₃PO₄(38mg，0.191mmol)、Pd(PCy₃)₂Cl₂(4mg，0.006mmol)、H₂O (1.5 mL). The resulting mixture was stirred at 140 ℃ under a nitrogen atmosphere for 1 h. When the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC. Obtaining N, N-dimethyl-4- [5- [4- (4-methylpiperazin-1-yl) -3- [2- (morpholin-4-yl) ethoxy]Phenyl radical]-1H-pyrrolo [2,3-b]Pyridin-3-yl]Benzamide (10mg, 27%).¹H NMR(400MHz,DMSO-d₆)δ12.13-12.03(m,1H),8.56(s,1H),8.43(s,1H),8.00(d,J＝2.7Hz,1H),7.86(d,J＝8.0Hz,2H),7.49(d,J＝8.0Hz,2H),7.31-7.22(m,2H),7.03-6.93(m,1H),4.27-4.17(m,2H),3.63-3.53(m,4H),3.50-3.35(m,4H),3.15-2.95(m,10H),2.78-2.70(m,2H),2.60-2.50(m,4H),2.25(s,3H)。LC-MS(M+H)⁺＝569.3。

Example 337: 4- [5- [ 3-hydroxy-5-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N, N-dimethylbenzamide (compound 337)

To 4- [5- [3- (benzyloxy) -5-methyl-4- (4-methylpiperazin-1-yl) phenyl under a nitrogen atmosphere]-1H-pyrrolo [2,3-b]Pyridin-3-yl]To a solution of-N, N-dimethylbenzamide (98mg, 0.175mmol) in MeOH (5mL) was added Pd/C (5mg, 10%). The reaction flask was evacuated and flushed with hydrogen. The reaction mixture was then hydrogenated with a hydrogen balloon at 60 ℃ under a hydrogen atmosphere for 1 h. When the reaction was complete, the reaction mixture was concentrated under reduced pressure andthe residue was purified by preparative HPLC. 4- [5- [ 3-hydroxy-5-methyl-4- (4-methylpiperazin-1-yl) phenyl]-1H-pyrrolo [2,3-b]Pyridin-3-yl]-N, N-dimethylbenzamide (10mg, 11.98%) d.¹H NMR(400MHz,DMSO-d6)δ12.06(s,1H),9.16(s,1H),8.46(s,1H),8.35(s,1H),7.99(s,1H),7.86-7.80(m,2H),7.52-7.46(m,2H),7.03-6.93(m,2H),3.51-3.33(m,4H),3.03-2.98(m,7H),2.50-2.10(m,9H)。LC-MS(M+H)⁺＝470.4。

Example 338: 4- [5- [3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N- [ (4-methoxyphenyl) methyl ] -N-methylbenzamide (Compound 338)

Step 1: (4- [ [ (4-methoxyphenyl) methyl ] (methyl) carbamoyl ] phenyl) boronic acid

Prepared from 4- (dihydroxyboranyl) benzoic acid and [ (4-methoxyphenyl) methyl group in a similar manner as in step 1 of example 304](methyl) amine the title compound was prepared. LCMS (M + H)⁺＝300.2。

Step 2: 4- [5- [3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N- [ (4-methoxyphenyl) methyl ] -N-methylbenzamide

Prepared from (4- [ [ (4-methoxyphenyl) methyl) in a similar manner to that in step 5 of example 141](methyl) carbamoyl group]Phenyl) boronic acids and 1- (4- [ 3-iodo-1H-pyrrolo [2,3-b ]]Pyridin-5-yl]-2, 6-dimethylphenyl) -4-methylpiperazine preparation example 338.¹H NMR(400MHz,DMSO-d6)δ12.08(s,1H),8.52(s,1H),8.41(s,1H),8.00(s,1H),7.86(d,J＝7.9Hz,2H),7.53(d,J＝7.8Hz,2H),7.37(s,2H),7.30(s,1H),7.16(s,1H),6.95(d,J＝8.1Hz,2H),4.68-4.45(m,2H),3.76(s,3H),3.09-3.02(m,4H),2.89(s,3H),2.47-2.40(m,4H),2.39-2.34(m,6H),2.25(s,3H)。LC-MS(M+H)⁺＝574.4。

Example 339: n, N-dimethyl-4- [5- [5- (4-methylpiperazin-1-yl) pyridin-2-yl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide (compound 339)

Step 1: 4- [ 5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N, N-dimethylbenzamide

Prepared in a similar manner to that in step 1 of example 311 from 3-bromo-5-chloro-1H-pyrrolo [2,3-b ]]Pyridine and [4- (dimethylcarbamoyl) phenyl]Boronic acid the title compound was prepared. LCMS (M + H)⁺＝300.2。

Step 2: 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

4- [ 5-chloro-1H-pyrrolo [2,3-b ] at room temperature under a nitrogen atmosphere]Pyridin-3-yl]BPD (2.55g, 10.042mmol), Pd and N-dimethylformamide (1.00g, 3.336mmol) in dioxane (18mL) were added₂(dba)₃.CHCl₃(345mg, 0.334mmol), SPhos (274mg, 0.667mmol), KOAc (980mg, 10.008 mmol). The final reaction mixture was irradiated with microwaves at 120 ℃ for 1.5h under a nitrogen atmosphere. When the reaction was complete, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography, eluting with MeOH in DCM (gradient 0% to 10%) to give N, N-dimethyl-4- [5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ] -c ]Pyridin-3-yl]Benzamide (274mg, 21%). LCMS (M + H)⁺＝392.2。

And step 3: 1- (6-chloropyridin-3-yl) -4-methylpiperazine

To a solution of 1-methylpiperazine (1.00g, 9.984mmol) in isopropanol (100mL) at room temperature under a nitrogen atmosphere was added 2-chloro-5-iodopyridine (2.39g, 9.982mmol), CuI (2.86g, 15.017mmol), K₃PO₄(6.40g, 30.151mmol), ethylene glycol (20 mL). The resulting mixture was stirred at 110 ℃ under a nitrogen atmosphere for 16 h. When the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with MeOH in DCM (gradient 0% to 10%) to give 1- (6-chloropyridin-3-yl) -4-methylPiperazine (294mg, 14%). LCMS (M + H)⁺＝212.0。

And 4, step 4: n, N-dimethyl-4- [5- [5- (4-methylpiperazin-1-yl) pyridin-2-yl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

Prepared in a similar manner to that in step 2 of example 311 from 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 and 1- (6-chloropyridin-3-yl) -4-methylpiperazine preparation example 339.¹H NMR(400MHz,DMSO-d6)δ12.08(s,1H),8.94(s,1H),8.82(s,1H),8.43(s,1H),8.00(s,1H),7.95(d,J＝8.8Hz,1H),7.84(d,J＝7.9Hz,2H),7.52(d,J＝7.9Hz,2H),7.47-7.40(m,1H),3.30-3.23(m,4H),3.01(s,6H),2.51-2.45(m,4H),2.24(s,3H)。LC-MS(M+H)⁺＝441.5。

Example 340: n- ((S) -2-hydroxypropyl) -N-methyl-4- (5- (3-methyl-4- ((S) -3- (methylamino) pyrrolidin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 340)

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

To a solution of 4-bromobenzoic acid (11.80g, 55.766mmol, 1.10 equiv., 95%) in DMF (120mL) were added DIEA (10.50g), HATU (22.40g) and (2S) -1-aminopropan-2-ol (4.00 g). The resulting mixture was stirred at room temperature for 6 h. The reaction was quenched by the addition of water. The resulting mixture was extracted with EtOAc (3 × 600 mL). The combined organic layers were washed with brine (1 × 100mL) and dried over anhydrous Na2SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with PE/EtOAc (30:70) to give 4-bromo-N- [ (2S) -2-hydroxypropyl ] benzamide (12g, 91.16%). LS-MS (M + H)258.1

Step 2: 4-bromo-N- [ (2S) -2- [ (tert-butyldimethylsilyl) oxy ] propyl ] benzamide

To 4-bromo-N- [ (2S) -2-hydroxypropyl ] at 0 deg.C]Benzamide (12g) and TBDMS-Cl (15.00g) were mixed with stirring in DCMEt was added dropwise to the mass₃N (15.00 g). The resulting mixture was stirred at room temperature for 15 h. The reaction was quenched by the addition of water. Subjecting the obtained mixture to CH₂Cl₂(3 × 500 mL). The combined organic layers were washed with brine (1 × 100mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. This gives 4-bromo-N- [ (2S) -2- [ (tert-butyldimethylsilyl) oxy ]Propyl radical]Benzamide (19g, 91.83%). The crude product was used directly in the next step without further purification. LS-MS (M + H)372.2

And step 3: 4-bromo-N- [ (2S) -2- [ (tert-butyldimethylsilyl) oxy ] propyl ] -N-methylbenzamide

4-bromo-N- [ (2S) -2- [ (tert-butyldimethylsilyl) oxy) was added under a nitrogen atmosphere at 0 deg.C]Propyl radical]A stirred solution of benzamide (19g) in DMF was added NaH (5.10g, 60%) in portions. The resulting mixture was stirred at 0 ℃ under a nitrogen atmosphere for 30 min. CH was added dropwise at 0 ℃ under a nitrogen atmosphere₃I (9.50g, 63.584mmol, 1.50 eq, 95%). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 h. The reaction was quenched with water/ice at 0 ℃. The resulting mixture was extracted with EtOAc (3 × 700 mL). The combined organic layers were washed with brine (1 × 150mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. This gives 4-bromo-N- [ (2S) -2- [ (tert-butyldimethylsilyl) oxy]Propyl radical]-N-methylbenzamide (18g, 87.34%). The crude product was used directly in the next step without further purification. LS-MS (M + H) ═ 386.3

And 4, step 4: 4-bromo-N- [ (2S) -2-hydroxypropyl ] -N-methylbenzamide

To the flask was added 4-bromo-N- [ (2S) -2- [ (tert-butyldimethylsilyl) oxy ] propyl ] -N-methylbenzamide (18g), THF (200mL), and TBAF (1M/L, 2.00 equiv., 70 mL). The resulting mixture was stirred at room temperature for 15 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with EtOAc (100%) to give 4-bromo-N- [ (2S) -2-hydroxypropyl ] -N-methylbenzamide (8.3g, 81.30%). LS-MS (M + H) ═ 272.0.

And 5: n- [ (2S) -2-hydroxypropyl ] -N-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide

To a solution of 4-bromo-N- [ (2S) -2-hydroxypropyl ] -N-methylbenzamide (8.30g) and BPD (12.00g, 44.893mmol) in dioxane was added Pd (dppf) Cl2.CH2Cl2(2.60g, 3.025mmol) and KOAc (9.30g, 90.022 mmol). The resulting mixture was stirred at 100 ℃ under a nitrogen atmosphere for 3 h. The mixture was allowed to cool to room temperature. The resulting mixture was filtered and the filter cake was washed with dioxane (3x10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc (100%) to give N- [ (2S) -2-hydroxypropyl ] -N-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide (7.8g, 80.44%). LS-MS (M + H) ═ 320.2

Step 6: 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -N- [ (2S) -2-hydroxypropyl ] -N-methylbenzamide

To N- [ (2S) -2-hydroxypropyl group]-N-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide (4.90g, 14.8mmol) and 5-bromo-3-iodo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyrrole]Pyridine (8.33g, 14.8mmol) in dioxane and water was added K₂CO₃(4.30g, 29.5mmol) and Pd (dppf) Cl₂.CH₂Cl₂(1.28g, 1.48 mmol). The resulting mixture was stirred at 70 ℃ under a nitrogen atmosphere for 3 h. The mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was dissolved in DCM (150 mL). The resulting mixture was filtered and the filter cake was washed with DCM (3 × 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (10:90) to give 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] as a pale yellow solid]Pyridin-3-yl]-N- [ (2S) -2-hydroxypropyl]-N-methylbenzamide (4.8g, 55%). LC-MS (M + H) + 544.1.

And 7: n- [ (2S) -2-hydroxypropyl ] -N-methyl-4- [1- (4-methylbenzenesulfonyl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

To 4- [ 5-bromo-1- (4-methyl)Phenylsulfonyl) pyrrolo [2,3-b]Pyridin-3-yl]-N- [ (2S) -2-hydroxypropyl]To a solution of (E) -N-methylbenzamide (4.70g, 8.0mmol) and BPD (3.21g, 12mmol) in dioxane were added KOAc (2.44g, 23.6mmol) and Pd (dppf) Cl₂.CH₂Cl₂(689mg, 0.801 mmol). The resulting mixture was stirred at 100 ℃ under a nitrogen atmosphere for 3 h. The mixture was cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with dioxane (3x8 mL). The filtrate was concentrated under reduced pressure. This gave N- [ (2S) -2-hydroxypropyl as a brown oil]-N-methyl-4- [1- (4-methylbenzenesulfonyl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b]Pyridin-3-yl]Benzamide (5.8g, 97%). LC-MS (M + H) + 590.2.

And 8: n- ((S) -2-hydroxypropyl) -N-methyl-4- (5- (3-methyl-4- ((S) -3- (methylamino) pyrrolidin-1-yl) phenyl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Prepared in a similar manner to that in example 311, step 2 from (S) -N- (2-hydroxypropyl) -N-methyl-4- (5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-toluenesulfonyl-1H-pyrrolo [2,3-b ]]Pyridin-3-yl) benzamide and (S) -1- (4-chloro-2-methylphenyl) -N-methylpyrrolidin-3-amine the title compound was prepared (43mg, 30%). LC-MS (M + H) ⁺＝652.5。

And step 9: n- ((S) -2-hydroxypropyl) -N-methyl-4- (5- (3-methyl-4- ((S) -3- (methylamino) pyrrolidin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Prepared from N- ((S) -2-hydroxypropyl) -N-methyl-4- (5- (3-methyl-4- ((S) -3- (methylamino) pyrrolidin-1-yl) phenyl) -1-toluenesulfonyl-1H-pyrrolo [2,3-b ] in a similar manner to that in example 369 step 6]Pyridin-3-yl) benzamide preparation example 340(11mg, 30%).¹H NMR(400MHz,DMSO-d6)δ12.01(s,1H),8.52(s,1H),8.39(s,1H),7.98(s,1H),7.87-7.81(m,2H),7.53-7.46(m,4H),6.93(d,J＝8.3Hz,1H),4.89-4.80(m,1H),4.05-3.85(m,1H),3.54-3.43(m,1H),3.40-3.18(m,6H),3.09-2.96(m,4H),2.38-2.30(m,6H),2.15-2.02(m,1H),1.78-1.66(m,1H),1.18-0.89(m,3H)。LC-MS(M+H)⁺＝498.3。

Example 341: n, N-dimethyl-4- [5- [4- (4-methylpiperazin-1-yl) -3- (propan-2-yloxy) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide (compound 341)

Step 1: 1- (4-bromo-2-isopropoxyphenyl) -4-methylpiperazine

The title compound was prepared from 5-bromo-2- (4-methylpiperazin-1-yl) phenol and propan-2-ol in a similar manner to that in example 336, step 1. LCMS (M + H)⁺＝313.2。

Step 2: n, N-dimethyl-4- [5- [4- (4-methylpiperazin-1-yl) -3- (propan-2-yloxy) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

Prepared in a similar manner to that in step 2 of example 311 from 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 and 1- (4-bromo-2-isopropoxyphenyl) -4-methylpiperazine preparation example 341. ¹H NMR(400MHz,DMSO-d6,ppm)δ8.48(s,1H),8.43(s,1H),7.87-7.81(m,2H),7.79(s,1H),7.58-7.52(m,2H),7.28-7.20(m,2H),7.08(d,J＝7.9Hz,1H),4.85-4.75(m,1H),3.36-3.03(m,10H),2.68(br s,4H),2.39(s,3H),1.42-1.35(m,6H)。LC-MS(M+H)⁺＝498.4。

Example 342: 2- (4- [5- [3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] phenoxy) -N, N-dimethylacetamide (compound 342)

Step 1: 2- (4- [5- [3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] phenoxy) acetic acid

Placing K into a vial₂CO₃(84.30mg，0.579mmol)、Pd(PCy₃)₂Cl₂(28.52mg, 0.035mmol), dioxane (4mL,47mmol)、H₂o (1mL), 2- (4- [ 5-chloro-1H-pyrrolo [2,3-b ]]Pyridin-3-yl]Phenoxy) acetic acid (100mg, 0.290mmol), 1- [2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-4-methylpiperazine (236mg, 0.579 mmol). The final reaction mixture was irradiated with microwave radiation at 120 ℃ for 1 h. The solid was filtered and the filtrate was concentrated. The residue was applied to a silica gel column with chloroform/methanol (10/90). The crude product was purified by preparative HPLC. This gives 2- (4- [5- [3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl)]-1H-pyrrolo [2,3-b]Pyridin-3-yl]Phenoxy) acetic acid (13mg, 8%). LS-MS (M + H)⁺＝471.2

Step 2: 2- (4- [5- [3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] phenoxy) -N, N-dimethylacetamide

Prepared in a similar manner to that described in step 1 of example 141 from 2- (4- [5- [3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) ]-1H-pyrrolo [2,3-b]Pyridin-3-yl]Phenoxy) acetic acid and dimethylamine example 342 was prepared.¹H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.49(s,1H),8.30(s,1H),7.78(s,1H),7.67(d,J＝8.2Hz,2H),7.36(s,2H),7.01(d,J＝8.2Hz,2H),4.85(s,2H),3.10-3.01(m,7H),2.87(s,3H),2.48-2.40(m,4H),2.36(s,6H),2.25(s,3H)。LC-MS(M+H)⁺＝498.4。

Example 343: 4- [5- [ 3-ethoxy-5-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N, N-dimethylbenzamide (compound 343)

Step 1: 5-bromo-3-methyl-2- (4-methylpiperazin-1-yl) phenol

To a solution of 1- (4-bromo-2-methoxy-6-methylphenyl) -4-methylpiperazine (662mg, 2.213mmol) in DCM (50mL) at-30 ℃ under a nitrogen atmosphere was added BBr dropwise₃(5545mg, 22.134 mmol). The resulting mixture was stirred at room temperature for 16 h. When the reaction was complete, the reaction mixture was cooled to 0 ℃ and quenched by ice water (60 mL). Subjecting the obtained product toThe mixture was extracted with DCM (50mLx 3). The organic phases were combined, washed with brine and over Na₂SO₄And (5) drying. The solvent was removed under reduced pressure and the residue was purified by flash chromatography, eluting with MeOH in DCM (gradient 0% to 15%) to give 5-bromo-3-methyl-2- (4-methylpiperazin-1-yl) phenol (495mg, 78%). LCMS (M + H)⁺＝285.0。

Step 2: 1- (4-bromo-2-ethoxy-6-methylphenyl) -4-methylpiperazine

The title compound was prepared from 5-bromo-3-methyl-2- (4-methylpiperazin-1-yl) phenol and EtOH in a similar manner to that in example 336, step 1. LCMS (M + H) ⁺＝315.0。

And step 3: 4- [5- [ 3-ethoxy-5-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N, N-dimethylbenzamide

Prepared in a similar manner to that in step 2 of example 311 from 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 and 1- (4-bromo-2-ethoxy-6-methylphenyl) -4-methylpiperazine preparation example 343.¹H NMR(400MHz,DMSO-d6)δ12.08(s,1H),8.54(s,1H),8.42(s,1H),8.00(s,1H),7.85(d,J＝8.2Hz,2H),7.49(d,J＝8.2Hz,2H),7.17-7.09(m,2H),4.12(t,J＝6.8Hz,2H),3.39-3.31(m,4H),3.01(s,6H),2.71-2.67(m,4H),2.33(s,3H),2.24(s,3H),1.40(t,J＝6.9Hz,4H)。LC-MS(M+H)⁺＝498.3。

Example 344: 3- (4- [5- [3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] phenoxy) -N, N-dimethylpropionamide (Compound 344)

Step 1: 3- (4- [ 5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl ] phenoxy) -N, N-dimethylpropionamide

Prepared from 3-bromo-5-chloro-1H-pyrrolo [2,3-b ] in a similar manner to that in step 2 of example 330]Pyridine and N, N-dimethyl-3- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxa)Cyclopentaborane-2-yl) phenoxy]Propionamide the title compound is prepared. LCMS (M + H)⁺＝344.1。

Step 2: 3- (4- [5- [3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] phenoxy) -N, N-dimethylpropionamide

Prepared from 3- (4- [ 5-chloro-1H-pyrrolo [2,3-b ] in a similar manner to that in step 2 of example 311 ]Pyridin-3-yl]Phenoxy) -N, N-dimethylpropionamide and 1- [2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-4-methylpiperazine preparation example 344.¹H NMR(400MHz,DMSO-d6,ppm)δ11.86(s,1H),8.49(s,1H),8.30(s,1H),7.78(s,1H),7.68(d,J＝8.1Hz,2H),7.35(s,2H),7.08-6.99(d,J＝8.1Hz,2H),4.29-4.19(m,2H),3.11-2.98(m,7H),2.90-2.75(m,5H),2.50-2.31(m,10H),2.25(s,3H)。LC-MS(M+H)⁺＝512.3。

Example 345: 1- (4- [5- [ 3-methoxy-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) -N, N-dimethylazetidin-3-amine (compound 345)

Step 1: [4- [3- (dimethylamino) azetidine-1-carbonyl ] phenyl ] boronic acid

The title compound was prepared from 4- (dihydroxyboranyl) benzoic acid and N, N-dimethylazetidin-3-amine in a similar manner as in example 304, step 1. LCMS (M + H)⁺＝249.2.

Step 2: 1- (4- [ 5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) -N, N-dimethylazetidin-3-amine

Prepared from [4- [3- (dimethylamino) azetidine-1-carbonyl ] in a similar manner to that in example 330 step 2]Phenyl radical]Boronic acid and 3-bromo-5-chloro-1H-pyrrolo [2,3-b]Pyridine the title compound was prepared. LCMS (M + H)⁺＝355.1.

And step 3: 1- (4- [5- [ 3-methoxy-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) -N, N-dimethylazetidin-3-amine

Prepared from 1- (4- [ 5-chloro-1H-pyrrolo [2,3-b ] in a similar manner to that in step 2 of example 311 ]Pyridin-3-yl]Benzoyl) -N, N-dimethylazetidin-3-amine and 1- [ 2-methoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-4-methylpiperazine preparation example 345.¹H NMR(400MHz,DMSO-d₆)δ12.13(s,1H),8.58(s,1H),8.44(s,1H),8.05(s,1H),7.92-7.85(m,2H),7.76-7.69(m,2H),7.30-7.22(m,2H),6.99(d,J＝8.0Hz,1H),4.41-4.33(m,1H),4.20-4.02(m,2H),3.90(s,3H),3.88-3.80(m,1H),3.14-2.95(m,5H),2.50-240(m,4H),2.24(s,3H),2.10(s,6H)。LC-MS(M+H)⁺＝525.4。

Example 346: 5- (3- [4- [3- (dimethylamino) azetidine-1-carbonyl ] phenyl ] -1H-pyrrolo [2,3-b ] pyridin-5-yl) -2- (4-methylpiperazin-1-yl) benzonitrile (compound 346)

In a similar manner to that in example 311, step 2, starting from 2- (4-methylpiperazin-1-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzonitrile and 1- (4- [ 5-chloro-1H-pyrrolo [2, 3-b)]Pyridin-3-yl]Benzoyl) -N, N-dimethylazetidin-3-amine preparation example 346.¹H NMR(400MHz,DMSO-d6)δ12.17(s,1H),8.60(s,1H),8.53(s,1H),8.20(s,1H),8.10-8.00(m,2H),7.95-7.90(m,2H),7.75-7.70(m,2H),7.28(d,J＝8.7Hz,1H),4.41-4.33(m,1H),4.20-4.02(m,2H),3.88-3.82(m,1H),3.26-3.18(m,4H),3.14-3.06(m,1H),2.60-2.50(m,4H),2.27(s,3H),2.10(s,6H)。LC-MS(M+H)⁺＝520.6。

Example 347: 4- [5- [3, 5-dimethoxy-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N- [2- (dimethylamino) ethyl ] -N-methylbenzamide (compound 347)

To and fromExample 311 in a similar manner to that described for step 2, starting from 1- [2, 6-dimethoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-4-methylpiperazine and 4- [ 5-chloro-1H-pyrrolo [2,3-b]Pyridin-3-yl]-N- [2- (dimethylamino) ethyl group]-N-methylbenzamide preparation example 347. ¹H NMR(400MHz,DMSO-d6)δ12.09(s,1H),8.58(s,1H),8.44(s,1H),8.01(s,1H),7.86(d,J＝7.9Hz,2H),7.46(d,J＝7.8Hz,2H),6.93(s,2H),3.86(s,6H),3.60-3.50(m,1H),3.40-3.30(m,1H),3.11-3.03(m,4H),2.99(s,3H),2.50-2.30(m,6H),2.22(s,6H),2.10-1.96(m,3H)。LC-MS(M+H)⁺＝557.4。

Example 348: 5- (7- [4- [3- (dimethylamino) azetidine-1-carbonyl ] phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-2-yl) -2- (4-methylpiperazin-1-yl) benzonitrile (compound 348)

Step 1: 2- (4-methylpiperazin-1-yl) -5- [ 5H-pyrrolo [2,3-b ] pyrazin-2-yl ] benzonitrile

Prepared from 2-bromo-5H-pyrrolo [2,3-b ] in a similar manner to that in step 4 of example 305]Pyrazine and 2- (4-methylpiperazin-1-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzonitrile the title compound is prepared. LCMS (M + H)⁺＝319.1.

Step 2: 5- [ 7-iodo-5H-pyrrolo [2,3-b ] pyrazin-2-yl ] -2- (4-methylpiperazin-1-yl) benzonitrile

Prepared in a similar manner to that described in step 4 of example 313 from 2- (4-methylpiperazin-1-yl) -5- [ 5H-pyrrolo [2,3-b]Pyrazin-2-yl radicals]Benzonitrile and NIS. LCMS (M + H)⁺＝445.0.

And step 3: 5- (7- [4- [3- (dimethylamino) azetidine-1-carbonyl ] phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-2-yl) -2- (4-methylpiperazin-1-yl) benzonitrile

Prepared from 5- [ 7-iodo-5H-pyrrolo [2,3-B ] in a similar manner to that in step 8 of example B03]Pyrazin-2-yl radicals]-2- (4-methylpiperazin-1-yl) benzonitrile and [4- [3- (dimethylamino) azetidine-1-carbonyl]Phenyl radical ]Preparation of boric acidExample 348 is prepared.¹H NMR(400MHz,DMSO-d6,ppm)δ12.56(s,1H),8.99(s,1H),8.63-8.57(m,1H),8.56-8.50(m,1H),8.52-8.44(m,1H),8.44-8.38(m,2H),7.77-7.71(m,2H),7.41-7.35(m,1H),4.46-4.38(m,1H),4.28-4.18(m,1H),4.16-4.10(m,1H),3.96-3.88(m,1H),3.50-3.29(m,5H),3.00-2.90(m,4H),2.56(s,3H),2.23(s,6H)。LC-MS(M+H)⁺＝521.5。

Example 349: 2- [ (5- [5- [3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] pyridin-2-yl) oxy ] -N, N-dimethylacetamide (compound 349)

Step 1: 2- [ (5- [ 5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl ] pyridin-2-yl) oxy ] -N, N-dimethylacetamide

Prepared in a similar manner to that in example 330, step 2, from N, N-dimethyl-2- [ [5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl]Oxy radical]Acetamide and 3-bromo-5-chloro-1H-pyrrolo [2,3-b ]]Pyridine the title compound was prepared. LCMS (M + H)⁺＝331.0.

Step 2: 2- [ (5- [5- [3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] pyridin-2-yl) oxy ] -N, N-dimethylacetamide

Prepared from 2- [ (5- [ 5-chloro-1H-pyrrolo [2,3-b ] in a similar manner to that in step 2 of example 311]Pyridin-3-yl]Pyridin-2-yl) oxy]-N, N-dimethylacetamide and 1- [2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-4-methylpiperazine preparation example 349.¹H NMR(400MHz,DMSO-d6)δ12.02-12.96(m,1H),8.56-8.48(m,2H),8.31(s,1H),8.15-8.09(m,1H),7.89(s,1H),7.39(s,2H),6.98(d,J＝8.5Hz,1H),5.09(s,2H),3.09-2.99(m,7H),2.85(s,3H),2.50-2.30(m,10H),2.25(s,3H)。LC-MS(M+H)⁺＝499.3。

Example 350: 3- (4- [5- [3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] phenoxy) propan-1-amine (Compound 350)

Step 1: 2- [3- (4- [ 5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl ] phenoxy) propyl ] -2, 3-dihydro-1H-isoindole-1, 3-dione

Prepared from 2- [3- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy ] in a similar manner to that in step 2 of example 330]Propyl radical]-2, 3-dihydro-1H-isoindole-1, 3-dione and 3-bromo-5-chloro-1H-pyrrolo [2,3-b]Pyridine the title compound was prepared. LCMS (M + H)⁺＝432.2。

Step 2: 2- [3- (4- [5- [3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] phenoxy) propyl ] -2, 3-dihydro-1H-isoindole-1, 3-dione

Prepared in a similar manner to that described in step 2 of example 311 from 1- [2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-4-methylpiperazine and 2- [3- (4- [ 5-chloro-1H-pyrrolo [2, 3-b)]Pyridin-3-yl]Phenoxy) propyl group]-2, 3-dihydro-1H-isoindole-1, 3-dione. LCMS (M + H)⁺＝600.4。

And step 3: 3- (4- [5- [3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] phenoxy) propan-1-amine

To 2- [3- (4- [5- [3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl group at room temperature]-1H-pyrrolo [2,3-b]Pyridin-3-yl]Phenoxy) propyl group ]To a solution of (E) -2, 3-dihydro-1H-isoindole-1, 3-dione (80mg, 0.133mmol) in EtOH (30mL) was added hydrazine hydrate (140mg, 2.797 mmol). The resulting mixture was stirred at 90 ℃ for 24 h. When the reaction was complete, the reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC. Obtaining 3- (4- [5- [3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl)]-1H-pyrrolo [2,3-b]Pyridin-3-yl]Phenoxy) propan-1-amine (15mg, 24%).¹H NMR(400MHz,DMSO-d6)δ11.90-11.78(m,1H),8.49(s,1H),8.29(s,1H),7.77(s,1H),7.67(d,J＝8.4Hz,2H),7.35(s,2H),7.03(d,J＝8.4Hz,2H),4.11-4.00(m,2H),3.10-3.02(m,4H),2.76-2.70(m,2H),2.50-2.41(m,4H),2.36(s,6H),2.25(s,3H),1.90-1.80(m,2H)。LC-MS(M+H)⁺＝470.3。

Example 351: 4- (5- [3, 5-dimethyl-4- [4- (1-methylpiperidin-4-yl) piperazin-1-yl ] phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl) -3-fluoro-N, N-dimethylbenzamide (compound 351)

Step 1: 4- [ 5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl ] -3-fluorobenzoic acid methyl ester

Prepared from [ 2-fluoro-4- (methoxycarbonyl) phenyl ] in a similar manner to that in example 330 step 2]Boronic acid and 3-bromo-5-chloro-1H-pyrrolo [2,3-b]Pyridine the title compound was prepared. LCMS (M + H)⁺＝305.1。

Step 2: 4- [ 5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl ] -3-fluoro-N, N-dimethylbenzamide

Prepared from 4- [ 5-chloro-1H-pyrrolo [2,3-B ] in a similar manner to that in step 9 of example B03]Pyridin-3-yl]Methyl-3-fluorobenzoate and dimethylamine the title compound was prepared. LCMS (M + H) ⁺＝318.1。

And step 3: 4- (5- [3, 5-dimethyl-4- [4- (1-methylpiperidin-4-yl) piperazin-1-yl ] phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl) -3-fluoro-N, N-dimethylbenzamide

Prepared in a similar manner to that described in step 2 of example 311 from 1- [2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-4- (1-methylpiperidin-4-yl) piperazine and 4- [ 5-chloro-1H-pyrrolo [2,3-b ]]Pyridin-3-yl]Preparation example 351 of (3-fluoro-N, N-dimethylbenzamide).¹H NMR(400MHz,DMSO-d6)δ12.19(s,1H),8.54(s,1H),8.23(s,1H),7.92-7.82(m,2H),7.45-7.30(m,4H),3.08-2.99(m,10H),2.85-2.79(m,2H),2.64-2.58(m,4H),2.36(s,6H),2.32-2.18(m,1H),2.15(s,3H),1.90-1.82(m,2H),1.79-1.71(m,2H),1.50-1.42(m,2H)。LC-MS(M+H)⁺＝569.4。

Example 352: 3- (4- [5- [ 3-cyano-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] phenoxy) -N, N-dimethylpropionamide (Compound 352)

In a similar manner to that in example 311, step 2, starting from 2- (4-methylpiperazin-1-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzonitrile and 3- (4- [ 5-chloro-1H-pyrrolo [2, 3-b)]Pyridin-3-yl]Phenoxy) -N, N-dimethylpropionamide preparation example 352.¹H NMR(400MHz,DMSO-d6)δ11.93(s,1H),8.56(s,1H),8.42(s,1H),8.18(s,1H),8.05-7.99(m,1H),7.82(s,1H),7.72(d,J＝8.2Hz,2H),7.28(d,J＝8.7Hz,1H),7.02(d,J＝8.2Hz,2H),4.27-4.21(m,2H),3.27-3.19(m,4H),3.02(s,3H),2.86(s,3H),2.85-2.79(m,2H),2.69-2.59(m,4H),2.34(s,3H)。LC-MS(M+H)⁺＝509.3。

Example 353: 6- [4- (2- [3, 5-dimethyl-4- [4- (1-methylpiperidin-4-yl) piperazin-1-yl ] phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl) benzoyl ] -2-oxa-6-azaspiro [3.3] heptane (compound 353)

Prepared in a similar manner to that described in step 8 of example B03 from 1- (4- [ 7-bromo-5H-pyrrolo [2,3-B ] ]Pyrazin-2-yl radicals]-2, 6-dimethylphenyl) -4- (1-methylpiperidin-4-yl) piperazine and (4- [ 2-oxa-6-azaspiro [ 3.3)]Heptane-6-carbonyl]Phenyl) boronic acid preparation example 353.¹H NMR(400MHz,DMSO-d6)δ12.47-12.41(m,1H),8.85(s,1H),8.55(s,1H),8.46-8.38(m,2H),7.80(s,2H),7.76-7.69(m,2H),4.71(s,4H),4.57(s,2H),4.24(s,2H),3.10-3.02(m,4H),2.86-2.76(m,2H),2.64-2.58(m,4H),2.40(s,6H),2.38-2.12(m,4H),1.92-1.82(m,2H),1.79-1.71(m,2H),1.52-1.39(m,2H)。LC-MS(M+H)⁺＝606.4。

Example 354: 2- (4-Methylpiperazin-1-yl) -5- [7- (4- [ 2-oxa-6-azaspiro [3.3] heptane-6-carbonyl ] phenyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl ] benzonitrile (Compound 354)

Prepared from 5- [ 7-iodo-5H-pyrrolo [2,3-B ] in a similar manner to that in step 8 of example B03]Pyrazin-2-yl radicals]-2- (4-methylpiperazin-1-yl) benzonitrile and (4- [ 2-oxa-6-azaspiro [ 3.3)]Heptane-6-carbonyl]Phenyl) boronic acid preparation example 354.¹H NMR(400MHz,DMSO-d6)δ12.56(s,1H),8.99(s,1H),8.60(s,1H),8.53(s,1H),8.51-8.45(m,1H),8.44-8.38(m,2H),7.77-7.71(m,2H),7.38(d,J＝8.8Hz,1H),4.46-4.38(m,1H),4.26-4.20(m,1H),4.16-4.08(m,1H),3.96-3.90(m,1H),3.50-3.29(m,5H),3.00-2.90(br s,4H),2.56(s,3H),2.23(s,6H)。LC-MS(M+H)⁺＝520.3。

Example 355: 3- (4- (1H-pyrazol-5-yl) phenyl) -5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine (compound 355)

Step 1: 5- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -1H-pyrazole-1-carboxylic acid tert-butyl ester

The title compound was prepared from tert-butyl 5- (4-bromophenyl) -1H-pyrazole-1-carboxylate and BPD in a similar manner to that in example 308, step 1. LCMS (M + H)⁺＝371.3。

Step 2: 3- (4- (1H-pyrazol-5-yl) phenyl) -5-chloro-1H-pyrrolo [2,3-b ] pyridine

Prepared in a similar manner to that in example 330, step 2 from tert-butyl 5- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -1H-pyrazole-1-carboxylate and 3-bromo-5-chloro-1H-pyrrolo [2,3-b ]Pyridine the title compound was prepared. LCMS (M + H)⁺＝295.1。

And step 3: 3- (4- (1H-pyrazol-5-yl) phenyl) -5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridine

Prepared in a similar manner to that in example 311, step 2 from 3- (4- (1H-pyrazol-5-yl) phenyl) -5-chloro-1H-pyrrolo [2,3-b ]]Pyridine and 1- (2, 6-dimethyl)Preparation of 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -4-methylpiperazine example 355.¹H NMR(400MHz,DMSO-d6)δ12.92-12.84(m,1H),12.04-11.94(m,1H),8.52(s,1H),8.41(s,1H),8.03-7.75(m,6H),7.39(s,2H),6.80-6.70(s,1H),3.10-3.02(m,4H),2.48-2.40(m,4H),2.37(s,6H),2.25(s,3H)。LC-MS(M+H)⁺＝463.3。

Example 356: (4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (3-methoxyazetidin-1-yl) methanone (Compound 356)

Step 1: 4- (3-Methoxyazetidine-1-carbonyl) phenylboronic acid

The title compound was prepared from 4-dihydroxybenzoic acid and 3-methoxyazetidine in a similar manner as in example 304, step 1. LCMS (M + H)⁺＝236.2。

Step 2: (4- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (3-methoxyazetidin-1-yl) methanone

Prepared from 4- (3-methoxyazetidine-1-carbonyl) phenylboronic acid and 3-bromo-5-chloro-1H-pyrrolo [2,3-b ] in a similar manner to that described in step 2, example 330]Pyridine the title compound was prepared. LCMS (M + H) ⁺＝342.1。

And step 3: (4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (3-methoxyazetidin-1-yl) methanone

Prepared from (4- (5-chloro-1H-pyrrolo [2, 3-b) in a similar manner to that in step 2 of example 311]Pyridin-3-yl) phenyl) (3-methoxyazetidin-1-yl) methanone and 1- (2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -4-methylpiperazine preparation example 356.¹H NMR(400MHz,DMSO-d6)δ12.12(s,1H),8.52(s,1H),8.41(s,1H),8.04(s,1H),7.88(d,J＝8.1Hz,2H),7.72(d,J＝8.1Hz,2H),7.37(s,2H),4.56-4.48(m,1H),4.30-4.18(m,3H),3.92-3.82(m,1H),3.24(s,3H),3.09-3.01(m,4H),2.47-2.41(m,4H),2.36(s,6H),2.25(s,3H)。LC-MS(M+H)⁺＝510.3。

Example 357: 3- (4- [5- [ 3-methoxy-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] phenoxy) -N, N-dimethylpropionamide (compound 357)

Prepared in a similar manner to that described in step 2 of example 311 from 1- [ 2-methoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-4-methylpiperazine and 3- (4- [ 5-chloro-1H-pyrrolo [2, 3-b)]Pyridin-3-yl]Phenoxy) -N, N-dimethylpropionamide preparation example 357.¹H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.54(s,1H),8.33(s,1H),7.78(s,1H),7.73-7.65(m,2H),7.27-7.20(m,2H),7.05-6.93(m,3H),4.27-4.19(m,2H),3.90(s,3H),3.07-2.97(m,7H),2.86(s,3H),2.85-2.79(m,2H),2.5(br s,4H),2.23(s,3H)。LC-MS(M+H)⁺＝514.4。

Example 358: 1- [4- (5- [3, 5-dimethyl-4- [4- (1-methylpiperidin-4-yl) piperazin-1-yl ] phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzoyl ] -N, N-dimethylazetidin-3-amine (compound 358)

Prepared in a similar manner to that described in step 2 of example 311 from 1- [2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ]-4- (1-methylpiperidin-4-yl) piperazine and 1- (4- [ 5-chloro-1H-pyrrolo [2, 3-b)]Pyridin-3-yl]Benzoyl) -N, N-dimethylazetidin-3-amine preparation example 358.¹H NMR(400MHz,DMSO-d6,ppm)δ12.18-12.10(m,1H),8.53(s,1H),8.41(s,1H),8.06(s,1H),7.93-7385(m,2H),7.76-7.69(m,2H),7.39(s,2H),4.50-3.80(m,5H),3.50-3.35(m,2H),3.25-3.00(m,5H),2.95-2.60(m,11H),2.38(s,6H),2.28-1.94(m,6H),1.87-1.64(m,2H)。LC-MS(M+H)⁺＝606.6。

Example 359: (4- (2- (3, 5-dimethyl-4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) (3-hydroxyazetidin-1-yl) methanone (Compound 359)

Step 1: (4- (3-hydroxyazetidine-1-carbonyl) phenyl) boronic acid

The title compound was prepared from 4-dihydroxybenzoic acid and azetidin-3-ol in a similar manner as in example 304, step 1. LCMS (M + H)⁺＝222.0。

Step 2: 2- (3, 5-dimethyl-4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) -7-iodo-5H-pyrrolo [2,3-b ] pyrazine

Prepared in a similar manner to that in example 305, step 4 from 2- (3, 5-dimethyl-4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b]Pyrazine and NIS. LCMS (M + H)⁺＝531.2。

And step 3: (4- (2- (3, 5-dimethyl-4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) (3-hydroxyazetidin-1-yl) methanone

Prepared in a similar manner to that in example B03 step 8 from 2- (3, 5-dimethyl-4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) -7-iodo-5H-pyrrolo [2,3-B ]Pyrazine and (4- (3-hydroxyazetidine-1-carbonyl) phenyl) boronic acid preparation example 359.¹H NMR(400MHz,DMSO-d₆)δ8.85(s,1H),8.54(s,1H),8.40(d,J＝8.2Hz,2H),7.80(s,2H),7.73(d,J＝8.2Hz,2H),6.82-5.63(m,2H),4.64-4.43(m,2H),4.35-4.22(m,1H),4.21-4.09(m,1H),3.89-3.75(m,1H),3.16-2.99(m,4H),2.87-2.74(m,2H),2.65-2.57(m,4H),2.41(s,6H),2.28-2.07(m,4H),1.94-1.68(m,4H),1.52-1.41(m,2H)。LC-MS(M+H)⁺＝580.4。

Example 360: (4- (2- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) (2-oxa-6-azaspiro [3.3] hept-6-yl) methanone (Compound 360)

Step 1: 2-bromo-7-iodo-5H-pyrrolo [2,3-b ] pyrazines

Prepared from 2-bromo-5H-pyrrolo [2,3-b ] in a similar manner to that in step 4 of example 141]Pyrazines and I₂The title compound was prepared. LCMS (M + H)⁺＝323.9。

Step 2: 2-bromo-7-iodo-5-tosyl-5H-pyrrolo [2,3-b ] pyrazine

To 2-bromo-7-iodo-5H-pyrrolo [2,3-b ] at 0 deg.C]To a solution of pyrazine (7.19g, 22.198mmol) in THF (100mL) was added sodium hydride (670mg, 28 mmol). The resulting mixture was stirred at 0 ℃ for 15min, and then TsCl (5.08g, 26.659mmol) was added and the mixture was allowed to reach room temperature and stirred for 3 h. When the reaction was complete, the reaction was then quenched by the addition of ice water (100 mL). The resulting solution was extracted with DCM (100mLx 3). The organic phases were combined, washed with brine and over Na₂SO₄And (5) drying. The solvent was concentrated under reduced pressure and the residue was purified by flash chromatography, eluting with EtOAc in hexanes (gradient 0% to 50%) to give 2-bromo-7-iodo-5-tosyl-5H-pyrrolo [2,3-b ] -c ]Pyrazine (7.0g, 67%). LCMS (M + H)⁺＝479.9。

And step 3: (4- (2-bromo-5-tosyl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) (2-oxa-6-azaspiro [3.3] hept-6-yl) methanone

Prepared in a similar manner to that described in step 2 of example 332 from 2-bromo-7-iodo-5-tosyl-5H-pyrrolo [2,3-b ]]Pyrazine and (4- (2-oxa-6-azaspiro [3.3]]Heptane-6-carbonyl) phenyl) boronic acid the title compound was prepared. LCMS (M + H)⁺＝553.1。

And 4, step 4: (4- (2- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -5-toluenesulfonyl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) (2-oxa-6-azaspiro [3.3] hept-6-yl) methanone

Prepared in a similar manner to that in step 2 of example 332 from (4- (2-bromo-5-tosyl-5H-pyrrolo [2, 3-b)]Pyrazin-7-yl) phenyl) (2-oxa-6-azaspiro [3.3]]Hept-6-yl) methanone and 1- (2-methoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -4-methylpiperazine the title compound was prepared. LCMS (M + H)⁺＝679.3.

And 5: (4- (2- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) (2-oxa-6-azaspiro [3.3] hept-6-yl) methanone

Prepared in a similar manner to that in example 369 step 6 from (4- (2- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -5-toluenesulfonyl-5H-pyrrolo [2, 3-b) ]Pyrazin-7-yl) phenyl) (2-oxa-6-azaspiro [3.3]Hept-6-yl) methanone preparation example 360.¹H NMR(400MHz,DMSO-d6)δ12.42(s,1H),8.92(s,1H),8.54(s,1H),8.43(d,J＝7.9Hz,2H),7.77-7.69(m,4H),7.03(d,J＝8.1Hz,1H),4.70(s,4H),4.56(s,2H),4.23(s,2H),3.95(s,3H),3.07(s,4H),2.52-2.48(m,4H),2.24(s,3H)。LC-MS(M+H)⁺＝525.3。

Example 361: 3- (4- (2- (3, 5-dimethyl-4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenoxy) -N, N-dimethylpropanamide (compound 361)

Prepared in a similar manner to that in example B03 step 8 from N, N-dimethyl-3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy) propanamide and 2- (3, 5-dimethyl-4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) -7-iodo-5H-pyrrolo [2,3-B]Pyrazine preparation example 361.¹H NMR(400MHz,DMSO-d₆)δ12.19(d,J＝2.9Hz,1H),8.80(s,1H),8.31(d,J＝2.8Hz,1H),8.25-8.19(m,2H),7.79(s,2H),7.07-6.99(m,2H),4.27-4.20(m,2H),3.16-3.05(m,7H),3.02(s,3H),2.86(s,3H),2.84-2.78(m,2H),2.70-2.59(m,4H),2.48-2.42(m,4H),2.40(s,6H),1.96-1.82(m,2H),1.74-1.54(m,2H)。LC-MS(M+H)⁺＝596.5。

Example 362: (3- (dimethylamino) azetidin-1-yl) (4- (2- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) methanone (Compound 362)

Step 1: (4- (2-bromo-5-tosyl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) (3- (dimethylamino) azetidin-1-yl) methanone

Prepared in a similar manner to that described in step 2 of example 332 from 2-bromo-7-iodo-5-tosyl-5H-pyrrolo [2,3-b ]]Pyrazine and (3- (dimethylamino) azetidin-1-yl) (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) methanone the title compound was prepared. LCMS (M + H) ⁺＝554.5。

Step 2: (3- (dimethylamino) azetidin-1-yl) (4- (2- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -5-tosyl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) methanone

Prepared in a similar manner to that in step 3 of example 332 from (4- (2-bromo-5-tosyl-5H-pyrrolo [2, 3-b)]Pyrazin-7-yl) phenyl) (3- (dimethylamino) azetidin-1-yl) methanone and 1- (2-methoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -4-methylpiperazine the title compound was prepared. LCMS (M + H)⁺＝680.6。

And step 3: (3- (dimethylamino) azetidin-1-yl) (4- (2- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) methanone

Prepared in a similar manner to that described in example 369, step 6 from (3- (dimethylamino) azetidin-1-yl) (4- (2- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -5-toluenesulfonyl-5H-pyrrolo [2,3-b ]]Pyrazin-7-yl) phenyl) methanone example 362 was prepared.¹H NMR(400MHz,DMSO-d6)δ12.43(brs,1H),8.93(s,1H),8.54(s,1H),8.43(d,J＝8.1Hz,2H),7.80-7.70(m,4H),7.04(d,J＝8.1Hz,1H),4.38-4.36(m,1H),4.17-4.07(m,2H),3.95(s,3H),3.86-3.85(m,1H),3.08-2.95(m,5H),2.55-2.43(m,4H),2.24(s,3H),2.10(s,6H)。LC-MS(M+H)⁺＝526.4。

Example 363: 3- (4- (2- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenoxy) -N, N-dimethylpropionamide (compound 363)

Prepared in a similar manner to that in step 2 of example 332 from N, N-dimethyl-3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy) propionamide and 2- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -7-iodo-5H-pyrrolo [2,3-b ] p ]Pyrazine preparation example 363.¹H NMR(400MHz,DMSO-d6)δ12.17(brs,1H),8.80(s,1H),8.30(d,J＝2.6Hz,1H),8.26-8.18(m,2H),7.79(s,2H),7.08-7.00(m,2H),4.26-4.23(m,2H),3.08(brs,4H),3.02(s,3H),2.86(s,3H),2.82-2.80(m,2H),2.49-2.42(m,4H),2.40(s,6H),2.26(s,3H)。LC-MS(M+H)⁺＝513.3。

Example 364: 3- (4- (2- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenoxy) -N, N-dimethylpropionamide (compound 364)

Step 1: 2- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazine

Prepared in a similar manner to that described in step 2 of example 332 from 1- [ 2-methoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-4-methylpiperazine and 2-bromo-5H-pyrrolo [2,3-b]Pyrazine the title compound was prepared. LCMS (M + H)⁺＝324.2。

Step 2: 7-iodo-2- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazine

Prepared from 2- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] in a similar manner to that in example 313 step 4]Pyrazine and NIS. LCMS (M + H)⁺＝450.1。

And step 3: 3- (4- (2- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenoxy) -N, N-dimethylpropionamide

Prepared in a similar manner to that in example B03 step 8 from N, N-dimethyl-3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy) propanamide and 3- (4- (2- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-B ] p ]Pyrazin-7-yl) phenoxy) -N, N-dimethylpropionamide preparation example 364.¹H NMR(400MHz,DMSO-d6)δ12.15(brs,1H),8.88(s,1H),8.30-8.24(m,4H),7.79-7.71(m,2H),7.04-7.02(m,3H),4.26-4.24(m,2H),3.95(s,3H),3.06-2.92(m,7H),2.86-2.80(m,5H),2.50-2.33(m,4H),2.24(s,3H)。LC-MS(M+H)⁺＝515.3。

Example 365: 2- (4- [2, 6-dimethyl-4- [7- (4- [ 2-oxa-6-azaspiro [3.3] heptane-6-carbonyl ] phenyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl ] phenyl ] piperazin-1-yl) ethan-1-ol (compound 365)

Step 1: 2- (4- (4-bromo-2, 6-dimethylphenyl) piperazin-1-yl) ethanol

To a solution of 1- (4-bromo-2, 6-dimethylphenyl) piperazine (600mg, 2.229mmol) in (60mL) at room temperature was added 2-bromoethan-1-ol (280mg, 2.241mmol), K₂CO₃(930mg, 6.729 mmol). The resulting mixture was stirred at 80 ℃ for 16 h. When the reaction was complete, the solvent was concentrated under reduced pressure and the residue was purified by flash chromatography, eluting with MeOH in DCM (gradient 0% to 10%) to give 2- [4- (4-bromo-2, 6-dimethylphenyl) piperazin-1-yl]Ethan-1-ol (225mg, 32%). LCMS (M + H)⁺＝315.2。

Step 2: 2- (4- (2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) piperazin-1-yl) ethanol

The title compound was prepared from 2- (4- (4-bromo-2, 6-dimethylphenyl) piperazin-1-yl) ethanol and BPD in a similar manner to that in example 308, step 1. LCMS (M + H)⁺＝361.2。

And step 3: 2- (4- [2, 6-dimethyl-4- [7- (4- [ 2-oxa-6-azaspiro [3.3] heptane-6-carbonyl ] phenyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl ] phenyl ] piperazin-1-yl) ethan-1-ol

In a similar manner to that in example 311, step 2, from 2- (4- (2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) piperazin-1-yl) ethanol and 6- [4- [ 2-bromo-5- (4-methylbenzenesulfonyl) -5H-pyrrolo [2,3-b ] ethanol]Pyrazin-7-yl]Benzoyl radical]-2-oxa-6-azaspiro [3.3]Heptane preparation example 365.¹H NMR(400MHz,DMSO-d6)δ12.44(brs,1H),8.84(s,1H),8.53(s,1H),8.40(d,J＝8.1Hz,2H),7.80(s,2H),7.72(d,J＝8.1Hz,2H),4.70(brs,4H),4.56-4.45(m,3H),4.23(brs,2H),3.56-3.55(m,2H),3.08-3.03(m,4H),2.57-2.50(m,4H),2.40(s,6H)。LC-MS(M+H)⁺＝553.4。

Example 366: 4- (2- (4- (4- (2-hydroxyethyl) piperazin-1-yl) -3, 5-dimethylphenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -N, N-dimethylbenzamide (compound 366)

Step 1: 2- (4- (2, 6-dimethyl-4- (5H-pyrrolo [2,3-b ] pyrazin-2-yl) phenyl) piperazin-1-yl) ethanol

From 2- (4- (2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) piperazin-1-yl) ethanol and 2-bromo-5H-pyrrolo [2,3-b ] in a similar manner to that in example 332, step 2]Pyrazine the title compound was prepared. LCMS (M + H)⁺＝352.2。

Step 2: 2- (4- (4- (7-iodo-5H-pyrrolo [2,3-b ] pyrazin-2-yl) -2, 6-dimethylphenyl) piperazin-1-yl) ethanol

Prepared from 2- (4- (2, 6-dimethyl-4- (5H-pyrrolo [2, 3-b) ] in a similar manner to that in step 4 of example 313]Pyrazin-2-yl) phenyl) piperazin-1-yl) ethanol and NIS. LCMS (M + H) ⁺＝478.1。

And step 3: 4- (2- (4- (4- (2-hydroxyethyl) piperazin-1-yl) -3, 5-dimethylphenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -N, N-dimethylbenzamide

Prepared from 2- (4- (4- (7-iodo-5H-pyrrolo [2, 3-B) in a similar manner to that in step 8 of example B03]Pyrazin-2-yl) -2, 6-dimethylphenyl) piperazin-1-yl) ethanol and 4- (dimethylcarbamoyl) phenylboronic acid preparation example 366.¹H NMR(400MHz,DMSO-d6)δ12.39(brs,1H),8.84(s,1H),8.51(s,1H),8.38(d,J＝7.8Hz,2H),7.80(s,2H),7.51(d,J＝7.9Hz,2H),4.45-4.42(m,1H),3.57-3.53(m,2H),3.11-3.04(m,4H),3.01(s,6H),2.57-2.53(m,4H),2.51-2.43(m,2H),2.40(s,6H)。LC-MS(M+H)⁺＝499.3。

Example 367: 4- [2- [3, 5-dimethoxy-4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -N- [2- (dimethylamino) ethyl ] -N-methylbenzamide (compound 367)

Step 1: 1- (2, 6-dimethoxy-4- [ 5H-pyrrolo [2,3-b ] pyrazin-2-yl ] phenyl) -4-methylpiperazine

Prepared in a similar manner to that described in step 2 of example 332 from 1- [2, 6-dimethoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-4-methylpiperazine and 2-bromo-5H-pyrrolo [2,3-b]Pyrazine the title compound was prepared. LCMS (M + H)⁺＝354.2。

Step 2: 1- (4- [ 7-iodo-5H-pyrrolo [2,3-b ] pyrazin-2-yl ] -2, 6-dimethoxyphenyl) -4-methylpiperazine

Prepared from 1- (2, 6-dimethoxy-4- [ 5H-pyrrolo [2,3-b ] in a similar manner to that described in step 4 of example 313]Pyrazin-2-yl radicals]Phenyl) -4-methylpiperazine and NIS the title compound was prepared. LCMS (M + H) ⁺＝480.1。

And step 3: 4- [2- [3, 5-dimethoxy-4- (4-methylpiperazin-1-yl) phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -N- [2- (dimethylamino) ethyl ] -N-methylbenzamide

Prepared in a similar manner to that described in step 8 of example B03 from 1- (4- [ 7-iodo-5H-pyrrolo [2,3-B ]]Pyrazin-2-yl radicals]-2, 6-dimethoxyphenyl) -4-methylpiperazine and (4- [ [2- (dimethylamino) amineYl) ethyl](methyl) carbamoyl group]Phenyl) boronic acid preparation example 367.¹H NMR(400MHz,DMSO-d6)δ12.42(brs,1H),8.98(s,1H),8.53(d,J＝2.8Hz,1H),8.45-8.39(m,2H),7.52-7.44(m,4H),3.91(s,6H),3.59-3.52(m,1H),3.35-3.32(m,1H),3.11-3.09(m,4H),2.99(s,3H),2.51-2.50(m,3H),2.50-2.42(m,5H),2.27-2.21(m,6H),2.02-1.95(m,2H)。LC-MS(M+H)⁺＝558.7。

Example 368: 4- (2- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -N- (2- (dimethylamino) ethyl) -N-methylbenzamide (compound 368)

Step 1: 4- ((2- (dimethylamino) ethyl) (methyl) carbamoyl) phenylboronic acid

The title compound was prepared from N1, N1, N2-trimethylethane-1, 2-diamine and 4-boronobenzoic acid in a similar manner to that in example 304, step 1. LCMS (M + H)⁺＝251.2。

Step 2: 4- (2- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -N- (2- (dimethylamino) ethyl) -N-methylbenzamide

Prepared in a similar manner to that in example B03 step 8 from 4- ((2- (dimethylamino) ethyl) (methyl) carbamoyl) phenylboronic acid and 2- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -7-iodo-5H-pyrrolo [2,3-B ]Pyrazine preparation example 368.¹H NMR(400MHz,DMSO-d6)δ12.37(s,1H),8.85(s,1H),8.50(s,1H),8.41-8.35(m,2H),7.83-7.79(m,2H),7.52-7.45(m,2H),3.62-3.30(m,4H),3.12-3.05(m,4H),3.00(s,3H),2.49-2.43(m,4H),2.41(s,6H),2.31-2.15(m,6H),2.06-2.01(m,3H)。LC-MS(M+H)⁺＝526.4。

Example 369: (4- (2- (3, 5-dimethoxy-4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) (3-hydroxyazetidin-1-yl) methanone (compound 369)

Step 1: (4- (2-bromo-5-tosyl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) (3-hydroxyazetidin-1-yl) methanone

Prepared in a similar manner to that described in example 332, step 2 from (3-hydroxyazetidin-1-yl) (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) methanone and 2-bromo-7-iodo-5-toluenesulfonyl-5H-pyrrolo [2,3-b ] -c]Pyrazine the title compound was prepared. LCMS (M + H)⁺＝527.2。

Step 2: 1- (4-bromo-2, 6-dimethoxyphenyl) piperazine

The title compound was prepared from 4-bromo-2, 6-dimethoxyaniline and bis (2-chloroethyl) amine in a similar manner to that in example 305, step 1. LCMS (M + H)⁺＝301.0。

And step 3: 1- (4-bromo-2, 6-dimethoxyphenyl) -4- (1-methylpiperidin-4-yl) piperazine

To a solution of 1- (4-bromo-2, 6-dimethoxyphenyl) piperazine (1.62g, 5.379mmol) in DCM (250mL) was added 1-methylpiperidin-4-one (0.92g, 8.143mmol), STAB (1.71g, 8.068mmol) portionwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 48 h. When the reaction was complete, the reaction was then quenched by the addition of water (150 mL). The resulting solution was extracted with DCM (200mLx 3). The organic phases were combined, washed with brine and over Na ₂SO₄And (5) drying. The solvent was concentrated under reduced pressure and the residue was purified by flash chromatography, eluting with MeOH in DCM (gradient 0% to 42%) to give 1- (4-bromo-2, 6-dimethoxyphenyl) -4- (1-methylpiperidin-4-yl) piperazine (0.90g, 42%). LCMS (M + H)⁺＝398.1。

And 4, step 4: 1- (2, 6-dimethoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -4- (1-methylpiperidin-4-yl) piperazine

The title compound was prepared from 1- (4-bromo-2, 6-dimethoxyphenyl) -4- (1-methylpiperidin-4-yl) piperazine and BPD in a similar manner to that in example 308, step 1. LCMS (M + H)⁺＝446.0。

And 5: (4- (2- (3, 5-dimethoxy-4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) -5-tosyl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) (3-hydroxyazetidin-1-yl) methanone

Prepared from (4- (2-bromo-5-toluenesulfonyl-5H-pyrrolo [2, 3-b) in a similar manner to that in example 330, step 3]Pyrazin-7-yl) phenyl) (3-hydroxyazetidin-1-yl) methanone and 1- (2, 6-dimethoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -4- (1-methylpiperidin-4-yl) piperazine the title compound is prepared. LCMS (M + H)⁺＝766.1。

Step 6: (4- (2- (3, 5-dimethoxy-4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) (3-hydroxyazetidin-1-yl) methanone

To 1- [4- (2- [3, 5-dimethoxy-4- [4- (1-methylpiperidin-4-yl) piperazin-1-yl group at room temperature]Phenyl radical]-5- (4-Methylbenzenesulfonyl) -5H-pyrrolo [2,3-b]Pyrazin-7-yl) benzoyl]To a solution of azetidin-3-ol (108mg, 0.141mmol) in MeOH (5mL) was added NaOH (0.3mL, 0.6mmol, 2M). The resulting mixture was stirred at 80 ℃ under nitrogen atmosphere for 2 h. When the reaction was complete, the solvent was concentrated under reduced pressure and the residue was purified by preparative HPLC. To obtain (4- (2- (3, 5-dimethoxy-4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) -5H-pyrrolo [2, 3-b)]Pyrazin-7-yl) phenyl) (3-hydroxyazetidin-1-yl) methanone (18mg, 21%).¹H NMR(400MHz,DMSO-d6)δ12.45(brs,1H),8.97(s,1H),8.55(s,1H),8.44(d,J＝8.2Hz,2H),7.72(d,J＝8.2Hz,2H),7.46(s,2H),5.78-5.75(m,1H),4.53-4.52(m,2H),4.27(brs,1H),4.11(brs,1H),3.91(s,6H),3.82(brs,1H),3.13-3.09(m,4H),2.84-2.82(m,2H),2.58-2.55(m,4H),2.18-2.16(m,4H),1.90-1.87(m,2H),1.79-1.71(m,2H),1.48-1.45(m,,2H)。LC-MS(M+H)⁺＝612.2。

Example 370: (4- (2- (3, 5-dimethoxy-4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) (3- (dimethylamino) azetidin-1-yl) methanone (compound 370)

Step 1: (4- (2- (3, 5-dimethoxy-4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) -5-tosyl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) (3- (dimethylamino) azetidin-1-yl) methanone

Prepared from (4- (2-bromo-5-toluenesulfonyl-5H-pyrrolo [2, 3-b) in a similar manner to that in example 330, step 3 ]Pyrazin-7-yl) phenyl) (3- (dimethylamino) azetidin-1-yl) methanone and 1- (2, 6-dimethoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -4- (1-methylpiperidin-4-yl) piperazine the title compound is prepared. LCMS (M + H)⁺＝793.5。

Step 2: (4- (2- (3, 5-dimethoxy-4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) (3- (dimethylamino) azetidin-1-yl) methanone

Prepared in a similar manner to that in example 369, step 6 from (4- (2- (3, 5-dimethoxy-4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) -5-toluenesulfonyl-5H-pyrrolo [2, 3-b)]Pyrazin-7-yl) phenyl) (3- (dimethylamino) azetidin-1-yl) methanone preparation example 370.¹H NMR(400MHz,DMSO-d6)δ12.46(brs,1H),8.97(s,1H),8.56(s,1H),8.47-.40(m,2H),7.77-7.70(m,2H),7.45(s,2H),4.38-4.36(m,1H),4.14-4.07(m,2H),3.91(s,6H),3.88-3.86(m,1H),3.13-3.03(m,5H),2.82-2.79(m,2H),2.58-2.55(m,4H),2.18-2.09(m,10H),1.89-1.86(m,2H),1.77-1.75(m,2H),1.46-1.43(m,2H)。LC-MS(M+H)⁺＝639.2。

Example 371: 4- (2- (3, 5-dimethyl-4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -N- (2- (dimethylamino) ethyl) -N, 2-dimethylbenzamide (compound 371)

Step 1: 4-bromo-N- (2- (dimethylamino) ethyl) -N, 2-dimethylbenzamide

The title compound was prepared from N1, N1, N2-trimethylethane-1, 2-diamine and 4-bromo-2-methylbenzoic acid in a similar manner to that in example 304, step 1. LCMS (M + H) ⁺＝299.1。

Step 2: n- (2- (dimethylamino) ethyl) -N, 2-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide

The title compound was prepared from 4-bromo-N- (2- (dimethylamino) ethyl) -N, 2-dimethylbenzamide and BPD in a similar manner to that in example 308, step 1. LCMS (M + H)⁺＝347.3。

And step 3: 4- (2- (3, 5-dimethyl-4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -N- (2- (dimethylamino) ethyl) -N, 2-dimethylbenzamide

Prepared in a similar manner to that in example B03 step 8 from N- (2- (dimethylamino) ethyl) -N, 2-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide and 2- (3, 5-dimethyl-4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) -7-iodo-5H-pyrrolo [2,3-B]Pyrazine preparation example 371.¹H NMR(400MHz,DMSO-d6)δ12.33(brs,1H),8.85(s,1H),8.46(s,1H),8.26(s,1H),8.19(d,J＝7.9Hz,1H),7.82(s,2H),7.26-7.20(m,1H),3.59(brs,1H),3.23(brs,1H),3.09-3.00(m,6H),2.82-2.79(m,4H),2.61-2.59(m,4H),2.40(s,6H),2.31(s,4H),2.24-2.19(m,7H),1.98(s,3H),1.88-1.86(m,2H),1.77-1.74(m,2H),1.52-1.39(m,2H)。LC-MS(M+H)⁺＝623.4。

Example 372: 6- [4- (2- [3, 5-dimethyl-4- [4- (1-methylpiperidin-4-yl) piperazin-1-yl ] phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -2-methylbenzoyl ] -2-oxa-6-azaspiro [3.3] heptane (compound 372)

Step 1: 6- (4-bromo-2-methylbenzoyl) -2-oxa-6-azaspiro [3.3] heptane

Prepared from 4-bromo in a similar manner to that in step 1 of example 304 -2-methylbenzoic acid and 2-oxa-6-azaspiro [3.3]Heptane the title compound was prepared. LCMS (M + H)⁺＝296.0。

Step 2: 6- [ 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoyl ] -2-oxa-6-azaspiro [3.3] heptane

Prepared from 6- (4-bromo-2-methylbenzoyl) -2-oxa-6-azaspiro [3.3] in a similar manner to that in example 308, step 1]Heptane and BPD the title compound was prepared. LCMS (M + H)⁺＝344.2。

And step 3: 6- [4- (2- [3, 5-dimethyl-4- [4- (1-methylpiperidin-4-yl) piperazin-1-yl ] phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -2-methylbenzoyl ] -2-oxa-6-azaspiro [3.3] heptane

Prepared in a similar manner to that described in step 8 of example B03 from 1- (4- [ 7-iodo-5H-pyrrolo [2,3-B ]]Pyrazin-2-yl radicals]-2, 6-dimethylphenyl) -4- (1-methylpiperidin-4-yl) piperazine and 6- [ 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoyl]-2-oxa-6-azaspiro [3.3]Heptane preparation example 372.¹H NMR(400MHz,DMSO-d6)δ12.36(brs,1H),8.85(s,1H),8.48(s,1H),8.27(d,J＝1.7Hz,1H),8.19-8.17(m,1H),7.82(s,2H),7.37(d,J＝8.0Hz,1H),4.71-4.68(m,4H),4.22-4.16(m,4H),3.07-3.06(m,4H),2.81-2.79(m,2H),2.63-2.56(m,4H),2.39(s,9H),2.24-2.14(m,4H),1.87-1.85(m,,2H),1.78-1.70(m,2H),1.47-1.44(m,2H)。LC-MS(M+H)⁺＝620.4。

Example 373: 4- (2- [3, 5-dichloro-4- [4- (1-methylpiperidin-4-yl) piperazin-1-yl ] phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -N, N-dimethylbenzamide (compound 373)

Step 1: 1- (2, 6-dichloro-4-nitrophenyl) -4- (1-methylpiperidin-4-yl) piperazine

To a solution of 1, 3-dichloro-2-fluoro-5-nitrobenzene (299mg, 1.425mmol) in DMSO (10mL) at room temperature was added K₂HPO₄(846mg, 4.854mmol), 1- (1-methylpiperidin-4-yl) piperazine (266mg, 1.451mmol). The resulting mixture was stirred at room temperature for 2 h. When the reaction was complete, the reaction was then quenched by the addition of water (30 mL). The resulting solution was extracted with ethyl acetate (50mLx 3). The organic phases were combined, washed with brine and over Na₂SO₄And (5) drying. The solvent was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with MeOH in DCM (containing 1% TEA, a gradient of 0% to 10%) to give 1- (2, 6-dichloro-4-nitrophenyl) -4- (1-methylpiperidin-4-yl) piperazine (480mg, 89%). LCMS (M + H)⁺＝375.1。

Step 2: 3, 5-dichloro-4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) aniline

The title compound was prepared from 1- (2, 6-dichloro-4-nitrophenyl) -4- (1-methylpiperidin-4-yl) piperazine in a similar manner as in example 320, step 3. LCMS (M + H)⁺＝343.2。

And step 3: 1- (4-bromo-2, 6-dichlorophenyl) -4- (1-methylpiperidin-4-yl) piperazine

The title compound was prepared from 3, 5-dichloro-4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) aniline in a similar manner to that in example 320, step 4. LCMS (M + H) ⁺＝408.2。

And 4, step 4: 1- (2, 6-dichloro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -4- (1-methylpiperidin-4-yl) piperazine

The title compound was prepared from 1- (4-bromo-2, 6-dichlorophenyl) -4- (1-methylpiperidin-4-yl) piperazine and BPD in a similar manner to that in example 308, step 1. LCMS (M-Pin)⁺＝372.1。

And 5: 4- [ 2-bromo-5- (4-methylbenzenesulfonyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl ] -N, N-dimethylbenzamide

Prepared from 2-bromo-7-iodo-5- (4-methylbenzenesulfonyl) -5H-pyrrolo [2,3-b ] in a similar manner to that in step 2 of example 332]Pyrazine and [4- (dimethylcarbamoyl) phenyl]Boronic acid the title compound was prepared. LCMS (M + H)⁺＝499.2。

Step 6: 4- (2- [3, 5-dichloro-4- [4- (1-methylpiperidin-4-yl) piperazin-1-yl ] phenyl ] -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -N, N-dimethylbenzamide

Prepared in a similar manner to that described in step 2 of example 332 from 4- [ 2-bromo-5- (4-methylbenzenesulfonyl) -5H-pyrrolo [2,3-b ]]Pyrazin-7-yl]-N, N-dimethylbenzamide and 1- [2, 6-dichloro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-4- (1-methylpiperidin-4-yl) piperazine preparation example 373.¹H NMR(400MHz,DMSO-d6)δ12.54(brs,1H),8.99(s,1H),8.57(s,1H),8.33(d,J＝7.9Hz,2H),8.22(s,2H),7.52(d,J＝7.8Hz,2H),3.22-3.20(m,4H),3.01(s,6H),2.88-2.81(m,2H),2.64-2.62(m,4H),2.22-2.18(m,4H),1.95-1.91(m,2H),1.77-1.75(m,2H),1.48-1.46(m,2H)。LC-MS(M+H)⁺＝592.3。

Example 374: 4- (2- (3, 5-dichloro-4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -N- (2- (dimethylamino) ethyl) -N-methylbenzamide (compound 374)

Step 1: 4-bromo-N- [2- (dimethylamino) ethyl ] -N-methylbenzamide

Into a flask were added 4-bromobenzoic acid (400mg, 1.89mmol) and [2- (dimethylamino) ethyl group](methyl) amine (163mg, 1.51mmol), DIEA (386mg, 2.84mmol), HATU (756.6mg, 1.89mmol) and DMF (4 mL). The mixture was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum. Purifying the residue by silica gel column chromatography using CH₂Cl₂MeOH (5:1) to give 4-bromo-N- [2- (dimethylamino) ethyl]-N-methylbenzamide (430mg, 76%). LCMS (M + H)⁺＝285.3。

Step 2: n- [2- (dimethylamino) ethyl ] -N-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide

Adding 4-bromo-N- [2- (dimethylamino) ethyl group to the tube]N-methylbenzamide (400mg, 1.37mmol), 3,3,4,4,4, 4-octamethyl-1, 1-bi-cyclopentylborane (532mg, 2.05mmol), KOAc (424mg, 4.11mmol), Pd (dppf) Cl₂.CH₂Cl₂(118mg, 0.14mmol) and dioxahexazineLoop (4 mL). The mixture was stirred at 90 ℃ for 3 h. The resulting mixture was concentrated under vacuum. The residue was purified by column chromatography on silica eluting with EtOAc/MeOH (5:95) to give N- [2- (dimethylamino) ethyl]-N-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide (181mg, 14%). LCMS (M + H) ⁺＝333.1。

And step 3: 4- (2-bromo-5-tosyl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -N- (2- (dimethylamino) ethyl) -N-methylbenzamide

Prepared from (N- [2- (dimethylamino) ethyl) in a similar manner to that in step 2 of example 332]-N-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide and 2-bromo-7-iodo-5-tosyl-5H-pyrrolo [2,3-b ]]Pyrazine the title compound was prepared. LCMS (M + H)⁺＝558.3。

And 4, step 4: 4- (2- (3, 5-dichloro-4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -N- (2- (dimethylamino) ethyl) -N-methylbenzamide

Prepared from 4- (2-bromo-5-tosyl-5H-pyrrolo [2,3-b ] in a similar manner to that in step 4 of example 285]Pyrazin-7-yl) -N- (2- (dimethylamino) ethyl) -N-methylbenzamide and 1- (2, 6-dichloro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -4- (1-methylpiperidin-4-yl) piperazine preparation example 374.¹H NMR(400MHz,DMSO-d6)δ12.52(brs,1H),8.98(s,1H),8.55(s,1H),8.32(d,J＝7.8Hz,2H),8.21(s,2H),7.48(d,J＝7.8Hz,2H),3.54(brs,2H),3.20-3.18(m,4H),2.99(s,3H),2.80-2.78(m,2H),2.62-2.60(m,4H),2.41(brs,2H),2.21-2.19(m,4H),2.14(s,3H),2.05-2.02(m,3H),1.87-1.84(m,2H),1.73-1.71(m,2H),1.48-1.43(m,2H),LC-MS(M+H)⁺＝651.0。

Example 375: (4- (2- (3, 5-dichloro-4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) (3-hydroxyazetidin-1-yl) methanone (compound 375)

Prepared in a similar manner to that in step 2 of example 332 from 1- (2, 6-dichloro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -4- (1-methylpiperidin-4-yl) piperazine and (4- (2-bromo-5-toluenesulfonyl-5H-pyrrolo [2, 3-b) ]Pyrazin-7-yl) phenyl) (3-hydroxyazetidin-1-yl) methanone example 375 was prepared.¹H NMR(400MHz,DMSO-d6)δ12.56(brs,1H),8.98(s,1H),8.59(s,1H),8.34(d,J＝8.0Hz,2H),8.20(s,2H),7.72(d,J＝8.0Hz,2H),5.76(br,1H),4.53(brs,2H),4.27(brs,1H),4.12(brs,1H),3.83-3.81(m,1H),3.20-3.18(m,4H),2.83-2.81(m,2H),2.63-2.61(m,4H),2.19-2.14(m,4H),1.87-1.85(m,2H),1.74-1.72(m,2H),1.51-1.41(m,2H)。LC-MS(M+H)⁺＝620.3。

Example 376: 4- (5- (3-fluoro-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (Compound 376)

Step 1: 1- (4-bromo-2-fluorophenyl) -4-methylpiperazine

The title compound was prepared from 2-chloro-N- (2-chloroethyl) -N-methylethyl-1-amine and 4-bromo-2-fluoroaniline in a similar manner to that in example 305, step 1. LCMS (M + H)⁺＝273.0。

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

Prepared from (4- (dimethylcarbamoyl) phenyl) boronic acid and 3-bromo-5-chloro-1H-pyrrolo [2,3-b ] in a similar manner to that described in step 2 of example 330]Pyridine the title compound was prepared. LCMS (M + H)⁺＝300.0。

And step 3: 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

Prepared from 4- (5-chloro-1H-pyrrolo [2,3-b ] in a similar manner to that in step 2 of example 339]Pyridin-3-yl) -N, N-dimethylbenzamide and BPD the title compound was prepared. LCMS (M + H)⁺＝392.3。

And 4, step 4: 4- (5- (3-fluoro-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide

Prepared in a similar manner to that in step 2 of example 311 from 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 and 1- (4-bromo-2-fluorophenyl) -4-methylpiperazine preparation example 376.¹H NMR(400MHz,DMSO-d6)δ12.10(brs,1H),8.57(d,J＝2.1Hz,1H),8.46(d,J＝2.1Hz,1H),8.01(s,1H),7.88(d,J＝8.0Hz,2H),7.65-7.63(m,1H),7.53-7.49(m,3H),7.13-7.11(m,1H),3.08-.05(m,4H),3.01(s,6H),2.60-2.58(m,2H),2.51-2.49(m,2H),2.24(s,3H)。LC-MS(M+H)⁺＝458.3。

Example 377: 1- (4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) -3- (4-methoxyphenyl) propan-1-ol (compound 377)

Step 1: (E) -1- (4-bromophenyl) -3- (4-methoxyphenyl) prop-2-en-1-one

To a solution of p-bromoacetophenone (1.90g, 9.545mmol) in EtOH (15mL) was added anisaldehyde (1.28g, 9.420mmol), NaOH (0.76g, 19.001mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. When the reaction was complete, the precipitated solid was collected by filtration and washed with water (15mLx 3). The resulting solid was dried under infrared light to give (E) -1- (4-bromophenyl) -3- (4-methoxyphenyl) prop-2-en-1-one (1.86g, 61%). LCMS (M + H)⁺＝318.9。

Step 2: (E) -3- (4-methoxyphenyl) -1- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) prop-2-en-1-one

The title compound was prepared from (E) -1- (4-bromophenyl) -3- (4-methoxyphenyl) prop-2-en-1-one and BPD in a similar manner as in example 308, step 1. LCMS (M + H) ⁺＝365.1。

And step 3: (E) -1- (4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) -3- (4-methoxyphenyl) prop-2-en-1-one

Prepared in a similar manner to that in example B03 step 8 from (E) -3- (4-methoxyphenyl) -1- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) prop-2-en-1-one and 5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -3-iodo-1H-pyrrolo [2,3-B]Pyridine the title compound was prepared. LCMS (M + H)⁺＝557.3。

And 4, step 4: 1- (4- [5- [3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] phenyl) -3- (4-methoxyphenyl) propan-1-ol

To (2E) -1- (4- [5- [3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) at 0 ℃ under a nitrogen atmosphere]-1H-pyrrolo [2,3-b]Pyridin-3-yl]To a solution of phenyl) -3- (4-methoxyphenyl) prop-2-en-1-one (60mg, 0.108mmol) in MeOH (5mL) was added NiCl in portions₂(29mg，0.227mmol)、NaBH₄(25mg, 0.628 mmol). The resulting mixture was stirred at room temperature for 1 h. When the reaction is complete, it is then quenched by addition of saturated NH₄The reaction was quenched with Cl (5 mL). The resulting solution was extracted with DCM (30mLx 3). The organic phases were combined, washed with brine and over Na₂SO₄And (5) drying. The solvent was concentrated under reduced pressure and the residue was purified by preparative HPLC. Obtaining 1- (4- [5- [3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) ]-1H-pyrrolo [2,3-b]Pyridin-3-yl]Phenyl) -3- (4-methoxyphenyl) propan-1-ol (4mg, 6%).¹H NMR(400MHz,DMSO-d6)δ11.89(d,J＝2.7Hz,1H),8.48(d,J＝2.1Hz,1H),8.33(d,J＝2.1Hz,1H),7.84(d,J＝2.5Hz,1H),7.71(d,J＝8.2Hz,2H),7.40(d,J＝7.9Hz,2H),7.33(s,2H),7.11(d,J＝8.6Hz,2H),6.86-6.80(m,2H),5.33-5.31(m,1H),4.55-4.53(m,1H),3.70(s,3H),3.06-3.03(m,4H),2.59-2.55(m,2H),2.48-2.41(m,4H),2.34(s,6H),2.24(s,3H),1.92-1.89(m,2H)。LC-MS(M+H)⁺＝561.3。

Example 378: 2- (4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenoxy) ethylamine (compound 378)

Step 1: 2- (4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenoxy) ethylcarbamic acid tert-butyl ester

Prepared in a similar manner to that in example B03 step 8 from tert-butyl (2- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy) ethyl) carbamate and 3-iodo-5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-B]Pyridine the title compound was prepared. LCMS (M + H)⁺＝542.3。

Step 2: 2- (4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenoxy) ethylamine

Prepared from 2- (4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that in step 4 of example 324]Pyridin-3-yl) phenoxy) ethylcarbamic acid tert-butyl ester preparation example 378.¹H NMR(400MHz,DMSO-d6)δ11.86(brs,1H),8.50(s,1H),8.31(s,1H),7.78(s,1H),7.72-7.66(m,2H),7.57-7.48(m,2H),7.13(d,J＝8.3Hz,1H),7.09-7.01(m,2H),4.03-4.01(m,2H),3.69-3.50(m,4H),2.98-2.96(m,2H),2.90-2.88(m,4H),2.34(s,3H),2.26(s,3H)。LC-MS(M+H)⁺＝442.3。

Example 379: 6- (4- [5- [3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) -2-oxa-6-azaspiro [3.3] heptane (compound 379)

Prepared from 6- (4- [ 5-chloro-1H-pyrrolo [2,3-b ] in a similar manner to that in step 2 of example 311]Pyridin-3-yl]Benzoyl) -2-oxa-6-azaspiro [3.3]Heptane and 1- [2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-4-methylpiperazine preparation example 379.¹H NMR(400MHz,DMSO-d6)δ12.12(brs,1H),8.53(d,J＝2.0Hz,1H),8.41(d,J＝2.1Hz,1H),8.05(d,J＝2.6Hz,1H),7.88(d,J＝8.1Hz,2H),7.71(d,J＝8.1Hz,2H),7.38(s,2H),4.71(s,4H),4.56(s,2H),4.24(s,2H),3.06(brs,4H),2.45(brs,4H),2.38(s,6H),2.26(s,3H)。LC-MS(M+H)⁺＝522.1。

Example 380: 4- (4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenoxy) butan-1-amine (Compound 380)

Step 1: 2- (4- (4-bromophenoxy) butyl) isoindoline-1, 3-dione

The title compound was prepared from 2- (4-hydroxybutyl) isoindoline-1, 3-dione and 4-bromophenol in analogy to the procedure in example 336, step 1. LCMS (M + H)⁺＝374.0。

Step 2: 2- (4- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy) butyl) isoindoline-1, 3-dione

The title compound was prepared from 2- (4- (4-bromophenoxy) butyl) isoindoline-1, 3-dione and BPD in a similar manner as in example 308, step 1. LCMS (M + Na)⁺＝444.2。

And step 3: 2- (4- (4- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) phenoxy) butyl) isoindoline-1, 3-dione

Prepared in a similar manner to that described in example 330, step 2 from 2- (4- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy) butyl) isoindoline-1, 3-dione and 3-bromo-5-chloro-1H-pyrrolo [2,3-b ] -c ]Pyridine the title compound was prepared. LCMS (M + H)⁺＝446.2。

And 4, step 4: 2- (4- (4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenoxy) butyl) isoindoline-1, 3-dione

Prepared from 2- (4- (4- (5-chloro-1H-pyrrolo [2, 3-b) in a similar manner to that in step 2 of example 311]Pyridin-3-yl) phenoxy) butyl) isoindoline-1, 3-dione and 1- (2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -4-methylpiperazine the title compounds were preparedA compound (I) is provided. LCMS (M + H)⁺＝614.3。

And 5: 4- (4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenoxy) butan-1-amine

Prepared from 2- (4- (4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] in a similar manner to that in example 350 step 3]Pyridin-3-yl) phenoxy) butyl) isoindoline-1, 3-dione preparation example 380.¹H NMR(400MHz,DMSO-d6)δ12.05-11.95(m,1H),8.51-8.45(m,2H),8.29(d,J＝2.1Hz,1H),7.77(s,1H),7.68(d,J＝8.6Hz,2H),7.35(s,2H),7.03(d,J＝8.6Hz,2H),4.04-4.02(m,2H),3.07-3.04(m,4H),2.79-2.77(m,2H),2.46-2.44(m,4H),2.36(s,6H),2.25(s,3H),1.80-1.78(m,2H),1.67-1.65(m,2H)。LC-MS(M+H)⁺＝484.3。

Example 381: (4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (3-hydroxyazetidin-1-yl) methanone (Compound 381)

Step 1: (4- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (3-hydroxyazetidin-1-yl) methanone

Prepared in a similar manner to that in step 2 of example 330 from 1- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoyl]Azetidin-3-ol and 3-bromo-5-chloro-1H-pyrrolo [2,3-b ]]Pyridine the title compound was prepared. LCMS (M + H)⁺＝328.1。

Step 2: (4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (3-hydroxyazetidin-1-yl) methanone

Prepared from (4- (5-chloro-1H-pyrrolo [2, 3-b) in a similar manner to that in step 2 of example 311]Pyridin-3-yl) phenyl) (3-hydroxyazetidin-1-yl) methanone and 1- [2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-4-methylpiperazine preparation example 381.¹H NMR(400MHz,DMSO-d6)δ12.12(brs,1H),8.52(d,J＝2.1Hz,1H),8.41(d,J＝2.1Hz,1H),8.04(d,J＝2.6Hz,1H),7.91-7.85(m,2H),7.74-7.68(m,2H),7.38(s,2H),5.79-5.77(m,1H),4.55-4.53(m,2H),4.30-4.28(m,1H),4.11-4.09(m,1H),3.82-3.80(m,1H),3.10-3.04(m,4H),2.46-2.43(m,4H),2.37(s,6H),2.25(s,3H)。LC-MS(M+H)⁺＝496.4。

Example 382: (4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -3-fluorophenyl) (3-hydroxyazetidin-1-yl) methanone (Compound 382)

Step 1: 4- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -3-fluorobenzoic acid

To 4- [ 5-chloro-1H-pyrrolo [2,3-b ] at room temperature]Pyridin-3-yl]To a solution of methyl (432mg, 1.417mmol) of (E) -3-fluorobenzoate in THF (4mL) were added LiOH (136mg, 5.670mmol), H₂O (4 mL). The mixture was stirred at room temperature overnight. When the reaction was complete, the mixture was acidified to pH 3 with concentrated HCl. The resulting solution was extracted with ethyl acetate (30mLx 3). The organic phases were combined, washed with brine and over Na ₂SO₄And (5) drying. The solvent was concentrated under reduced pressure to give 4- [ 5-chloro-1H-pyrrolo [2,3-b ]]Pyridin-3-yl]-3-fluorobenzoic acid (374mg, 91%). LCMS (M + H)⁺＝291.1。

Step 2: (4- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -3-fluorophenyl) (3-hydroxyazetidin-1-yl) methanone

Prepared from 4- (5-chloro-1H-pyrrolo [2,3-b ] in a similar manner to that in step 1 of example 304]Pyridin-3-yl) -3-fluorobenzoic acid and azetidin-3-ol the title compound was prepared. LCMS (M + H)⁺＝346.1。

And step 3: (4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -3-fluorophenyl) (3-hydroxyazetidin-1-yl) methanone

Prepared from 1- [2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxolane in a similar manner to that described in step 2 of example 311Borane-2-yl) phenyl]-4-methylpiperazine and (4- (5-chloro-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) -3-fluorophenyl) (3-hydroxyazetidin-1-yl) methanone preparation example 382.¹H NMR(400MHz,DMSO-d6)δ12.23(brs,1H),8.54(s,1H),8.25(s,1H),7.96-7.86(m,2H),7.60-7.52(m,2H),7.34(s,2H),5.79(d,J＝5.8Hz,1H),4.60-4.52(m,2H),4.30-4.28(m,1H),4.16-4.13(m,1H),3.85-3.81(m,1H),3.09-3.02(m,4H),2.50-2.41(m,4H),2.36(s,6H),2.26(s,3H)。LC-MS(M+H)⁺＝514.3。

Example 383: 4- (5- (4- (4-hydroxy-1-methylpiperidin-4-yl) -3, 5-dimethylphenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (compound 383)

Step 1: 4- (4-chloro-2, 6-dimethylphenyl) -1-methyl-1, 2,3, 6-tetrahydropyridine

The title compound was prepared from 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,2,3, 6-tetrahydropyridine and 2-bromo-5-chloro-1, 3-dimethylbenzene in a similar manner to that in example 332, step 2. LCMS (M + H)⁺＝236.2。

Step 2: 4- (2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -1-methyl-1, 2,3, 6-tetrahydropyridine

To a solution of 4- (4-chloro-2, 6-dimethylphenyl) -1-methyl-1, 2,3, 6-tetrahydropyridine (255mg, 1.081mmol) in dioxane (6mL) was added BPD (551mg, 2.170mmol), Pd (PCy) at room temperature₃)₂Cl₂(125mg, 0.161mmol, 0.15 equiv., 95%), KOAc (323mg, 3.291 mmol). The resulting mixture was stirred at 110 ℃ for 3h under a nitrogen atmosphere. When the reaction was complete, the solvent was concentrated under reduced pressure and the residue was purified by flash chromatography, eluting with EtOAc in hexanes (gradient 0% to 50%) to give 4- (2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -1-methyl-1, 2,3, 6-tetrahydropyridine (322mg, 91%) as a brown solid. LCMS (M + H)⁺＝328.2。

And step 3: 4- (5- (3, 5-dimethyl-4- (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide

Prepared in a similar manner to that in example 311, step 2, from 4- (2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -1-methyl-1, 2,3, 6-tetrahydropyridine and 4- (5-chloro-1H-pyrrolo [2,3-b ] p]Pyridin-3-yl) -N, N-dimethylbenzamide the title compound was prepared. LCMS (M + H)⁺＝465.3。

And 4, step 4: 4- (5- (4- (4-hydroxy-1-methylpiperidin-4-yl) -3, 5-dimethylphenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide

4- [5- [3, 5-dimethyl-4- (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) phenyl at 0 DEG C]-1H-pyrrolo [2,3-b]Pyridin-3-yl]To a solution of N, N-dimethylformamide (85mg, 0.184mmol) in DCM (1mL) and IPA (4mL) was added manganese (III) tris (2,2,6, 6-tetramethyl-3, 5-heptanedionate) (12mg, 0.019mmol), and the resulting mixture was stirred under a nitrogen atmosphere for 15 min. The reaction temperature was allowed to rise to 40 ℃ and phenylsilane (40mg, 0.367mmol) was added. The resulting mixture was stirred at 40 ℃ under a nitrogen atmosphere for 2 h. When the reaction was complete, then by addition of saturated Na₂SO₄The reaction was quenched (5 mL). The resulting solution was extracted with ethyl acetate (10mLx 3). The organic phases were combined, washed with brine and over Na₂SO₄And (5) drying. The solvent was concentrated under reduced pressure and the residue was purified by preparative HPLC under the following conditions: column: XBridge prep C18 OBD column, 150x30mm, 5 um; mobile phase: acetonitrile in water (containing 10mmol/L NH) ₄HCO₃) Gradient from 30% to 55% over 7 min; a detector: UV 254 nm. Obtaining 4- (5- (4- (4-hydroxy-1-methylpiperidin-4-yl) -3, 5-dimethylphenyl) -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) -N, N-dimethylbenzamide (6mg, 6%).¹H NMR(400MHz,DMSO-d6)δ8.20(s,1H),7.51-7.43(m,2H),7.41-7.34(m,3H),7.15(s,2H),6.81(s,1H),6.20(s,1H),5.40-5.35(m,1H),3.70-3.66(m,2H),2.97-2.91(m,8H),2.59-2.56(m,2H),2.29(s,3H),2.18(s,6H),2.16-2.13(m,2H)。LC-MS(M+H)⁺＝483.3。

Example 384: 6- [4- (5- [3, 5-dimethyl-4- [4- (1-methylpiperidin-4-yl) piperazin-1-yl ] phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl) -3-fluorobenzoyl ] -2-oxa-6-azaspiro [3.3] heptane (compound 384)

Step 1: 6- (4- [ 5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl ] -3-fluorobenzoyl) -2-oxa-6-azaspiro [3.3] heptane

Prepared from 4- [ 5-chloro-1H-pyrrolo [2,3-b ] in a similar manner to that described in step 1 of example 304]Pyridin-3-yl]-3-fluorobenzoic acid and 2-oxa-6-azaspiro [3.3]Heptane the title compound was prepared. LCMS (M + H)⁺＝372.1。

Step 2: 6- [4- (5- [3, 5-dimethyl-4- [4- (1-methylpiperidin-4-yl) piperazin-1-yl ] phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl) -3-fluorobenzoyl ] -2-oxa-6-azaspiro [3.3] heptane

Prepared from 6- (4- [ 5-chloro-1H-pyrrolo [2,3-b ] in a similar manner to that in step 2 of example 311]Pyridin-3-yl]-3-fluorobenzoyl) -2-oxa-6-azaspiro [3.3]Heptane and 1- [2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ]-4- (1-methylpiperidin-4-yl) piperazine preparation example 384.¹H NMR(400MHz,DMSO-d6)δ12.24(brs,1H),8.54(s,1H),8.24(s,1H),7.96-7.87(m,2H),7.60-7.51(m,2H),7.34(s,2H),4.71(s,4H),4.59(s,2H),4.25(s,2H),3.10-3.05(m,4H),2.83-2.80(m,2H),2.62-2.58(m,4H),2.36(s,6H),2.20-2.12(m,4H),1.88-1.85(m,2H),1.77-1.74(m,2H),1.53-1.40(m,2H)。LC-MS(M+H)⁺＝623.4。

Example 385: 4- (5- (4- (4-hydroxypiperidin-1-yl) -3-methylphenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (Compound 385)

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

Prepared in a similar manner to that in step 2 of example 332 from [4- (dimethylcarbamoyl) phenyl]Boronic acid and 5-bromo-3-iodo-1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b]Pyridine the title compound was prepared. LCMS (M + H)⁺＝500.0。

Step 2: n, N-dimethyl-4- [1- (4-methylbenzenesulfonyl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

Prepared from 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b ] in a similar manner to that in example 308, step 1]Pyridin-3-yl]-N, N-dimethylbenzamide and BPD. LCMS (M + H)⁺＝546.3。

And step 3: 8- (4-bromo-2-methylphenyl) -1, 4-dioxa-8-azaspiro [4.5] decane

To a solution of 4-bromo-1-iodo-2-methylbenzene (1900mg, 6.399mmol) in toluene (57mL) at room temperature was added 1, 4-dioxa-8-azaspiro [ 4.5%]Decane (1100mg, 7.678mmol), Cs ₂CO₃(4170mg, 12.797mmol), BINAP (398mg, 0.640mmol), and Pd (AcO)₂(143mg, 0.640 mmol). The resulting mixture was stirred at 100 ℃ under a nitrogen atmosphere for 16 h. When the reaction was complete, the solvent was concentrated under reduced pressure and the residue was purified by flash chromatography, eluting with MeOH in DCM (gradient of 0% to 10%) to give 8- (4-bromo-2-methylphenyl) -1, 4-dioxa-8-azaspiro [4.5] as an off-white solid]Decane (392mg, 20%). LCMS (M + H)⁺＝312.2。

And 4, step 4: 4- [5- (4- [1, 4-dioxa-8-azaspiro [4.5] decan-8-yl ] -3-methylphenyl) -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -N, N-dimethylbenzamide

Prepared in a similar manner to that described in step 2 of example 332 from N, N-dimethyl-4- [1- (4-methylbenzenesulfonyl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ]]Pyridin-3-yl]Benzamide and 8- (4-bromo-2-methylphenyl) -1, 4-dioxa-8-azaspiro [4.5]Decane the title compound was prepared. LCMS (M + H)⁺＝651.4。

And 5: n, N-dimethyl-4- (5- (3-methyl-4- (4-oxopiperidin-1-yl) phenyl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Reaction of 4- [5- (4- [1, 4-dioxa-8-azaspiro [4.5] at room temperature under nitrogen atmosphere ]Decan-8-yl]-3-methylphenyl) -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl]To a solution of-N, N-dimethylbenzamide (105mg, 0.162mmol) in EtOH (8mL) was added HCl (2mL, 2.000mmol, 1M). The resulting mixture was stirred at 70 ℃ under a nitrogen atmosphere for 4 h. When the reaction was complete, the reaction was then diluted by the addition of water (15 mL). The resulting solution was extracted with ethyl acetate (30mLx 3). The organic phases were combined, washed with brine and over Na₂SO₄And (5) drying. The solvent was concentrated under reduced pressure to give N, N-dimethyl-4- [5- [ 3-methyl-4- (4-oxopiperidin-1-yl) phenyl ] as an off-white solid]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl]Benzamide (74mg, 75%). LCMS (M + H)⁺＝607.4。

Step 6: n, N-dimethyl-4- (5- (3-methyl-4- (4-oxopiperidin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Prepared in a similar manner to that described in example 369, step 6 from N, N-dimethyl-4- [5- [ 3-methyl-4- (4-oxopiperidin-1-yl) phenyl]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl]Benzamide the title compound was prepared. LCMS (M + H)⁺＝453.4。

And 7: 4- (5- (4- (4-hydroxypiperidin-1-yl) -3-methylphenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide

Prepared in a similar manner to that described in example 377, step 4 from N, N-dimethyl-4- (5- (3-methyl-4- (4-oxopiperidin-1-yl) phenyl) -1H-pyrrolo [2,3-b ]]Pyridin-3-yl) benzamide example 385 was prepared.¹H NMR(400MHz,DMSO-d6)δ12.04(brs,1H),8.22(s,1H),8.16(s,1H),8.01(d,J＝2.6Hz,1H),7.87-7.77(m,2H),7.46(d,J＝8.2Hz,2H),7.15(d,J＝8.4Hz,1H),6.91(d,J＝2.6Hz,1H),6.87-6.85(m,1H),4.70-4.67(m,1H),3.70-3.55(m,3H),2.99(s,6H),2.89-2.86(m,2H),2.24(s,3H),1.86-1.83(m,2H),1.52-1.49(m,2H)。LC-MS(M+H)⁺＝455.3。

Example 386: 4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (3-methoxycyclobutyl) -N-methylbenzamide (Compound 386)

Step 1: (4- ((3-methoxycyclobutyl) (methyl) carbamoyl) phenyl) boronic acid

The title compound was prepared from 3-methoxy-N-methylcyclobutylamine and 4- (dihydroxyboryl) benzoic acid in a similar manner as in example 304, step 1.

Step 2: 4- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (3-methoxycyclobutyl) -N-methylbenzamide

Prepared from (4- ((3-methoxycyclobutyl) (methyl) carbamoyl) phenyl) boronic acid and 3-bromo-5-chloro-1H-pyrrolo [2,3-b ] in a similar manner to that in example 330 step 2]Pyridine the title compound was prepared. LCMS (M + H)⁺＝370.1。

And step 3: 4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (3-methoxycyclobutyl) -N-methylbenzamide

Prepared in a similar manner to that in example 311, step 2, from 1- (2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -4-methylpiperazine and 4- (5-chloro-1H-pyrrolo [2, 3-b) ]Pyridin-3-yl) -N- (3-methoxycyclobutyl) -N-methylbenzamide preparation example 386.¹H NMR(400MHz,DMSO-d6)δ12.08(brs,1H),8.52(s,1H),8.41(s,1H),8.01(s,1H),7.88-7.84(m,2H),7.46-7.44(m,2H),7.37(s,2H),3.53(brs,1H),3.32-3.30(m,1H),3.16-3.03(m,7H),2.99-2.96(m,3H),2.50-2.42(m,6H),2.37(s,6H),2.25(s,3H),2.15-2.09(m,2H)。LC-MS(M+H)⁺＝538.7。

Example 387: 4- (5- (3-cyano-4- (1-methylpiperidin-4-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (compound 387)

Step 1: 5-chloro-2- (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) benzonitrile

The title compound was prepared from 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,2,3, 6-tetrahydropyridine and 2-bromo-5-chlorobenzonitrile in a similar manner to that in example 332, step 2. LCMS (M + H)⁺＝233.1。

Step 2: 2- (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzonitrile

The title compound was prepared from 5-chloro-2- (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) benzonitrile and BPD in a similar manner to that in example 339, step 2. LCMS (M + H)⁺＝325.3。

And step 3: 4- (5- (3-cyano-4- (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) phenyl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide

Prepared in a similar manner to that described in step 2 of example 332 from 2- (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzonitrile and 4- (5-bromo-1-toluenesulfonyl-1H-pyrrolo [2, 3-b) ]Pyridin-3-yl) -N, N-dimethylbenzamide the title compound was prepared. LCMS (M + H)⁺＝616.4。

And 4, step 4: 4- (5- (3-cyano-4- (1-methylpiperidin-4-yl) phenyl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide

Prepared in a similar manner to that in example 293, step 8 from 4- (5- (3-cyano-4- (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) phenyl) -1-toluenesulfonyl-1H-pyrrolo [2,3-b ] p]Pyridin-3-yl) -N, N-dimethylbenzamide the title compound was prepared. LCMS (M + H)⁺＝618.5。

And 5: 4- (5- (3-cyano-4- (1-methylpiperidin-4-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide

In a manner similar to that in example 369, step 6By reacting 4- (5- (3-cyano-4- (1-methylpiperidin-4-yl) phenyl) -1-toluenesulfonyl-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) -N, N-dimethylbenzamide preparation example 387.¹H NMR(400MHz,DMSO-d6)δ12.18(brs,1H),8.64(s,1H),8.58(s,1H),8.28(s,1H),8.12-8.06(m,2H),7.94-7.87(m,2H),7.64-7.60(m,1H),7.53-7.46(m,2H),3.01(s,6H),2.98-2.92(m,3H),2.23(s,3H),2.10-1.97(m,2H),1.89-1.76(m,4H)。LC-MS(M+H)⁺＝464.3。

Example 388: (4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (6-methyl-2, 6-diazaspiro [3.3] hept-2-yl) methanone (Compound 388)

Step 1: (4- (6-methyl-2, 6-diazaspiro [3.3] heptane-2-carbonyl) phenyl) boronic acid

Prepared from 2-methyl-2, 6-diazaspiro [3.3] in a similar manner to that described in step 1, example 304 ]Heptane and 4-boronobenzoic acid the title compound was prepared. LCMS (M + H)⁺＝261.2。

Step 2: (4- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (6-methyl-2, 6-diazaspiro [3.3] hept-2-yl) methanone

Prepared from 3-bromo-5-chloro-1H-pyrrolo [2,3-b ] in a similar manner to that in step 2 of example 330]Pyridine and (4- (6-methyl-2, 6-diazaspiro [3.3]]Heptane-2-carbonyl) phenyl) boronic acid the title compound was prepared. LCMS (M + H)⁺＝367.2。

And step 3: (4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (6-methyl-2, 6-diazaspiro [3.3] hept-2-yl) methanone

Prepared from (4- (5-chloro-1H-pyrrolo [2, 3-b) in a similar manner to that in step 2 of example 311]Pyridin-3-yl) phenyl) (6-methyl-2, 6-diazaspiro [3.3]Hept-2-yl) methanone and 1- (2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -4-methylpiperazine preparation example 388.¹H NMR(400MHz,DMSO-d6)δ12.11(brs,1H),8.52(s,1H),8.40(s,1H),8.04(s,1H),7.87(d,J＝8.2Hz,2H),7.71(d,J＝8.2Hz,2H),7.37(s,2H),4.44(s,2H),4.11(s,2H),3.10-3.04(m,4H),2.50-2.42(m,4H),2.37(s,6H),2.25(s,3H),2.16(s,3H)。LC-MS(M+H)⁺＝535.6。

Example 389: 4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N-methyl-N- ((1-methylazetidin-3-yl) methyl) benzamide (compound 389)

Step 1: (4- (methyl ((1-methylazetidin-3-yl) methyl) carbamoyl) phenyl) boronic acid

The title compound was prepared from N-methyl-1- (1-methylazetidin-3-yl) methylamine and 4-boronobenzoic acid in a similar manner to that in example 304, step 1. LCMS (M + H)⁺＝263.2。

Step 2: 4- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -N-methyl-N- ((1-methylazetidin-3-yl) methyl) benzamide

Prepared from (4- (methyl ((1-methylazetidin-3-yl) methyl) carbamoyl) phenyl) boronic acid and 3-bromo-5-chloro-1H-pyrrolo [2,3-b ] in a similar manner to that in step 2 of example 332]Pyridine the title compound was prepared. LCMS (M + H)⁺＝369.1。

And step 3: 4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N-methyl-N- ((1-methylazetidin-3-yl) methyl) benzamide

Prepared from 4- (5-chloro-1H-pyrrolo [2,3-b ] in a similar manner to that in step 2 of example 311]Pyridin-3-yl) -N-methyl-N- ((1-methylazetidin-3-yl) methyl) benzamide and 1- (2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -4-methylpiperazine preparation example 389.¹H NMR(400MHz,DMSO-d6)δ12.07(brs,1H),8.52(s,,1H),8.40(s,1H),8.01(s,1H),7.85(d,J＝8.0Hz,2H),7.45(d,J＝7.9Hz,2H),7.37(s,2H),3.70-3.54(m,2H),3.28-3.15(m,2H),3.09-3.04(m,4H),2.94(s,3H),2.88-2.85(m,1H),2.68-2.62(m,2H),2.50-2.42(m,4H),2.37(s,6H),2.25(s,3H),2.20-2.10(m,3H)。LC-MS(M+H)⁺＝537.3。

Example 390: 3- (4- (5- (3, 5-dimethyl-4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenoxy) -N, N-dimethylpropanamide (Compound 390)

Prepared in a similar manner to that described in step 2 of example 311 from 1- [2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-4- (1-methylpiperidin-4-yl) piperazine and 3- (4- [ 5-chloro-1H-pyrrolo [2, 3-b)]Pyridin-3-yl]Phenoxy) -N, N-dimethylpropionamide preparation example 390.¹H NMR(400MHz,DMSO-d6)δ11.86(brs,1H),8.49(s,1H),8.30(s,1H),7.78(s,1H),7.72-7.64(m,2H),7.35(s,2H),7.06-6.98(m,2H),4.26-4.23(m,2H),3.12-2.76(m,14H),2.65-2.60(m,4H),2.36(s,6H),2.30-2.26(m,4H),2.10-2.06(m,2H),1.89-1.81(m,2H),1.54-1.50(m,2H)。LC-MS(M+H)⁺＝595.4。

Example 391: 2- (4- [2, 6-dimethyl-4- [3- (4- [ 2-oxa-6-azaspiro [3.3] heptane-6-carbonyl ] phenyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl ] phenyl ] piperazin-1-yl) ethan-1-ol (Compound 391)

Prepared in a similar manner to that described in step 2 of example 311 from 2- [4- [2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Piperazin-1-yl]Ethan-1-ol and 6- (4- [ 5-chloro-1H-pyrrolo [2,3-b ]]Pyridin-3-yl]Benzoyl) -2-oxa-6-azaspiro [3.3]Heptane preparation example 391.¹H NMR(400MHz,DMSO-d6)δ12.11(brs,1H),8.52(s,1H),8.41(s,1H),8.04(s,1H),7.91-7.85(m,2H),7.74-7.67(m,2H),7.37(s,2H),4.71(s,4H),4.58-4.55(m,2H),4.43-4.41(m,1H),4.25-4.23(m,2H),3.57-3.53(m,2H),3.09-3.03(m,4H),2.55-2.47(m,6H),2.38(s,6H)。LC-MS(M+H)⁺＝552.4。

Example 392: (3- (dimethylamino) azetidin-1-yl) (4- (5- (4- (4- (2-hydroxyethyl) piperazin-1-yl) -3, 5-dimethylphenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone (Compound 392)

Step 1: (4- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (3- (dimethylamino) azetidin-1-yl) methanone

Prepared from 4- (3- (dimethylamino) azetidine-1-carbonyl) phenylboronic acid and 3-bromo-5-chloro-1H-pyrrolo [2,3-b ] in a similar manner to that described in step 2, example 330 ]Pyridine the title compound was prepared. LCMS (M + H)⁺＝357.1。

Step 2: (3- (dimethylamino) azetidin-1-yl) (4- (5- (4- (4- (2-hydroxyethyl) piperazin-1-yl) -3, 5-dimethylphenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone

From 2- (4- (2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) piperazin-1-yl) ethanol and (4- (5-chloro-1H-pyrrolo [2,3-b ] in a similar manner to that in example 311, step 2]Pyridin-3-yl) phenyl) (3- (dimethylamino) azetidin-1-yl) methanone preparation example 392.¹H NMR(400MHz,DMSO-d₆)δ12.10(brs,1H),8.52(s,1H),8.41(s,1H),8.04(s,1H),7.88(d,J＝8.4Hz,2H),7.76-7.70(m,2H),7.37(s,2H),4.46-4.33(m,2H),4.09(dd,J＝22.2,13.1Hz,2H),3.87-3.83(m,1H),3.60-3.51(m,2H),3.14-3.03(m,5H),2.61-2.43(m,6H),2.37(s,6H),2.10(s,6H)。LC-MS(M+H)⁺＝553.5。

Example 393: 4- (5- (4- (4- (2-hydroxyethyl) piperazin-1-yl) -3, 5-dimethylphenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (compound 393)

Prepared in a similar manner to that described in step 2 of example 311 from 2- [4- [2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Piperazin-1-yl]Ethan-1-ol and 4- [ 5-chloro-1H-pyrrolo [2,3-b ]]Pyridin-3-yl]-N, N-dimethylbenzamide preparation example 393.¹H NMR(400MHz,DMSO-d6)δ12.12(brs,1H),8.52(s,1H),8.40(s,1H),8.00(s,1H),7.88-7.82(m,2H),7.53-7.46(m,2H),7.37(s,2H),4.50-4.43(m,1H),3.58-3.53(m,2H),3.10-3.04(m,4H),3.01(s,6H),2.60-2.53(m,4H),2.50-2.45(m,2H),2.37(s,6H)。LC-MS(M+H)⁺＝498.4。

Example 394: 1- (4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) -N-methylcyclopropylamine (Compound 394)

Step 1: 1- (4-bromophenyl) cyclopropyl (methyl) carbamic acid tert-butyl ester

To N- [1- (4-bromophenyl) cyclopropyl at room temperature]To a solution of tert-butyl carbamate (483mg, 1.546mmol) in DMF (10mL) was added NaH (55mg, 2.319 mmol). The resulting mixture was stirred at 40 ℃ under a nitrogen atmosphere for 10 min. And then MeI (329mg, 2.319mmol) was added at 40 ℃. The resulting mixture was stirred at 40 ℃ for an additional 2 h. When the reaction was complete, the reaction was then quenched by the addition of ice water (20 mL). The resulting solution was extracted with ethyl acetate (60mLx 3). The organic phases were combined, washed with brine and over Na₂SO₄And (5) drying. The solvent was concentrated under reduced pressure and the residue was purified by flash chromatography, eluting with EtOAc in hexanes (gradient 0% to 50%) to give N- [1- (4-bromophenyl) cyclopropyl as a colorless oil]-N-methyl-carbamic acid tert-butyl ester (244mg, 48%). LCMS (M + H)⁺＝226.0。

Step 2: methyl (1- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) cyclopropyl) carbamic acid tert-butyl ester

Prepared from 1- (4-bromo) in a similar manner to that in step 1 of example 308Phenyl) cyclopropyl (methyl) carbamic acid tert-butyl ester and BPD the title compound was prepared. LCMS (M + H)⁺＝274.3。

And step 3: 1- (4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) cyclopropyl (methyl) carbamic acid tert-butyl ester

Prepared in a similar manner to that in example 308, step 8 from tert-butyl methyl (1- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) cyclopropyl) carbamate and 5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -3-iodo-1H-pyrrolo [2,3-b ] phenyl]Pyridine the title compound was prepared. LCMS (M + H)⁺＝566.5。

And 4, step 4: 1- (4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) -N-methylcyclopropylamine

Prepared in a similar manner to that in step 4 of example 324 from 1- (4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) phenyl) cyclopropyl (methyl) carbamic acid tert-butyl ester preparation example 394.¹H NMR(400MHz,DMSO-d6)δ11.92(brs,1H),8.50(s,1H),8.33(s,1H),7.84(s,1H),7.72-7.66(m,2H),7.41-7.33(m,4H),3.10-3.04(m,4H),2.48-2.41(m,4H),2.36(s,6H),2.26(s,3H),2.20(s,3H),0.98-0.87(m,4H)。LC-MS(M+H)⁺＝466.4。

Example 395: azetidin-3-yl (4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone (compound 395)

Step 1: 3- (4-bromobenzoyl) azetidine-1-carboxylic acid tert-butyl ester

To a solution of 3- (4-bromobenzoyl) azetidine hydrochloride (700mg, 2.531mmol) in DCM (140mL) at room temperature was added pyridine (1.00g, 12.642mmol), Boc₂O (1.68g, 7.695 mmol). The resulting mixture was stirred at room temperature for 16 h. When the reaction was complete, the solvent was concentrated under reduced pressure and the residue was taken up Purification by flash chromatography eluting with MeOH in DCM (gradient 0% to 10%) gave tert-butyl 3- (4-bromobenzoyl) azetidine-1-carboxylate (648mg, 75%) as a white solid. LCMS (M + H-100)⁺＝240.0。

Step 2: 3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoyl) azetidine-1-carboxylic acid tert-butyl ester

The title compound was prepared from tert-butyl 3- (4-bromobenzoyl) azetidine-1-carboxylate and BPD in a similar manner to that in example 308, step 1. LCMS (M + H-100)⁺＝288.2。

And step 3: tert-butyl 3- (4- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) benzoyl) azetidine-1-carboxylic acid tert-butyl ester

Prepared in a similar manner to that in example 330, step 2 from tert-butyl 3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoyl) azetidine-1-carboxylate and 3-bromo-5-chloro-1H-pyrrolo [2,3-b]Pyridine the title compound was prepared. LCMS (M + H)⁺＝412.0。

And 4, step 4: 3- (4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzoyl) azetidine-1-carboxylic acid tert-butyl ester

Prepared in a similar manner to that described in step 2 of example 311 from 1- [2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ]-4-methylpiperazine and 3- (4- [ 5-chloro-1H-pyrrolo [2, 3-b)]Pyridin-3-yl]Benzoyl) azetidine-1-carboxylic acid tert-butyl ester the title compound was prepared. LCMS (M + H)⁺＝580.3。

And 5: azetidin-3-yl (4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone

Prepared in a similar manner to that in step 5 of example 309 from 3- (4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) benzoyl) azetidine-1-carboxylic acid tert-butyl ester preparation example 395.¹H NMR(400MHz,DMSO-d6)δ12.21(brs,1H),8.54(s,1H),8.48(s,1H),8.13(s,1H),8.01-7.92(m,4H),7.39(s,2H),4.50-4.44(m,1H),3.80-3.71(m,4H),3.10-3.04(m,4H),2.52-2.43(m,4H),2.38(s,6H),2.26(s,3H)。LC-MS(M+H)⁺＝480.3。

Example 396: azetidin-3-yl (4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanol (compound 396)

Prepared from azetidin-3-yl (4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2, 3-b) in a similar manner to that in example 377, step 4]Pyridin-3-yl) phenyl) methanone preparation example 396.¹H NMR (400MHz, methanol-d 4) δ 8.44(s,1H),8.36(s,1H),7.75-7.66(m,3H),7.48(d, J ═ 7.8Hz,2H),7.28(s,2H),4.05-4.01(m,1H),3.86-3.80(m,3H),3.20-3.16(m,5H),2.65-2.60(m,4H),2.44-2.39(m, 10H). LC-MS (M + H)⁺＝482.4。

Example 397: (4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (1-methylazetidin-3-yl) methanone (Compound 397)

To 1- (4- [3- [4- (azetidine-3-carbonyl) phenyl) at room temperature]-1H-pyrrolo [2,3-b]Pyridin-5-yl]To a solution of (E) -2, 6-dimethylphenyl) -4-methylpiperazine (260mg, 0.542mmol) in MeOH (20mL) was added paraformaldehyde ((CH)₂O)_n)(2.45g，55.68mmol)、AcOH(578mg，9.625mmol)、NaBH(AcO)₃(230mg, 1.085 mmol). The resulting mixture was stirred at room temperature for 4 h. When the reaction was complete, the reaction was then quenched by the addition of water (20 mL). The resulting solution was extracted with ethyl acetate (100mLx 3). The organic phases were combined, washed with brine and over Na₂SO₄And (5) drying. 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, 150x19mm, 5 um; mobile phase: acetonitrile in water (containing 10mmol/L NH)₄HCO₃) Gradient from 60% to 80% over 7 min; a detector: UV 254 nm. To obtain (4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) phenyl) (1-methylazetidin-3-yl) methanone (3mg, 1%).¹H NMR(400MHz,DMSO-d6)δ12.20(brs,1H),8.53(s,1H),8.44(s,1H),8.11(s,1H),7.99-7.90(m,4H),7.38(s,2H),4.23-4.20(m,1H),3.65-3.59(m,2H),3.28-3.20(m,2H),3.10-3.04(m,4H),2.50-2.42(m,4H),2.37(s,6H),2.25-2.20(m,6H)。LC-MS(M+H)⁺＝494.4。

Example 398: (4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (1-methylazetidin-3-yl) methanol (Compound 398)

Prepared from (4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2, 3-b) in a similar manner to that in example 377, step 4 ]Pyridin-3-yl) phenyl) (1-methylazetidin-3-yl) methanone preparation example 398.¹H NMR(400MHz,DMSO-d6)δ11.95(brs,1H),8.50(s,1H),8.34(s,1H),7.87(s,1H),7.75-7.68(m,2H),7.42-7.33(m,4H),5.43(brs,1H),4.66(d,J＝7.8Hz,1H),3.38-3.24(m,3H),3.10-3.04(m,5H),2.67-2.64(m,1H),2.50-2.40(m,4H),2.37(s,6H),2.31(s,3H),2.25(s,3H)。LC-MS(M+H)⁺＝496.3。

Example 399: cyclopropyl (4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanol (compound 399)

Prepared in a similar manner to that in example 377, step 4 from cyclopropyl (4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) phenyl) methanone preparation example 399.¹H NMR(400MHz,DMSO-d6)δ11.93(brs,1H),8.50(s,1H),8.35(s,1H),7.85(s,1H),7.71(d,J＝8.2Hz,2H),7.46(d,J＝8.0Hz,2H),7.36(s,2H),5.17(d,J＝4.4Hz,1H),4.05-3.99(m,1H),3.10-3.04(m,4H),2.50-2.42(m,4H),2.37(s,6H),2.26(s,3H),1.14-1.02(m,1H),0.54-0.31(m,4H)。LC-MS(M+H)⁺＝467.3。

Example 400: 6- [4- (5- [3, 5-dimethoxy-4- [4- (1-methylpiperidin-4-yl) piperazin-1-yl ] phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzoyl ] -2-oxa-6-azaspiro [3.3] heptane (compound 400)

Prepared in a similar manner to that described in step 3 of example 377 from 1- [2, 6-dimethoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-4- (1-methylpiperidin-4-yl) piperazine and 6- (4- [ 5-chloro-1H-pyrrolo [2, 3-b)]Pyridin-3-yl]Benzoyl) -2-oxa-6-azaspiro [3.3]Heptane preparation example 400.¹H NMR(400MHz,DMSO-d6)δ12.17-12.12(m,1H),8.59(s,1H),8.45(s,1H),8.05(s,1H),7.93-7.86(m,2H),7.73-7.67(m,2H),6.93(s,2H),4.71(s,4H),4.60-4.51(m,2H),4.26-4.21(m,2H),3.86(s,6H),3.10-3.04(m,4H),2.85-2.81(m,2H),2.60-2.54(m,4H),2.19-2.16(m,4H),1.91-1.87(m,2H),1.77-1.73(m,2H),1.52-1.39(m,2H)。LC-MS(M+H)⁺＝637.4。

Example 401: 4- (5- (3, 5-dimethoxy-4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (2- (dimethylamino) ethyl) -N-methylbenzamide (compound 401)

Step 1: 5-bromo-3-iodo-1-tosyl-1H-pyrrolo [2,3-b ] pyridine

Prepared from 5-bromo-3-iodo-1H-pyrrolo [2,3-b ] in a similar manner to that in step 2 of example 360]Pyridine and TsCl. LCMS (M + H)⁺＝478.1。

Step 2: 4- (5-bromo-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (2- (dimethylamino) ethyl) -N-methylbenzamide

Prepared from 5-bromo-3-iodo-1-tosyl-1H-pyrrolo [2,3-b ] in a similar manner to that described in step 2 of example 332]Pyridine and (4- [ [2- (dimethylamino) ethyl](methyl) carbamoyl group]Phenyl) boronic acid the title compound was prepared. LCMS (M + H)⁺＝557.1。

3: 4- (5- (3, 5-dimethoxy-4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (2- (dimethylamino) ethyl) -N-methylbenzamide

Prepared in a similar manner to that in step 2 of example 332 from 4- (5-bromo-1-tosyl-1H-pyrrolo [2,3-b ]]Pyridin-3-yl) -N- (2- (dimethylamino) ethyl) -N-methylbenzamide and 1- (2, 6-dimethoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -4- (1-methylpiperidin-4-yl) piperazine preparation example 401.¹H NMR(400MHz,DMSO-d6)δ12.11(brs,1H),8.58(s,1H),8.44(s,1H),8.01(s,1H),7.90-7.83(m,2H),7.49-7.42(m,2H),6.92(s,2H),3.85(s,6H),3.58-3.53(m,1H),3.10-3.04(m,4H),2.99(s,3H),2.82-2.76(m,2H),2.60-2.53(m,4H),2.44-1.95(m,13H),1.89-1.79(m,2H),1.75-1.71(m,2H),1.50-1.37(m,2H)。LC-MS(M+H)⁺＝640.4。

Example 402: 4- (5- (3, 5-dimethyl-4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) -4-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (2- (dimethylamino) ethyl) -N-methylbenzamide (compound 402)

Step 1: 4- (5-bromo-4-methyl-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (2- (dimethylamino) ethyl) -N-methylbenzamide

Prepared in a similar manner to that in step 2 of example 332 from 5-bromo-3-iodo-4-methyl-1-toluenesulfonyl-1H-pyrrolo [2,3-b ]]Pyridine and 4- ((2- (dimethylamino) ethyl) (methyl) carbamoylYl) phenyl boronic acid the title compound was prepared. LCMS (M + H)⁺＝569.2。

Step 2: 4- (5- (3, 5-dimethyl-4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) -4-methyl-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (2- (dimethylamino) ethyl) -N-methylbenzamide

In a similar manner to that in example 332, step 2, from 1- (2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -4- (1-methylpiperidin-4-yl) piperazine and 4- (5-bromo-4-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) -N- (2- (dimethylamino) ethyl) -N-methylbenzamide the title compound was prepared. LCMS (M + H)⁺＝776.6。

And step 3: 4- (5- (3, 5-dimethyl-4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) -4-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (2- (dimethylamino) ethyl) -N-methylbenzamide

Prepared in a similar manner to that in example 369, step 6 from 4- (5- (3, 5-dimethyl-4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenyl) -4-methyl-1-toluenesulfonyl-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) -N- (2- (dimethylamino) ethyl) -N-methylbenzamide preparation example 402.¹H NMR(400MHz,DMSO-d6)δ11.89-11.84(m,1H),8.04(s,1H),7.52(d,J＝8.2Hz,3H),7.39(d,J＝7.7Hz,2H),6.99(s,2H),3.60-3.53(m,1H),3.04-2.97(m,7H),2.82-2.79(m,2H),2.62-2.55(m,4H),2.43(s,3H),2.32(s,6H),2.22-2.05(m,10H),1.98-1.94(m,3H),1.86-1.82(m,2H),1.77-1.72(m,2H),1.51-1.40(m,2H)。LC-MS(M+H)⁺＝622.5。

Example 403: 1- [4- (5- [3, 5-dimethyl-4- [4- (1-methylpiperidin-4-yl) piperazin-1-yl ] phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl) -2-methylbenzoyl ] azetidin-3-ol (compound 403)

Step 1: (4-bromo-2-methylphenyl) (3-hydroxyazetidin-1-yl) methanone

To example 304 step 1 the title compound is prepared in a similar manner from 4-bromo-2-methylbenzoic acid and azetidin-3-ol. LCMS (M + H)⁺＝270.0。

Step 2: (3-hydroxyazetidin-1-yl) (2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) methanone

The title compound was prepared from (4-bromo-2-methylphenyl) (3-hydroxyazetidin-1-yl) methanone and BPD in a similar manner to that in example 308, step 1. LCMS (M + H)⁺＝318.3。

And step 3: (4- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -2-methylphenyl) (3-hydroxyazetidin-1-yl) methanone

Prepared in a similar manner to that in example 330, step 2 from (3-hydroxyazetidin-1-yl) (2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) methanone and 3-bromo-5-chloro-1H-pyrrolo [2,3-b ]Pyridine the title compound was prepared. LCMS (M + H)⁺＝342.1。

And 4, step 4: 1- [4- (5- [3, 5-dimethyl-4- [4- (1-methylpiperidin-4-yl) piperazin-1-yl ] phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl) -2-methylbenzoyl ] azetidin-3-ol

Prepared in a similar manner to that described in step 2 of example 311 from 1- [2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-4- (1-methylpiperidin-4-yl) piperazine and 1- (4- [ 5-chloro-1H-pyrrolo [2, 3-b)]Pyridin-3-yl]-2-methylbenzoyl) azetidin-3-ol preparation example 403.¹H NMR(400MHz,DMSO-d6)δ12.04(brs,1H),8.50(s,1H),8.37(s,1H),7.96(s,1H),7.68-7.60(m,2H),7.37-7.29(m,3H),5.80-5.75(m,1H),4.53-4.49(m,1H),4.29-4.20(m,1H),4.15-4.09(m,1H),3.82-3.77(m,1H),3.75-3.71(m,1H),3.10-3.04(m,4H),2.88-2.82(m,2H),2.63-2.57(m,4H),2.42-2.35(m,9H),2.21-2.15(m,4H),1.93-1.89(m,2H),1.79-1.75(m,2H),1.53-1.41(m,2H)。LC-MS(M+H)⁺＝593.4。

Example 404: 5- (3- (4- (3-hydroxyazetidin-1-carbonyl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) -3-methyl-2- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) benzonitrile (compound 404)

Step 1: (4-bromophenyl) (3-hydroxyazetidin-1-yl) methanone

The title compound was prepared from 4-bromobenzoic acid and azetidin-3-ol in a similar manner to that in example 304, step 1. LCMS (M + H)⁺＝256.1。

Step 2: (3-hydroxyazetidin-1-yl) (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) methanone

The title compound was prepared from (4-bromophenyl) (3-hydroxyazetidin-1-yl) methanone and BPD in a similar manner as in example 308, step 1. LCMS (M + H) ⁺＝304.2。

And step 3: (4- (5-bromo-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (3-hydroxyazetidin-1-yl) methanone

Prepared in a similar manner to that described in step 2 of example 332 from (3-hydroxyazetidin-1-yl) (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) methanone and 5-bromo-3-iodo-1-toluenesulfonyl-1H-pyrrolo [2,3-b ] -c]Pyridine the title compound was prepared. LCMS (M + H)⁺＝526.0。

And 4, step 4: (3-hydroxyazetidin-1-yl) (4- (5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone

Prepared from (4- (5-bromo-1-toluenesulfonyl-1H-pyrrolo [2, 3-b) in a similar manner to that in example 308, step 1]Pyridin-3-yl) phenyl) (3-hydroxyazetidin-1-yl) methanone and BPD the title compound was prepared. LCMS (M + H)⁺＝574.4。

And 5: 3-methyl-2- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) -5-nitrobenzonitrile

To a solution of 2-fluoro-3-methyl-5-nitrobenzonitrile (342mg, 1.899mmol) in DMF (10mL) at room temperature was added 1- (1-methylpiperidin-4-yl) piperazine (418mg, 2.278mmol), Cs₂CO₃(937.25mg, 2.848 mmol). The resulting mixture was stirred at 120 ℃ under a nitrogen atmosphere for 2 h. When the reaction was complete, the reaction was then diluted by the addition of water (10 mL). The resulting solution was extracted with ethyl acetate (30mLx 3). The organic phases were combined, washed with brine and over Na ₂SO₄And (5) drying. The solution was concentrated under reduced pressure and the residue was applied to a C18 gel column and purified by flash chromatography using MeCN (containing 10mmol/L NH) in water₄HCO₃) Eluting with a gradient of 0% to 80% over 45min to give 3-methyl-2- [4- (1-methylpiperidin-4-yl) piperazin-1-yl as a pale yellow solid]-5-nitrobenzonitrile (241mg, 37%). LCMS (M + H)⁺＝344.2。

Step 6: 5-amino-3-methyl-2- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) benzonitrile

To 3-methyl-2- [4- (1-methylpiperidin-4-yl) piperazin-1-yl under a nitrogen atmosphere at room temperature]To a solution of-5-nitrobenzonitrile (208mg, 0.606mmol) in THF (10mL) were added Pd/C (8mg, 0.073mmol), H₂O (5 mL). The reaction flask was evacuated and flushed with hydrogen. The resulting mixture was stirred at room temperature under a hydrogen atmosphere with a hydrogen balloon for 2 h. The solids were removed by filtration. The filtrate was concentrated under reduced pressure to give 5-amino-3-methyl-2- [4- (1-methylpiperidin-4-yl) piperazin-1-yl as a yellow solid]Benzonitrile (190mg, 99%). LC-MS (M + H)⁺＝314.2。

And 7: 5-bromo-3-methyl-2- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) benzonitrile

To a solution of CuBr (280mg, 1.952mmol) in MeCN (10mL) at 0 deg.C was added 5-amino-3-methyl-2- [4- (1-methylpiperidin-4-yl) piperazin-1-yl ]Benzonitrile (61mg, 0.195mmol) solution. The resulting mixture was stirred at 0 ℃ for 15min, and then tert-butyl nitrite (400mg, 3.900mmol) was added slowly at 0 ℃. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 h. When the reaction was complete, the reaction was then quenched by the addition of ice water (5 mL). NH for the resulting solution₄OH was adjusted to pH 8 and extracted with DCM (50mLx 3). The organic phases were combined, washed with brine and over Na₂SO₄And (5) drying. The solvent was concentrated under reduced pressure and the residue was taken upThe material was purified by flash chromatography, eluting with EtOAc in hexanes (gradient 0% to 10%) to yield (45mg, 61%) as a yellow solid. LC-MS (M + H)⁺＝377.3。

And 8: 5- (3- (4- (3-hydroxyazetidin-1-carbonyl) phenyl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridin-5-yl) -3-methyl-2- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) benzonitrile

Prepared in a similar manner to that described in step 2 of example 332 from (3-hydroxyazetidin-1-yl) (4- (5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-toluenesulfonyl-1H-pyrrolo [2,3-b ] ne]Pyridin-3-yl) phenyl) methanone and 5-bromo-3-methyl-2- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) benzonitrile the title compound is prepared. LCMS (M + H) ⁺＝744.4。

And step 9: 5- (3- (4- (3-hydroxyazetidin-1-carbonyl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) -3-methyl-2- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) benzonitrile

To 5- [3- [4- (3-hydroxyazetidine-1-carbonyl) phenyl at room temperature]-1- (4-Methylbenzenesulfonyl) -1H-pyrrolo [2,3-b]Pyridin-5-yl]-3-methyl-2- [4- (1-methylpiperidin-4-yl) piperazin-1-yl]To a solution of benzonitrile (40mg, 0.054mmol) in DMF (4mL) was added LiOH₂O (91mg, 2.151mmol), 2-sulfanylacetic acid (99mg, 1.075 mmol). The resulting mixture was stirred at 40 ℃ under a nitrogen atmosphere for h. When the reaction was complete, the reaction was then diluted by the addition of water (10 mL). The resulting solution was extracted with ethyl acetate (40mLx 3). The organic phases were combined, washed with brine and over Na₂SO₄And (5) drying. The solvent was concentrated under reduced pressure and the residue was purified by preparative HPLC under the following conditions: column: XBridge prep C18 OBD column, 150x19mm, 5 um; mobile phase: acetonitrile in water (containing 10mmol/L NH)₄HCO₃And 0.1% NH₃.H₂O), gradient 25% to 53% over 7 min; a detector: UV 254 nm. To obtain 5- (3- (4- (3-hydroxyazetidine-1-carbonyl) phenyl) -1H-pyrrolo [2,3-b]Pyridin-5-yl) -3-methyl-2- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) benzonitrile (16mg, 50%). ¹H NMR(400MHz,DMSO-d6)δ12.18(brs,1H),8.59(s,1H),8.53(s,1H),8.07(s,1H),8.01-7.99(m,1H),7.96-7.88(m,3H),7.75-7.68(m,2H),5.83-5.80(m,1H),4.55-4.51(m,2H),4.30-4.25(m,1H),4.12-4.08(m,1H),3.83-3.79(m,1H),3.27-3.11(m,4H),2.84-2.75(m,2H),2.66-2.61(m,4H),2.39(s,3H),2.23-2.10(m,4H),1.90-1.79(m,2H),1.78-1.72(m,2H),1.48-1.42(m,2H)。LC-MS(M+H)⁺＝590.4。

Example 405: 2- [4- (5- [3, 5-dimethyl-4- [4- (1-methylpiperidin-4-yl) piperazin-1-yl ] phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl) -2-methylbenzoyl ] -2-azaspiro [3.3] hept-6-ol (compound 405)

Step 1: 2- (4-bromo-2-methylbenzoyl) -2-azaspiro [3.3] hept-6-ol

Prepared from 4-bromo-2-methylbenzoic acid and 2-azaspiro [3.3] in a similar manner to that in example 304, step 1]Hept-6-ol the title compound was prepared. LCMS (M + H)⁺＝310.0。

Step 2: 2- [ 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoyl ] -2-azaspiro [3.3] heptan-6-ol

Prepared from 2- (4-bromo-2-methylbenzoyl) -2-azaspiro [3.3] in a similar manner to that in example 308, step 1]Hept-6-ol and BPD the title compound was prepared. LCMS (M + H)⁺＝358.2。

And step 3: 2- (4- [ 5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl ] -2-methylbenzoyl) -2-azaspiro [3.3] hept-6-ol

Prepared in a similar manner to that in step 2 of example 330 from 2- [ 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoyl]-2-azaspiro [3.3]Hept-6-ol and 3-bromo-5-chloro-1H-pyrrolo [2,3-b ]]Pyridine the title compound was prepared. LCMS (M + H)⁺＝382.2。

And 4, step 4: 2- [4- (5- [3, 5-dimethyl-4- [4- (1-methylpiperidin-4-yl) piperazin-1-yl ] phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl) -2-methylbenzoyl ] -2-azaspiro [3.3] hept-6-ol

Prepared in a similar manner to that described in step 2 of example 311 from 1- [2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-4- (1-methylpiperidin-4-yl) piperazine and 2- (4- [ 5-chloro-1H-pyrrolo [2, 3-b)]Pyridin-3-yl]-2-methylbenzoyl) -2-azaspiro [3.3]Hept-6-ol preparation example 405.¹H NMR(400MHz,DMSO-d6)δ12.04(brs,1H),8.50(s,1H),8.36(s,1H),7.95(s,1H),7.67-7.58(m,2H),7.37-7.29(m,3H),5.10-5.04(m,1H),4.04-3.88(m,5H),3.10-3.03(m,4H),2.83-2.78m,2H),2.62-2.54(m,4H),2.47-2.41(m,3H),2.38-2.31(m,9H),2.19-2.15(m,1H),2.14(s,3H),2.04-1.91(m,2H),1.88-1.82(m,2H),1.80-1.71(m,2H),1.52-1.39(m,2H)。LC-MS(M+H)⁺＝633.4。

Example 406: 2- [4- (5- [3, 5-dimethyl-4- [4- (1-methylpiperidin-4-yl) piperazin-1-yl ] phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzoyl ] -2-azaspiro [3.3] hept-6-ol (compound 406)

Step 1: (4- [ 6-hydroxy-2-azaspiro [3.3] heptane-2-carbonyl ] phenyl) boronic acid

Prepared from 4-dihydroxybenzoic acid and 2-azaspiro [3.3] in a similar manner to that in step 1 of example 304]Hept-6-ol the title compound was prepared. LCMS (M + H)⁺＝262.1。

Step 2: 2- (4- [ 5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) -2-azaspiro [3.3] hept-6-ol

Prepared from (4- [ 6-hydroxy-2-azaspiro [3.3] in a similar manner to that in step 2 of example 330]Heptane-2-carbonyl]Phenyl) boronic acid and 3-bromo-5-chloro-1H-pyrrolo [2,3-b]Pyridine the title compound was prepared. LCMS (M + H)⁺＝368.1。

And step 3: 2- [4- (5- [3, 5-dimethyl-4- [4- (1-methylpiperidin-4-yl) piperazin-1-yl ] phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzoyl ] -2-azaspiro [3.3] hept-6-ol

Prepared from 1- [2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan in a similar manner to that described in step 2 of example 311Alk-2-yl) phenyl]-4- (1-methylpiperidin-4-yl) piperazine and 2- (4- [ 5-chloro-1H-pyrrolo [2, 3-b)]Pyridin-3-yl]Benzoyl) -2-azaspiro [3.3]Hept-6-ol preparation example 406.¹H NMR(400MHz,DMSO-d6)δ12.11(brs,1H),8.52(s,1H),8.40(s,1H),8.04(s,1H),7.86(d,J＝8.3Hz,2H),7.70(d,J＝8.2Hz,2H),7.37(s,2H),5.10-5.04(m,1H),4.36-4.28(m,2H),4.30-3.99(m,3H),3.10-3.04(m,4H),2.87-2.83(m,2H),2.68-2.58(m,4H),2.50-2.43(m,2H),2.37(s,6H),2.23-2.11(m,5H),2.18-1.92(m,4H),1.80-1.75(m,2H),1.51-1.45(m,2H)。LC-MS(M+H)⁺＝619.8。

Example 407: 2- (4- [5- [3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) -2-azaspiro [3.3] hept-6-ol (compound 407)

Prepared in a similar manner to that described in step 2 of example 311 from 1- [2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-4-methylpiperazine and 2- (4- [ 5-chloro-1H-pyrrolo [2, 3-b)]Pyridin-3-yl]Benzoyl) -2-azaspiro [3.3]Hept-6-ol preparation example 407.¹H NMR(400MHz,DMSO-d6)δ12.11(brs,1H),8.52(s,1H),8.40(s,1H),8.04(s,1H),7.90-7.83(m,2H),7.70(d,J＝8.2Hz,2H),7.37(s,2H),5.08-5.05(m,1H),4.36-4.30(m,2H),4.05-3.99(m,3H),3.10-3.04(m,4H),2.52-2.42(m,6H),2.37(s,6H),2.26(s,3H),2.10-1.90(m,2H)。LC-MS(M+H)⁺＝536.3。

Example 408: 2- (4- [5- [ 3-methoxy-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) -2-azaspiro [3.3] hept-6-ol (compound 408)

Prepared in a similar manner to that described in step 2 of example 311 from 1- [ 2-methoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-4-methylpiperazine and 2- (4- [ 5-chloro-1H-)Pyrrolo [2,3-b]Pyridin-3-yl ]Benzoyl) -2-azaspiro [3.3]Hept-6-ol preparation example 408.¹H NMR(400MHz,DMSO-d6)δ12.12(s,1H),8.58(s,1H),8.43(s,1H),8.04(s,1H),7.87(d,J＝8.3Hz,2H),7.70(d,J＝8.1Hz,2H),7.29-7.25(m,2H),7.05-6.95(m,1H),5.10-5.04(m,1H),4.35-4.30(m,2H),4.04-3.99(s,2H),3.91(s,3H),3.12-3.08(m,4H),2.50-2.40(m,7H),2.24(s,3H),2.02-1.97(m,2H)。LC-MS(M+H)⁺＝538.3。

Example 409: 1- [4- [5- (4- [4- [1- (2-hydroxyethyl) piperidin-4-yl ] piperazin-1-yl ] -3, 5-dimethylphenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl ] azetidin-3-ol (compound 409)

Step 1: 1- (4-chloro-2, 6-dimethylphenyl) piperazine

The title compound was prepared from 2-bromo-5-chloro-1, 3-dimethylbenzene and piperazine in a similar manner to that in example 385 step 3. LCMS (M + H)⁺＝225.2。

Step 2: 4- (4- (4-chloro-2, 6-dimethylphenyl) piperazin-1-yl) piperidine-1-carboxylic acid tert-butyl ester

The title compound was prepared from 1- (4-chloro-2, 6-dimethylphenyl) piperazine and 4-oxopiperidine-1-carboxylic acid tert-butyl ester in a similar manner to that in example 369, step 3. LCMS (M + H)⁺＝408.2。

And step 3: 1- (4-chloro-2, 6-dimethylphenyl) -4- (piperidin-4-yl) piperazine

The title compound was prepared from tert-butyl 4- (4- (4-chloro-2, 6-dimethylphenyl) piperazin-1-yl) piperidine-1-carboxylate in a similar manner to that in example 309, step 5. LCMS (M + H)⁺＝308.2。

And 4, step 4: 2- (4- (4- (4-chloro-2, 6-dimethylphenyl) piperazin-1-yl) piperidin-1-yl) ethanol

The title compound was prepared from 1- (4-chloro-2, 6-dimethylphenyl) -4- (piperidin-4-yl) piperazine and 2-bromoethanol in a similar manner to that in example 472 step 1. LCMS (M + H) ⁺＝352.2。

And 5: 2- (4- (4- (2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) piperazin-1-yl) piperidin-1-yl) ethanol

The title compound was prepared from 2- (4- (4- (4-chloro-2, 6-dimethylphenyl) piperazin-1-yl) piperidin-1-yl) ethanol and BPD in a similar manner to that in example 308, step 1. LCMS (M + H)⁺＝444.3。

Step 6: (3-hydroxyazetidin-1-yl) (4- (5- (4- (4- (1- (2-hydroxyethyl) piperidin-4-yl) piperazin-1-yl) -3, 5-dimethylphenyl) -1-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone

In a manner analogous to that in example 332, step 2, from 2- (4- (4- (2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) piperazin-1-yl) piperidin-1-yl) ethanol and (4- (5-bromo-1-toluenesulfonyl-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) phenyl) (3-hydroxyazetidin-1-yl) methanone the title compound was prepared. LCMS (M + H)⁺＝763.3。

And 7: 1- [4- [5- (4- [4- [1- (2-hydroxyethyl) piperidin-4-yl ] piperazin-1-yl ] -3, 5-dimethylphenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl ] azetidin-3-ol

Prepared in a similar manner to that in example 369, step 6 from (3-hydroxyazetidin-1-yl) (4- (5- (4- (4- (1- (2-hydroxyethyl) piperidin-4-yl) piperazin-1-yl) -3, 5-dimethylphenyl) -1-toluenesulfonyl-1H-pyrrolo [2, 3-b) ]Pyridin-3-yl) phenyl) methanone preparation example 409.¹H NMR(400MHz,DMSO-d₆)δ12.12(brs,1H),8.52(s,1H),8.41(s,1H),8.04(d,J＝2.7Hz,1H),7.91-7.84(m,2H),7.74-7.68(m,2H),,7.37(s,2H),5.82-5.76(m,1H),4.55-4.51(m,3H),4.36-4.02(m,2H),3.84-3.80(m,1H),3.54-3.49(m,3H),3.14-2.85(m,6H),2.64-2.58(m,4H),2.48-2.43(m,1H),2.37(s,6H),2.29-2.24(m,1H),2.15-1.93(m,2H),1.82-1.74(m,2H),1.53-1.45(m,3H)。LC-MS(M+H)⁺＝609.4。

Example 410: 1- [4- (5- [4- [4- (2-hydroxyethyl) piperazin-1-yl ] -3, 5-dimethylphenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzoyl ] azetidin-3-ol (Compound 410)

Step 1: 2- (4- (4- (4-chloro-2, 6-dimethylphenyl) piperazin-1-yl) piperidin-1-yl) ethanol

The title compound was prepared from 1- (4-chloro-2, 6-dimethylphenyl) piperazine and 2-bromoethanol in a similar manner to that in example 472, step 1. LCMS (M + H)⁺＝269.1。

Step 2: 2- [4- [2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] piperazin-1-yl ] ethanol

Prepared in a similar manner to that in example 308, step 1 from 2- [4- (4-chloro-2, 6-dimethylphenyl) piperazin-1-yl]Ethanol and BPD the title compound was prepared. LCMS (M + H)⁺＝361.2。

And step 3: (3-hydroxyazetidin-1-yl) (4- (5- (4- (4- (2-hydroxyethyl) piperazin-1-yl) -3, 5-dimethylphenyl) -1-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone

Prepared in a similar manner to that described in step 2 of example 332 from 2- [4- [2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Piperazin-1-yl]Ethanol and 1- [4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] ]Pyridin-3-yl]Benzoyl radical]Azetidin-3-ol the title compound was prepared. LCMS (M + H)⁺＝680.4。

And 4, step 4: 1- [4- (5- [4- [4- (2-hydroxyethyl) piperazin-1-yl ] -3, 5-dimethylphenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzoyl ] azetidin-3-ol

Prepared from 1- [4- (5- [4- [4- (2-hydroxyethyl) piperazin-1-yl ] in a similar manner to that described in example 369, step 6]-3, 5-dimethylphenyl]-1- (4-Methylbenzenesulfonyl) -1H-pyrrolo [2,3-b]Pyridin-3-yl) benzoyl]Azetidin-3-ol preparation example 410.¹H NMR(400MHz,DMSO-d6)δ12.11(brs,1H),8.52(s,1H),8.41(s,1H),8.04(s,1H),7.88(d,J＝8.0Hz,2H),7.71(d,J＝8.0Hz,2H),7.37(s,2H),5.80-5.75(m,1H),4.55-4.35(m,3H),,4.30-4.26(m,1H),4.12-4.08(m,1H),3.90-3.76(m,1H),3.60-3.52(m,2H),3.10-3.04(m,4H),2.60-2.53(m,4H),2.46-2.39(m,4H),2.38(s,6H),2.08(s,1H)。LC-MS(M+H)⁺＝526.2。

Example 411: 5- (3- (4- (3-Hydroxyazetidine-1-carbonyl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) -2- (4- (2-hydroxyethyl) piperazin-1-yl) -3-methylbenzonitrile (Compound 411)

Step 1: 2-fluoro-3-methyl-5-nitrobenzonitrile

To 2-fluoro-3-methylbenzonitrile (1.80g, 13.186mmol) in H at 0 deg.C₂SO₄KNO was added to the solution (25mL)₃(1.35g, 13.186 mmol). The resulting mixture was stirred at room temperature for 2 h. When the reaction was complete, the mixture was poured into ice water (100 mL). The precipitated solid was collected by filtration and washed with water (50mLx 2). The crude product was purified by flash chromatography eluting with EtOAc in hexanes (gradient 0% to 65%) to give 2-fluoro-3-methyl-5-nitrobenzonitrile (1.22g, 52%) as a pale yellow solid. ¹H NMR(400MHz,DMSO-d6,ppm)δ881-8.71(m,1H),8.66-8.56(m,1H),3.34(s,3H)。

Step 2: 2- (4- (2-hydroxyethyl) piperazin-1-yl) -3-methyl-5-nitrobenzonitrile

To a solution of 2-fluoro-3-methyl-5-nitrobenzonitrile (500mg, 2.635mmol) in DMSO (20mL) was added 2- (piperazin-1-yl) ethan-1-ol (513mg, 3.955mmol), DIEA (685mg, 1.055mmol) at room temperature. The resulting mixture was stirred at 100 ℃ under a nitrogen atmosphere for 16 h. When the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with EtOAc in hexanes (gradient 0% to 50%) to give 2- (4- (2-hydroxyethyl) piperazin-1-yl) -3-methyl-5-nitrobenzonitrile (523mg, 60%) as a yellow solid. LCMS (M + H)⁺＝291.1。

And step 3: 5-amino-2- (4- (2-hydroxyethyl) piperazin-1-yl) -3-methylbenzonitrile

Prepared from 2- (4- (2-hydroxyethyl) piperazine in a similar manner to that in step 6 of example 404Oxazin-1-yl) -3-methyl-5-nitrobenzonitrile the title compound was prepared. LCMS (M + H)⁺＝261.2。

And 4, step 4: 5-bromo-2- [4- (2-hydroxyethyl) piperazin-1-yl ] -3-methylbenzonitrile

The title compound was prepared from 5-amino-2- (4- (2-hydroxyethyl) piperazin-1-yl) -3-methylbenzonitrile in a similar manner to that in example 330, step 4. LCMS (M + H)⁺＝324.1。

And 5: 2- [4- (2-hydroxyethyl) piperazin-1-yl ] -3-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzonitrile

The title compound was prepared from 5-bromo-2- (4- (2-hydroxyethyl) piperazin-1-yl) -3-methylbenzonitrile and BPD in a similar manner to that in example 308, step 1. LCMS (M + H)⁺＝361.3。

Step 6: 5- (3- (4- (3-hydroxyazetidine-1-carbonyl) phenyl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridin-5-yl) -2- (4- (2-hydroxyethyl) piperazin-1-yl) -3-methylbenzonitrile

From 2- [4- (2-hydroxyethyl) piperazin-1-yl in a similar manner to that in example 311, step 2]-3-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzonitrile and 1- [4- [ 5-bromo-1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b ] -pyrrole]Pyridin-3-yl]Benzoyl radical]Azetidin-3-ol the title compound was prepared. LCMS (M + H)⁺＝691.4。

And 7: 5- (3- (4- (3-hydroxyazetidine-1-carbonyl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) -2- (4- (2-hydroxyethyl) piperazin-1-yl) -3-methylbenzonitrile

Prepared in a similar manner to that described in example 369, step 6 from 5- (3- (4- (3-hydroxyazetidine-1-carbonyl) phenyl) -1-toluenesulfonyl-1H-pyrrolo [2,3-b]Pyridin-5-yl) -2- (4- (2-hydroxyethyl) piperazin-1-yl) -3-methylbenzonitrile preparation example 411.¹H NMR(400MHz,DMSO-d6)δ12.17(brs,1H),8.59(s,1H),8.53(s,1H),8.06(s,1H),8.00(s,1H),7.96-7.87(m,3H),7.78-7.67(m,2H),5.82-5.80(m,1H),4.55-4.46(m,3H),4.30-4.25(m,1H),4.12-4.09(m,1H),3.84-3.79(m,1H),3.60-3.50(m,2H),3.25-3.19(m,4H),2.62-2.56(m,4H),2.50-2.45(m,1H),2.40(s,3H)。LC-MS(M+H)⁺＝537.3。

Example 412: (3-Hydroxyazetidin-1-yl) (4- (5- (4- (4- (2-hydroxyethyl) piperazin-1-yl) -3-methoxyphenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone (Compound 412)

Step 1: 2- (4- (4-chloro-2-methoxyphenyl) piperazin-1-yl) ethanol

The title compound was prepared from 1-bromo-4-chloro-2-methoxybenzene and 2- (piperazin-1-yl) ethanol in a similar manner to that in example 385 step 3. LCMS (M + H)⁺＝271.1。

Step 2: 2- (4- (2-methoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) piperazin-1-yl) ethanol

Prepared from 2- [4- (4-chloro-2-methoxyphenyl) piperazin-1-yl in a similar manner to that described in step 1 of example 308]Ethanol and BPD the title compound was prepared. LCMS (M + H)⁺＝363.1。

And step 3: (3-hydroxyazetidin-1-yl) (4- (5- (4- (4- (2-hydroxyethyl) piperazin-1-yl) -3-methoxyphenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone

Prepared in a similar manner to that described in step 2 of example 311 from 2- [4- [ 2-methoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Piperazin-1-yl]Ethanol and 1- (4- [ 5-chloro-1H-pyrrolo [2,3-b ]]Pyridin-3-yl]Benzoyl) azetidin-3-ol preparation example 412.¹H NMR(400MHz,DMSO-d6)δ12.09(brs,1H),8.56(s,1H),8.44(s,1H),8.02(s,1H),7.88(d,J＝8.1Hz,2H),7.70(d,J＝8.1Hz,2H),7.25(d,J＝6.7Hz,2H),6.99(d,J＝8.2Hz,1H),5.85-5.82(m,1H),4.55-4.49(m,3H),4.29-4.25(m,1H),4.12-4.07(m,1H),3.89(s,3H),3.85-3.75(m,1H),3.60-3.50(m,2H),3.05-2.95(m,4H),2.62-2.55(m,4H),2.48-2.42(m,2H)。LC-MS(M+H)⁺＝528.2。

Example 413: 5- (3- (4- (3-Hydroxyazetidine-1-carbonyl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) -2- (4- (2-hydroxyethyl) piperazin-1-yl) benzonitrile (Compound 413)

Step 1: 5-bromo-2- (4- (2-hydroxyethyl) piperazin-1-yl) benzonitrile

The title compound was prepared from 5-bromo-2-fluorobenzonitrile and 2- (piperazin-1-yl) ethanol in a similar manner to that in example 404, step 5. LCMS (M + H)⁺＝310.1。

Step 2: 2- (4- (2-hydroxyethyl) piperazin-1-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzonitrile

Prepared in a similar manner to that in step 1 of example 308 from 5-bromo-2- [4- (2-hydroxyethyl) piperazin-1-yl]Benzonitrile and BPD the title compound was prepared. LCMS (M + H)⁺＝358.2。

And step 3: 2- (4- (2-hydroxyethyl) piperazin-1-yl) -5- (1H-pyrrolo [2,3-b ] pyridin-5-yl) benzonitrile

From 2- [4- (2-hydroxyethyl) piperazin-1-yl in a similar manner to that in example 311, step 2]-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzonitrile and 5-bromo-1H-pyrrolo [2,3-b ]]Pyridine the title compound was prepared. LCMS (M + H)⁺＝348.2。

And 4, step 4: 2- (4- (2-hydroxyethyl) piperazin-1-yl) -5- (3-iodo-1H-pyrrolo [2,3-b ] pyridin-5-yl) benzonitrile

Prepared in a similar manner to that in example 313, step 4 from 2- (4- (2-hydroxyethyl) piperazin-1-yl) -5- (1H-pyrrolo [2,3-b ]]Pyridin-5-yl) benzonitrile and NIS the title compound was prepared. LCMS (M + H)⁺＝474.2。

And 5: 5- (3- (4- (3-hydroxyazetidine-1-carbonyl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) -2- (4- (2-hydroxyethyl) piperazin-1-yl) benzonitrile

From 2- [4- (2-hydroxyethyl) piperazin-1-yl in a similar manner to that in step 8 of example B03]-5- [ 3-iodo-1H-pyrrolo [2,3-b]Pyridin-5-yl]Benzonitrile and 1- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoyl]Azetidin-3-ol preparation example 413.¹H NMR(400MHz,DMSO-d6)δ12.18(brs,1H),8.59(s,1H),8.53(s,1H),8.20(s,1H),8.08(s,1H),8.05-8.02(m,1H),7.96-7.89(m,2H),7.74-7.68(m,2H),7.29-7.25(m,1H),5.81-5.79(m,1H),4.53-4.43(m,3H),4.30-4.26(m,1H),4.12-4.08(m,1H),3.85-3.79(m,1H),3.66-3.50(m,2H),3.25-3.19(m,4H),2.67-2.60(m,4H),2.48-2.42(m,1H)。LC-MS(M+H)⁺＝523.4。

Example 414: n, N-dimethyl-4- (5- (4- (4-methylpiperazin-1-yl) -3- (trifluoromethoxy) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 414)

Step 1: 1- (4-bromo-2- (trifluoromethoxy) phenyl) -4-methylpiperazine

The title compound was prepared from 4-bromo-2- (trifluoromethoxy) aniline and 2-chloro-N- (2-chloroethyl) -N-methylethylamine in a similar manner to that in example 305, step 1. LCMS (M + H)⁺＝339.0。

Step 2: 1-methyl-4- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2- (trifluoromethoxy) phenyl) piperazine

Prepared from 1- [ 4-bromo-2- (trifluoromethoxy) phenyl ] in a similar manner to that in example 308, step 1]-4-methylpiperazine and BPD the title compound was prepared. LCMS (M + H)⁺＝387.3。

And step 3: n, N-dimethyl-4- (5- (4- (4-methylpiperazin-1-yl) -3- (trifluoromethoxy) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Prepared in a similar manner to that described in step 2 of example 311 from 1-methyl-4- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2- (trifluoromethoxy) phenyl ]Piperazine and 4- [ 5-chloro-1H-pyrrolo [2,3-b ]]Pyridin-3-yl]-N, N-dimethylbenzamide preparation example 414.¹H NMR(400MHz,DMSO-d6)δ12.13(brs,1H),8.56(s,1H),8.46(s,1H),8.03(s,1H),7.91-7.84(m,2H),7.75-7.73(m,1H),7.71-7.67(m,1H),7.53-7.45(m,2H),7.25(d,J＝8.4Hz,1H),3.10-3.04(m,4H),3.01(s,6H),2.48-2.42(m,4H),2.25(s,3H)。LC-MS(M+H)⁺＝524.2。

Example 415: 2- (4-Ethylpiperazin-1-yl) -5- (3- (4- (3-hydroxyazetidin-1-carbonyl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) benzonitrile (Compound 415)

Step 1: 5-bromo-2- (4-ethylpiperazin-1-yl) benzonitrile

The title compound was prepared from 5-bromo-2-fluorobenzonitrile and 1-ethylpiperazine in a similar manner to that in example 404, step 5. LCMS (M + H)⁺＝294.0。

Step 2: 2- (4-ethylpiperazin-1-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzonitrile

The title compound was prepared from 5-bromo-2- (4-ethylpiperazin-1-yl) benzonitrile and BPD in a similar manner to that in example 308, step 1. LCMS (M + H)⁺＝342.2。

And step 3: 2- (4-ethylpiperazin-1-yl) -5- (3- (4- (3-hydroxyazetidin-1-carbonyl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) benzonitrile

In a similar manner to that in example 311, step 2, starting from 2- (4-ethylpiperazin-1-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzonitrile and 1- (4- [ 5-chloro-1H-pyrrolo [2,3-b ] benzene]Pyridin-3-yl]Benzoyl) azetidin-3-ol preparation example 415. ¹H NMR(400MHz,DMSO-d6)δ12.17(brs,1H),8.59(s,1H),8.53(s,1H),8.19(s,1H),8.07-8.02(m,2H),7.92(d,J＝8.3Hz,2H),7.70(d,J＝8.3Hz,2H),7.26(d,J＝8.7Hz,1H),5.79-5.76(m,1H),4.56-4.46(m,2H),4.29-4.25(m,1H),4.12-4.08(m,1H),3.85-3.80(m,1H),3.27-3.06(m,4H),2.60-2.57(m,4H),2.42-2.30(m,2H),1.10-1.00m,3H)。LC-MS(M+H)⁺＝507.2。

Example 416: 4- (5- (3-methoxy-4- (1-methylpiperidin-4-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (Compound 416)

Step 1: 4- (2-methoxy-4-nitrophenyl) -1-methyl-1, 2,3, 6-tetrahydropyridine

The title compound was prepared from 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,2,3, 6-tetrahydropyridine and 1-bromo-2-methoxy-4-nitrobenzene in a similar manner to that in example 332, step 2. LCMS (M + H)⁺＝249.1。

Step 2: 3-methoxy-4- (1-methylpiperidin-4-yl) aniline

The title compound was prepared from 4- (2-methoxy-4-nitrophenyl) -1-methyl-1, 2,3, 6-tetrahydropyridine in a similar manner to that in example 293, step 8. LCMS (M + H)⁺＝221.2。

And step 3: 4- (4-bromo-2-methoxyphenyl) -1-methylpiperidine

The title compound was prepared from 3-methoxy-4- (1-methylpiperidin-4-yl) aniline in a similar manner to the procedure in example 320, step 4. LCMS (M + H)⁺＝286.1。

And 4, step 4: 4- (2-methoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -1-methylpiperidine

The title compound was prepared from 4- (4-bromo-2-methoxyphenyl) -1-methylpiperidine and BPD in a similar manner to the process described in example 308, step 1. LCMS (M + H) ⁺＝332.2。

And 5: 4- (5- (3-methoxy-4- (1-methylpiperidin-4-yl) phenyl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide

Prepared in a similar manner to that described in step 2 of example 311 from 4- [ 2-methoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-1-methylpiperidine and 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b ]]Pyridin-3-yl]-N, N-dimethylbenzamide. LCMS (M + H)⁺＝623.3。

Step 6: 4- (5- (3-methoxy-4- (1-methylpiperidin-4-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide

Prepared in a similar manner to that described in example 369, step 6 from 4- [5- [ 3-methoxy-4- (1-methylpiperidin-4-yl) phenyl]-1- (4-Methylbenzenesulfonyl) -1H-pyrrolo [2,3-b]Pyridin-3-yl]-N, N-dimethylbenzamide preparation example 416.¹H NMR(400MHz,DMSO-d6)δ12.13-12.08(m,1H),8.60(s,1H),8.47(s,1H),8.02(s,1H),7.87(d,J＝8.0Hz,2H),7.49(d,J＝7.9Hz,2H),7.30-7.27(m,3H),3.91(s,3H),3.01(s,6H),2.90-2.80(m,3H),2.20(s,3H),2.02-1.92(m,2H),1.73-1.60(m,4H)。LC-MS(M+H)⁺＝469.3。

Example 417: 5- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -2-methylisoindolin-1-one (Compound 417)

Step 1: 2-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoindolin-1-one

The title compound was prepared from 5-bromo-2-methylisoindolin-1-one and BPD in analogy to the procedure in example 332, step 2. LCMS (M + H) ⁺＝274.1。

Step 2: 5- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -2-methylisoindolin-1-one

Prepared in a similar manner to that described in example 330, step 2 from 2-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoindolin-1-one and 3-bromo-5-chloro-1H-pyrrolo [2,3-b ]]Pyridine the title compound was prepared. LCMS (M + H)⁺＝298.1。

And step 3: 5- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -2-methylisoindolin-1-one

Prepared from 5- [ 5-chloro-1H-pyrrolo [2,3-b ] in a similar manner to that in step 2 of example 311]Pyridin-3-yl]-2-methyl-2, 3-dihydro-1H-isoindol-1-one and 1- [2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-4-methylpiperazine preparation example 417.¹H NMR(400MHz,DMSO-d6)δ12.11(s,1H),8.52(s,1H),8.45(s,1H),8.05(s,1H),8.00(s,1H),7.90(d,J＝7.9Hz,1H),7.72(d,J＝7.9Hz,1H),7.37(s,2H),4.53(s,2H),3.12-3.02(m,7H),2.50-2.40(m,4H),2.37(s,6H),2.26(s,3H)。LC-MS(M+H)⁺＝466.5。

Example 418: 6- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -2-methyl-3, 4-dihydroisoquinolin-1 (2H) -one (compound 418)

Step 1: 6-bromo-2-methyl-3, 4-dihydroisoquinolin-1 (2H) -one

The title compound was prepared from 6-bromo-3, 4-dihydroisoquinolin-1 (2H) -one and MeI in a similar manner to that in example 394 step 1. LCMS (M + H)⁺＝240.0。

Step 2: 2-methyl-6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydroisoquinoline-1 (2H) -one

The title compound was prepared from 6-bromo-2-methyl-3, 4-dihydroisoquinolin-1-one and BPD in a similar manner to that in example 308, step 1. LCMS (M + H)⁺＝288.2。

And step 3: 6- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -2-methyl-3, 4-dihydroisoquinolin-1 (2H) -one

In a similar manner to that described in step 2 of example 330 from 2-methyl-6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydroisoquinolin-1 (2H) -one and 3-bromo-5-chloro-1H-pyrrolo [2,3-b ]]Pyridine the title compound was prepared. LCMS (M + H)⁺＝312.2。

And 4, step 4: 6- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -2-methyl-3, 4-dihydroisoquinolin-1 (2H) -one

Prepared from 6- [ 5-chloro-1H-pyrrolo [2,3-b ] in a similar manner to that in step 2 of example 311]Pyridin-3-yl]-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-1-one and 1- [2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-4-methylpiperazine preparation example 418.¹H NMR(400MHz,DMSO-d6)δ12.10(brs,1H),8.51(s,1H),8.43(s,1H),8.03(s,1H),7.93(d,J＝8.1Hz,1H),7.78(d,J＝8.1Hz,1H),7.69(d,J＝1.7Hz,1H),7.37(s,2H),3.60-3.57(m,2H),3.11-3.03(m,9H),2.48-2.41(m,4H),2.37(s,6H),2.26(s,3H)。LC-MS(M+H)⁺＝480.5。

Example 419: 8- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -4-methyl-3, 4-dihydrobenzo [ f ] [1,4] oxazepin-5 (2H) -one (Compound 419)

Step 1: 4-bromo-2- (2- (tert-butoxycarbonyl (methyl) amino) ethoxy) benzoic acid methyl ester

The title compound was prepared from methyl 4-bromo-2-hydroxybenzoate and tert-butyl N- (2-hydroxyethyl) -N-methylcarbamate in a similar manner to that in example 336, step 1. LCMS (M + H)⁺＝388.1。

Step 2: 4-bromo-2- (2- (tert-butoxycarbonyl (methyl) amino) ethoxy) benzoic acid

Prepared in a similar manner to that in step 1 of example 382 from 4-bromo-2- (2- [ [ (tert-butoxy) carbonyl)](methyl) amino group]Ethoxy) benzoic acid methyl ester the title compound was prepared. LCMS (M + H)⁺＝374.1。

And step 3: 4-bromo-2- (2- (methylamino) ethoxy) benzoic acid

Prepared in a similar manner to that in step 4 of example 324 from 4-bromo-2- (2- [ [ (tert-butoxy) carbonyl](methyl) amino group]Ethoxy) benzoic acid the title compound was prepared. LCMS (M + H)⁺＝274.0。

And 4, step 4: 8-bromo-4-methyl-3, 4-dihydrobenzo [ f ] [1,4] oxazepin-5 (2H) -one

The title compound was prepared from 4-bromo-2- (2- (methylamino) ethoxy) benzoic acid in a similar manner as in example 304, step 1. LCMS (M + H)⁺＝256.0。

And 5: 4-methyl-8- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydrobenzo [ f ] [1,4] oxazepin-5 (2H) -one

Prepared in a similar manner to that in step 1 of example 308 from 8-bromo-4-methyl-3, 4-dihydrobenzo [ f ][1,4]Oxazepin-5 (2H) -one and BPD the title compound was prepared. LCMS (M + H)⁺304.2. Step 6: 8- (5-bromo-1-tosyl-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) -4-methyl-3, 4-dihydrobenzo [ f][1,4]Oxazepin-5 (2H) -ones

Prepared in a similar manner to that described in example 311, step 2 from 4-methyl-8- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2,3,4, 5-tetrahydro-1, 4-benzoxazepin-5-one and 5-bromo-3-iodo-1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b]Pyridine the title compound was prepared. LCMS (M + H)⁺＝528.0。

And 7: 8- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -4-methyl-3, 4-dihydrobenzo [ f ] [1,4] oxazepin-5 (2H) -one

Prepared in a similar manner to that described in step 2 of example 311 from 8- [ 5-bromo-1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b ]]Pyridin-3-yl]-4-methyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-5-one and 1- [2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-4-methylpiperazine the title compound was prepared. LCMS (M + H)⁺＝650.2。

And 8: 8- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -4-methyl-3, 4-dihydrobenzo [ f ] [1,4] oxazepin-5 (2H) -one

Prepared in a similar manner to that in example 369, step 6 from 8- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1-toluenesulfonyl-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) -4-methyl-3, 4-dihydrobenzo [ f][1,4]Oxazepin-5 (2H) -one example 419 was prepared.¹H NMR(400MHz,DMSO-d6)δ12.11(brs,1H),8.51(s,1H),8.37(s,1H),8.04(s,1H),7.75(d,J＝8.1Hz,1H),7.63-7.50(m,2H),7.40-7.33(m,2H),4.45-4.35(m,2H),3.68-3.60(m,2H),3.11(s,3H),3.10-3.04(m,4H),2.50-2.40(m,4H),2.37(s,6H),2.26(s,3H)。LCMS(M+H)⁺＝496.3。

Example 420: 6- (4- [5- [ 3-fluoro-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) -2-oxa-6-azaspiro [3.3] heptane (compound 420)

Step 1: 1- (2-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -4-methylpiperazine

The title compound was prepared from 1- (4-chloro-2-fluorophenyl) -4-methylpiperazine and BPD in a similar manner to that in example 308, step 1. LCMS (M + H)⁺＝321.2。

Step 2: 6- [4- [ 5-bromo-1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl ] -2-oxa-6-azaspiro [3.3] heptane

Prepared from (4- [ 2-oxa-6-azaspiro [3.3] in a similar manner to that in step 2 of example 332]Heptane-6-carbonyl]Phenyl) boronic acid and 5-bromo-3-iodo-1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b]Pyridine the title compound was prepared. LCMS (M + H)⁺＝552.0。

And step 3: 6- (4- [5- [ 3-fluoro-4- (4-methylpiperazin-1-yl) phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) -2-oxa-6-azaspiro [3.3] heptane

Prepared from 6- [4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] in a similar manner to that described in step 2 of example 311]Pyridin-3-yl]Benzoyl radical]-2-oxa-6-azaspiro [3.3]Heptane and 1- [ 2-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-4-methylpiperazine the title compound was prepared. LCMS (M + H)⁺＝666.4。

And 4, step 4: 6- (4- [5- [ 3-fluoro-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) -2-oxa-6-azaspiro [3.3] heptane

Prepared in a similar manner to that described in example 369, step 6 from 6- (4- [5- [ 3-fluoro-4- (4-methylpiperazin-1-yl) phenyl)]-1- (4-Methylbenzenesulfonyl) -1H-pyrrolo [2,3-b]Pyridin-3-yl]Benzoyl) -2-oxa-6-azaspiro [3.3]Heptane preparation example 420.¹H NMR(400MHz,DMSO-d6)δ12.16(brs,1H),8.58(s,1H),8.47(s,1H),8.07(s,1H),7.91(d,J＝7.9Hz,2H),7.73-7.65(m,3H),7.60-7.53(m,1H),7.20-7.16(m,1H),4.70(s,4H),4.55(s,2H),4.23(s,2H),3.30-3.20(m,4H),3.08-2.92(m,4H),2.60(s,3H)。LC-MS(M+H)⁺＝512.3。

Example 421: (4- (5- (3-fluoro-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (3-hydroxyazetidin-1-yl) methanone (Compound 421)

Step 1: (4- (5- (3-fluoro-4- (4-methylpiperazin-1-yl) phenyl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (3-hydroxyazetidin-1-yl) methanone

Prepared in a similar manner to that described in step 2 of example 311 from 1- [4- [ 5-bromo-1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b ] ]Pyridin-3-yl]Benzoyl radical]Azetidin-3-ol and 1- [ 2-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-4-methylpiperazine the title compound was prepared. LCMS (M + H)⁺＝640.2。

Step 2: (4- (5- (3-fluoro-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (3-hydroxyazetidin-1-yl) methanone

Prepared in a similar manner to that described in example 369, step 6 from 1- (4- [5- [ 3-fluoro-4- (4-methylpiperazin-1-yl) phenyl]-1- (4-Methylbenzenesulfonyl) -1H-pyrrolo [2,3-b]Pyridin-3-yl]Benzoyl) azetidin-3-ol preparation example 421.¹H NMR(400MHz,DMSO-d6)δ12.13(brs,1H),8.57(s,1H),8.47(s,1H),8.05(s,1H),7.90(d,J＝8.0Hz,2H),7.70(d,J＝8.0Hz,2H),7.66-7.63(m,1H),7.57-7.50(m,1H),7.15-7.11m,1H),5.80-5.75(m,1H),4.55-4.50(m,2H),4.30-4.25(m,1H),4.15-4.05(m,1H),3.86-3.78(m,1H),3.10-3.00(m,4H),2.50-2.40(m,4H),2.24(s,3H)。LC-MS(M+H)⁺＝486.3。

Example 422: (3-Hydroxyazetidin-1-yl) (4- (5- (4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone (Compound 422)

Step 1: 1- (4-bromo-2- (trifluoromethyl) phenyl) -4-methylpiperazine

The title compound was prepared from 4-bromo-1-fluoro-2- (trifluoromethyl) benzene and 1-methylpiperazine in a similar manner as in example 404, step 5. LCMS (M + H)⁺＝323.1。

Step 2: (4- (5-bromo-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (3-hydroxyazetidin-1-yl) methanone

Prepared in a similar manner to that in step 2 of example 311 from 1- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoyl ]Azetidin-3-ol and 5-bromo-3-iodo-1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b]Pyridine the title compound was prepared. LCMS (M + H)⁺＝528.2。

And step 3: (3-hydroxyazetidin-1-yl) (4- (5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone

Prepared in a similar manner to that described in step 1 of example 308 from 1- [4- [ 5-bromo-1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b ]]Pyridin-3-yl]Benzoyl radical]Azetidin-3-ol and 4,4,5, 5-tetramethyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3, 2-dioxaborolan the title compound was prepared. LCMS (M + H)⁺＝574.4。

And 4, step 4: 1- [4- [1- (4-Methylbenzenesulfonyl) -5- [4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl ] azetidin-3-ol

Prepared in a similar manner to that described in step 2 of example 332 from (3-hydroxyazetidin-1-yl) (4- (5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-toluenesulfonyl-1H-pyrrolo [2,3-b ] ne]Pyridin-3-yl) phenyl) methanone and 1- (4-bromo-2- (trifluoromethyl) phenyl) -4-methylpiperazine the title compound was prepared. LCMS (M + H) ⁺＝690.5。

And 5: (3-hydroxyazetidin-1-yl) (4- (5- (4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone

Prepared in a similar manner to that described in example 369, step 6 from 1- [4- [1- (4-methylphenylsulfonyl) -5- [4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl]-1H-pyrrolo [2,3-b]Pyridin-3-yl]Benzoyl radical]Azetidin-3-ol preparation example 422.¹H NMR(400MHz,DMSO-d6)δ12.20(brs,1H),8.59(s,1H),8.53(s,1H),8.11-8.01(m,2H),7.97(d,J＝2.2Hz,1H),7.93-7.90(m,2H),7.75-7.65(m,3H),5.83-5.79(m,1H),4.60-4.43(m,2H),4.30-4.25(m,1H),4.15-4.05(m,1H),3.85-3.80(m,1H),2.98-2.89(m,4H),2.50-2.40(m,3H),2.25(s,3H)。LC-MS(M+H)⁺＝536.2。

Example 423: (4- (5- (4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (2-oxa-6-azaspiro [3.3] hept-6-yl) methanone (Compound 423)

Step 1: 1-methyl-4- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2- (trifluoromethyl) phenyl) piperazine

The title compound was prepared from 1- (4-bromo-2- (trifluoromethyl) phenyl) -4-methylpiperazine and BPD in a similar manner as in example 308 step 1. LCMS (M + H)⁺＝371.3。

Step 2: 6- [4- [1- (4-Methylbenzenesulfonyl) -5- [4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl ] -2-oxa-6-azaspiro [3.3] heptane

Prepared from 6- [4- [ 5-bromo-1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b ] in a similar manner to that described in step 2 of example 311 ]Pyridin-3-yl]Benzoyl radical]-2-oxa-6-azaspiro [3.3]Heptane and 1-methyl-4- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2- (trifluoromethyl) phenyl]Piperazine the title compound was prepared. LCMS (M + H)⁺＝716.3。

And step 3: (4- (5- (4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (2-oxa-6-azaspiro [3.3] hept-6-yl) methanone

Prepared in a similar manner to that described in example 369, step 6 from 6- [4- [1- (4-methylphenylsulfonyl) -5- [4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl]-1H-pyrrolo [2,3-b]Pyridin-3-yl]Benzoyl radical]-2-oxa-6-azaspiro [3.3]Heptane preparation example 423.¹H NMR(400MHz,DMSO-d6)δ12.19(brs,1H),8.58(s,1H),8.51(s,1H),8.13-7.82(m,5H),7.72-7.62(m,3H),4.70(s,4H),4.54(s,2H),4.23(s,2H),3.45-3.30(m,4H),2.92-2.82(m,4H),2.24(s,3H)。LC-MS(M+H)⁺＝562.3。

Example 424: 4- (5- (3-fluoro-5-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (Compound 424)

Step 1: 1- (2, 6-difluoro-4-nitrophenyl) -4-methylpiperazine

To a solution of 1,2, 3-trifluoro-5-nitrobenzene (7.13g, 40.236mmol) in DMSO (50mL) at room temperature was added K₂HPO₄(10.45g, 59.997mmol), 1-methylpiperazine (4.09g, 40.783 mmol). The resulting mixture was stirred at 120 ℃ for 5 h. When the reaction was complete, the reaction was then diluted by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (250mLx 3). The organic phases were combined, washed with brine and over Na ₂SO₄And (5) drying. The solvent was concentrated under reduced pressure and the residue was purified by flash chromatography, eluting with EtOAc in hexanes (gradient 0% to 50%) to give 1- (2, 6-difluoro-4-nitrophenyl) -4-methylpiperazine (6.43g, 91%) as a yellow solid. LCMS (M + H)⁺＝258.1。

Step 2: 1- (2-fluoro-6-methoxy-4-nitrophenyl) -4-methylpiperazine

To 1- (2, 6-difluoro-4-nitrophenyl) -4-methylpiperazine (2) at room temperature.30g, 8.931mmol) in MeOH (15mL) was added KOH (2.00g, 35.558 mmol). The resulting mixture was stirred at 85 ℃ for 6 h. When the reaction was complete, the reaction was then diluted by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (200mLx 3). The organic phases were combined, washed with brine and over Na₂SO₄And (5) drying. The solvent was concentrated under reduced pressure to give (1.72g, crude). LCMS (M + H)⁺＝270.1。

And step 3: 3-fluoro-5-methoxy-4- (4-methylpiperazin-1-yl) aniline

The title compound was prepared from 1- (2-fluoro-6-methoxy-4-nitrophenyl) -4-methylpiperazine in analogy to the procedure in example 320, step 3. LCMS (M + H)⁺＝240.1。

And 4, step 4: 1- (4-bromo-2-fluoro-6-methoxyphenyl) -4-methylpiperazine

The title compound was prepared from 3-fluoro-5-methoxy-4- (4-methylpiperazin-1-yl) aniline in a similar manner to that in example 320 step 4. LCMS (M + H) ⁺＝303.0。

And 5: 1- [ 2-fluoro-6-methoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] -4-methylpiperazine

The title compound was prepared from 1- (4-bromo-2-fluoro-6-methoxyphenyl) -4-methylpiperazine and BPD in a similar manner as in example 339, step 2. LCMS (M + H)⁺＝269.1。

Step 6: 4- (5- (3-fluoro-5-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide

Prepared in a similar manner to that described in example 369, step 6 from 1- [ 2-fluoro-6-methoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-4-methylpiperazine and 4- [ 5-chloro-1H-pyrrolo [2,3-b]Pyridin-3-yl]-N, N-dimethylbenzamide preparation example 424.¹H NMR(400MHz,DMSO-d6)δ12.14(brs,1H),8.61(s,1H),8.48(s 1H),8.03(d,J＝2.7Hz,1H),7.91(d,J＝8.1Hz,2H),7.49(d,J＝8.1Hz,2H),7.27-7.21(m,1H),7.17(d,J＝1.9Hz,1H),3.93(s,3H),3.20-3.10(m,4H),3.01(s,6H),2.55-2.45(m,4H),2.37(s,3H)。LC-MS(M+H)⁺＝488.3。

Example 425: 6- (4- [5- [ 3-fluoro-5-methoxy-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) -2-oxa-6-azaspiro [3.3] heptane (compound 425)

Prepared in a similar manner to that described in step 2 of example 311 from 1- [ 2-fluoro-6-methoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-4-methylpiperazine and 6- (4- [ 5-chloro-1H-pyrrolo [2, 3-b)]Pyridin-3-yl]Benzoyl) -2-oxa-6-azaspiro [3.3 ]Heptane preparation example 425. 1H NMR (400MHz, DMSO-d6) Δ 12.31(brs,1H),8.50(s,1H),8.44(s,1H),8.13(s,1H),7.90-7.84(m,2H),7.72-7.66(m,2H),7.65-7.55(m,1H),7.42-7.35(m,1H),4.70(s,4H),4.55(s,2H),4.23(s,2H),3.35-2.90(m,4H),2.48-2.40(m,4H),2.25(s, 3H). LC-MS (M + H)⁺＝542.2。

Example 426: 1- (4- [5- [ 3-fluoro-5-methoxy-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) azetidin-3-ol (compound 426)

Prepared in a similar manner to that described in step 2 of example 311 from 1- [ 2-fluoro-6-methoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-4-methylpiperazine and 1- (4- [ 5-chloro-1H-pyrrolo [2, 3-b)]Pyridin-3-yl]Benzoyl) azetidin-3-ol preparation example 426.¹H NMR(400MHz,DMSO-d6)δ12.17(brs,1H),8.61(s,1H),8.49(s,1H),8.06(s,1H),7.94-7.87(m,2H),7.74-7.67(m,2H),7.25-7.20(m,1H),7.16(s,1H),5.80-5.76(m,1H),4.58-4.48(m,2H),4.29-4.24(m,1H),4.15-4.05(m,1H),3.92(s,3H),3.85-3.75(m,1H),3.15-3.05(m,4H),2.45-2.35(m,4H),2.23(s,3H)。LC-MS(M+H)⁺＝516.2。

Example 427: 4- [5- [ 3-cyano-4- (1-methylpiperidin-4-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N, N, 2-trimethylbenzamide (compound 427)

Step 1: 5-methoxy-2- (1-methyl-3, 6-dihydro-2H-pyridin-4-yl) benzonitrile

The title compound was prepared from 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydro-2H-pyridine and 2-bromo-5-methoxybenzonitrile in a similar manner to that in example 332, step 2. LC-MS (M + H) ⁺＝229.2。

Step 2: 5-methoxy-2- (1-methylpiperidin-4-yl) benzonitrile

The title compound was prepared from 5-methoxy-2- (1-methyl-3, 6-dihydro-2H-pyridin-4-yl) benzonitrile in a similar manner to that in example 293, step 8. LC-MS (M + H)⁺＝231.2。

And step 3: 5-hydroxy-2- (1-methylpiperidin-4-yl) benzonitrile

To a solution of 5-methoxy-2- (1-methylpiperidin-4-yl) benzonitrile (125mg, 0.541mmol) in DCM (6mL) was added MeSNa (185mg, 2.140mmol) at room temperature. The resulting mixture was stirred at 155 ℃ under a nitrogen atmosphere for 2 h. When the reaction was complete, the solvent was concentrated under reduced pressure and the residue was purified by flash chromatography, eluting with MeOH in DCM (gradient 0% to 20%) to give 5-hydroxy-2- (1-methylpiperidin-4-yl) benzonitrile (112mg, 96%) as a brown solid. LC-MS (M + H)⁺＝217.2。

And 4, step 4: 3-cyano-4- (1-methylpiperidin-4-yl) phenyl trifluoromethanesulfonate

Prepared in a similar manner to that in step 3 of example 455 from 5-hydroxy-2- (1-methylpiperidin-4-yl) benzonitrile and PhNTf₂The title compound was prepared. LC-MS (M + H)⁺＝349.2。

And 5: n, N, 2-trimethyl-4- [1- (4-methylbenzenesulfonyl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

To the same as that in step 1 of example 308In a similar manner from 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl]-N, 2-trimethylbenzamide and BPD. LC-MS (M + H)⁺＝560.5。

Step 6: 4- [5- [ 3-cyano-4- (1-methylpiperidin-4-yl) phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -N, 2-trimethylbenzamide

Prepared in a similar manner to that described in step 2 of example 332 from N, N, 2-trimethyl-4- [1- (4-methylbenzenesulfonyl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ]]Pyridin-3-yl]Benzamide and trifluoromethanesulfonic acid 3-cyano-4- (1-methylpiperidin-4-yl) phenyl ester the title compound was prepared. LC-MS (M + H)⁺＝632.3。

And 7: 4- [5- [ 3-cyano-4- (1-methylpiperidin-4-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N, N, 2-trimethylbenzamide

Prepared in a similar manner to that described in example 369, step 6 from 4- [5- [ 3-cyano-4- (1-methylpiperidin-4-yl) phenyl]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl]-N, 2-trimethylbenzamide preparative example 427.¹H NMR(400MHz,DMSO-d6)δ12.10(d,J＝2.8Hz,1H),8.62(d,J＝2.1Hz,1H),8.55(d,J＝2.2Hz,1H),8.25(d,J＝2.1Hz,1H),8.12-8.05(m,1H),7.98(d,J＝2.6Hz,1H),7.73-7.66(m,2H),7.63(d,J＝8.3Hz,1H),7.22(d,J＝7.8Hz,1H),3.03(s,3H),2.98-2.91(m,2H),2.84(s,4H),2.29(s,3H),2.24(s,3H),2.0-1.98(m,2H),1.86-1.76(m,4H)。LC-MS(M+H)⁺＝478.5。

Example 428: n, N-dimethyl-4- (5- (4- (4-methylpiperazin-1-yl) -3- (1H-pyrazol-4-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 428)

Step 1: 1- (2-iodo-4-nitrophenyl) -4-methylpiperazine

The title compound was prepared from 1-fluoro-2-iodo-4-nitrobenzene and 1-methylpiperazine in a similar manner to that in example 404, step 5. LCMS(M+H)⁺＝348.0。

Step 2: 1-methyl-4- (4-nitro-2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) phenyl) piperazine

The title compound was prepared from 1- (dioxan-2-yl) -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazole and 1- (2-iodo-4-nitrophenyl) -4-methylpiperazine in a similar manner to that in example 332, step 2. LCMS (M + H)⁺＝372.1。

And step 3: 4- (4-methylpiperazin-1-yl) -3- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) aniline

Prepared in a similar manner to that in example 320, step 3 from 1-methyl-4- [ 4-nitro-2- [1- (oxan-2-yl) pyrazol-4-yl]Phenyl radical]Piperazine the title compound was prepared. LCMS (M + H)⁺＝342.1。

And 4, step 4: 1- (4-bromo-2- (1H-pyrazol-4-yl) phenyl) -4-methylpiperazine

Prepared in a similar manner to that in example 320, step 4 from 4- (4-methylpiperazin-1-yl) -3- [1- (oxan-2-yl) pyrazol-4-yl]Aniline the title compound was prepared. LCMS (M + H)⁺＝323.0。

And 5: n, N-dimethyl-4- [1- (4-methylbenzenesulfonyl) -5- [4- (4-methylpiperazin-1-yl) -3- (1H-pyrazol-4-yl) phenyl ] pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

Prepared in a similar manner to that described in step 2 of example 332 from N, N-dimethyl-4- [1- (4-methylbenzenesulfonyl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ]]Pyridin-3-yl]Benzamide and 1- [ 4-bromo-2- (1H-pyrazol-4-yl) phenyl]-4-methylpiperazine the title compound was prepared. LCMS (M + H)⁺＝660.3。

Step 6: n, N-dimethyl-4- (5- (4- (4-methylpiperazin-1-yl) -3- (1H-pyrazol-4-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Prepared in a similar manner to that described in example 369, step 6 from N, N-dimethyl-4- [1- (4-methylbenzenesulfonyl) -5- [4- (4-methylpiperazin-1-yl) -3- (1H-pyrazol-4-yl) phenyl]-1H-pyrrolo [2,3-b]Pyridin-3-yl]Benzamide preparation example 428.¹H NMR(400MHz,DMSO-d6)δ12.90(brs,1H),12.08(brs,1H),8.61(s,1H),8.48(s,1H),8.34(s,1H),8.20-8.00(m,2H),7.92-7.84(m,2H),7.82-7.72(m,1H),7.62-7..58(m,1H),7.54-7.46(m,2H),7.28-7.18(m,1H),3.01(s,6H),2.90-2.80(m,4H),2.50-2.40(m,4H),2.25(s,3H)。LC-MS(M+H)⁺＝506.2。

Example 429: n, N-dimethyl-4- [5- [4- (4-methylpiperazin-1-yl) -3- (5-oxopyrrolidin-3-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide (compound 429)

Step 1: 5-bromo-2- (4-methylpiperazin-1-yl) benzaldehyde

The title compound was prepared from 5-bromo-2-fluorobenzaldehyde and 1-methylpiperazine in a similar manner to that in example 404, step 5. LCMS (M + H)⁺＝283.2。

Step 2: 3- (5-bromo-2- (4-methylpiperazin-1-yl) phenyl) acrylic acid ethyl ester

To a solution of 5-bromo-2- (4-methylpiperazin-1-yl) benzaldehyde (475mg, 1.677mmol) in toluene (25mL) was added ethyl 2- (triphenyl- λ 5-phosphoranylidene) acetate (584mg, 1.677mmol) at room temperature. The resulting mixture was stirred at 120 ℃ under a nitrogen atmosphere for 3 h. When the reaction was complete, the solvent was concentrated under reduced pressure and the residue was purified by flash chromatography, eluting with EtOAc in hexanes (gradient 0% to 15%) to give ethyl 3- (5-bromo-2- (4-methylpiperazin-1-yl) phenyl) acrylate (600mg, 61%) as a colorless liquid. LCMS (M + H) ⁺＝353.2。

And step 3: 3- (5-bromo-2- (4-methylpiperazin-1-yl) phenyl) -4-nitrobutanoic acid ethyl ester

To a solution of ethyl 3- (5-bromo-2- (4-methylpiperazin-1-yl) phenyl) acrylate (515mg, 1.459mmol) in nitromethane (10mL) was added DBU (211mg, 1.386mmol) at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere overnight. When the reaction was complete, the solvent was concentrated under reduced pressure and the residue was purified by flash chromatography, eluting with EtOAc in hexane (gradient 0% to 50%)To give 3- [ 5-bromo-2- (4-methylpiperazin-1-yl) phenyl as a pale yellow syrup]-ethyl 4-nitrobutyrate (510mg, 85%). LCMS (M + H)⁺＝414.1。

And 4, step 4: 4- (5-bromo-2- (4-methylpiperazin-1-yl) phenyl) pyrrolidin-2-one

To 3- [ 5-bromo-2- (4-methylpiperazin-1-yl) phenyl at room temperature]Ethyl-4-nitrobutyrate (368mg, 0.889mmol) in EtOH (25mL) was added H₂O(20mL)、Fe(1985mg，35.542mmol)、NH₄Cl (1920.37mg, 35.542 mmol). The resulting mixture was stirred at 80 ℃ under nitrogen atmosphere for h. The mixture was allowed to cool to room temperature. When the reaction was complete, the solids were removed by filtration. The filtrate was concentrated and the residue was applied to a silica gel column, eluting with MeOH in DCM (gradient 0% to 50%) to give 4- (5-bromo-2- (4-methylpiperazin-1-yl) phenyl) pyrrolidin-2-one (160mg, 53%) as a brown slurry. LCMS (M + H) ⁺＝338.1。

And 5: n, N-dimethyl-4- [1- (4-methylbenzenesulfonyl) -5- [4- (4-methylpiperazin-1-yl) -3- (5-oxopyrrolidin-3-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

Prepared in a similar manner to that in step 2 of example 332 from [3- [4- (dimethylcarbamoyl) phenyl ]]-1- (4-Methylbenzenesulfonyl) -1H-pyrrolo [2,3-b]Pyridin-5-yl]Boronic acid and 4- (5-bromo-2- (4-methylpiperazin-1-yl) phenyl) pyrrolidin-2-one the title compound was prepared. LCMS (M + H)⁺＝677.3。

Step 6: n, N-dimethyl-4- [5- [4- (4-methylpiperazin-1-yl) -3- (5-oxopyrrolidin-3-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

Prepared in a similar manner to that described in example 369, step 6 from N, N-dimethyl-4- [1- (4-methylbenzenesulfonyl) -5- [4- (4-methylpiperazin-1-yl) -3- (5-oxopyrrolidin-3-yl) phenyl]-1H-pyrrolo [2,3-b]Pyridin-3-yl]Benzamide preparation example 429.¹H NMR (400MHz, chloroform-d) delta 10.44-10.39(m,1H),8.56(s,1H),8.34(s,1H),7.76-7.66(m,2H),7.64-7.49(m,5H),7.39-7.31(m,1H),6.42-6.30(m,1H),4.43-4.33(m,1H),3.92.9.84(m,1H),3.58-3.50(m,1H),3.23-2.91(m,10H),2.89-2.53(m,6H), 2.44-2.(s,Hz,3H)。LC-MS(M+H)⁺＝523.4。

Example 430: n, N-dimethyl-4- [5- [4- (4-methylpiperazin-1-yl) -3- (oxetan-3-yloxy) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide (compound 430)

Step 1: 3- (2-bromo-5-chlorophenoxy) oxetane

The title compound was prepared from 2-bromo-5-chlorophenol and 4-methylbenzene-1-sulfonic acid oxetan-3-yl ester in a similar manner to that in example 404, step 5.¹H NMR(400MHz,CDCl₃,ppm)δ7.51(d,J＝8.4Hz,1H),6.92-6.87(m,1H),6.44(d,J＝2.2Hz,1H),5.28-5.21(m,1H),5.06-4.99(m,2H),4.88-4.82(m,2H)。

Step 2: 1- (4-chloro-2- (oxetan-3-yloxy) phenyl) -4-methylpiperazine

To a solution of 3- (2-bromo-5-chlorophenoxy) oxetane (950mg, 3.605mmol) in toluene (15mL) at room temperature was added BINAP (224mg, 0.360mmol), Pd₂(dba)₃(67mg, 0.073mmol), t-BuONa (694mg, 7.216mmol), and 1-methylpiperazine (570mg, 5.691 mmol). The resulting mixture was stirred at 90 ℃ under a nitrogen atmosphere for 15 h. When the reaction was complete, the reaction was then quenched by the addition of water (30 mL). The resulting solution was extracted with ethyl acetate (50mL x 3). The organic phases were combined, washed with brine and over Na₂SO₄And (5) drying. The solvent was concentrated under reduced pressure and the residue was purified by flash chromatography, eluting with MeOH in EtOAc hexanes (gradient 0% to 20%) to give 1- [ 4-chloro-2- (oxetan-3-yloxy) phenyl as a pale yellow oil]-4-methylpiperazine (823mg, 81%). LC-MS (M + H)⁺＝283.2。

And step 3: 1-methyl-4- (2- (oxetan-3-yloxy) -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) piperazine

Prepared from 1- [ 4-chloro-2- (oxo) in a similar manner to that in step 2 of example 383Heterocyclobutane-3-yloxy) phenyl]-4-methylpiperazine and BPD the title compound was prepared. LC-MS (M + H)⁺＝375.3。

And 4, step 4: n, N-dimethyl-4- [5- [4- (4-methylpiperazin-1-yl) -3- (oxetan-3-yloxy) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

Prepared in a similar manner to that described in step 2 of example 311 from 1-methyl-4- [2- (oxetan-3-yloxy) -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Piperazine and 4- [ 5-chloro-1H-pyrrolo [2,3-b ]]Pyridin-3-yl]-N, N-dimethylbenzamide preparation example 430.¹H NMR(400MHz,DMSO-d6)δ12.07(s,1H),8.52(s,1H),8.39(s,1H),8.00(s,1H),7.89-7.82(m,2H),7.53-7.46(m,2H),7.36-7.26(m,1H),7.09-7.00(m,1H),6.89(s,1H),5.52-5.42(m,1H),5.01-4.93(m,2H),4.67-4.57(m,2H),3.15-2.98(m,10H),2.60-2.55(m,4H),2.26(s,3H)。LC-MS(M+H)⁺＝512.2。

Example 431: n, N-dimethyl-4- (5- (4- (4-methylpiperazin-1-yl) -3- (tetrahydrofuran-3-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 431)

Step 1: 1- (2-bromo-4-nitrophenyl) -4-methylpiperazine

The title compound was prepared from bis (2-bromo-1-fluoro-4-nitrobenzene) and bis (1-methylpiperazine) in a similar manner to that in example 373, step 1. LC-MS (M + H)⁺＝300.0。

Step 2: 1- (2- (furan-3-yl) -4-nitrophenyl) -4-methylpiperazine

The title compound was prepared from 1- (2-bromo-4-nitrophenyl) -4-methylpiperazine and 2- (furan-3-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan in a similar manner as in step 2, example 332. LC-MS (M + H) ⁺＝288.1。

And step 3: 3- (furan-3-yl) -4- (4-methylpiperazin-1-yl) aniline

In a manner similar to that in step 3 of example 3201- [2- (furan-3-yl) -4-nitrophenyl]-4-methylpiperazine the title compound was prepared. LC-MS (M + H)⁺＝258.1。

And 4, step 4: 4- (4-methylpiperazin-1-yl) -3- (oxolan-3-yl) aniline

The title compound was prepared from 3- (furan-3-yl) -4- (4-methylpiperazin-1-yl) aniline in a similar manner to that in example 293, step 8. LC-MS (M + H)⁺＝262.1。

And 5: 1- (4-bromo-2- (oxolan-3-yl) phenyl) -4-methylpiperazine

The title compound was prepared from 4- (4-methylpiperazin-1-yl) -3- (oxolan-3-yl) aniline in a similar manner to that in example 320 step 4. LC-MS (M + H)⁺＝325.1。

Step 6: n, N-dimethyl-4- [1- (4-methylbenzenesulfonyl) -5- [4- (4-methylpiperazin-1-yl) -3- (oxolan-3-yl) phenyl ] pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

Prepared in a similar manner to that described in step 2 of example 332 from N, N-dimethyl-4- [1- (4-methylbenzenesulfonyl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ]]Pyridin-3-yl]Benzamide and 1- (4-bromo-2- (oxolan-3-yl) phenyl) -4-methylpiperazine the title compound was prepared. LC-MS (M + H) ⁺＝664.5。

And 7: n, N-dimethyl-4- (5- (4- (4-methylpiperazin-1-yl) -3- (tetrahydrofuran-3-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Prepared in a similar manner to that described in example 369, step 6 from N, N-dimethyl-4- [1- (4-methylbenzenesulfonyl) -5- [4- (4-methylpiperazin-1-yl) -3- (oxolan-3-yl) phenyl]Pyrrolo [2,3-b]Pyridin-3-yl]Benzamide preparation example 431.¹H NMR(400MHz,DMSO-d6)δ12.08(s,1H),8.54(s,1H),8.41(s,1H),8.00(s,1H),7.89-7.82(m,2H),7.64(m,2H),7.53-7.46(m,2H),7.26(d,J＝8.3Hz,1H),4.12-3.99(m,2H),3.94-3.82(m,2H),3.69-3.61(m,1H),3.40-3.30(m,2H),3.01(s,6H),2.97-2.79(m,4H),2.60-2.50(m,2H),2.37-2.30(m,1H),2.27(s,3H),2.09-1.99(m,1H)。LC-MS(M+H)⁺＝510.3。

Example 432: n, N-dimethyl-4- (5- (4- (1-methylpiperidin-3-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 432)

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

Prepared in a similar manner to that described in step 2 of example 332 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 1-bromo-4-iodobenzene. LC-MS (M + H)⁺＝574.1。

Step 2: 5- (4- (3- (4- (dimethylcarbamoyl) phenyl) -1-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-5-yl) phenyl) -3, 4-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester

Prepared in a similar manner to that described in step 2 of example 332 from 4- (5- (4-bromophenyl) -1-toluenesulfonyl-1H-pyrrolo [2, 3-b) ]Pyridin-3-yl) -N, N-dimethylbenzamide and tert-butyl 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydropyridine-1 (2H) -carboxylate the title compound was prepared. LC-MS (M + H)⁺＝677.8。

And step 3: 3- (4- (3- (4- (dimethylcarbamoyl) phenyl) -1-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-5-yl) phenyl) piperidine-1-carboxylic acid tert-butyl ester

To 5- (4- (3- (4- (dimethylcarbamoyl) phenyl) -1-tosyl-1H-pyrrolo [2, 3-b) at room temperature]Pyridin-5-yl) phenyl) -3, 4-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (60mg, 0.089mmol) to a solution in MeOH (10mL) was added Pd/C (22mg, 0.200mmol), HCOONH₄(315mg 5.000 mmol). The reaction mixture was stirred at 60 ℃ for 24 h. When the reaction was complete, the solids were removed by filtration. The filtrate was concentrated to give 3- (4- (3- (4- (dimethylcarbamoyl) phenyl) -1-tosyl-1H-pyrrolo [2,3-b ] as a yellow solid]Pyridin-5-yl) phenyl) piperidine-1-carboxylic acid tert-butyl ester (30mg, 50%). LCMS (M + H)⁺＝679.4。

And 4, step 4: n, N-dimethyl-4- (5- (4- (1-methylpiperidin-3-yl) phenyl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Reacting 3- (4- [3- [4- (dimethylcarbamoyl) phenyl) ]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-5-yl]A solution of phenyl) piperidine-1-carboxylic acid tert-butyl ester (200mg, 0.250mmol) and paraformaldehyde (7.9mg, 0.25mmol) in AcOH (6mL) was stirred at room temperature under a nitrogen atmosphere overnight. The reaction was quenched by addition of water (10mL) and then concentrated in vacuo. Purifying the residue by silica gel column chromatography using CH₂Cl₂MeOH (10:1) to give the title compound (230mg, 82%). LCMS (M + H)⁺＝593.4。

And 5: n, N-dimethyl-4- (5- (4- (1-methylpiperidin-3-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Prepared in a similar manner to that described in example 369, step 6 from N, N-dimethyl-4- (5- (4- (1-methylpiperidin-3-yl) phenyl) -1-toluenesulfonyl-1H-pyrrolo [2,3-b ]]Pyridin-3-yl) benzamide example 432 was prepared.¹H NMR(400MHz,DMSO-d6)δ12.10(s,1H),8.56(s,1H),8.46(s,1H),8.02(s,1H),7.90-7.83(m,2H),7.73-7.67(m,2H),7.52-7.46(m,2H),7.42-7.34(m,2H),3.01(s,6H),2.91-2.80(m,3H),2.22(s,3H),2.10-1.55(m,5H),1.67-1.59(m,1H)。LC-MS(M+H)⁺＝439.3。

Example 433: n, N-dimethyl-4- [5- [4- (1-methylpyrrolidin-3-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide (compound 433)

Step 1: 4- (4- (3- (4- (dimethylcarbamoyl) phenyl) -1-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-5-yl) phenyl) -2, 3-dihydropyrrole-1-carboxylic acid tert-butyl ester

Prepared in a similar manner to that described in step 2 of example 332 from 4- (5- (4-bromophenyl) -1-toluenesulfonyl-1H-pyrrolo [2, 3-b) ]Pyridin-3-yl) -N, N-dimethylbenzamide and 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxanPentaborane-2-yl) -2, 3-dihydropyrrole-1-carboxylic acid tert-butyl ester the title compound was prepared. LC-MS (M + H)⁺＝663.5。

Step 2: 3- (4- (3- (4- (dimethylcarbamoyl) phenyl) -1-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-5-yl) phenyl) pyrrolidine-1-carboxylic acid tert-butyl ester

Prepared from 4- (4- (3- (4- (dimethylcarbamoyl) phenyl) -1-toluenesulfonyl-1H-pyrrolo [2,3-b ] in a similar manner to that described in step 8, example 293]Pyridin-5-yl) phenyl) -2, 3-dihydropyrrole-1-carboxylic acid tert-butyl ester the title compound was prepared. LC-MS (M + H)⁺＝665.3。

And step 3: n, N-dimethyl-4- (5- (4- (1-methylpyrrolidin-3-yl) phenyl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Prepared from 3- (4- (3- (4- (dimethylcarbamoyl) phenyl) -1-toluenesulfonyl-1H-pyrrolo [2,3-b ] in a similar manner to that in step 4 of example 432]Pyridin-5-yl) phenyl) pyrrolidine-1-carboxylic acid tert-butyl ester and formalin the title compound was prepared. LC-MS (M + H)⁺＝579.4。

And 4, step 4: n, N-dimethyl-4- [5- [4- (1-methylpyrrolidin-3-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

Prepared in a similar manner to that described in example 369, step 6 from N, N-dimethyl-4- (5- (4- (1-methylpyrrolidin-3-yl) phenyl) -1-toluenesulfonyl-1H-pyrrolo [2,3-b ] ]Pyridin-3-yl) benzamide preparative example 433.¹H NMR(400MHz,DMSO-d6)δ12.09(s,1H),8.56(s,1H),8.45(s,1H),8.02(s,1H),7.89-7.82(m,2H),7.73-7.66(m,2H),7.52-7.46(m,2H),7.45-7.37(m,2H),3.45-3.32(m,1H),3.01(s,6H),2.95-2.90(m,1H),2.71-2.60(m,2H),2.55-2.50(m,1H),2.40-2.20(m,4H),1.86-1.76(m,1H)。LC-MS(M+H)⁺＝425.3。

Example 434: 1- (4- [5- [ 3-fluoro-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) -N, N-dimethylazetidin-3-amine (compound 434)

Step 1: 1- [4- [ 5-bromo-1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl ] -N, N-dimethylazetidin-3-amine

Prepared from [3- [3- (dimethylamino) azetidine-1-carbonyl ] in a similar manner to that in example 332, step 2]Phenyl radical]Boronic acid and 5-bromo-3-iodo-1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b]Pyridine the title compound was prepared. LC-MS (M + H)⁺＝553.1。

Step 2: 1- (4- [5- [ 2-fluoro-4- (4-methylpiperazin-1-yl) phenyl ] -1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) -N, N-dimethylazetidin-3-amine

Prepared in a similar manner to that described in step 2 of example 332 from 1- [4- [ 5-bromo-1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b ]]Pyridin-3-yl]Benzoyl radical]-N, N-dimethylazetidin-3-amine and 1- [ 2-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-4-methylpiperazine the title compound was prepared. LC-MS (M + H)⁺＝667.4。

And step 3: 1- (4- [5- [ 3-fluoro-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) -N, N-dimethylazetidin-3-amine

Prepared in a similar manner to that described in example 369, step 6 from 1- (4- [5- [ 3-fluoro-4- (4-methylpiperazin-1-yl) phenyl]-1- (4-Methylbenzenesulfonyl) -1H-pyrrolo [2,3-b]Pyridin-3-yl]Benzoyl) -N, N-dimethylazetidin-3-amine preparation example 434.¹H NMR(400MHz,DMSO-d6)δ12.15(s,1H),8.58(s,1H),8.47(s,1H),8.06(s,1H),7.94-7.87(m,2H),7.76-7.69(m,2H),7.70-7.60(m,1H),7.58-7.52(m,1H),7.17-7.69(m,1H),4.43-4.33(m,1H),4.20-4.04(m,2H),3.89-3.81 9m,1H),3.15-3.04(m,5H),2.55-2.45(m,4H),2.25(s,3H),2.10(s,6H)。LC-MS(M+H)⁺＝513.5。

Example 435: 5- [3- (2-methyl-1-oxo-1, 2,3, 4-tetrahydroisoquinolin-6-yl) -1H-pyrrolo [2,3-b ] pyridin-5-yl ] -2- (4-methylpiperazin-1-yl) benzonitrile (Compound 435)

Prepared from 6- [ 5-chloro-1H-pyrrolo [2,3-b ] in a similar manner to that in step 2 of example 311]Pyridin-3-yl]-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-1-one and 2- (4-methylpiperazin-1-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzonitrile example 435 is prepared.¹H NMR(400MHz,DMSO-d6)δ12.17(s,1H),8.61-8.53(m,2H),8.19(s,1H),8.09-7.99(m,2H),7.97-7.89(m,1H),7.85-7.77(m,1H),7.76-7.70(m,1H),7.34-7.26(m,1H),3.63-3.55(m,2H),3.25-3.16(m,4H),3.11-3.01(m,5H),2.60-2.50(m,4H),2.28(s,3H)。LC-MS(M+H)⁺＝477.4。

Example 436: 6- (5- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -2-methyl-3, 4-dihydroisoquinolin-1 (2H) -one (Compound 436)

Prepared from 6- [ 5-chloro-1H-pyrrolo [2,3-b ] in a similar manner to that in step 2 of example 311]Pyridin-3-yl]-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-1-one and 1- [ 2-methoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-4-methylpiperazine preparation example 436. ¹H NMR(400MHz,DMSO-d6)δ12.06(s,1H),8.54(s,1H),8.44(s,1H),7.99(s,1H),7.96-7.88(m,1H),7.81-7.71(m,1H),7.72-7.64(m,1H),7.30-7.20(m,2H),7.03-6.95(m,1H),3.88(s,3H),3.62-3.50(m,3H),3.14-2.90(m,9H),2.54-2.42(s,4H),2.22(s,3H)。LC-MS(M+H)⁺＝482.2。

Example 437: 6- (5- (3-fluoro-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -2-methyl-3, 4-dihydroisoquinolin-1 (2H) -one (Compound 437)

Prepared from 1- [ 2-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxo) in a similar manner to that in step 2 of example 332Heterocyclopentylboran-2-yl) phenyl]-4-methylpiperazine and 6- [ 5-chloro-1H-pyrrolo [2,3-b]Pyridin-3-yl]-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-1-one preparation example 437.¹H NMR(400MHz,DMSO-d6)δ12.13(s,1H),8.57(s,1H),8.49(s,1H),8.05(s,1H),7.97-7.89(m,1H),7.84-7.76(m,1H),7.76-7.68(m,1H),7.70-7.60(m,1H),7.59-7.49(m,1H),7.18-7.08(m,1H),3.64-3.54(m,2H),3.12-3.03(m,9H),2.55-2.45(m,4H),2.24(s,3H)。LC-MS(M+H)⁺＝470.2。

Example 438: 2-methyl-6- [5- [4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -2,3,4, 5-tetrahydro-1H-2-benzazepin-1-one (compound 438)

Step 1: n- [ (1E) -6-bromo-1, 2,3, 4-tetrahydronaphthalen-1-ylidene ] hydroxylamine

From 6-bromo-1, 2,3, 4-tetrahydronaphthalen-1-one and NH in a similar manner to that in step 4 of example B03₂Hcl the title compound was prepared. LC-MS (M + H)⁺＝242.2。

Step 2: 7-bromo-2, 3,4, 5-tetrahydrobenzo [ c ] azepin-1-one

Reacting N- [ (1E) -6-bromo-1, 2,3, 4-tetrahydronaphthalen-1-ylidene at room temperature]Hydroxylamine (855mg, 3.561mmol) was added to SOCl₂(6 mL). The resulting mixture was stirred at 50 ℃ for 4 h. When the reaction was complete, the solvent was concentrated under reduced pressure and the residue was purified by flash chromatography, eluting with EtOAc in hexanes (gradient 0% to 50%) to give 7-bromo-2, 3,4, 5-tetrahydro-1H-2-benzazepin-1-one (581mg, 68%) as a green solid. LC-MS (M + H) ⁺＝240.0。

And step 3: 7-bromo-2-methyl-2, 3,4, 5-tetrahydro-1H-2-benzazepin-1-one

The title compound was prepared from 7-bromo-2, 3,4, 5-tetrahydro-1H-2-benzazepin-1-one and MeI in a similar manner to that in example 394 step 1. LC-MS (M + H)⁺＝254.1。

And 4, step 4: 2-methyl-7- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2,3,4, 5-tetrahydrobenzo [ c ] azepin-1-one

The title compound was prepared from 7-bromo-2-methyl-2, 3,4, 5-tetrahydro-1H-2-benzazepin-1-one and BPD in a similar manner to that in example 308, step 1. LC-MS (M + H)⁺＝302.2。

And 5: 7- (5-bromo-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -2-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ c ] azepin-1-one

Prepared in a similar manner to that described in step 2 of example 332 from 2-methyl-7- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2,3,4, 5-tetrahydro-1H-2-benzazepin-1-one and 5-bromo-3-iodo-1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b]Pyridine the title compound was prepared. LC-MS (M + H)⁺＝525.0。

Step 6: 2-methyl-7- (5- (4- (4-methylpiperazin-1-yl) phenyl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -2,3,4, 5-tetrahydrobenzo [ c ] azepin-1-one

Prepared in a similar manner to that described in step 2 of example 332 from 6- [ 5-bromo-1- (4-methylbenzenesulfonyl) -1H-indol-3-yl ]-2-methyl-2, 3,4, 5-tetrahydro-1H-2-benzazepin-1-one and 1-methyl-4- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Piperidine the title compound was prepared. LC-MS (M + H)⁺＝623.0。

And 7: 2-methyl-6- [5- [4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -2,3,4, 5-tetrahydro-1H-2-benzazepin-1-one

Prepared in a similar manner to that described in step 9 of example 404 from 2-methyl-6- [1- (4-methylbenzenesulfonyl) -5- [4- (4-methylpiperazin-1-yl) phenyl]-1H-pyrrolo [2,3-b]Pyridin-3-yl]-2,3,4, 5-tetrahydro-1H-2-benzazepin-1-one preparation example 438.¹H NMR(400MHz,DMSO-d6)δ12.02(s,1H),8.52(s,1H),8.40(s,1H),7.98(s,1H),7.80-7.82(m,1H),7.67-7.60(m,3H),7.59-7.52(m,1H),7.10-7.02(m,2H),3.26-3.16(m,6H),3.08(s,3H),2.84-2.74(m,2H),2.50-2.42(m,4H),2.24(s,3H),2.09-1.99(m,2H)。LC-MS(M+H)⁺＝466.4。

Example 439: 2-methyl-6- [5- [4- (1-methylpiperidin-4-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -1,2,3, 4-tetrahydroisoquinolin-1-one (Compound 439)

Prepared from 6- [ 5-chloro-1H-pyrrolo [2,3-b ] in a similar manner to that in step 2 of example 311]Pyridin-3-yl]-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-1-one and 1-methyl-4- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Piperidine preparation example 439.¹H NMR(400MHz,DMSO-d6)δ12.14(s,1H),8.56(s,1H),8.49(s,1H),8.05(s,1H),7.96-7.88(m,1H),7.82-7.76(m,1H),7.74-7.66(m,3H),7.41-7.33(m,2H),3.64-3.54(m,2H),3.12-3.00(m,5H),2.93-2.83(m,2H),2.50-2.43(m,1H),2.21(s,3H),2.04-1.94(m,2H),1.81-1.65(m,4H)。LC-MS(M+H)⁺＝451.4。

Example 440: 1- (4- [5- [4- (1-methylpiperidin-4-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) azetidin-3-ol (compound 440)

Prepared in a similar manner to that described in step 2 of example 311 from 1-methyl-4- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Piperidine and 1- (4- [ 5-chloro-1H-pyrrolo [2,3-b ]]Pyridin-3-yl]Benzoyl) azetidin-3-ol preparation example 440.¹H NMR(400MHz,DMSO-d6)δ12.11(brs,1H),8.55(s,1H),8.46(s,1H),8.02(s,1H),7.93-7.83(m,2H),7.75-7.63(m,4H),7.41-7.31(m,2H),5.95-5.87(m,1H),4.57-4.47(m,2H),4.32-4.22(m,1H),4.15-4.05(m,1H),3.85-3.75(m,2H),2.92-2.82(m,2H),2.19(s,3H),2.04-1.94(m,2H),1.82-1.62(m,4H)。LC-MS(M+H)⁺＝467.2。

Example 441: n, N-dimethyl-1- (4- [5- [4- (1-methylpiperidin-4-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) azetidin-3-amine (compound 441)

Step 1: n, N-dimethyl-1- [4- [1- (4-methylbenzenesulfonyl) -5- [4- (1-methylpiperidin-4-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl ] azetidin-3-amine

Prepared in a similar manner to that described in step 2 of example 332 from 1- [4- [ 5-bromo-1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b ]]Pyridin-3-yl]Benzoyl radical]-N, N-dimethylazetidin-3-amine and 1-methyl-4- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Piperidine the title compound was prepared. LC-MS (M + H)⁺＝648.2。

Step 2: n, N-dimethyl-1- (4- [5- [4- (1-methylpiperidin-4-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) azetidin-3-amine

Prepared in a similar manner to that described in example 369, step 6 from N, N-dimethyl-1- [4- [1- (4-methylphenylsulfonyl) -5- [4- (1-methylpiperidin-4-yl) phenyl ]-1H-pyrrolo [2,3-b]Pyridin-3-yl]Benzoyl radical]Azetidin-3-amine preparation example 441.¹H NMR(400MHz,DMSO-d6)δ12.15(s,1H),8.57(s,1H),8.47(s,1H),8.07(s,1H),7.95-7.85(m,2H),7.75-7.66(m,4H),7.41-7.33(m,2H),4.41-4.33(m,1H),422-4.04(m,2H),3.88-3.80(m,1H),3.13-3.05(m,1H),2.93-2.83(m,2H),2.60-2.50(m,1H),2.21(s,3H),2.10(s,6H),2.05-1.91(m,2H),1.81-1.63(m,4H)。LC-MS(M+H)⁺＝494.2。

Example 442: n- [2- (dimethylamino) ethyl ] -N-methyl-4- [5- [4- (1-methylpiperidin-4-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide (compound 442)

Prepared from 4- [ 5-chloro-1H-pyrrolo [2,3-b ] in a similar manner to that in step 2 of example 311]Pyridin-3-yl]-N- [2- (dimethylamino) ethyl group]-N-methylbenzamide and 1-methyl-4- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Piperidine preparation example 442.¹H NMR(400MHz,DMSO-d6)δ12.09(s,1H),8.56(s,1H),8.46(s,1H),8.02(s,1H),7.90-7.84(m,2H),7.73-7.66(m,2H),7.49-7.42(m,2H),7.40-7.33(m,2H),3.60-3.40(m,3H),2.99(s,3H),2.95-2.85(m,2H),2.60-2.40(m,2H),2.22(s,6H),2.07-1.96(m,5H),1.82-1.64(m,4H)。LC-MS(M+H)⁺＝496.3。

Example 443: n, N-dimethyl-4- (5- (3-methyl-4- (1-methylpiperidin-4-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 443)

Step 1: 1-methyl-4- (2-methyl-4-nitrophenyl) -1,2,3, 6-tetrahydropyridine

The title compound was prepared from 1-bromo-2-methyl-4-nitrobenzene and 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,2,3, 6-tetrahydropyridine in a similar manner to that in example 332, step 2. LC-MS (M + H)⁺＝233.2。

Step 2: 3-methyl-4- (1-methylpiperidin-4-yl) aniline

The title compound was prepared from 1-methyl-4- (2-methyl-4-nitrophenyl) -1,2,3, 6-tetrahydropyridine in a similar manner to that described in example 293, step 8. LC-MS (M + H) ⁺＝205.2。

And step 3: 4- (4-bromo-2-methylphenyl) -1-methylpiperidine

The title compound was prepared from 3-methyl-4- (1-methylpiperidin-4-yl) aniline in a similar manner to the procedure in example 320, step 4. LC-MS (M + H)⁺＝268.0。

And 4, step 4: n, N-dimethyl-4- (5- (3-methyl-4- (1-methylpiperidin-4-yl) phenyl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Prepared in a similar manner to that described in step 2 of example 332 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- (4-bromo-2-methylphenyl) -1-methylpiperidine the title compound is prepared. LC-MS (M + H)⁺＝607.4。

And 5: n, N-dimethyl-4- (5- (3-methyl-4- (1-methylpiperidin-4-yl) phenyl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Prepared in a similar manner to that described in step 9 of example 404 from N, N-dimethyl-4- [5- [ 3-methyl-4- (1-methylpiperidin-4-yl) phenyl]-1- (4-Methylbenzenesulfonyl) -1H-pyrrolo [2,3-b]Pyridin-3-yl]Benzamide preparation example 443.¹H NMR(400MHz,DMSO-d6)δ12.08(s,1H),8.55(s,1H),8.44(s,1H),8.01(s,1H),7.89-7.83(m,2H),7.58-7.46(m,4H),7.36-7.28(m,1H),3.09-2.95(s,8H),2.80-2.71(m,1H),2.40(s,3H),2.29(s,3H),2.20-2.08(m,2H),1.77-1.67(m,4H)。LC-MS(M+H)⁺＝453.3。

Example 444: n- (2- (dimethylamino) ethyl) -N-methyl-4- (5- (3-methyl-4- (1-methylpiperidin-4-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 444)

Step 1: 1-methyl-4- [ 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] piperidine

The title compound was prepared from 4- (4-bromo-2-methylphenyl) -1-methylpiperidine and BPD in a similar manner to that in example 308, step 1. LC-MS (M + H)⁺＝316.3。

Step 2: n- [2- (dimethylamino) ethyl ] -N-methyl-4- [5- [ 3-methyl-4- (1-methylpiperidin-4-yl) phenyl ] -1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

Prepared in a similar manner to that described in step 2 of example 332 from 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b ]]Pyridin-3-yl]-N- [2- (dimethylamino) ethyl group]-N-methylbenzamide and 1-methyl-4- [ 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Piperidine the title compound was prepared. LC-MS (M + H)⁺＝664.4。

And step 3: n- (2- (dimethylamino) ethyl) -N-methyl-4- (5- (3-methyl-4- (1-methylpiperidin-4-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Prepared from N- [2- (dimethylamino) ethyl group in a similar manner to that in step 9 of example 404]-N-methyl-4- [5- [ 3-methyl-4- (1-methylpiperidin-4-yl) phenyl]-1- (4-Methylbenzenesulfonyl) -1H-pyrrolo [2,3-b ]Pyridin-3-yl]Benzamide preparative example 444.¹H NMR(400MHz,DMSO-d6)12.08(s,1H),8.55(d,J＝2.0Hz,1H),8.44(d,J＝2.1Hz,1H),8.01(d,J＝2.3Hz,1H),7.86(d,J＝8.0Hz,2H),7.54-7.44(m,2H),7.46(d,J＝8.1Hz,2H),7.36-7.28(m,1H),3.55(brs,2H),2.99(s,3H),2.92-2.89(m,2H),2.74-2.65(m,1H),2.39-2.36(m,4H),2.23(s,5H),2.22(s,6H),2.02(m,5H),1.72-1.68(m,5H)。LC-MS(M+H)⁺＝511.2。

Example 445: (3- (dimethylamino) azetidin-1-yl) (4- (5- (3-methyl-4- (1-methylpiperidin-4-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone (Compound 445)

Step 1: (3- (dimethylamino) azetidin-1-yl) (4- (5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone

Prepared from (4- (5-bromo-1-toluenesulfonyl-1H-pyrrolo [2, 3-b) in a similar manner to that in example 308, step 1]Pyridin-3-yl) phenyl) (3- (dimethylamino) azetidin-1-yl) methanone and BPD the title compound was prepared. LC-MS (M + H)⁺＝601.1。

Step 2: (3- (dimethylamino) azetidin-1-yl) (4- (5- (3-methyl-4- (1-methylpiperidin-4-yl) phenyl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone

Prepared in a similar manner to that described in step 2 of example 332 from N, N-dimethyl-1- [4- [1- (4-methylbenzenesulfonyl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ] b]Pyridin-3-yl]Benzoyl radical]Azetidin-3-amine and 4- (4-bromo-2-methylphenyl) -1-methylpiperidine the title is prepared A compound is provided. LC-MS (M + H)⁺＝662.2。

And step 3: (3- (dimethylamino) azetidin-1-yl) (4- (5- (3-methyl-4- (1-methylpiperidin-4-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone

Prepared in a similar manner to that described in example 369, step 6 from (3- (dimethylamino) azetidin-1-yl) (4- (5- (3-methyl-4- (1-methylpiperidin-4-yl) phenyl) -1-toluenesulfonyl-1H-pyrrolo [2,3-b ]]Pyridin-3-yl) phenyl) methanone preparation example 445.¹H NMR(400MHz,DMSO-d6)12.14(s,1H),8.55(d,J＝2.0Hz,1H),8.45(d,J＝2.1Hz,1H),8.05(s,1H),7.89(d,J＝8.1Hz,2H),7.72(d,J＝8.1Hz,2H),7.54(d,J＝5.7Hz,2H),7.33(d,J＝8.5Hz,1H),4.37-4.35(m,1H),4.15-4.05(m,2H),3.85-3.82(m,1H),3.11-3.08(m,1H),2.91-2.88(m,2H),2.73-2.65(m,1H),2.39(s,3H),2.32(s,3H),2.28-2.09(m,8H),1.76-1.67(m,4H)。LC-MS(M+H)⁺＝508.4。

Example 446: 4- (5- (3-fluoro-4- (1-methylpiperidin-4-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (compound 446)

Step 1: 4- (2-fluoro-4-nitrophenyl) pyridine

The title compound was prepared from 1-bromo-2-fluoro-4-nitrobenzene and pyridin-4-ylboronic acid in a similar manner to that in example 332, step 2. LC-MS (M + H)⁺＝219.0。

Step 2: 4- (2-fluoro-4-nitrophenyl) -1-methylpyridin-1-ium iodide

To a solution of 4- (2-fluoro-4-nitrophenyl) pyridine (5.00g, 22.893mmol) in acetone (35mL) was added MeI (9.75g, 68.737mmol) at room temperature. The resulting mixture was stirred at room temperature over 1 night. When the reaction was complete, the precipitated solid was collected by filtration and washed with acetone (10mLx 3). The resulting solid was dried under infrared light to give 4- (2-fluoro-4-nitrophenyl) -1-methylpyridin-1-ium iodide (4.50g, 55%) as a yellow solid. LC-MS (M + H) ⁺＝233.1。

And step 3: 4- (2-fluoro-4-nitrophenyl) -1-methyl-1, 2,3, 6-tetrahydropyridine

To a solution of 4- (2-fluoro-4-nitrophenyl) -1-methylpyridin-1-ium (1.30g, 5.557mmol) in MeOH (20mL) at 0 deg.C was added NaBH in portions₄(627mg, 16.573 mmol). The resulting mixture was stirred at room temperature for 4 h. When the reaction is complete, by addition of saturated NH₄The reaction was quenched with Cl (30mL), and then H was added₂O (30 mL). The resulting solution was extracted with DCM (30mLx 3). The organic phases were combined, washed with brine and over Na₂SO₄And (5) drying. The solvent was concentrated under reduced pressure to give 4- (2-fluoro-4-nitrophenyl) -1-methyl-3, 6-dihydro-2H-pyridine (1.13g, 86%) as a pale yellow solid. LC-MS (M + H)⁺＝237.1。

And 4, step 4: 3-fluoro-4- (1-methylpiperidin-4-yl) aniline

To a solution of 4- (2-fluoro-4-nitrophenyl) -1-methyl-1, 2,3, 6-tetrahydropyridine (1.12g, 4.775mmol) in MeOH (15mL) in a pressure pot was added Pd/C (0.25g, 10%). The mixture was hydrogenated at room temperature under 30psi hydrogen pressure overnight. When the reaction was complete, the solids were removed by filtration. The filtrate was concentrated to give 3-fluoro-4- (1-methylpiperidin-4-yl) aniline (936mg, 94%) as a yellow solid. LC-MS (M + H)⁺＝209.1。

And 5: 4- (4-bromo-2-fluorophenyl) -1-methylpiperidine

The title compound was prepared from 3-fluoro-4- (1-methylpiperidin-4-yl) aniline in a similar manner to that in example 320 step 4. LC-MS (M + H)⁺＝272.1。

Step 6: 4- (5- (3-fluoro-4- (1-methylpiperidin-4-yl) phenyl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide

Prepared in a similar manner to that described in step 2 of example 332 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- (4-bromo-2-fluorophenyl) -1-methylpiperidine the title compound is prepared. LC-MS (M + H)⁺＝611.3。

And 7: 4- (5- (3-fluoro-4- (1-methylpiperidin-4-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide

Prepared in a similar manner to that described in example 369, step 6 from 4- [5- [ 3-fluoro-4- (1-methylpiperidin-4-yl) phenyl]-1- (4-Methylbenzenesulfonyl) -1H-pyrrolo [2,3-b]Pyridin-3-yl]-N, N-dimethylbenzamide preparation example 446.¹H NMR(400MHz,DMSO-d6)12.14(d,J＝2.5Hz,1H),8.60(d,J＝2.1Hz,1H),8.51(d,J＝2.1Hz,1H),8.04(d,J＝2.2Hz,1H),7.89(d,J＝8.1Hz,2H),7.64-7.57(m,2H),7.50-7.41(m,3H),3.00(s,6H),2.89(d,J＝11.3Hz,2H),2.80-2.74(m,1H),2.20(s,3H),2.03-1.96(m,2H),1.82-1.75(m,4H)。LC-MS(M+H)⁺＝457.3。

Example 447: 6- (5- (3-methoxy-4- (1-methylpiperidin-4-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -2-methyl-3, 4-dihydroisoquinolin-1 (2H) -one (compound 447)

Prepared in a similar manner to that described in step 2 of example 311 from 4- [ 2-methoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ]-1-methylpiperidine and 6- [ 5-chloro-1H-pyrrolo [2,3-b ]]Pyridin-3-yl]-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-1-one preparation example 447.¹H NMR(400MHz,DMSO-d6)12.17-12.12(m,1H),8.59(d,J＝2.1Hz,1H),8.50(d,J＝2.1Hz,1H),8.05(d,J＝2.6Hz,1H),7.93(d,J＝8.1Hz,1H),7.79(d,J＝8.1Hz,1H),7.72(s,1H),7.29(s,3H),3.92(s,3H),3.60-3.52(m,2H),3.09-3.04(m,5H),2.91(d,J＝11.5Hz,4H),2.23(s,3H),2.08(s,1H),2.03(brs,3H),1.71(s,4H),1.24(s,2H)。LC-MS(M+H)⁺＝481.2。

Example 448: 2-methyl-6- (5- (3-methyl-4- (1-methylpiperidin-4-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -3, 4-dihydroisoquinolin-1 (2H) -one (Compound 448)

Step 1: 6- [ 5-bromo-1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -2-methyl-1, 2,3, 4-tetrahydroisoquinolin-1-one

In a manner similar to that described in step 2 of example 332, from 2-methyl-6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,2,3, 4-tetrahydroisoquinolin-1-one and 5-bromo-3-iodo-1- (4-methylphenylsulfonyl) -1H-pyrrolo [2,3-b ] -a]Pyridine the title compound was prepared. LC-MS (M + H)⁺＝510.1。

Step 2: 2-methyl-6- [1- (4-methylbenzenesulfonyl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ] pyridin-3-yl ] -3, 4-dihydroisoquinolin-1-one

Prepared from 6- [ 5-bromo-1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b ] in a similar manner to that in example 308, step 1]Pyridin-3-yl]-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-1-one and BPD. LC-MS (M + H)⁺＝558.2。

And step 3: 2-methyl-6- [5- [ 3-methyl-4- (1-methylpiperidin-4-yl) phenyl ] -1- (4-methylphenylsulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -3, 4-dihydroisoquinolin-1-one

Prepared in a similar manner to that described in step 2 of example 332 from 2-methyl-6- [1- (4-methylbenzenesulfonyl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ]]Pyridin-3-yl]-3, 4-dihydroisoquinolin-1-one and 4- (4-bromo-2-methylphenyl) -1-methylpiperidine the title compound is prepared. LC-MS (M + H)⁺＝619.5。

And 4, step 4: 2-methyl-6- (5- (3-methyl-4- (1-methylpiperidin-4-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -3, 4-dihydroisoquinolin-1 (2H) -one

Prepared in a similar manner to that described in step 9 of example 404 from 2-methyl-6- [5- [ 3-methyl-4- (1-methylpiperidin-4-yl) phenyl]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl]-3, 4-dihydroisoquinolin-1-one preparation example 448.¹H NMR(400MHz,DMSO-d6)12.11(s,1H),8.54(d,J＝2.1Hz,1H),8.47(d,J＝2.1Hz,1H),8.03(d,J＝2.6Hz,1H),7.93(d,J＝8.0Hz,1H),7.79-7.76(m,1H),7.70(d,J＝1.8Hz,1H),7.55-7.55(m,2H),7.33(d,J＝8.6Hz,1H),3.60-3.57(m,2H),3.06(d,J＝11.1Hz,5H),2.92(d,J＝11.0Hz,2H),2.74-2.66(m,1H),2.40(s,3H),2.23(s,3H),2.04(s,2H),1.78-1.66(m,4H)。LC-MS(M+H)+＝465.5。

Example 449: 8- [5- [ 3-methoxy-4- (1-methylpiperidin-4-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -4-methyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-5-one (compound 449)

Step 1: 8- (5- (3-methoxy-4- (1-methylpiperidin-4-yl) phenyl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -4-methyl-3, 4-dihydrobenzo [ f ] [1,4] oxazepin-5 (2H) -one

Prepared from 8- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] in a similar manner to that described in step 2 of example 332 ]Pyridin-3-yl]-4-methyl-2, 3-dihydro-1, 4-benzoxazepin-5-one and 4- [ 2-methoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]1-methylpiperidine the title compound is prepared. LC-MS (M + H)⁺＝651.4。

Step 2: 8- [5- [ 3-methoxy-4- (1-methylpiperidin-4-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -4-methyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-5-one

Prepared from 8- [5- [ 3-methoxy-4- (1-methylpiperidin-4-yl) phenyl ] in a similar manner to that in example 369 step 6]-1- (4-Methylbenzenesulfonyl) -1H-pyrrolo [2,3-b]Pyridin-3-yl]Preparation example 449 of (E) -4-methyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-5-one.¹H NMR(400MHz,DMSO-d₆)δ12.15(d,J＝2.8Hz,1H),8.59(d,J＝2.1Hz,1H),8.45(d,J＝2.1Hz,1H),8.07(d,J＝2.6Hz,1H),7.74(d,J＝8.1Hz,1H),7.64-7.62(m,1H),7.41(d,J＝1.7Hz,1H),7.30-7.24(m,3H),4.42-4.40(m,2H),3.91(s,3H),3.61-3.59(m,2H),3.11(s,3H),2.89(d,J＝11.3Hz,3H),2.21(s,3H),2.02-1.94(m,2H),1.71-1.66(m,4H)。LC-MS(M+H)⁺＝497.2。

Example 450: 4-methyl-8- (5- (3-methyl-4- (1-methylpiperidin-4-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -3, 4-dihydrobenzo [ f ] [1,4] oxazepin-5 (2H) -one (Compound 450)

Step 1: 4-methyl-8- (5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -3, 4-dihydrobenzo [ f ] [1,4] oxazepin-5 (2H) -one

Prepared in a similar manner to that described in step 2 of example 332 from 8- [ 5-bromo-1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b ]]Pyridin-3-yl ]-4-methyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-5-one and BPD the title compound was prepared. LC-MS (M + H)⁺＝574.3。

Step 2: 4-methyl-8- [5- [ 3-methyl-4- (1-methylpiperidin-4-yl) phenyl ] -1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -2,3,4, 5-tetrahydro-1, 4-benzoxazepin-5-one

Prepared in a similar manner to that described in step 2 of example 332 from 4-methyl-8- [1- (4-methylbenzenesulfonyl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ]]Pyridin-3-yl]-2,3,4, 5-tetrahydro-1, 4-benzoxazepin-5-one and 4- (4-bromo-2-methylphenyl) -1-methylpiperidine the title compound is prepared. LC-MS (M + H)⁺＝635.4。

And step 3: 4-methyl-8- (5- (3-methyl-4- (1-methylpiperidin-4-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -3, 4-dihydrobenzo [ f ] [1,4] oxazepin-5 (2H) -one

Prepared in a similar manner to that described in example 369, step 6 from 4-methyl-8- [5- [ 3-methyl-4- (1-methylpiperidin-4-yl) phenyl]-1- (4-Methylbenzenesulfonyl) -1H-pyrrolo [2,3-b]Pyridin-3-yl]-2,3,4, 5-tetrahydro-1, 4-benzoxazepin-5-one preparation example 450.¹H NMR(400MHz,DMSO-d6)12.13(s,1H),8.54(d,J＝2.1Hz,1H),8.41(d,J＝2.1Hz,1H),8.06(d,J＝2.7Hz,1H),7.75(d,J＝8.2Hz,1H),7.63-7.61(m,1H),7.54-7.51(m,2H),7.40(d,J＝1.7Hz,1H),7.33(d,J＝8.6Hz,1H),4.43-4.04(m,2H),3.59-3.61(m,2H),3.12(s,3H),2.94(s,2H),2.55(s,1H),2.40(s,3H),2.26(s,2H),1.71(s,4H)。LC-MS(M+H)⁺＝481.4。

Example 451: (4- (5- (3-methoxy-4- (1-methylpiperidin-4-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (1-methylazetidin-3-yl) methanone (Compound 451)

Step 1: 3- (4-bromobenzoyl) -1-methylazetidine

The title compound was prepared from azetidin-3-yl (4-bromophenyl) methanone and formalin in a similar manner as in example 397, step 1. LC-MS (M + H)⁺＝254.0。

Step 2: (1-methylazetidin-3-yl) (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) methanone

The title compound was prepared from 3- (4-bromobenzoyl) -1-methylazetidine and BPD in a similar manner to that described in example 308, step 1. LC-MS (M + H)⁺＝302.2。

And step 3: (4- (5-bromo-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (1-methylazetidin-3-yl) methanone

Prepared in a similar manner to that described in step 2 of example 332 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) benzoyl]Azetidine the title compound was prepared. LC-MS (M + H)⁺＝524.1。

And 4, step 4: (4- (5- (3-methoxy-4- (1-methylpiperidin-4-yl) phenyl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (1-methylazetidin-3-yl) methanone

Prepared from 3- [4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] in a similar manner to that described in step 2 of example 332 ]Pyridin-3-yl]Benzoyl radical]-1-methylazetidine and 4- [ 2-methoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]1-methylpiperidine the title compound is prepared. LC-MS (M + H)⁺＝649.4。

And 5: (4- (5- (3-methoxy-4- (1-methylpiperidin-4-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (1-methylazetidin-3-yl) methanone

Prepared in a similar manner to that in example 369, step 6 from (4- (5- (3-methoxy-4- (1-methylpiperidin-4-yl) phenyl) -1-toluenesulfonyl-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) phenyl) (1-methylazetidin-3-yl) methanone example 451 was prepared.¹H NMR(400MHz,DMSO-d6)12.24(s,1H),8.61(d,J＝2.1Hz,1H),8.52(d,J＝2.1Hz,1H),8.14(d,J＝2.2Hz,1H),8.01-7.90(m,4H),7.29(s,3H),4.24-4.16(m,1H),3.92(s,3H),3.60-3.56(m,2H),3.23-3.20(m,2H),2.89(d,J＝10.5Hz,3H),2.21(d,J＝3.8Hz,6H),2.03-1.91(m,2H),1.71(s,4H)。LC-MS(M+H)⁺＝495.3。

Example 452: (4- (5- (3-methyl-4- (1-methylpiperidin-4-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (1-methylazetidin-3-yl) methanone (Compound 452)

Step 1: (1-methylazetidin-3-yl) (4- (5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone

Prepared from 3- [4- [ 5-bromo-1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b ] in a similar manner to that described in step 1 of example 308]Pyridin-3-yl]Benzoyl radical]-1-methylazetidine and BPD. LC-MS (M + H) ⁺＝572.3。

Step 2: (4- (5- (3-methyl-4- (1-methylpiperidin-4-yl) phenyl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (1-methylazetidin-3-yl) methanone

Prepared in a similar manner to that described in step 2 of example 332 from 1-methyl-3- [4- [1- (4-methylbenzenesulfonyl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ]]Pyridin-3-yl]Benzoyl radical]Azetidine and 4- (4-bromo-2-methylphenyl) -1-methylpiperidine the title compound is prepared. LC-MS (M + H)⁺＝633.2。

And step 3: (4- (5- (3-methyl-4- (1-methylpiperidin-4-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (1-methylazetidin-3-yl) methanone

Prepared in a similar manner to that described in example 369, step 6 from 1-methyl-4- (2-methyl-4- [3- [4- (1-methylazetidine-3-carbonyl) phenyl]-1- (4-Methylbenzenesulfonyl) -1H-pyrrolo [2,3-b]Pyridin-5-yl]Phenyl) piperidine preparation example 452.¹H NMR(400MHz,DMSO-d6)12.22(s,1H),8.57(d,J＝2.0Hz,1H),8.48(d,J＝2.1Hz,1H),8.14(d,J＝2.7Hz,1H),8.05-7.95(m,4H),7.56(d,J＝5.4Hz,2H),7.33(d,J＝8.6Hz,1H),4.25-4.17(m,1H),3.63-3.59(m,2H),3.27-3.24(m,2H),2.97(d,J＝11.0Hz,2H),2.73(s,1H),2.41(s,3H),2.28(s,3H),2.23(s,3H),2.13(s,3H),1.78-1.68(m,4H),1.24(s,2H)。LC-MS(M+H)⁺＝479.4。

Example 453: n, N-dimethyl-4- (5- (4- (piperidin-2-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 453)

Step 1: n, N-dimethyl-4- (5- (4- (piperidin-2-yl) phenyl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Prepared in a similar manner to that described in step 2 of example 332 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 2- (4-bromophenyl) piperidine. LC-MS (M + H)⁺＝579.3。

Step 2: n, N-dimethyl-4- (5- (4- (piperidin-2-yl) phenyl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Prepared in a similar manner to that described in example 369, step 6 from N, N-dimethyl-4- [1- (4-methylbenzenesulfonyl) -5- [4- (piperidin-2-yl) phenyl]-1H-pyrrolo [2,3-b]Pyridin-3-yl]Benzamide preparation example 453.¹H NMR(400MHz,DMSO-d6)12.11(s,1H),8.57(s,1H),8.46(s,1H),8.02(s,1H),7.90-7.83(m,2H),7.74-7.67(m,2H),7.53-7.43(m,4H),3.63-3.55(m,1H),3.07(d,J＝11.5Hz,1H),3.01(s,5H),2.73-2.63(m,1H),1.82(d,J＝9.2Hz,1H),1.76-1.68(m,1H),1.61-1.52(m,1H),1.48-1.32(m,3H)。LC-MS(M+H)⁺＝425.2。

Example 454: n, N-dimethyl-4- [5- (3-methyl-4- [ 5-methyl-hexahydropyrrolo [3,4-c ] pyrrol-2-yl ] phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide (compound 454)

Step 1: 2- (4-chloro-2-methylphenyl) -5-methyl-hexahydropyrrolo [3,4-c ] pyrrole

Prepared in a similar manner to that in step 2 of example 469 from 1-bromo-4-chloro-2-methylbenzene and 2-methyl-hexahydro-1H-pyrrolo [3,4-c ]]Pyrrole the title compound was prepared. LC-MS (M + H)⁺＝251.1。

Step 2: 2-methyl-5- [ 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] -hexahydropyrrolo [3,4-c ] pyrrole

Prepared in a similar manner to that in example 308, step 1 from 2- (4-chloro-2-methylphenyl) -5-methyl-octahydropyrrolo [3,4-c]Pyrrole and BPD the title compound was prepared. LC-MS (M + H)⁺＝343.3。

And step 3: n, N-dimethyl-4- [5- (3-methyl-4- [ 5-methyl-hexahydropyrrolo [3,4-c ] pyrrol-2-yl ] phenyl) -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

Prepared in a similar manner to that described in step 2 of example 332 from 2-methyl-5- [ 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-hexahydropyrrolo [3,4-c]Pyrrole and 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ]]Pyridin-3-yl]-N, N-dimethylbenzamide. LC-MS (M + H)⁺＝634.3。

And 4, step 4: n, N-dimethyl-4- [5- (3-methyl-4- [ 5-methyl-hexahydropyrrolo [3,4-c ] pyrrol-2-yl ] phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

Prepared in a similar manner to that described in example 369, step 6 from N, N-dimethyl-4- [5- (3-methyl-4- [ 5-methyl-hexahydropyrrolo [3,4-c ]]Pyrrol-2-yl]Phenyl) -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl]Benzamide preparation example 454.¹H NMR (400MHz, methanol-d 4) Δ 8.52-8.42(m,2H),7.90-7.75(m,3H),7.60-7.53(m,2H),7.51-7.42(m,2H),7.18-7.10(m,1H),3.20-2.90(m,14H),2.50-2.35(m, 8H). LC-MS (M + H) ⁺＝480.3。

Example 455: 4- (5- (4- (2, 5-dioxopyrrolidin-3-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (Compound 455)

Step 1: 3- (4-methoxyphenyl) pyrrolidine-2, 5-dione

To a solution of anisole (5.41g, 50.00mmol) in DCE (60mL) was added maleimide (4.85g, 50.00mmol), BF, and water at room temperature₃Ether (14.20g, 0.100 mol). The resulting mixture was stirred at reflux for 8 h. When the reaction was complete, the reaction solution was added to HCl (50mL, 2N) and stirred for 10min, then filtered with suction, washed with water, and the resulting solid was recrystallized from EtOH to yield 3- (4-methoxyphenyl) pyrrolidine-2, 5-dione (5.01g, 49%) as a white solid. LC-MS (M + H)⁺＝206.3。

Step 2: 3- (4-hydroxyphenyl) pyrrolidine-2, 5-dione

The title compound was prepared from 3- (4-methoxyphenyl) pyrrolidine-2, 5-dione in a similar manner to that in example 343, step 1. LC-MS (M + H)⁺＝192.1。

And step 3: 4- (2, 5-dioxopyrrolidin-3-yl) phenyl trifluoromethanesulfonate

To 3- (4-hydroxyphenyl) pyrrolidine-2, 5-dione (77mg, 0.403mmol) in CHCl at room temperature₃PhNTf was added to the solution (20mL)₂(431g, 1.209mmol), TEA (122mg, 1.209 mmol). The resulting mixture was stirred at 55 ℃ for 16 h. When the reaction was complete, the solvent was concentrated under reduced pressure And the residue was purified by flash chromatography eluting with MeOH in DCM (gradient 0% to 5%) to give 4- (2, 5-dioxopyrrolidin-3-yl) phenyl trifluoromethanesulfonate (50mg, 38%) as a brown solid. LC-MS (M + H)⁺＝322.1。

And 4, step 4: 4- [5- [4- (2, 5-dioxopyrrolidin-3-yl) phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -N, N-dimethylbenzamide

To a solution of 4- (2, 5-dioxopyrrolidin-3-yl) phenyl trifluoromethanesulfonate (152mg, 0.470mmol) in dioxane (15mL) was added H at room temperature₂O(1.5mL)、K₂CO₃(190mg，1.375mmol)、Pd(PPh₃)₄(95mg, 0.082mmol), and N, N-dimethyl-4- [1- (4-methylbenzenesulfonyl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ] pyrrole]Pyridin-3-yl]Benzamide (467mg, 0.857 mmol). The resulting mixture was irradiated with microwave radiation at 100 ℃ for 1h, when the reaction was complete, the solvent was concentrated under reduced pressure and the residue was purified by flash chromatography, eluting with MeOH in DCM (gradient 0% to 5%) to give 4- [5- [4- (2, 5-dioxopyrrolidin-3-yl) phenyl ] as a light brown solid]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl]-N, N-dimethylbenzamide (110mg, 39%). LC-MS (M + H) ⁺＝593.3。

And 5: n, N-dimethyl-4- (5- (4- (1-methyl-6-oxopiperidin-2-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Prepared in a similar manner to that described in example 369, step 6, from 4- [5- [4- (2, 5-dioxopyrrolidin-3-yl) phenyl]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl]-N, N-dimethylbenzamide preparation example 455.¹H NMR(400MHz,DMSO-d6)δ12.11(s,1H),11.35(s,1H),8.58(s,1H),8.48(s,1H),8.02(s,1H),7.91-7.84(m,2H),7.80-7.73(m,2H),7.53-7.47(m,2H),7.47-7.39(m,2H),4.23-4.19(m,1H),3.20-3.14(m,1H),3.01(s,6H),2.82-2.76(m,1H)。LC-MS(M+H)⁺＝439.2。

Example 456: (4- (5- (3-methoxy-4- (1-methylpiperidin-4-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (1-methylazetidin-3-yl) methanol (Compound 456)

Step 1: 4- (2-methoxy-4- [3- [4- (1-methylazetidine-3-carbonyl) phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-5-yl ] phenyl) -1-methylpiperidine

Prepared from 3- [4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] in a similar manner to that described in step 2 of example 332]Pyridin-3-yl]Benzoyl radical]-1-methylazetidine and 4- [ 2-methoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]1-methylpiperidine the title compound is prepared. LC-MS (M + H)⁺＝649.4。

Step 2: 4- (2-methoxy-4- [3- [4- (1-methylazetidine-3-carbonyl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-5-yl ] phenyl) -1-methylpiperidine

Prepared in a similar manner to that described in example 369, step 6 from 4- (2-methoxy-4- [3- [4- (1-methylazetidine-3-carbonyl) phenyl]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-5-yl]Phenyl) -1-methylpiperidine the title compound is prepared. LC-MS (M + H)⁺＝495.5。

And step 3: (4- (5- (3-methoxy-4- (1-methylpiperidin-4-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (1-methylazetidin-3-yl) methanol

Prepared in a similar manner to that described in step 4 of example 377 from 4- (2-methoxy-4- [3- [4- (1-methylazetidine-3-carbonyl) phenyl]-1H-pyrrolo [2,3-b]Pyridin-5-yl]Phenyl) -1-methylpiperidine preparation example 456.¹H NMR(400MHz,DMSO-d6)δ11.97(s,1H),8.57(s,1H),8.41(s,1H),7.87(s,1H),7.76-7.69(m,2H),7.37(d,J＝8.1Hz,2H),7.27(d,J＝1.8Hz,3H),5.32(s,1H),4.63(d,J＝8.2Hz,1H),3.91(s,3H),3.28-3.25(m,1H),3.11-3.05(m,2H),2.89-2.85(m,4H),2.59-2.50(m,1H),2.20(s,6H),1.98-1.95(m,2H),1.71-1.61(m,4H)。LC-MS(M+H)⁺＝497.5。

Example 457: [1- [2- (dimethylamino) ethyl ] azetidin-3-yl ] (4- [5- [ 3-methoxy-4- (1-methylpiperidin-4-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] phenyl) methanol (compound 457)

Step 1: [2- [3- (4-bromobenzoyl) azetidin-1-yl ] ethyl ] dimethylamine

To a solution of (2-bromoethyl) dimethylamine (577mg, 3.605mmol) in DCM (15mL) was added TEA (973mg, 9.614mmol), 3- (4-bromobenzoyl) azetidine hydrochloride (665mg, 2.405mmol) at room temperature. The resulting mixture was stirred at room temperature for 4 h. When the reaction was complete, the reaction was then diluted by the addition of water (30 mL). The resulting solution was extracted with DCM (50mLx 3). The organic phases were combined, washed with brine and over Na ₂SO₄And (5) drying. The solvent was concentrated under reduced pressure to give [2- [3- (4-bromobenzoyl) azetidin-1-yl ] as a pale yellow oil]Ethyl radical]Dimethylamine (600mg, crude). LC-MS (M + H)⁺＝311.0。

Step 2: dimethyl (2- [3- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoyl ] azetidin-1-yl ] ethyl) amine

Prepared in a similar manner to that described in example 308, step 1 from [2- [3- (4-bromobenzoyl) azetidin-1-yl]Ethyl radical]Dimethylamine and BPD prepared the title compound. LC-MS (M + H)⁺＝359.2。

And step 3: [2- (3- [4- [ 5-bromo-1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl ] azetidin-1-yl) ethyl ] dimethylamine

Prepared in a similar manner to that described in step 2 of example 332 from dimethyl (2- [3- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoyl]Azetidin-1-yl]Ethyl) amine and 5-bromo-3-iodo-1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b]Pyridine the title compound was prepared. LC-MS (M + H)⁺＝583.2。

And 4, step 4: [2- [3- (4- [5- [ 3-methoxy-4- (1-methylpiperidin-4-yl) phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) azetidin-1-yl ] ethyl ] dimethylamine

Prepared in a similar manner to that described in step 2 of example 332 from [2- (3- [4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ]]Pyridin-3-yl]Benzoyl radical]Azetidin-1-yl) ethyl]Dimethylamine and 4- [ 2-methoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]1-methylpiperidine the title compound is prepared. LC-MS (M + H)⁺＝706.4。

And 5: [2- [3- (4- [5- [ 3-methoxy-4- (1-methylpiperidin-4-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) azetidin-1-yl ] ethyl ] dimethylamine

Prepared from [2- [3- (4- [5- [ 3-methoxy-4- (1-methylpiperidin-4-yl) phenyl ] in a similar manner to that in example 369 step 6]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl]Benzoyl) azetidin-1-yl]Ethyl radical]Dimethylamine the title compound was prepared. LC-MS (M + H)⁺＝552.3。

Step 6: [1- [2- (dimethylamino) ethyl ] azetidin-3-yl ] (4- [5- [ 3-methoxy-4- (1-methylpiperidin-4-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] phenyl) methanol

Prepared from [2- [3- (4- [5- [ 3-methoxy-4- (1-methylpiperidin-4-yl) phenyl ] in a similar manner to the process described in example 377 step 4]-1H-pyrrolo [2,3-b]Pyridin-3-yl]Benzoyl) azetidin-1-yl ]Ethyl radical]Dimethylamine preparation example 457.¹H NMR(400MHz,DMSO-d6)δ11.96(s,1H),8.57(s,1H),8.41(s,1H),7.87(s,1H),7.72(d,J＝8.0Hz,2H),7.37(d,J＝7.9Hz,2H),7.27(d,J＝1.9Hz,3H),5.28(s,1H),4.61(d,J＝8.1Hz,1H),3.91(s,3H),3.26-3.23(m,1H),3.09-3.01(m,2H),2.92-2.79(m,4H),2.62-2.51(m,1H),2.50-2.42(m,2H),2.20(s,3H),2.20-2.10(m,8H),2.03-1.92(m,2H),1.73-1.61(m,4H)。LC-MS(M+H)⁺＝554.4。

Example 458: 1- (4- [5- [ 3-methyl-4- (1-methylpiperidin-4-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) azetidin-3-ol (compound 458)

Step 1: 1- (4- [5- [ 3-methyl-4- (1-methylpiperidin-4-yl) phenyl ] -1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) azetidin-3-ol

Prepared in a similar manner to that described in step 2 of example 332 from 1- [4- [1- (4-methylbenzenesulfonyl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ]]Pyridin-3-yl]Benzoyl radical]Azetidin-3-ol and 4- (4-bromo-2-methylphenyl) -1-methylpiperidine the title compound is prepared. LC-MS (M + H)⁺＝635.5。

Step 2: 1- (4- [5- [ 3-methyl-4- (1-methylpiperidin-4-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) azetidin-3-ol

Prepared in a similar manner to that described in step 9 of example 404 from 1- (4- [5- [ 3-methyl-4- (1-methylpiperidin-4-yl) phenyl]-1- (4-Methylbenzenesulfonyl) -1H-pyrrolo [2,3-b]Pyridin-3-yl]Benzoyl) azetidin-3-ol preparation example 458.¹H NMR(400MHz,DMSO-d6)δ12.12(s,1H),8.60(s,1H),8.54(s,1H),8.04(s,1H),7.89(d,J＝8.0Hz,2H),7.71(d,J＝8.0Hz,2H),7.55(s,2H),7.33(d,J＝8.3Hz,1H),5.81(s,1H),4.53(s,2H),4.28(s,1H),4.10(s,1H),3.82(s,1H),2.90(d,J＝10.9Hz,2H),2.69(brs,1H),2.40(s,3H),2.22(s,3H),2.14-2.01(m,2H),1.69(brs,4H)。LC-MS(M+H)⁺＝481.2。

Example 459: (4- [5- [ 3-fluoro-4- (1-methylpiperidin-4-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] phenyl) (1-methylazetidin-3-yl) methanol (Compound 459)

Step 1: 4- (2-fluoro-4- [3- [4- (1-methylazetidine-3-carbonyl) phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-5-yl ] phenyl) -1-methylpiperidine

Prepared from 3- [4- [ 5-bromo-1- (4-methylbenzenesulfonyl) in a similar manner to that in step 2 of example 332) Pyrrolo [2,3-b]Pyridin-3-yl]Benzoyl radical]-1-methylazetidine and 4- [ 2-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]1-methylpiperidine the title compound is prepared. LC-MS (M + H)⁺＝637.3。

Step 2: 4- (2-fluoro-4- [3- [4- (1-methylazetidine-3-carbonyl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-5-yl ] phenyl) -1-methylpiperidine

Prepared in a similar manner to that described in example 369, step 6 from 4- (2-fluoro-4- [3- [4- (1-methylazetidine-3-carbonyl) phenyl]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-5-yl]Phenyl) -1-methylpiperidine the title compound is prepared. LC-MS (M + H)⁺＝483.3。

And step 3: (4- [5- [ 3-fluoro-4- (1-methylpiperidin-4-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] phenyl) (1-methylazetidin-3-yl) methanol

Prepared in a similar manner to that described in step 4 of example 377 from 4- (2-fluoro-4- [3- [4- (1-methylazetidine-3-carbonyl) phenyl]-1H-pyrrolo [2,3-b ]Pyridin-5-yl]Phenyl) -1-methylpiperidine preparation example 459.¹H NMR(400MHz,DMSO-d6)δ12.00(s,1H),8.58(s,1H),8.44(s,1H),7.89(s,1H),7.74(d,J＝8.1Hz,2H),7.65-7.53(m,2H),7.44-7.36(m,3H),5.30(s,1H),4.63(d,J＝8.2Hz,1H),3.28-3.24(m,1H),3.10-3.05(m,2H),2.94-2.84(m,3H),2.81-2.79(m,1H),2.60-5.51(m,1H),2.21(s,6H),2.03-1.97(m,2H),1.84-1.73(m,4H)。LC-MS(M+H)⁺＝485.2。

Example 460: 6- (4- [5- [ 3-fluoro-4- (1-methylpiperidin-4-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) -2-oxa-6-azaspiro [3.3] heptane (compound 460)

Step 1: 6- (4- [5- [ 3-fluoro-4- (1-methylpiperidin-4-yl) phenyl ] -1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) -2-oxa-6-azaspiro [3.3] heptane

Prepared from 6- [4- [ 5-bromo-1-(4-Methylbenzenesulfonyl) -1H-pyrrolo [2,3-b]Pyridin-3-yl]Benzoyl radical]-2-oxa-6-azaspiro [3.3]Heptane and 4- [ 2-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]1-methylpiperidine the title compound is prepared. LC-MS (M + H)⁺＝665.3。

Step 2: 6- (4- [5- [ 3-fluoro-4- (1-methylpiperidin-4-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) -2-oxa-6-azaspiro [3.3] heptane

Prepared in a similar manner to that described in example 369, step 6 from 6- (4- [5- [ 3-fluoro-4- (1-methylpiperidin-4-yl) phenyl]-1- (4-Methylbenzenesulfonyl) -1H-pyrrolo [2,3-b]Pyridin-3-yl]Benzoyl) -2-oxa-6-azaspiro [3.3]Heptane preparation example 460. ¹H NMR(400MHz,DMSO-d6)δ12.18(s,1H),8.61(s,1H),8.52(s,1H),8.08(s,1H),7.92(d,J＝8.0Hz,2H),7.70(d,J＝8.0Hz,2H),7.67-7.56(m,2H),7.46-7.42(m,1H),4.71(s,4H),4.55(s,2H),4.24(s,2H),2.91(d,J＝10.7Hz,2H),2.89-2.70(m,1H),2.22(s,3H),2.02-2.00(m,2H),1.98-1.75(m,4H)。LC-MS(M+H)⁺＝511.2。

Example 461: 6- (4- [5- [4- (4-methylpiperazin-1-yl) -3- (trifluoromethoxy) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) -2-oxa-6-azaspiro [3.3] heptane (compound 461)

Step 1: 1-methyl-4- [ 4-nitro-2- (trifluoromethoxy) phenyl ] piperazine

The title compound was prepared from 1-fluoro-4-nitro-2- (trifluoromethoxy) benzene and 1-methylpiperazine in a similar manner as in example 404, step 5. LC-MS (M + H)⁺＝306.1。

Step 2: 4- (4-methylpiperazin-1-yl) -3- (trifluoromethoxy) aniline

Prepared in a similar manner to that in step 4 of example 446 from 1-methyl-4- [ 4-nitro-2- (trifluoromethoxy) phenyl]Piperazine the title compound was prepared. LC-MS (M + H)⁺＝276.1。

And step 3: [4- (4-methylpiperazin-1-yl) -3- (trifluoromethoxy) phenyl ] boronic acid

To a solution of 4- (4-methylpiperazin-1-yl) -3- (trifluoromethoxy) aniline (2.20g, 7.992mmol) in MeOH (80mL) at 0 ℃ was added HCl (3mL, 9.000mmol, 3N). The resulting mixture was stirred for 10min and then added to H₂NaNO in O₂(2.5mL, 8.75mmol, 3.5N). The mixture was stirred for 0.5h, and then 4,4,5, 5-tetramethyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3, 2-dioxaborolan (8.14g, 32.048mmol) was added. The resulting reaction was stirred at room temperature for 8 h. When the reaction was complete, the solution was concentrated under reduced pressure and the residue was applied to a C18 gel column and purified by flash chromatography, eluting with a gradient of MeCN in water (containing 10mmol/L NH4HCO3) from 30% to 70% over 30min to give [4- (4-methylpiperazin-1-yl) -3- (trifluoromethoxy) phenyl ] as a white solid ]Boric acid (578mg, 24%). LC-MS (M + H)⁺＝305.1。

And 4, step 4: 6- [4- [1- (4-Methylbenzenesulfonyl) -5- [4- (4-methylpiperazin-1-yl) -3- (trifluoromethoxy) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl ] -2-oxa-6-azaspiro [3.3] heptane

Prepared in a similar manner to that described in step 2 of example 332 from 6- [4- [ 5-bromo-1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b ]]Pyridin-3-yl]Benzoyl radical]-2-oxa-6-azaspiro [3.3]Heptane and [4- (4-methylpiperazin-1-yl) -3- (trifluoromethoxy) phenyl]Boronic acid the title compound was prepared. LC-MS (M + H)⁺＝732.2。

And 5: 6- (4- [5- [4- (4-methylpiperazin-1-yl) -3- (trifluoromethoxy) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) -2-oxa-6-azaspiro [3.3] heptane

Prepared in a similar manner to that described in example 369, step 6 from 6- [4- [1- (4-methylphenylsulfonyl) -5- [4- (4-methylpiperazin-1-yl) -3- (trifluoromethoxy) phenyl]-1H-pyrrolo [2,3-b]Pyridin-3-yl]Benzoyl radical]-2-oxa-6-azaspiro [3.3]Heptane preparation example 461.¹H NMR(400MHz,DMSO-d6)δ12.16(d,J＝2.7Hz,1H),8.56(s,1H),8.47(s,1H),8.07(s,1H),7.94-7.87(m,2H),7.75-7.68(m,2H),7.26(d,J＝8.4Hz,1H),4.71(s,4H),4.55(s,2H),4.24(s,2H),3.08-3.06(m,4H),2.48(s,4H),2.25(s,3H)。LC-MS(M+H)⁺＝578.2。

Example 462: n, N-dimethyl-1- (4- [5- [4- (4-methylpiperazin-1-yl) -3- (trifluoromethoxy) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) azetidin-3-amine (compound 462)

Step 1: n, N-dimethyl-1- [4- [1- (4-methylbenzenesulfonyl) -5- [4- (4-methylpiperazin-1-yl) -3- (trifluoromethoxy) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl ] azetidin-3-amine

Prepared in a similar manner to that described in step 2 of example 332 from 1- [4- [ 5-bromo-1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b ]]Pyridin-3-yl]Benzoyl radical]-N, N-dimethylazetidin-3-amine and [4- (4-methylpiperazin-1-yl) -3- (trifluoromethoxy) phenyl]Boronic acid the title compound was prepared. LC-MS (M + H)⁺＝733.3。

Step 2: n, N-dimethyl-1- (4- [5- [4- (4-methylpiperazin-1-yl) -3- (trifluoromethoxy) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) azetidin-3-amine

Prepared in a similar manner to that described in example 369, step 6 from N, N-dimethyl-1- [4- [1- (4-methylbenzenesulfonyl) -5- [4- (4-methylpiperazin-1-yl) -3- (trifluoromethoxy) phenyl]Pyrrolo [2,3-b]Pyridin-3-yl]Benzoyl radical]Azetidin-3-amine preparation example 462.¹H NMR(400MHz,DMSO-d6)δ12.16(s,1H),8.56(s,1H),8.47(s,1H),8.06(s,1H),7.94-7.87(m,2H),7.74-7.68(m,4H),7.70-7.66(m,1H),7.25(d,J＝8.4Hz,1H),4.37(s,1H),4.14-4.05(m,2H),3.86(s,1H),3.15-3.04(m,5H),2.48(d,J＝4.9Hz,4H),2.25(s,3H),2.11(s,6H)。LC-MS(M+H)⁺＝579.5。

Example 463: n, N-dimethyl-4- (5- (4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 463)

Step 1: n, N-dimethyl-4- [1- (4-methylbenzenesulfonyl) -5- [4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

Prepared in a similar manner to that described in step 2 of example 332 from 1-methyl-4- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2- (trifluoromethyl) phenyl]Piperazine and 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b ]]Pyridin-3-yl]-N, N-dimethylbenzamide. LC-MS (M + H)⁺＝662.4。

Step 2: n, N-dimethyl-4- (5- (4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Prepared in a similar manner to that described in step 9 of example 404 from N, N-dimethyl-4- [1- (4-methylbenzenesulfonyl) -5- [4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl]-1H-pyrrolo [2,3-b]Pyridin-3-yl]Benzamide preparation example 463.¹H NMR(400MHz,DMSO-d6)δ12.16(d,J＝2.5Hz,1H),8.73(s,1H),8.65(s,1H),8.12-8.06(m,2H),8.09(s,1H),7.88-7.86(m,2H),7.51-7.47(m,2H),3.01(s,6H),2.95-2.91(m,4H),2.51-2.50(m,4H),2.25(s,3H)。LC-MS(M+H)⁺＝508.3。

Example 464: n- [2- (dimethylamino) ethyl ] -N-methyl-4- [5- [4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide (compound 464)

Step 1: n- [2- (dimethylamino) ethyl ] -N-methyl-4- [1- (4-methylbenzenesulfonyl) -5- [4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

Prepared in a similar manner to that described in step 2 of example 332 from 1-methyl-4- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2- (trifluoromethyl) phenyl ]Piperazine and 4- [ 5-bromo-1- (4-methylbenzenesulfonyl)1H-pyrrolo [2,3-b ] yl]Pyridin-3-yl]-N- [2- (dimethylamino) ethyl group]-N-methylbenzamide the title compound was prepared. LC-MS (M + H)⁺＝719.3。

Step 2: n- [2- (dimethylamino) ethyl ] -N-methyl-4- [5- [4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

Prepared by reacting N- [2- (dimethylamino) ethyl group in a similar manner to that in step 6 of example 369]-N-methyl-4- [1- (4-methylbenzenesulfonyl) -5- [4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl]-1H-pyrrolo [2,3-b]Pyridin-3-yl]Benzamide preparation example 464.¹H NMR(400MHz,DMSO-d6)δ12.16(s,1H),8.59(s,1H),8.51(s,1H),8.04(s,2H),7.97(s,1H),7.88(d,J＝7.9Hz,2H),7.67(d,J＝8.6Hz,1H),7.46(d,J＝7.9Hz,2H),3.34(s,10H),2.99(s,2H),2.93(s,6H),2.25(s,5H),2.02(s,3H)。LC-MS(M+H)⁺＝565.2。

Example 465: n, N-dimethyl-1- (4- [5- [4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) azetidin-3-amine (compound 465)

Step 1: n, N-dimethyl-1- [4- [1- (4-methylbenzenesulfonyl) -5- [4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl ] azetidin-3-amine

Prepared in a similar manner to that described in step 2 of example 332 from 1-methyl-4- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2- (trifluoromethyl) phenyl ]Piperazine and 1- [4- [ 5-bromo-1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b ]]Pyridin-3-yl]Benzoyl radical]-N, N-dimethylazetidin-3-amine the title compound was prepared. LC-MS (M + H)⁺＝717.4。

Step 2: n, N-dimethyl-1- (4- [5- [4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) azetidin-3-amine

To and fromEXAMPLE 369 step 6 in an analogous manner to that described for N, N-dimethyl-1- [4- [1- (4-methylbenzenesulfonyl) -5- [4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl]-1H-pyrrolo [2,3-b]Pyridin-3-yl]Benzoyl radical]Azetidin-3-amine preparation example 465.¹H NMR(400MHz,DMSO-d6)δ12.21(s,1H),8.59(s,1H),8.53(s,1H),8.09(d,J＝2.6Hz,2H),8.04(d,J＝8.8Hz,1H),7.97(s,1H),7.91(d,J＝8.3Hz,2H),7.72-7.67(m,3H),4.37(s,1H),4.14-4.07(m,2H),3.85(s,1H),3.13-3.05(m,1H),2.95-2.91(m,4H),2.25(s,3H),2.10(s,6H),1.23(s,1H)。LC-MS(M+H)⁺＝563.4。

Example 466: 4- [5- [3- (ethylamino) -4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N, N-dimethylbenzamide (compound 466)

Step 1: 1- (4-bromo-2-nitrophenyl) -4-methylpiperazine

The title compound was prepared from 4-bromo-1-fluoro-2-nitrobenzene and 1-methylpiperazine in a similar manner to that in example 404, step 5. LC-MS (M + H)⁺＝300.0。

Step 2: 5-bromo-2- (4-methylpiperazin-1-yl) aniline

The title compound was prepared from 1- (4-bromo-2-nitrophenyl) -4-methylpiperazine in analogy to the procedure in example 320, step 3. LC-MS (M + H) ⁺＝270.1。

And step 3: 5-bromo-N-ethyl-2- (4-methylpiperazin-1-yl) aniline

The title compound was prepared from 5-bromo-2- (4-methylpiperazin-1-yl) aniline and acetaldehyde in a similar manner to that in example 397, step 1. LC-MS (M + H)⁺＝270.1。

And 4, step 4: 4- [5- [3- (ethylamino) -4- (4-methylpiperazin-1-yl) phenyl ] -1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N, N-dimethylbenzamide

Prepared in a similar manner to that described in step 2 of example 332 from N, N-dimethyl-4- [1- (4-methylbenzenesulfonyl) -5- (4,4,5, 5-tetra-N-methyl-benzenesulfonyl) -acetic acidMethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b]Pyridin-3-yl]Benzamide and 5-bromo-N-ethyl-2- (4-methylpiperazin-1-yl) aniline. LC-MS (M + H)⁺＝637.5。

And 5: 4- [5- [3- (ethylamino) -4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N, N-dimethylbenzamide

Prepared in a similar manner to that described in example 369, step 6 from 4- [5- [3- (ethylamino) -4- (4-methylpiperazin-1-yl) phenyl]-1- (4-Methylbenzenesulfonyl) -1H-pyrrolo [2,3-b]Pyridin-3-yl]-N, N-dimethylbenzamide preparation example 466.¹H NMR(400MHz,DMSO-d6)δ12.06(d,J＝2.7Hz,1H),8.52(s,1H),8.39(s,1H),8.00(s,1H),7.88-7.82(m,2H),7.52-7.46(m,2H),7.07(d,J＝8.0Hz,1H),6.94-6.92(m,1H),6.86(s,1H),4.76-4.72(m,1H),3.26-3.19(m,2H),3.01(s,6H),2.84(s,4H),2.26(s,4H),1.25-1.18(m,3H)。LC-MS(M+H)⁺＝483.2。

Example 467: 4- [5- [3- (cyclopropylamino) -4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N, N-dimethylbenzamide (Compound 467)

Step 1: 5-bromo-N-cyclopropyl-2- (4-methylpiperazin-1-yl) aniline

The title compound was prepared from 5-bromo-2- (4-methylpiperazin-1-yl) aniline and (1-ethoxycyclopropoxy) trimethylsilane in a similar manner to that in example 397, step 1. LC-MS (M + H)⁺＝310.1。

Step 2: 4- [5- [3- (cyclopropylamino) -4- (4-methylpiperazin-1-yl) phenyl ] -1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N, N-dimethylbenzamide

Prepared in a similar manner to that described in step 2 of example 332 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-N-cyclopropyl-2- (4-methylpiperazin-1-yl) anilineThe title compound was prepared. LC-MS (M + H)⁺＝649.3。

And step 3: 4- [5- [3- (cyclopropylamino) -4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N, N-dimethylbenzamide

Prepared in a similar manner to that described in example 369, step 6 from 4- [5- [3- (cyclopropylamino) -4- (4-methylpiperazin-1-yl) phenyl]-1- (4-Methylbenzenesulfonyl) -1H-pyrrolo [2,3-b]Pyridin-3-yl]-N, N-dimethylbenzamide preparation example 467.¹H NMR(400MHz,DMSO-d6)δ12.07(s,1H),8.53(s,1H),8.39(s,1H),8.00(s,1H),7.88-7.81(m,2H),7.53-7.46(m,2H),7.21(d,J＝2.1Hz,1H),7.07(d,J＝8.0Hz,1H),7.00-6.98(m,1H),5.18(s,1H),3.01(s,6H),2.82-2.78(m,4H),2.48(s,2H),2.25(s,3H),0.81-0.73(m,2H),0.56-0.47(m,2H)。LC-MS(M+H)⁺＝495.4。

Example 468: 4- [5- [3- (benzylamino) -4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N, N-dimethylbenzamide (Compound 468)

Step 1: n-benzyl-5-bromo-2- (4-methylpiperazin-1-yl) aniline

The title compound was prepared from 5-bromo-2- (4-methylpiperazin-1-yl) aniline and benzaldehyde in a similar manner to that in example 397, step 1. LC-MS (M + H)⁺＝360.2。

Step 2: 4- [5- [3- (benzylamino) -4- (4-methylpiperazin-1-yl) phenyl ] -1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N, N-dimethylbenzamide

Prepared in a similar manner to that described in step 2 of example 332 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 N-benzyl-5-bromo-2- (4-methylpiperazin-1-yl) aniline. LC-MS (M + H)⁺＝699.3。

And step 3: 4- [5- [3- (benzylamino) -4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N, N-dimethylbenzamide

Prepared in a similar manner to that described in example 369, step 6 from 4- [5- [3- (benzylamino) -4- (4-methylpiperazin-1-yl) phenyl]-1- (4-Methylbenzenesulfonyl) -1H-pyrrolo [2,3-b]Pyridin-3-yl]-N, N-dimethylbenzamide preparation example 468.¹H NMR(400MHz,DMSO-d6)δ12.03(s,1H),8.39(s,1H),8.21(s,1H),7.98(s,1H),7.82-7.75(m,2H),7.53-7.46(m,2H),7.42(d,J＝7.2Hz,2H),7.39-7.27(m,2H),7.28-7.16(m,1H),7.07(d,J＝8.0Hz,1H),6.98-6.88(m,1H),6.77(d,J＝2.0Hz,1H),5.65-5.57(m,1H),4.48(d,J＝5.9Hz,2H),3.02(s,6H),2.55(brs,4H),2.26(s,3H)。LC-MS(M+H)⁺＝545.2。

Example 469: n, N-dimethyl-4- [5- (4- [ 7-methyl-2, 7-diazaspiro [3.5] non-2-yl ] phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide (compound 469)

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

Prepared in a similar manner to that described in step 2 of example 332 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 1-bromo-4-chlorobenzene. LC-MS (M + H)⁺＝531.1。

Step 2: n, N-dimethyl-4- [5- (4- [ 7-methyl-2, 7-diazaspiro [3.5] non-2-yl ] phenyl) -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

To 4- [5- (4-chlorophenyl) -1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b ] at room temperature]Pyridin-3-yl]Addition of 7-methyl-2, 7-diazaspiro [3.5] to a solution of (E) -N, N-Dimethylbenzamide (123mg, 0.232mmol) in toluene (8mL)]Nonane dihydrochloride (76mg, 0.357mmol), t-BuONa (68mg, 0.712mmol), RuPhos (30mg, 0.065mmol), and Pd₂(dba)₃(62mg, 0.067 mmol). Mixing the obtained mixtureStirring was carried out at 100 ℃ for 16h under a nitrogen atmosphere. When the reaction was complete, the solvent was concentrated under reduced pressure and the residue was purified by flash chromatography, eluting with EtOAc in hexanes (gradient 0% to 10%) to give N, N-dimethyl-4- [5- (4- [ 7-methyl-2, 7-diazaspiro [3.5] as a brown solid ]Non-2-yl]Phenyl) -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl]Benzamide (500mg, crude). LC-MS (M + H)⁺＝634.3。

And step 3: n, N-dimethyl-4- [5- (4- [ 7-methyl-2, 7-diazaspiro [3.5] non-2-yl ] phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

Prepared from N, N-dimethyl-4- [5- (4- [ 7-methyl-2, 7-diazaspiro [3.5] in a similar manner to that described in example 369, step 6]Non-2-yl]Phenyl) -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl]Benzamide preparation example 469.¹H NMR(400MHz,DMSO-d6)δ12.01(s,1H),8.50(s,1H),8.36(d,J＝2.1Hz,1H),7.98(d,J＝2.3Hz,1H),7.88-7.82(m,2H),7.62-7.55(m,2H),7.52-7.46(m,2H),6.58-6.51(m,2H),3.57(s,4H),3.01(s,6H),2.27(s,4H),2.15(s,3H),1.76-1.73(m,4H)。LC-MS(M+H)⁺＝480.3。

Example 470: n, N-dimethyl-4- [5- (4- [ 6-methyl-2, 6-diazaspiro [3.5] non-2-yl ] phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide (compound 470)

Step 1: 2- (4- [3- [4- (dimethylcarbamoyl) phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-5-yl ] phenyl) -2, 6-diazaspiro [3.5] nonane-6-carboxylic acid tert-butyl ester

To 4- [5- (4-chlorophenyl) -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] at room temperature]Pyridin-3-yl]To a solution of (E) -N, N-dimethylbenzamide (50mg, 0.094mmol) in dioxane (4mL) was added 2, 6-diazaspiro [3.5]]Nonane-6-carboxylic acid tert-butyl ester hemioxalate (31mg, 0.057mmol), Pd (AcO)₂(6mg, 0.028mmol), t-BuOK (32mg, 0.283mmol), RuPhos (13mg, 0.028 mmol). The resulting mixture is at 10 Irradiating with microwave radiation at 0 deg.C for 2 h. When the reaction was complete, the solvent was concentrated under reduced pressure and the residue was purified by flash chromatography, eluting with MeOH in DCM (gradient 0% to 10%) to give 2- (4- [3- [4- (dimethylcarbamoyl) phenyl) as a yellow solid]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-5-yl]Phenyl) -2, 6-diazaspiro [3.5]Nonane-6-carboxylic acid tert-butyl ester (135mg, 50%). LC-MS (M + H)⁺＝720.2。

Step 2: 4- [5- (4- [2, 6-diazaspiro [3.5] non-2-yl ] phenyl) -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -N, N-dimethylbenzamide

Prepared in a similar manner to that in step 5 of example 309 from 2- (4- [3- [4- (dimethylcarbamoyl) phenyl)]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-5-yl]Phenyl) -2, 6-diazaspiro [3.5]Nonane-6-carboxylic acid tert-butyl ester the title compound was prepared. LC-MS (M + H)⁺＝620.2。

And step 3: n, N-dimethyl-4- [5- (4- [ 6-methyl-2, 6-diazaspiro [3.5] non-2-yl ] phenyl) -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

Prepared from 4- [5- (4- [2, 6-diazaspiro [3.5] in a similar manner to that in example 397, step 1]Non-2-yl]Phenyl) -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ]Pyridin-3-yl]-N, N-dimethylbenzamide and formalin. LC-MS (M + H)⁺＝634.2。

And 4, step 4: n, N-dimethyl-4- [5- (4- [ 6-methyl-2, 6-diazaspiro [3.5] non-2-yl ] phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

Prepared from N, N-dimethyl-4- [5- (4- [ 6-methyl-2, 6-diazaspiro [3.5] in a similar manner to that described in example 369, step 6]Non-2-yl]Phenyl) -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl]Benzamide preparative example 470.¹H NMR(400MHz,DMSO-d6)δ12.00(s,1H),8.50(s,1H),8.36(s,1H),7.97(s,1H),7.85(d,J＝8.0Hz,2H),7.58(d,J＝8.3Hz,2H),7.49(d,J＝8.2Hz,2H),6.54(d,J＝8.5Hz,2H),3.60(d,J＝7.2Hz,2H),3.53(d,J＝7.1Hz,2H),3.01(s,6H),2.46-2.32(m,2H),2.28-2.19(m,5H),1.61-1.54(s,4H)。LC-MS(M+H)⁺＝480.3。

Example 471: n, N-dimethyl-4- [5- [4- (1-methylpiperidin-4-yl) -3- (trifluoromethyl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide (compound 471)

Step 1: 1-methyl-4- [ 4-nitro-2- (trifluoromethyl) phenyl ] -1,2,3, 6-tetrahydropyridine

The title compound was prepared from 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,2,3, 6-tetrahydropyridine and 1-bromo-4-nitro-2- (trifluoromethyl) benzene in a similar manner to that in example 332, step 2. LC-MS (M + H)⁺＝287.1。

Step 2: 4- (1-methylpiperidin-4-yl) -3- (trifluoromethyl) aniline

Prepared in a similar manner to that described in step 1 of example 430 from 1-methyl-4- [ 4-nitro-2- (trifluoromethyl) phenyl]-1,2,3, 6-tetrahydropyridine the title compound is prepared. LC-MS (M + H) ⁺＝259.1。

And step 3: 4- [ 4-bromo-2- (trifluoromethyl) phenyl ] -1-methylpiperidine

The title compound was prepared from 4- (1-methylpiperidin-4-yl) -3- (trifluoromethyl) aniline in a similar manner to that in example 320 step 4. LC-MS (M + H)⁺＝322.1。

And 4, step 4: n, N-dimethyl-4- [1- (4-methylbenzenesulfonyl) -5- [4- (1-methylpiperidin-4-yl) -3- (trifluoromethyl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

Prepared in a similar manner to that described in step 2 of example 332 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- [ 4-bromo-2- (trifluoromethyl) phenyl]1-methylpiperidine the title compound is prepared. LC-MS (M + H)⁺＝661.3。

And 5: n, N-dimethyl-4- [5- [4- (1-methylpiperidin-4-yl) -3- (trifluoromethyl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

Prepared in a similar manner to that described in example 369, step 6 from N, N-dimethyl-4- [1- (4-methylbenzenesulfonyl) -5- [4- (1-methylpiperidin-4-yl) -3- (trifluoromethyl) phenyl]-1H-pyrrolo [2,3-b]Pyridin-3-yl]Benzamide preparation example 471.¹H NMR(400MHz,DMSO-d6)δ12.18(s,1H),8.61(s,1H),8.55(s,1H),8.05-8.05(m,2H),7.98(d,J＝2.0Hz,1H),7.92-7.85(m,2H),7.74(d,J＝8.2Hz,1H),7.52-7.46(m,2H),3.01-2.96(m,8H),2.87-2.81(m,1H),2.28(s,3H),2.08(brs,2H),1.92-1.84(m,2H),1.71(d,J＝12.5Hz,2H)。LC-MS(M+H)⁺＝507.4。

Example 472: 4- [5- [4- (1, 4-dimethylpiperidin-4-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N, N-dimethylbenzamide (Compound 472)

Step 1: 4- (4-bromophenyl) -1, 4-dimethylpiperidine

The title compound was prepared from 4- (4-bromophenyl) -4-methylpiperidine in a similar manner to that in example 397 step 1. LC-MS (M + H)⁺＝269.9。

Step 2: 4- [5- [4- (1, 4-dimethylpiperidin-4-yl) phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -N, N-dimethylbenzamide

Prepared in a similar manner to that described in step 2 of example 332 from N, N-dimethyl-4- [1- (4-methylbenzenesulfonyl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ]]Pyridin-3-yl]Benzamide and 4- (4-bromophenyl) -1, 4-dimethylpiperidine. LC-MS (M + H)⁺＝607.3。

And step 3: 4- [5- [4- (1, 4-dimethylpiperidin-4-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N, N-dimethylbenzamide

Prepared from 4- [5- [4- (1, 4-dimethylpiperidin-4-yl) phenyl in a similar manner to that described in example 369, step 6]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl]-N, N-dimethylbenzamide preparation example 472.¹H NMR(400MHz,DMSO-d6)δ12.10(s,1H),8.58(s,1H),8.48(s,1H),8.02(s,1H),7.87(d,J＝7.9Hz,2H),7.72(d,J＝7.9Hz,2H),7.49(d,J＝7.9Hz,4H),3.01(s,6H),2.50-2.38(m,4H),2.15(s,3H),2.07(brs,2H),1.98-1.77(m,2H),1.22(s,3H)。LC-MS(M+H)⁺＝453.3。

Example 473: n, N-dimethyl-4- [5- (4- [ 5-methyl-octahydropyrrolo [3,4-c ] pyrrol-2-yl ] phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide (compound 473)

Prepared in a similar manner to that described in example 369, step 6 from 4- [5- (4-chlorophenyl) -1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b ]]Pyridin-3-yl]-N, N-dimethylbenzamide and 2-methyl-octahydropyrrolo [3,4-c]Pyrrole preparation example 473.¹H NMR(400MHz,DMSO-d6)δ12.00(s,1H),8.52(s,1H),8.38(s,1H),7.97(s,1H),7.85(d,J＝8.0Hz,2H),7.60(d,J＝8.4Hz,2H),7.49(d,J＝8.0Hz,2H),6.75(d,J＝8.3Hz,2H),3.44-3.32(m,2H),3.13-3.10(m,2H),3.01(s,6H),2.95-2.91(m,2H),2.59-2.55(m,2H),2.44-2.42(m,2H),2.24(s,3H)。LC-MS(M+H)⁺＝466.2。

Example 474: n, N-dimethyl-4- (5- [ 3-methyl-4- [ (3R) -3- (methylamino) piperidin-1-yl ] phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 474)

Step 1: n- [ (3R) -1- (4-chloro-2-methylphenyl) piperidin-3-yl ] -N-methylcarbamic acid tert-butyl ester

Prepared in a similar manner to that in step 2 of example 430 from N-methyl-N- [ (3R) -piperidin-3-yl]Tert-butyl carbamate and 1-bromo-4-chloro-2-methylbenzene the title compound was prepared. LC-MS (M + H)⁺＝339.2。

Step 2: (3R) -1- (4-chloro-2-methylphenyl) -N-methylpiperidine-3-amine

Prepared in a similar manner to that in step 5 of example 309 from N- [ (3R) -1- (4-chloro-2-methylphenyl) piperidin-3-yl]-N-methyl-carbamic acid tert-butyl ester the title compound is prepared. LC-MS (M + H)⁺＝239.1。

And step 3: n, N-dimethyl-4- (5- [ 3-methyl-4- [ (3R) -3- (methylamino) piperidin-1-yl ] phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Prepared in a similar manner to that in step 2 of example 311 from N, N-dimethyl-4- [1- (4-methylbenzenesulfonyl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ] ]Pyridin-3-yl]Benzamide and (3R) -1- (4-chloro-2-methylphenyl) -N-methylpiperidin-3-amine the title compound is prepared. LC-MS (M + H)⁺＝622.4。

And 4, step 4: n, N-dimethyl-4- (5- [ 3-methyl-4- [ (3R) -3- (methylamino) piperidin-1-yl ] phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Prepared in a similar manner to that described in example 369, step 6 from N, N-dimethyl-4- (5- [ 3-methyl-4- [ (3R) -3- (methylamino) piperidin-1-yl)]Phenyl radical]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl) benzamide example 474 was prepared.¹H NMR(400MHz,DMSO-d6)δ12.05(s,1H),8.53(s,1H),8.41(s,1H),8.00(s,1H),7.89-7.82(m,2H),7.57-7.46(m,4H),7.10(d,J＝8.2Hz,1H),3.21-3.19(m,1H),3.01-2.97(m,7H),2.61-2.51(m,2H),2.36-2.30(m,7H),1.96-1.88(m,1H),1.81-1.73(m,1H),1.68-1.60(m,1H),1.22-1.15(m,1H)。LC-MS(M+H)⁺＝468.4。

Example 475: n, N-dimethyl-4- (5- [ 3-methyl-4- [ (3S) -3- (methylamino) piperidin-1-yl ] phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 475)

Step 1: n- [ (3S) -1- (4-chloro-2-methylphenyl) piperidin-3-yl ] -N-methylcarbamic acid tert-butyl ester

Prepared from N-methyl-N- [ (3S) -piperidin-3-yl group in a similar manner to that in step 2 of example 430]Tert-butyl carbamate and 1-bromo-4-chloro-2-methylbenzene the title compound was prepared. LC-MS (M + H)⁺＝339.2。

Step 2: (3S) -1- (4-chloro-2-methylphenyl) -N-methylpiperidine-3-amine

To and withExample 309 in a similar manner to that described in step 5 starting from N- [ (3S) -1- (4-chloro-2-methylphenyl) piperidin-3-yl]-N-methyl-carbamic acid tert-butyl ester the title compound is prepared. LC-MS (M + H) ⁺＝239.1。

And step 3: n, N-dimethyl-4- (5- [ 3-methyl-4- [ (3S) -3- (methylamino) piperidin-1-yl ] phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Prepared in a similar manner to that in step 2 of example 311 from N, N-dimethyl-4- [1- (4-methylbenzenesulfonyl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ]]Pyridin-3-yl]Benzamide and (3S) -1- (4-chloro-2-methylphenyl) -N-methylpiperidin-3-amine the title compound is prepared. LC-MS (M + H)⁺＝622.4。

And 4, step 4: n, N-dimethyl-4- (5- [ 3-methyl-4- [ (3S) -3- (methylamino) piperidin-1-yl ] phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Prepared in a similar manner to that described in example 369, step 6 from N, N-dimethyl-4- (5- [ 3-methyl-4- [ (3S) -3- (methylamino) piperidin-1-yl)]Phenyl radical]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl) benzamide example 475 was prepared.¹H NMR(400MHz,DMSO-d6)δ12.05(s,1H),8.53(s,1H),8.41(s,1H),8.00(s,1H),7.89-7.82(m,2H),7.57(s,1H),7.56-7.46(m,3H),7.10(d,J＝8.2Hz,1H),3.21-3.19(m,1H),3.01-2.97(m,7H),2.61-2.51(m,2H),2.36-2.30(m,7H),1.96-1.88(m,1H),1.81-1.73(m,1H),1.68-1.60(m,1H),1.22-1.15(m,1H)。LC-MS(M+H)⁺＝468.4。

Example 476: (R) -N, N-dimethyl-4- (5- (3-methyl-4- (3- (methylamino) pyrrolidin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (Compound 476)

Step 1: n- [ (3R) -1- (4-chloro-2-methylphenyl) pyrrolidin-3-yl ] -N-methylcarbamic acid tert-butyl ester

Prepared in a similar manner to that in step 2 of example 430 from N-methyl-N- [ (3R) -pyrrolidin-3-yl ]Tert-butyl carbamate and 1-bromo-4-chloro-2-methylbenzene the title compound was prepared. LC-MS (M + H)⁺＝325.1。

Step 2: (3R) -1- (4-chloro-2-methylphenyl) -N-methylpyrrolidine-3-amine

Prepared in a similar manner to that in step 5 of example 309 from N- [ (3R) -1- (4-chloro-2-methylphenyl) pyrrolidin-3-yl]-N-methyl-carbamic acid tert-butyl ester the title compound is prepared. LC-MS (M + H)⁺＝225.1。

And step 3: (R) -N, N-dimethyl-4- (5- (3-methyl-4- (3- (methylamino) pyrrolidin-1-yl) phenyl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Prepared in a similar manner to that in step 2 of example 311 from N, N-dimethyl-4- [1- (4-methylbenzenesulfonyl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ]]Pyridin-3-yl]Benzamide and (3R) -1- (4-chloro-2-methylphenyl) -N-methylpyrrolidin-3-amine the title compound is prepared. LC-MS (M + H)⁺＝608.3。

And 4, step 4: (R) -N, N-dimethyl-4- (5- (3-methyl-4- (3- (methylamino) pyrrolidin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Prepared in a similar manner to that described in example 369, step 6 from (R) -N, N-dimethyl-4- (5- (3-methyl-4- (3- (methylamino) pyrrolidin-1-yl) phenyl) -1-tosyl-1H-pyrrolo [2, 3-b) ]Pyridin-3-yl) benzamide preparation example 476.¹H NMR(400MHz,DMSO-d6)δ12.01(s,1H),8.53(s,1H),8.39(s,1H),7.98(s,1H),7.89-7.82(m,2H),7.51-7.45(m,4H),6.93(d,J＝8.3Hz,1H),3.38-3.36(m,1H),3.30-3.19(m,4H),3.02-2.98(m,7H),2.36(s,3H),2.32(s,3H),2.11-2.05(m,1H),1.74-1.71(m,1H)。LC-MS(M+H)⁺＝454.2。

Example 477: (S) -N, N-dimethyl-4- (5- (3-methyl-4- (3- (methylamino) pyrrolidin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (Compound 477)

Step 1: n- [ (3S) -1- (4-chloro-2-methylphenyl) pyrrolidin-3-yl ] -N-methylcarbamic acid tert-butyl ester

Prepared from N-methyl-N- [ (3S) -pyrrolidin-3-yl in a similar manner to that in step 2 of example 430]Tert-butyl carbamate and 1-bromo-4-chloro-2-methylbenzene the title compound was prepared. LC-MS (M + H)⁺＝325.1。

Step 2: (3S) -1- (4-chloro-2-methylphenyl) -N-methylpyrrolidine-3-amine

Prepared in a similar manner to that in step 5 of example 309 from N- [ (3S) -1- (4-chloro-2-methylphenyl) pyrrolidin-3-yl]-N-methyl-carbamic acid tert-butyl ester the title compound is prepared. LC-MS (M + H)⁺＝225.1。

And step 3: (R) -N, N-dimethyl-4- (5- (3-methyl-4- (3- (methylamino) pyrrolidin-1-yl) phenyl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Prepared in a similar manner to that in step 2 of example 311 from N, N-dimethyl-4- [1- (4-methylbenzenesulfonyl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ]]Pyridin-3-yl]Benzamide and (3S) -1- (4-chloro-2-methylphenyl) -N-methylpyrrolidin-3-amine the title compound is prepared. LC-MS (M + H) ⁺＝608.3。

And 4, step 4: (S) -N, N-dimethyl-4- (5- (3-methyl-4- (3- (methylamino) pyrrolidin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Prepared in a similar manner to that described in example 369, step 6 from (R) -N, N-dimethyl-4- (5- (3-methyl-4- (3- (methylamino) pyrrolidin-1-yl) phenyl) -1-tosyl-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) benzamide preparation example 477.¹H NMR(400MHz,DMSO-d6)δ12.01(s,1H),8.53(s,1H),8.39(s,1H),7.98(s,1H),7.89-7.82(m,2H),7.51-7.45(m,4H),6.93(d,J＝8.3Hz,1H),3.38-3.36(m,1H),3.30-3.19(m,4H),3.02-2.98(m,7H),2.36(s,3H),2.32(s,3H),2.11-2.05(m,1H),1.74-1.71(m,1H)。LC-MS(M+H)⁺＝454.2。

Example 478: (4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] phenyl) (1-methylpyrrolidin-3-yl) methanol (Compound 478)

Step 1: 3- (4-bromobenzoyl) -1-methylpyrrolidine

The title compound was prepared from 3- (4-bromobenzoyl) pyrrolidine and formalin in a similar manner as in example 397, step 1. LC-MS (M + H)⁺＝268.3。

Step 2: 1-methyl-3- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoyl ] pyrrolidine

The title compound was prepared from 3- (4-bromobenzoyl) -1-methylpyrrolidine and BPD in a similar manner to that described in example 308, step 1. LC-MS (M + H)⁺＝316.2。

And step 3: 3- [4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl ] -1-methylpyrrolidine

Prepared in a similar manner to that described in step 2 of example 332 from 1-methyl-3- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoyl ]Pyrrolidine and 5-bromo-3-iodo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridine the title compound was prepared. LC-MS (M + H)⁺＝538.5。

And 4, step 4: 1-methyl-4- [ 2-methyl-4- [1- (4-methylbenzenesulfonyl) -3- [4- (1-methylpyrrolidine-3-carbonyl) phenyl ] pyrrolo [2,3-b ] pyridin-5-yl ] phenyl ] piperazine

Prepared from 3- [4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] in a similar manner to that described in step 2 of example 332]Pyridin-3-yl]Benzoyl radical]-1-methylpyrrolidine and 1-methyl-4- [ 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Piperazine the title compound was prepared. LC-MS (M + H)⁺＝648.2。

And 5: (4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] phenyl) (1-methylpyrrolidin-3-yl) methanol

Prepared from 1-methyl-4- [ 2-methyl-4- [1- (4) methyl ester in a similar manner to that in step 4 of example 377-Methylbenzenesulfonyl) -3- [4- (1-methylpyrrolidine-3-carbonyl) phenyl]Pyrrolo [2,3-b]Pyridin-5-yl]Phenyl radical]Piperazine the title compound was prepared. LC-MS (M + H)⁺＝650.5。

Step 6: (4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] phenyl) (1-methylpyrrolidin-3-yl) methanol

Prepared from (4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl) in a similar manner to that in example 369 step 6]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl]Phenyl) (1-methylpyrrolidin-3-yl) methanol example 478 was prepared.¹H NMR (400MHz, methanol-d 4) δ 8.52-8.36(m,2H),7.76-7.65(m,3H),7.49-7.47(m,4H),7.19(d, J ═ 8.2Hz,1H),4.54(d, J ═ 7.9Hz,1H),3.03-3.00(m,4H),2.85-2.81(m,1H),2.70-2.56(m,7H),2.48(s,1H),2.40(s,9H),2.20-1.90(m,2H),1.76-1.63(m, 1H). LC-MS (M + H)⁺＝496.4。

Example 479: n, N-dimethyl-4- [5- [ 3-methyl-4- (1-methylpiperidin-3-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide (compound 479)

Step 1: 4- [5- (4-bromo-3-methylphenyl) -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -N, N-dimethylbenzamide

Prepared in a similar manner to that described in step 2 of example 332 from N, N-dimethyl-4- [1- (4-methylbenzenesulfonyl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ]]Pyridin-3-yl]Benzamide and 1-bromo-4-iodo-2-methylbenzene. LC-MS (M + H)⁺＝588.0。

Step 2: 3- (4- [3- [4- (dimethylcarbamoyl) phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-5-yl ] -2-methylphenyl) -5, 6-dihydro-4H-pyridine-1-carboxylic acid tert-butyl ester

Prepared in a similar manner to that described in step 2 of example 332 from 4- [5- (4-bromo-3-methylphenyl) -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ]]Pyridin-3-yl]-N, N-dimethylBenzamide and 3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydro-4H-pyridine-1-carboxylic acid tert-butyl ester. LC-MS (M + H)⁺＝691.7。

And step 3: 3- (4- [3- [4- (dimethylcarbamoyl) phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-5-yl ] -2-methylphenyl) piperidine-1-carboxylic acid tert-butyl ester

To 3- (4- [3- [4- (dimethylcarbamoyl) phenyl group under nitrogen atmosphere]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-5-yl](iii) -2-methylphenyl) -5, 6-dihydro-4H-pyridine-1-carboxylic acid tert-butyl ester (300mg, 0.434mmol) in EtOH (10mL) to which Pd (OH) was added₂C (300mg, 2.136 mmol). The reaction flask was evacuated and flushed with hydrogen. The reaction mixture was then hydrogenated in a pressure pot at 40 ℃ under a hydrogen atmosphere of 5atm for 48 h. When the reaction was complete, the solids were removed by filtration. The filtrate was concentrated and the residue was purified by flash chromatography, eluting with MeOH in DCM (gradient 0% to 10%) to give 3- (4- [3- [4- (dimethylcarbamoyl) phenyl) as a yellow oil ]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-5-yl]-2-methylphenyl) piperidine-1-carboxylic acid tert-butyl ester (254mg, 85%). LC-MS (M + H)⁺＝693.3。

And 4, step 4: n, N-dimethyl-4- [5- [ 3-methyl-4- (piperidin-3-yl) phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

Prepared in a similar manner to that in step 5 of example 309 from 3- (4- [3- [4- (dimethylcarbamoyl) phenyl)]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-5-yl]-2-methylphenyl) piperidine-1-carboxylic acid tert-butyl ester. LC-MS (M + H)⁺＝593.2。

And 5: n, N-dimethyl-4- [5- [ 3-methyl-4- (1-methylpiperidin-3-yl) phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

Prepared in a similar manner to that described in example 397, step 1 from N, N-dimethyl-4- [5- [ 3-methyl-4- (piperidin-3-yl) phenyl]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl]Benzamide and formalin. LC-MS (M)+H)⁺＝607.4。

Step 6: n, N-dimethyl-4- [5- [ 3-methyl-4- (1-methylpiperidin-3-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

Prepared in a similar manner to that described in example 369, step 6 from N, N-dimethyl-4- [5- [ 3-methyl-4- (1-methylpiperidin-3-yl) phenyl ]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl]Benzamide preparation example 479.¹H NMR(400MHz,DMSO-d6)δ12.08(s,1H),8.61-8.28(m,2H),8.06-7.78(m,3H),7.60-7.38(m,4H),7.34(d,J＝7.9Hz,1H),3.41-2.89(m,7H),2.86-2.74(m,2H),2.41(s,3H),2.20(s,3H),1.98-1.88(m,2H),1.80-1.60(m,3H),1.50-1.37(m,1H)。LC-MS(M+H)⁺＝453.2。

Example 480: 2- (4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) -6-oxa-2-azaspiro [3.4] octane (compound 480)

Step 1: 2- (4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) -6-oxa-2-azaspiro [3.4] octane

Prepared from 2- [4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] in a similar manner to that described in step 2 of example 332]Pyridin-3-yl]Benzoyl radical]-6-oxa-2-azaspiro [3.4]Octane and 1-methyl-4- [ 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Piperazine the title compound was prepared. LC-MS (M + H)⁺＝676.6。

Step 2: 2- (4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) -6-oxa-2-azaspiro [3.4] octane

Prepared from 1-methyl-4- [ 2-methyl-4- [1- (4-methylbenzenesulfonyl) -3- (4- [ 6-oxaspiro [3.4] in a similar manner to that described in example 369, step 6]Octane-2-carbonyl]Phenyl) pyrrolo [2,3-b]Pyridin-5-yl]Phenyl radical]Piperazine preparation example 480. ¹H NMR(400MHz,DMSO-d6)δ12.10(s,1H),8.54(s,1H),8.42(s,1H),8.04(s,1H),7.91-7.85(m,2H),7.77-7.71(m,2H),7.60-7.50(m,2H),7.13(d,J＝8.2Hz,1H),4.37(s,2H),4.05(s,2H),3.84-3.79(m,2H),3.77-3.68(m,2H),2.93-2.86(m,4H),2.58-2.48(m,4H),2.35(s,3H),2.26(s,3H),2.20-2.11(m,2H)。LC-MS(M+H)⁺＝522.4。

Example 481: n, N-dimethyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] pyrimidine-2-carboxamide (Compound 481)

Step 1: 1- (4- [ 3-bromo-1H-pyrrolo [2,3-b ] pyridin-5-yl ] -2-methylphenyl) -4-methylpiperazine

Prepared from 1-methyl-4- (2-methyl-4- [ 1H-pyrrolo [2,3-b ] in a similar manner to that described in step 5 of example 305]Pyridin-5-yl]Phenyl) piperazine and NBS the title compound was prepared. LC-MS (M + H)⁺＝385.2。

Step 2: 1- [4- [ 3-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-5-yl ] -2-methylphenyl ] -4-methylpiperazine

Prepared in a similar manner to that in step 2 of example 360 from 1- (4- [ 3-bromo-1H-pyrrolo [2,3-b ]]Pyridin-5-yl]-2-methylphenyl) -4-methylpiperazine and TsCl. LC-MS (M + H)⁺＝539.0。

And step 3: 5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-ylboronic acid

To 1- [4- [ 3-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] at room temperature]Pyridin-5-yl]-2-methylphenyl radical]BPD (209mg, 0.823mmol), KOAc (200mg, 2.033mmol), and Pd (PPh) were added to a solution of (372mg, 0.690mmol) 4-methylpiperazine in THF (10mL)₃)₂Cl₂(19mg, 0.027 mmol). The resulting mixture was irradiated with microwave radiation at 125 ℃ for 3 h. The solvent was concentrated under reduced pressure and the residue was applied to a C18 gel column and purified by flash chromatography using MeCN (containing 10mmol/L NH) in water ₄HCO₃) In thatEluting with a gradient of 40% to 80% over 30min to give 5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-ylboronic acid (166mg, 48%). LC-MS (M + H)⁺＝505.2。

And 4, step 4: 4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] pyrimidine-2-carbonitrile

Prepared from 5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl group in a similar manner to that in step 2 of example 332]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-ylboronic acid and 4-chloropyrimidine-2-carbonitrile the title compound was prepared. LC-MS (M + H)⁺＝564.4。

And 5: 4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] pyrimidine-2-carboxylic acid

4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl]Pyrimidine-2-carbonitrile (70mg, 0.124mmol) was added to HCl (1.00mL, 12N). The resulting mixture was stirred at 80 ℃ for 5 h. When the reaction was complete, the solution was concentrated under reduced pressure and the residue was applied to a C18 gel column and purified by flash chromatography using MeCN (containing 10mmol/L NH) in water₄HCO₃) Eluting with a gradient of 30% to 50% over 30min to give 4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] as a pale yellow solid ]-1H-pyrrolo [2,3-b]Pyridin-3-yl]Pyrimidine-2-carboxylic acid (20mg, 37%). LC-MS (M + H)⁺＝429.2。

Step 6: n, N-dimethyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] pyrimidine-2-carboxamide

4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] n at room temperature under a nitrogen atmosphere]-1H-pyrrolo [2,3-b]Pyridin-3-yl]To a solution of pyrimidine-2-carboxylic acid (19mg, 0.046mmol) in DMF (5mL) was added T₃P (18mg, 0.057mmol), DIEA (12mg, 0.088mmol), and dimethylamine (12mg, 0.252 mmol). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 15 h. When the reaction was complete, the solvent was concentrated under reduced pressure and the residue was purified by preparative HPLC on the following stripsPurifying under the condition: column: XBridge prep C18 OBD column, 150x30mm, 5 um; mobile phase: acetonitrile in water (containing 10mmol/L NH)₄HCO₃) Gradient 25% to 42% over 7 min; a detector: UV 254 nm. Obtaining N, N-dimethyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl]-1H-pyrrolo [2,3-b]Pyridin-3-yl]Pyrimidine-2-carboxamide (10mg, 47%).¹H NMR(400MHz,DMSO-d6)δ12.54(s,1H),8.85(s,1H),8.74(d,J＝5.5Hz,1H),8.65-8.56(m,2H),8.01(d,J＝5.5Hz,1H),7.54-7.45(m,2H),7.16(d,J＝8.2Hz,1H),3.07(s,3H),2.94-2.87(m,7H),2.57-2.46(m,4H),2.35(s,3H),2.26(s,3H)。LC-MS(M+H)⁺＝456.3。

Example 482: 2-methyl-6- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -3, 4-dihydroisoquinolin-1-one (Compound 482)

Step 1: 2-methyl-6- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1- (4-methylphenylsulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -3, 4-dihydroisoquinolin-1-one

Prepared from 6- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] in a similar manner to that described in step 2 of example 332]Pyridin-3-yl]-2-methyl-3, 4-dihydroisoquinolin-1-one and 1-methyl-4- [ 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Piperazine the title compound was prepared. LC-MS (M + H)⁺＝620.3。

Step 2: 2-methyl-6- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -3, 4-dihydroisoquinolin-1-one

Prepared in a similar manner to that described in example 369, step 6 from 2-methyl-6- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl]-3, 4-dihydroisoquinolin-1-one preparation example 482.¹H NMR(400MHz,DMSO-d6)δ12.09(s,1H),8.53(s,1H),8.44(s,1H),8.02(s,1H),7.93(d,J＝8.1Hz,1H),7.78(d,J＝8.1Hz,1H),7.70(s,1H),7.59-7.50(m,2H),7.13(d,J＝8.2Hz,1H),3.59(t,J＝6.6Hz,2H),3.11-3.03(m,5H),2.93-2.86(m,4H),2.53-2.47(m,4H),2.34(s,3H),2.26(s,3H)。LC-MS(M+H)⁺＝466.2。

Example 483: 2-methyl-6- (5- [ 3-methyl-4- [4- (methylamino) piperidin-1-yl ] phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl) -3, 4-dihydroisoquinolin-1-one (Compound 483)

Step 1: n- [1- (4-chloro-2-methylphenyl) piperidin-4-yl ] -N-methylcarbamic acid tert-butyl ester

The title compound was prepared from 1-bromo-4-chloro-2-methylbenzene and N-methyl-N- (piperidin-4-yl) carbamic acid tert-butyl ester in a similar manner as in example 469, step 2. LC-MS (M + H) ⁺＝339.8。

Step 2: 1- (4-chloro-2-methylphenyl) -N-methylpiperidin-4-amine

Prepared in a similar manner to that described in step 5 of example 309 from N- [1- (4-chloro-2-methylphenyl) piperidin-4-yl]-N-methyl-carbamic acid tert-butyl ester the title compound is prepared. LC-MS (M + H)⁺＝239.7。

And step 3: 2-methyl-6- (5- [ 3-methyl-4- [4- (methylamino) piperidin-1-yl ] phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl) -3, 4-dihydroisoquinolin-1-one

Prepared in a similar manner to that in step 2 of example 311 from 2-methyl-6- [1- (4-methylbenzenesulfonyl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b]Pyridin-3-yl]-3, 4-dihydroisoquinolin-1-one and 1- (4-chloro-2-methylphenyl) -N-methylpiperidin-4-amine. LC-MS (M + H)⁺＝634.8。

And 4, step 4: 2-methyl-6- (5- [ 3-methyl-4- [4- (methylamino) piperidin-1-yl ] phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl) -3, 4-dihydroisoquinolin-1-one

Prepared in a similar manner to that described in example 369, step 6 from 2-methyl-6- (5- [ 3-methyl-4- [4- (methylamino) piperidin-1-yl)]Phenyl radical]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl) -3, 4-dihydroisoquinolin-1-one preparation example 483.¹H NMR(400MHz,DMSO-d6)δ12.10(s,1H),8.60-8.38(m,2H),8.02(s,1H),7.93(d,J＝8.1Hz,1H),7.78(d,J＝8.1Hz,1H),7.70(s,1H),7.58-7.48(m,2H),7.13(d,J＝8.3Hz,1H),3.59(t,J＝6.6Hz,2H),3.32(s,1H),3.13-2.99(m,6H),2.65(t,J＝10.9Hz,2H),2.46-2.24(m,6H),1.97-1.75(m,3H),1.48-1.36(m,3H)。LC-MS(M+H)⁺＝480.6。

Example 484: 4- [5- [3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N- [ (2S) -2-hydroxypropyl ] -N-methylbenzamide (Compound 484)

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

The title compound was prepared from 4-bromobenzoic acid and (2S) -1-aminopropan-2-ol in a similar manner as in example 304, step 1. LC-MS (M + H)⁺＝260.1。

Step 2: 3- (4-methoxy-2-methylphenyl) piperidine

Prepared from 4-bromo-N- [ (2S) -2-hydroxypropyl in a similar manner to that in step 2 of example 490]Benzamide and TBDMS-Cl. LC-MS (M + H)⁺＝426.5。

And step 3: 4-bromo-N- [ (2S) -2- [ (tert-butyldimethylsilyl) oxy ] propyl ] -N-methylbenzamide

Prepared from 4-bromo-N- [ (2S) -2- [ (tert-butyldimethylsilyl) oxy ] in a similar manner to that in step 1 of example 394]Propyl radical]Benzamide and MeI. LC-MS (M + H)⁺＝388.2。

And 4, step 4: 4-bromo-N- [ (2S) -2-hydroxypropyl ] -N-methylbenzamide

Prepared in a similar manner to that in step 4 of example 492 from 4-bromo-N- [ (2S) -2- [ (tert-butyldimethylsilyl) oxy]Propyl radical]-N-methylbenzamide the title compound was prepared. LC-MS (M + H)⁺＝272.0。

And 5: n- [ (2S) -2-hydroxypropyl ] -N-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide

Prepared from 4-bromo-N- [ (2S) -2-hydroxypropyl in a similar manner to that described in step 1 of example 383 ]-N-methylbenzamide and BPD the title compound was prepared. LC-MS (M + H)⁺＝320.2。

Step 6: 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -N- [ (2S) -2-hydroxypropyl ] -N-methylbenzamide

Prepared from N- [ (2S) -2-hydroxypropyl group in a similar manner to that in step 2 of example 332]-N-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide and 5-bromo-3-iodo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridine the title compound was prepared. LC-MS (M + H)⁺＝544.1。

And 7: 4- [5- [3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -N- [ (2S) -2-hydroxypropyl ] -N-methylbenzamide

Prepared from 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] in a similar manner to that described in step 2 of example 332]Pyridin-3-yl]-N- [ (2S) -2-hydroxypropyl]-N-methylbenzamide and 1- [2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-4-methylpiperazine the title compound was prepared. LC-MS (M + H)⁺＝666.3。

And 8: 4- [5- [3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N- [ (2S) -2-hydroxypropyl ] -N-methylbenzamide

Prepared in a similar manner to that described in example 369, step 6 from 4- [5- [3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl]-N- [ (2S) -2-hydroxypropyl]-N-methylbenzamide preparation example 484.¹H NMR(400MHz,DMSO-d6)δ12.05(s,1H),8.52(d,J＝2.1Hz,1H),8.41(d,J＝2.1Hz,1H),8.00(d,J＝2.2Hz,1H),7.85(d,J＝7.8Hz,2H),7.50(d,J＝7.9Hz,2H),7.38(s,2H),4.86(d,J＝19.0Hz,1H),3.95(d,J＝41.6Hz,1H),3.49(s,1H),3.38-3.28(m,1H),3.19(s,1H),3.10-3.03(m,6H),2.48-2.41(m,4H),2.38(s,6H),2.26(s,3H),1.25(s,1H),1.13(s,2H),0.94(s,2H)。LC-MS(M+H)⁺＝512.4。

Example 485: 4- (5- (3, 5-dimethyl-4- (1-methylpiperidin-4-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide (Compound 485)

Step 1: 5-methoxy-2- (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) benzene-1, 3-diol

To a solution of 5-methoxybenzene-1, 3-diol (14.00g, 0.1mol) in AcOH (30mL) was added 1-methylpiperidin-4-one (11.3g, 0.1mol) at room temperature. HCl (g) was bubbled through for 15min and the resulting mixture was stirred at room temperature for 3 h. When the reaction was complete, the solvent was concentrated under reduced pressure to give (24.00g, crude). LC-MS (M + H) + 236.1.

Step 2: 5-methoxy-2- (1-methylpiperidin-4-yl) benzene-1, 3-diol

The title compound was prepared from 5-methoxy-2- (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) benzene-1, 3-diol in a similar manner to that in example 430, step 1. LC-MS (M + H)⁺＝238.1。

And step 3: 5-methoxy-2- (1-methylpiperidin-4-yl) -1, 3-phenylenebis (trifluoromethanesulfonate)

Prepared from 5-methoxy-2- (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) benzene-1, 3-diol and PhNTf in a similar manner to that in step 3 of example 455₂The title compound was prepared. LC-MS (M + H)⁺＝520.0。¹H NMR (400MHz, methanol-d 4) Δ 7.02(s,2H),3.88(s,3H),3.08-2.91(m,3H),2.35-2.17(m,5H),2.14-2.04(m,2H),1.76-1.66(m, 2H).

And 4, step 4: 4- (4-methoxy-2, 6-dimethylphenyl) -1-methylpiperidine

The title compound was prepared from 5-methoxy-2- (1-methylpiperidin-4-yl) -1, 3-phenylenebis (trifluoromethanesulfonate) and methylboronic acid in a similar manner to that in example 455, step 4. LC-MS (M + H)⁺＝234.2。

And 5: 3, 5-dimethyl-4- (1-methylpiperidin-4-yl) phenol

The title compound was prepared from 4- (4-methoxy-2, 6-dimethylphenyl) -1-methylpiperidine in a similar manner to that in example 343, step 1. LC-MS (M + H)⁺＝220.2。

Step 6: 3, 5-dimethyl-4- (1-methylpiperidin-4-yl) phenyl trifluoromethanesulfonate

Prepared in a similar manner to that in step 3 of example 455 from 3, 5-dimethyl-4- (1-methylpiperidin-4-yl) phenol and PhNTf₂The title compound was prepared. LC-MS (M + H)⁺＝352.2。

And 7: 4- (5- (3, 5-dimethyl-4- (1-methylpiperidin-4-yl) phenyl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide

Prepared in a similar manner to that in step 4 of example 455 from 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 and trifluoromethanesulfonic acid 3, 5-dimethyl-4- (1-methylpiperidin-4-yl) phenyl ester the title compound was prepared. LC-MS (M + H)⁺＝621.3。

And 8: 4- (5- (3, 5-dimethyl-4- (1-methylpiperidin-4-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N, N-dimethylbenzamide

Prepared in a similar manner to that described in example 369, step 6 from 4- (5- (3, 5-dimethyl-4- (1-methylpiperidin-4-yl) phenyl) -1-toluenesulfonyl-1H-pyrrolo [2,3-b ]]Pyridin-3-yl) -N, N-dimethylbenzamide preparation example 485.¹H NMR (400MHz, methanol-d 4) Δ 8.97(s,1H),8.71(s,1H),8.04-7.88(m,3H),7.63-7.58(m,2H),7.49-7.44(m,2H),3.78-3.43(m,4H),3.32-3.10(m,7H),2.98-2.94(m,3H),2.62-2.58(m,8H),2.02-1.93(m, 2H). LC-MS (M + H)⁺＝467.3。

Example 486: N-isopropyl-N-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide (compound 486)

Step 1: 4- [ isopropyl (methyl) carbamoyl ] phenylboronic acid

The title compound was prepared from 4-carboxyphenylboronic acid and N-methylpropan-2-amine in a similar manner to that described in example 304, step 1. LC-MS (M + H) ⁺＝222.0。

Step 2: 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -N-isopropyl-N-methylbenzamide

Prepared from 5-bromo-3-iodo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] in a similar manner to that in step 2 of example 332]Pyridine and 4- [ isopropyl (methyl) carbamoyl group]Phenylboronic acid the title compound was prepared. LC-MS (M + H)⁺＝526.1。

And step 3: N-isopropyl-N-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

Prepared from 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] in a similar manner to that described in step 2 of example 332]Pyridin-3-yl]-N-isopropyl-N-methylbenzamide and 1-methyl-4- [ 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Piperazine the title compound was prepared. LC-MS (M + H)⁺＝636.3。

And 4, step 4: N-isopropyl-N-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

Prepared in a similar manner to that described in example 369, step 6 from N-isopropyl-N-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl ]Benzamide preparation example 486.¹H NMR(400MHz,DMSO-d6)δ12.05(s,1H),8.57-8.37(m,2H),7.99(d,J＝2.7Hz,1H),7.89-7.82(m,2H),7.59-7.50(m,2H),7.47-7.41(m,2H),7.13(d,J＝8.2Hz,1H),4.80-3.90(m,1H),2.95-2.79(m,7H),2.51-2.44(m,4H),2.34(s,3H),2.26(s,3H),1.19-1.12(m,6H)。LC-MS(M+H)⁺＝482.5。

Example 487: N-cyclopropyl-N-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide (compound 487)

Step 1: 4- [ cyclopropyl (methyl) carbamoyl ] phenylboronic acid

The title compound was prepared from 4-carboxyphenylboronic acid and N-methylcyclopropylamine in a similar manner to that described in example 304, step 1. LC-MS (M + H)⁺＝222.1。

Step 2: 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -N-cyclopropyl-N-methylbenzamide

Prepared from 5-bromo-3-iodo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] in a similar manner to that in step 2 of example 332]Pyridine and 4- [ cyclopropyl (methyl) carbamoyl]Phenylboronic acid the title compound was prepared. LC-MS (M + H)⁺＝524.0。

And step 3: N-cyclopropyl-N-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

Prepared from 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] in a similar manner to that described in step 2 of example 332]Pyridin-3-yl]-N-cyclopropyl-N-methylbenzamide and 1-methyl-4- [ 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ]Piperazine the title compound was prepared. LC-MS (M + H)⁺＝634.3。

And 4, step 4: N-cyclopropyl-N-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

Prepared in a similar manner to that described in example 369, step 6 from N-cyclopropyl-N-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl]Benzamide preparation example 487.¹H NMR(400MHz,DMSO-d6)δ12.06(s,1H),8.55-8.40(m,2H),8.04-7.99(m,1H),7.88-7.81(m,2H),7.63-7.50(m,4H),7.13(d,J＝8.2Hz,1H),3.01-2.95(m,4H),2.93-2.86(m,4H),2.53-2.47(m,4H),2.34(s,3H),2.26(s,3H),0.68-0.46(m,4H)。LC-MS(M+H)⁺＝480.0。

Example 488: n-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N- (1-methylpyrrolidin-3-yl) benzamide (compound 488)

Step 1: 4- [ methyl (1-methylpyrrolidin-3-yl) carbamoyl ] phenylboronic acid

The title compound was prepared from 4-carboxyphenylboronic acid and N, 1-dimethylpyrrolidin-3-amine in a similar manner to that described in example 304, step 1. LC-MS (M + H)⁺＝263.2。

Step 2: 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -N-methyl-N- (1-methylpyrrolidin-3-yl) benzamide

Prepared from 5-bromo-3-iodo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] in a similar manner to that in step 2 of example 332]Pyridine and 4- [ methyl (1-methylpyrrolidin-3-yl) carbamoyl ]Phenylboronic acid the title compound was prepared. LC-MS (M + H)⁺＝567.3。

And step 3: n-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -N- (1-methylpyrrolidin-3-yl) benzamide

Prepared from 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] in a similar manner to that described in step 2 of example 332]Pyridin-3-yl]-N-methyl-N- (1-methylpyrrolidin-3-yl) benzamide and 1-methyl-4- [ 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Piperazine the title compound was prepared. LC-MS (M + H)⁺＝677.4。

And 4, step 4: n-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N- (1-methylpyrrolidin-3-yl) benzamide

Prepared in a similar manner to that described in example 369, step 6 from N-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl]-N- (1-methylpyrrolidin-3-yl) benzamide preparative example 488.¹H NMR(400MHz,DMSO-d6)δ12.05(s,1H),8.53(s,1H),8.42(s,1H),8.00(s,1H),7.89-7.83(m,2H),7.60-7.50(m,2H),7.47-7.41(m,2H),7.13(d,J＝8.2Hz,1H),5.01-4.32(m,1H),2.99-2.84(m,7H),2.74-2.66(m,2H),2.46-2.38(m,2H),2.38-2.36(m,2H),2.36-2.25(m,7H),2.25-2.14(m,4H),2.12-1.79(m,2H)。LC-MS(M+H)⁺＝523.5。

Example 489: n-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N- (1-methylpiperidin-4-yl) benzamide (compound 489)

Step 1: 4- [ methyl (1-methylpiperidin-4-yl) carbamoyl ] phenylboronic acid

The title compound was prepared from 4-carboxyphenylboronic acid and N, 1-dimethylpiperidin-4-amine in a similar manner to that described in example 304, step 1. LC-MS (M + H)⁺＝277.1。

Step 2: 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -N-methyl-N- (1-methylpiperidin-4-yl) benzamide

Prepared from 5-bromo-3-iodo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] in a similar manner to that in step 2 of example 332]Pyridine and 4- [ methyl (1-methylpiperidin-4-yl) carbamoyl]Phenylboronic acid the title compound was prepared. LC-MS (M + H)⁺＝582.5。

And step 3: n-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -N- (1-methylpiperidin-4-yl) benzamide

Prepared from 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] in a similar manner to that described in step 2 of example 332]Pyridin-3-yl]-N-methyl-N- (1-methylpiperidin-4-yl) benzamide and 1-methyl-4- [ 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Piperazine the title compound was prepared. LC-MS (M + H)⁺＝691.3。

And 4, step 4: n-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N- (1-methylpiperidin-4-yl) benzamide

Prepared in a similar manner to that described in example 369, step 6 from N-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl]-N- (1-methylpiperidin-4-yl) benzamide preparation example 489.¹H NMR(400MHz,DMSO-d6)δ12.05(s,1H),8.53(s,1H),8.42(s,1H),8.01(s,1H),7.89-7.83(m,2H),7.60-7.50(m,2H),7.48-7.41(m,2H),7.13(d,J＝8.2Hz,1H),3.35-3.28(m,4H),2.94-2.77(m,9H),2.51-2.46(m,2H),2.34(s,3H),2.26(s,3H),2.15-2.11(m,3H),1.85-1.81(m,3H),1.64-1.57(m,2H)。LC-MS(M+H)⁺＝537.3。

Example 490: n-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N- [ (1r,4r) -4-hydroxy-4-methylcyclohexyl ] benzamide (compound 490)

Step 1: 4-bromo-N- ((1r,4r) -4-hydroxy-4-methylcyclohexyl) benzamide

The title compound was prepared from 4-bromobenzoic acid and (1r,4r) -4-amino-1-methylcyclohex-1-ol in a similar manner to that in example 304, step 1. LC-MS (M + H)⁺＝314.5。

Step 2: 4-bromo-N- [ (1r,4r) -4- [ (tert-butyldimethylsilyl) oxy ] -4-methylcyclohexyl ] benzamide

4-bromo-N- [ (1r,4r) -4-hydroxy-4-methylcyclohexyl group was reacted at room temperature under a nitrogen atmosphere]To a solution of benzamide (784mg, 2.511mmol) in DCM (10mL) was added TBDMSCl (568mg, 3.767mmol), 2, 6-lutidine (538mg, 5.022 mmol). The resulting mixture was stirred at 50 ℃ under a nitrogen atmosphere overnight. When the reaction was complete, the solvent was concentrated under reduced pressure to give 4-bromo-N- [ (1r,4r) -4- [ (tert-butyldimethylsilyl) oxy) as a pale yellow solid ]-4-methylcyclohexyl group]Benzamide (1.20g, crude). LC-MS(M+H)⁺＝426.5。

And step 3: 4-bromo-N-methyl-N- [ (1r,4r) -4- [ (tert-butyldimethylsilyl) oxy ] -4-methylcyclohexyl ] benzamide

Prepared from 4-bromo-N- [ (1r,4r) -4- [ (tert-butyldimethylsilyl) oxy ] in a similar manner to that in step 1 of example 394]-4-methylcyclohexyl group]Benzamide and MeI. LC-MS (M + H)⁺＝440.1。

And 4, step 4: 4-bromo-N-methyl-N- [ (1r,4r) -4-hydroxy-4-methylcyclohexyl ] benzamide

4-bromo-N-methyl-N- [ (1r,4r) -4- [ (tert-butyldimethylsilyl) oxy ] N at room temperature under a nitrogen atmosphere]-4-methylcyclohexyl group]To a solution of benzamide (451mg, 1.025mmol) in THF (10mL) was added TBAF (293mg, 1.180 mmol). The resulting mixture was stirred at 50 ℃ under a nitrogen atmosphere overnight. When the reaction was complete, the organic phases were combined, washed with brine and over Na₂SO₄And (5) drying. The solvent was concentrated under reduced pressure and the residue was purified by flash chromatography, eluting with MeOH in DCM (gradient 0% to 10%) to give 4-bromo-N-methyl-N- [ (1r,4r) -4-hydroxy-4-methylcyclohexyl) as a pale yellow solid]Benzamide (315mg, 94%). LC-MS (M + H) ⁺＝326.1。

And 5: N-methyl-N- [ (1r,4r) -4-hydroxy-4-methylcyclohexyl ] -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide

Prepared from 4-bromo-N-methyl-N- [ (1r,4r) -4-hydroxy-4-methylcyclohexyl group in a similar manner to that in step 1 of example 308]Benzamide and BPD the title compound was prepared. LC-MS (M + H)⁺＝374.3。

Step 6: 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ]]Pyridin-3-yl]-N-methyl-N- [ (1r,4r) -4-hydroxy-4-methylcyclohexyl group]A benzamide. Prepared from N-methyl-N- [ (1r,4r) -4-hydroxy-4-methylcyclohexyl group in a similar manner to that in step 2 of example 332]-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide and 5-bromo-3-iodo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ]]Pyridine the title compound was prepared. LC-MS (M + H)⁺＝596.2。

And 7: n-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -N- [ (1r,4r) -4-hydroxy-4-methylcyclohexyl ] benzamide

Prepared from 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] in a similar manner to that described in step 2 of example 332]Pyridin-3-yl]-N-methyl-N- [ (1r,4r) -4-hydroxy-4-methylcyclohexyl group]Benzamide and 1-methyl-4- [ 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ]Piperazine the title compound was prepared. LC-MS (M + H)⁺＝706.4。

And 8: n-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N- [ (1r,4r) -4-hydroxy-4-methylcyclohexyl ] benzamide

Prepared in a similar manner to that described in example 369, step 6 from N-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl]-N- [ (1r,4r) -4-hydroxy-4-methylcyclohexyl group]Benzamide preparation example 490.¹H NMR(400MHz,DMSO-d6)δ12.04(s,1H),8.53(s,1H),8.42(s,1H),8.00(s,1H),7.89-7.83(m,2H),7.60-7.50(m,2H),7.47-7.40(m,2H),7.13(d,J＝8.2Hz,1H),4.28(s,1H),3.58-3.38(m,2H),2.89-2.86(m,7H),2.54-2.48(m,2H),2.35(s,3H),2.26(s,3H),1.79-1.49(m,7H),1.26-1.10(m,4H)。LC-MS(M+H)⁺＝552.4。

Example 491: n-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N- [ (1s,4s) -4-hydroxy-4-methylcyclohexyl ] benzamide (compound 491)

Step 1: 4-bromo-N- ((1s,4s) -4-hydroxy-4-methylcyclohexyl) benzamide

The title compound was prepared from 4-bromobenzoic acid and (1s,4s) -4-amino-1-methylcyclohex-1-ol in a similar manner to that in example 304, step 1. LC-MS (M + H)⁺＝314.5。

Step 2: 4-bromo-N- [ (1s,4s) -4- [ (tert-butyldimethylsilyl) oxy ] -4-methylcyclohexyl ] benzamide

Prepared from 4-bromo-N- [ (1s,4s) -4-hydroxy-4-methylcyclohexyl group in a similar manner to that in step 2 of example 490]Benzamide and TBDMS-Cl. LC-MS (M + H) ⁺＝426.5。

And step 3: 4-bromo-N-methyl-N- [ (1s,4s) -4- [ (tert-butyldimethylsilyl) oxy ] -4-methylcyclohexyl ] benzamide

Prepared from 4-bromo-N- [ (1s,4s) -4- [ (tert-butyldimethylsilyl) oxy ] in a similar manner to that in step 1 of example 394]-4-methylcyclohexyl group]Benzamide and MeI. LC-MS (M + H)⁺＝440.1。

And 4, step 4: 4-bromo-N-methyl-N- [ (1s,4s) -4-hydroxy-4-methylcyclohexyl ] benzamide

Prepared in a similar manner to that in step 4 of example 490 from 4-bromo-N-methyl-N- [ (1s,4s) -4- [ (tert-butyldimethylsilyl) oxy]-4-methylcyclohexyl group]Benzamide the title compound was prepared. LC-MS (M + H)⁺＝326.1。

And 5: N-methyl-N- [ (1s,4s) -4-hydroxy-4-methylcyclohexyl ] -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide

Prepared from 4-bromo-N-methyl-N- [ (1s,4s) -4-hydroxy-4-methylcyclohexyl group in a similar manner to that in step 1 of example 308]Benzamide and BPD the title compound was prepared. LC-MS (M + H)⁺＝374.3。

Step 6: 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -N-methyl-N- [ (1s,4s) -4-hydroxy-4-methylcyclohexyl ] benzamide

Prepared from N-methyl-N- [ (1s,4s) -4-hydroxy-4-methylcyclohexyl group in a similar manner to that in step 2 of example 332 ]-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide and 5-bromo-3-iodo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ]]Pyridine the title compound was prepared. LC-MS (M + H)⁺＝596.2。

And 7: n-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -N- [ (1s,4s) -4-hydroxy-4-methylcyclohexyl ] benzamide

Prepared from 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] in a similar manner to that described in step 2 of example 332]Pyridin-3-yl]-N-methyl-N- [ (1s,4s) -4-hydroxy-4-methylcyclohexyl]Benzamide and 1-methyl-4- [ 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Piperazine the title compound was prepared. LC-MS (M + H)⁺＝706.4。

And 8: n-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N- [ (1s,4s) -4-hydroxy-4-methylcyclohexyl ] benzamide

Prepared in a similar manner to that described in example 369, step 6 from N-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl]-N- [ (1s,4s) -4-hydroxy-4-methylcyclohexyl group]Benzamide preparation example 491. ¹H NMR(400MHz,DMSO-d6)δ12.04(s,1H),8.53(s,1H),8.41(s,1H),8.00(s,1H),7.88-7.82(m,2H),7.60-7.50(m,2H),7.46-7.40(m,2H),7.13(d,J＝8.2Hz,1H),4.12(s,1H),3.32(s,1H),2.93-2.84(m,8H),2.36-2.32(m,4H),2.28-2.24(m,4H),1.99-1.94(m,3H),1.59-1.55(m,2H),1.45-1.38(m,3H),1.20-0.95(m,4H)。LC-MS(M+H)⁺＝552.4。

Example 492: n-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N- [2- (4-methylpiperazin-1-yl) ethyl ] benzamide (compound 492)

Step 1: 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] benzoic acid methyl ester

Prepared from 5-bromo-3-iodo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] in a similar manner to that in step 2 of example 332]Pyridine and methyl 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate the title compound was prepared. LC-MS (M + H)⁺＝487.2。

Step 2: 4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] benzoic acid methyl ester

Prepared in a similar manner to that described in step 2 of example 332 from 1-methyl-4- [ 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Piperazine and 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ]]Pyridin-3-yl]Methyl benzoate the title compound was prepared. LC-MS (M + H)⁺＝495.4。

And step 3: 4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] benzoic acid

Prepared from 4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] in a similar manner to that in step 1 of example 382 ]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl]Methyl benzoate the title compound was prepared. LC-MS (M + H)⁺＝581.4。

And 4, step 4: n-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -N- [2- (4-methylpiperazin-1-yl) ethyl ] benzamide

Prepared from 4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] in a similar manner to that in step 6 of example 481]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl]Benzoic acid and methyl [2- (4-methylpiperazin-1-yl) ethyl]Amine the title compound was prepared. LC-MS (M + H)⁺＝720.4。

And 5: n-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N- [2- (4-methylpiperazin-1-yl) ethyl ] benzamide

Prepared in a similar manner to that described in example 369, step 6 from N-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl]-N- [2- (4-methylpiperazin-1-yl) ethyl]Benzamide preparative example 492.¹H NMR(400MHz,DMSO-d6)δ12.06(s,1H),8.54(s,1H),8.41(s,1H),8.00(s,1H),7.89-7.82(m,2H),7.60-7.49(m,2H),7.49-7.44(m,2H),7.13(d,J＝8.2Hz,1H),3.57(s,1H),3.00(s,3H),2.94-2.87(m,4H),2.58-2.52(m,6H),2.40-2.32(m,11H),2.28(s,3H),2.19-2.14(m,4H)。LC-MS(M+H)⁺＝566.4。

Example 493: n-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N- (oxolan-3-ylmethyl) benzamide (compound 493)

Step 1: 4- [ (Oxolan-3-ylmethyl) carbamoyl ] phenylboronic acid

The title compound was prepared from 4-carboxyphenylboronic acid and 1- (oxolan-3-yl) methylamine in a similar manner to that described in example 304, step 1. LC-MS (M + H)⁺＝250.2。

Step 2: 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -N- (oxolane-3-ylmethyl) benzamide

Prepared from 4- [ (oxolan-3-ylmethyl) carbamoyl in a similar manner to that in step 2 of example 332]Phenylboronic acid and 5-bromo-3-iodo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridine the title compound was prepared. LC-MS (M + H)⁺＝556.1。

And step 3: 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -N-methyl-N- (oxolane-3-ylmethyl) benzamide

Prepared from 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] in a similar manner to that described in step 1 of example 394]Pyridin-3-yl]-N- (oxolan-3-ylmethyl) benzamide and MeI the title compound was prepared. LC-MS (M + H)⁺＝570.1。

And 4, step 4: n-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -N- (oxolane-3-ylmethyl) benzamide

Prepared from 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] in a similar manner to that described in step 2 of example 332 ]Pyridin-3-yl]-N-methyl-N- (oxolan-3-ylmethyl) benzamide and 1-methyl-4- [ 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Piperazine derivativesThe title compound was prepared. LC-MS (M + H)⁺＝678.5。

And 5: n-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N- (oxolan-3-ylmethyl) benzamide

Prepared in a similar manner to that described in example 369, step 6 from N-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl]-N- (oxolan-3-ylmethyl) benzamide preparation example 493.¹H NMR(400MHz,DMSO-d6)δ12.06(s,1H),8.53(s,1H),8.41(s,1H),8.01(s,1H),7.89-7.83(m,2H),7.60-7.50(m,2H),7.50-7.43(m,2H),7.13(d,J＝8.2Hz,1H),3.86-3.36(m,5H),3.33(s,2H),3.00(s,3H),2.93-2.86(m,4H),2.65-2.61(m,1H),2.52-2.45(m,2H),2.34(s,3H),2.26(s,3H),2.00-1.95(m,1H),1.65-1.60(m,1H)。LC-MS(M+H)⁺＝524.5。

Example 494: n-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N-phenylbenzamide (compound 494)

Step 1: 4- [ methyl (phenyl) carbamoyl ] phenylboronic acid

Prepared from 4-carboxyphenylboronic acid and Me in a similar manner to that described in step 1 of example 304₂NH the title compound was prepared. LC-MS (M + H)⁺＝256.2。

Step 2: 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -N-methyl-N-phenylbenzamide

Prepared in a similar manner to that in step 2 of example 332 from 4- [ methyl (phenyl) carbamoyl ]Phenylboronic acid and 5-bromo-3-iodo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridine the title compound was prepared. LC-MS (M + H)⁺＝560.1。

And step 3: n-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -N-phenylbenzamide

Prepared from 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] in a similar manner to that described in step 2 of example 332]Pyridin-3-yl]-N-methyl-N-phenylbenzamide and 1-methyl-4- [ 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Piperazine the title compound was prepared. LC-MS (M + H)⁺＝670.5。

And 4, step 4: n-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N-phenylbenzamide

Prepared in a similar manner to that described in example 369, step 6 from N-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl]-N-phenylbenzamide preparation example 494.¹H NMR(400MHz,DMSO-d6)δ12.02(s,1H),8.50(s,1H),8.33(s,1H),7.94(s,1H),7.70-7.63(m,2H),7.57-7.48(m,2H),7.39-7.26(m,4H),7.27-7.14(m,3H),7.12(d,J＝8.2Hz,1H),3.41(s,3H),2.93-2.86(m,4H),2.56-2.50(m,4H),2.34(s,3H),2.26(s,3H)。LC-MS(M+H)⁺＝516.4。

Example 495: n- (4-fluorophenyl) -N-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide (compound 495)

Step 1: 4- [ (4-fluorophenyl) (methyl) carbamoyl ] phenylboronic acid

The title compound was prepared from 4-carboxyphenylboronic acid and 4-fluoro-N-methylaniline in a similar manner as in example 304, step 1. LC-MS (M + H)⁺＝274.1。

Step 2: 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -N- (4-fluorophenyl) -N-methylbenzamide

Prepared in a similar manner to that in step 2 of example 332 from 4- [ (4-fluorophenyl) (methyl) carbamoyl]Phenylboronic acid and 5-bromo-3-iodo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridine the title compound was prepared. LC-MS (M + H)⁺＝580.0。

And step 3: n- (4-fluorophenyl) -N-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

Prepared from 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] in a similar manner to that described in step 2 of example 332]Pyridin-3-yl]-N- (4-fluorophenyl) -N-methylbenzamide and 1-methyl-4- [ 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Piperazine the title compound was prepared. LC-MS (M + H)⁺＝688.4。

And 4, step 4: n- (4-fluorophenyl) -N-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

Prepared in a similar manner to that described in example 369, step 6 from N- (4-fluorophenyl) -N-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl]Benzamide preparation example 495.¹H NMR(400MHz,DMSO-d6)δ12.02(s,1H),8.50(s,1H),8.34(s,1H),7.95(s,1H),7.72-7.65(m,2H),7.57-7.48(m,2H),7.37-7.25(m,4H),7.19-7.09(m,3H),3.42-3.28(m,3H),2.92-2.86(m,4H),2.59-2.48(m,4H),2.34(s,3H),2.26(s,3H)。LC-MS(M+H)⁺＝534.4。

Example 496: n-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N- [ (1-methylpyrazol-3-yl) methyl ] benzamide (compound 496)

Step 1: 4-bromo-N- [ (1-methylpyrazol-3-yl) methyl ] benzamide

The title compound was prepared from 4-bromobenzoic acid and 1- (1-methylpyrazol-3-yl) methylamine in a similar manner as in example 304, step 1. LC-MS (M + H)⁺＝295.8。

Step 2: 4-bromo-N-methyl-N- [ (1-methylpyrazol-3-yl) methyl ] benzamide

Prepared from 4-bromo in a similar manner to that in step 1 of example 394-N- [ (1-methylpyrazol-3-yl) methyl]Benzamide and MeI. LC-MS (M + H)⁺＝308.2。

And step 3: N-methyl-N- [ (1-methylpyrazol-3-yl) methyl ] -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide

Prepared in a similar manner to that in example 308, step 1 from 4-bromo-N-methyl-N- [ (1-methylpyrazol-3-yl) methyl]Benzamide and BPD the title compound was prepared. LC-MS (M + H)⁺＝356.3。

And 4, step 4: 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -N-methyl-N- [ (1-methylpyrazol-3-yl) methyl ] benzamide

Prepared in a similar manner to that in step 2 of example 332 from N-methyl-N- [ (1-methylpyrazol-3-yl) methyl]-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide and 5-bromo-3-iodo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ]]Pyridine the title compound was prepared. LC-MS (M + H)⁺＝580.1。

And 5: n-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -N- [ (1-methylpyrazol-3-yl) methyl ] benzamide

Prepared from 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] in a similar manner to that described in step 2 of example 332]Pyridin-3-yl]-N-methyl-N- [ (1-methylpyrazol-3-yl) methyl]Benzamide and 1-methyl-4- [ 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Piperazine the title compound was prepared. LC-MS (M + H)⁺＝688.5。

Step 6: n-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N- [ (1-methylpyrazol-3-yl) methyl ] benzamide

Prepared in a similar manner to that described in example 369, step 6 from N-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl ]-N- [ (1-methylpyrazol-3-yl) methyl]Benzamide preparation example 496.¹H NMR(400MHz,DMSO-d6)δ12.05(s,1H),8.53(s,1H),8.41(s,1H),8.00(s,1H),7.89-7.83(m,2H),7.68-7.63(m,1H),7.61-7.42(m,4H),7.13(d,J＝8.2Hz,1H),6.18(s,1H),4.70-4.33(m,2H),3.82(s,3H),2.96-2.86(m,7H),2.52-2.46(m,4H),2.34(s,3H),2.26(s,3H)。LC-MS(M+H)⁺＝534.6。

Embodiment 497: n-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N- (1-methylpyrazol-3-yl) benzamide (compound 497)

Step 1: 4-bromo-N- (1-methylpyrazol-3-yl) benzamide

The title compound was prepared from 4-bromobenzoic acid and 1-methylpyrazol-3-amine in a similar manner to that described in example 304, step 1. LC-MS (M + H)⁺＝280.1。

Step 2: 4-bromo-N-methyl-N- (1-methylpyrazol-3-yl) benzamide

The title compound was prepared from 4-bromo-N- (1-methylpyrazol-3-yl) benzamide and MeI in a similar manner to that in example 394 step 1. LC-MS (M + H)⁺＝293.0。

3: N-methyl-N- (1-methylpyrazol-3-yl) -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide

The title compound was prepared from 4-bromo-N-methyl-N- (1-methylpyrazol-3-yl) benzamide and BPD in a similar manner to that in example 308, step 1. LC-MS (M + H)⁺＝342.2。

And 4, step 4: 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -N-methyl-N- (1-methylpyrazol-3-yl) benzamide

Prepared in a similar manner to that in step 2 of example 332 from N-methyl-N- (1-methylpyrazol-3-yl) -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide and 5-bromo-3-iodo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyrrole ]Pyridine the title compound was prepared. LC-MS (M + H)⁺＝564.5。

And 5: n-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -N- (1-methylpyrazol-3-yl) benzamide

Prepared from 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] in a similar manner to that described in step 2 of example 332]Pyridin-3-yl]-N-methyl-N- (1-methylpyrazol-3-yl) benzamide and 1-methyl-4- [ 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Piperazine the title compound was prepared. LC-MS (M + H)⁺＝674.3。

Step 6: n-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N- (1-methylpyrazol-3-yl) benzamide

Prepared in a similar manner to that described in example 369, step 6 from N-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl]-N- (1-methylpyrazol-3-yl) benzamide preparative example 497.¹H NMR(400MHz,DMSO-d6)δ12.05(s,1H),8.52(s,1H),8.39(s,1H),7.99(s,1H),7.79-7.73(m,2H),7.59-7.50(m,3H),7.44(d,J＝7.9Hz,2H),7.12(d,J＝8.2Hz,1H),5.97(s,1H),3.74(s,3H),3.35(s,3H),2.92-2.85(m,4H),2.56-2.47(m,4H),2.34(s,3H),2.26(s,3H)。LC-MS(M+H)⁺＝520.4。

Example 498: n- (2-chloro-6-methylphenyl) -N-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide (compound 498)

Step 1: 4-bromo-N- (2-chloro-6-methylphenyl) benzamide

The title compound was prepared from 2-chloro-6-methyl-aniline and 4-bromobenzoyl chloride in a similar manner to that in example 333, step 2. LC-MS (M + H)⁺＝326.0。

Step 2: 4-bromo-N- (2-chloro-6-methylphenyl) -N-methylbenzamide

The title compound was prepared from 4-bromo-N- (2-chloro-6-methylphenyl) benzamide and MeI in analogy to the procedure in example 394 step 1A compound (I) is provided. LC-MS (M + H)⁺＝338.0。

And step 3: 1- [4- [ 3-iodo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-5-yl ] -2-methylphenyl ] -4-methylpiperazine

Prepared in a similar manner to that in step 2 of example 360 from 1- (4- [ 3-iodo-1H-pyrrolo [2,3-b ]]Pyridin-5-yl]-2-methylphenyl) -4-methylpiperazine and TsCl. LC-MS (M + H)⁺＝587.1。

And 4, step 4: n- (2-chloro-6-methylphenyl) -N-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide

The title compound was prepared from 4-bromo-N- (2-chloro-6-methylphenyl) -N-methylbenzamide and BPD in a similar manner to that in example 308, step 1. LC-MS (M + H)⁺＝386.3。

And 5: n- (2-chloro-6-methylphenyl) -N-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

In a similar manner to that in step 8 of example B03, starting from N- (2-chloro-6-methylphenyl) -N-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide and 1- [4- [ 3-iodo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-B ] benzamide]Pyridin-5-yl]-2-methylphenyl radical]-4-methylpiperazine the title compound was prepared. LC-MS (M + H)⁺＝718.4。

Step 6: n- (2-chloro-6-methylphenyl) -N-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

Prepared in a similar manner to that in example 369, step 6 from N- (2-chloro-6-methylphenyl) -N-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl]Benzamide preparation example 498.¹H NMR(400MHz,DMSO-d6)δ12.01(s,1H),8.49(s,1H),8.34(s,1H),7.94(s,1H),7.71-7.63(m,2H),7.62-7.43(m,2H),7.39-7.30(m,3H),7.26-7.17(m,2H),7.12(d,J＝8.1Hz,1H),3.22(s,3H),2.93-2.86(m,4H),2.54-2.47(m,4H),2.34(s,3H),2.30-2.24(m,6H)。LC-MS(M+H)⁺＝564.4。

Example 499: n-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N- (oxolan-3-yl) benzamide (compound 499)

Step 1: 4-bromo-N- (1-methylpyrazol-3-yl) benzamide

The title compound was prepared from 4-carboxyphenylboronic acid and N-methyloxolan-3-amine in a similar manner to that described in example 304, step 1. LC-MS (M + H)⁺＝250.2。

Step 2: 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -N-methyl-N- (oxolane-3-yl) benzamide

Prepared from 4- [ methyl (oxolane-3-yl) carbamoyl in a similar manner to that in step 2 of example 332]Phenylboronic acid and 5-bromo-3-iodo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridine the title compound was prepared. LC-MS (M + H)⁺＝556.0。

And step 3: n-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -N- (oxolane-3-yl) benzamide

Prepared from 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] in a similar manner to that described in step 2 of example 332]Pyridin-3-yl]-N-methyl-N- (oxolan-3-yl) benzamide and 1-methyl-4- [ 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Piperazine the title compound was prepared. LC-MS (M + H)⁺＝664.3。

And 4, step 4: n-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N- (oxolan-3-yl) benzamide

Prepared in a similar manner to that described in step 9 of example 404 from N-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl]-N- (oxolan-3-yl) benzamide example 499 was prepared.¹H NMR(400MHz,DMSO-d6)δ12.05(s,1H),8.53(s,1H),8.42(s,1H),8.00(s,1H),7.90-7.83(m,2H),7.60-7.50(m,2H),7.50-7.44(m,2H),7.13(d,J＝8.2Hz,1H),4.01-3.91(m,1H),3.86-3.78(m,1H),3.71-3.66(m,1H),3.59-3.54(m,1H),3.32-3.21(m,3H),2.94-2.86(m,7H),2.52-2.47(m,4H),2.34(s,3H),2.26(s,3H),2.20-2.16(m,1H),2.06-1.95(m,1H)。LC-MS(M+H)⁺＝510.4。

Example 500: n-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N- (6-methylpyridin-3-yl) benzamide (Compound 500)

Step 1: 4-bromo-N- (6-methylpyridin-3-yl) benzamide

The title compound was prepared from 4-bromobenzoic acid and 6-methylpyridin-3-amine in a similar manner to that described in example 304, step 1. LC-MS (M + H)⁺＝291.1。

Step 2: 4-bromo-N-methyl-N- (6-methylpyridin-3-yl) benzamide

The title compound was prepared from 4-bromo-N- (6-methylpyridin-3-yl) benzamide and MeI in a similar manner to that in example 394 step 1. LC-MS (M + H)⁺＝293.0。

And step 3: N-methyl-N- (6-methylpyridin-3-yl) -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide

The title compound was prepared from 4-bromo-N-methyl-N- (6-methylpyridin-3-yl) benzamide and BPD in a similar manner to that in example 308, step 1. LC-MS (M + H)⁺＝353.2。

And 4, step 4: 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -N-methyl-N- (6-methylpyridin-3-yl) benzamide

Prepared in a similar manner to that described in step 2 of example 332 from N-methyl-N- (6-methylpyridin-3-yl) -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide and 5-bromo-3-iodo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyrrole]Pyridine the title compound was prepared. LC-MS (M + H)⁺＝577.0。

And 5: n-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -N- (6-methylpyridin-3-yl) benzamide

Prepared from 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] in a similar manner to that described in step 2 of example 332]Pyridin-3-yl]-N-methyl-N- (6-methylpyridin-3-yl) benzamide and 1-methyl-4- [ 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Piperazine the title compound was prepared. LC-MS (M + H)⁺＝685.4。

Step 6: n-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -N- (6-methylpyridin-3-yl) benzamide

Prepared in a similar manner to that described in example 369, step 6 from N-methyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl]-N- (6-methylpyridin-3-yl) benzamide preparative example 500.¹H NMR(400MHz,DMSO-d6)δ12.04(s,1H),8.51(s,1H),8.35(s,1H),8.25(s,1H),7.97(d,J＝2.7Hz,1H),7.74-7.67(m,2H),7.67-7.60(m,1H),7.58-7.48(m,2H),7.38-7.31(m,2H),7.22(d,J＝8.3Hz,1H),7.12(d,J＝8.3Hz,1H),3.40(s,3H),2.93-2.86(m,4H),2.53-2.48(m,4H),2.39(s,3H),2.34(s,3H),2.27(s,3H)。LC-MS(M+H)⁺＝530.6。

Example 501: (3S) -N-methyl-1- (4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) pyrrolidin-3-amine (Compound 501)

Step 1: 4- [ (3S) -3- [ (tert-butoxycarbonyl) (methyl) amino ] pyrrolidine-1-carbonyl ] phenylboronic acid

Prepared in a similar manner to that described in step 1 of example 304 from 4-carboxyphenylboronic acid and N-methyl-N- [ (3S) -pyrrolidin-3-yl]Tert-butyl carbamate the title compound was prepared. LC-MS (M + H) ⁺＝349.2。

Step 2: n- [ (3S) -1- [4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl ] pyrrolidin-3-yl ] -N-methylcarbamic acid tert-butyl ester

Prepared from 4- [ (3S) -3- [ (tert-butoxycarbonyl) (methyl) amino group in a similar manner to that in step 2 of example 332]Pyrrolidine-1-carbonyl]Phenylboronic acid and 5-bromo-3-iodo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridine the title compound was prepared. LC-MS (M + H)⁺＝655.1。

And step 3: (S) -tert-butylmethyl (1- (4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) benzoyl) pyrrolidin-3-yl) carbamate

Prepared from N- [ (3S) -1- [4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] in a similar manner to that described in step 2 of example 332]Pyridin-3-yl]Benzoyl radical]Pyrrolidin-3-yl radical]-N-methylcarbamic acid tert-butyl ester and 1-methyl-4- [ 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Piperazine the title compound was prepared. LC-MS (M + H)⁺＝763.6。

And 4, step 4: (3S) -N-methyl-1- (4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) pyrrolidin-3-amine

Prepared from (S) -tert-butylmethyl (1- (4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1-toluenesulfonyl-1H-pyrrolo [2, 3-b) in a similar manner to that in step 5 of example 309 ]Pyridin-3-yl) benzoyl) pyrrolidin-3-yl) carbamate the title compound was prepared. LC-MS (M + H)⁺＝663.4。

And 5: (3S) -N-methyl-1- (4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) pyrrolidin-3-amine

Prepared in a similar manner to that in example 369, step 6 from (3S) -N-methyl-1- (4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl]Benzoyl) pyrrolidin-3-amine preparation example 501.¹H NMR(400MHz,DMSO-d6)δ12.07(s,1H),8.53(s,1H),8.42(s,1H),8.01(s,1H),7.89-7.82(m,2H),7.65-7.44(m,4H),7.13(d,J＝8.2Hz,1H),3.68-3.55(m,2H),3.58-3.43(m,1H),3.34-3.17(m,1H),3.15-3.08(m,1H),2.92-2.86(m,4H),2.58-2.47(m,4H),2.39-2.28(m,5H),2.29-2.18(m,5H),2.05-1.90(m,1H),1.75-1.71(m,1H)。LC-MS(M+H)⁺＝509.5。

Example 502: (3R) -N-methyl-1- (4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) pyrrolidin-3-amine (Compound 502)

Step 1: 4- [ (3R) -3- [ (tert-butoxycarbonyl) (methyl) amino ] pyrrolidine-1-carbonyl ] phenylboronic acid

Prepared in a similar manner to that described in step 1 of example 304 from 4-carboxyphenylboronic acid and N-methyl-N- [ (3R) -pyrrolidin-3-yl]Tert-butyl carbamate the title compound was prepared. LC-MS (M + H)⁺＝349.3。

Step 2: n- [ (3R) -1- [4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl ] pyrrolidin-3-yl ] -N-methylcarbamic acid tert-butyl ester

Prepared from 4- [ (3R) -3- [ (tert-butoxycarbonyl) (methyl) amino group in a similar manner to that in step 2 of example 332 ]Pyrrolidine-1-carbonyl]Phenylboronic acid and 5-bromo-3-iodo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridine the title compound was prepared. LC-MS (M + H)⁺＝655.1。

And step 3: (R) -tert-butylmethyl (1- (4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) benzoyl) pyrrolidin-3-yl) carbamate

Prepared from N- [ (3R) -1- [4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] in a similar manner to that described in step 2 of example 332]Pyridin-3-yl]Benzoyl radical]Pyrrolidin-3-yl radical]-N-methylcarbamic acid tert-butyl ester and 1-methyl-4- [ 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Piperazine the title compound was prepared. LC-MS (M + H)⁺＝763.9。

And 4, step 4: (3R) -N-methyl-1- (4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) pyrrolidin-3-amine

Prepared from (R) -tert-butylmethyl (1- (4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1-toluenesulfonyl-1H-pyrrolo [2, 3-b) in a similar manner to that in example 309 step 5]Pyridin-3-yl) benzoyl) pyrrolidin-3-yl) carbamate the title compound was prepared. LC-MS (M + H) ⁺＝663.7。

And 5: (3R) -N-methyl-1- (4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzoyl) pyrrolidin-3-amine

Prepared in a similar manner to that in example 369, step 6 from (3R) -N-methyl-1- (4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl]Benzoyl) pyrrolidin-3-amine preparation example 502.¹H NMR(400MHz,DMSO-d6)δ12.06(s,1H),8.53(s,1H),8.41(s,1H),8.00(s,1H),7.89-7.82(m,2H),7.65-7.49(m,4H),7.13(d,J＝8.2Hz,1H),3.63-3.59(m,2H),3.52-3.46(m,1H),3.31-3.25(m,1H),3.23-3.09(m,1H),2.93-2.86(m,4H),2.57-2.50(m,4H),2.34(s,3H),2.32-2.18(m,6H),1.99-1.94(m,2H),1.76-1.72(m,1H)。LC-MS(M+H)⁺＝509.6。

Example 503: 6- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -3, 4-dihydro-2H-1, 4-benzoxazine (Compound 503)

Step 1: 6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydro-2H-1, 4-benzoxazine

The title compound was prepared from 6-bromo-3, 4-dihydro-2H-1, 4-benzoxazine and BPD in a similar manner as in example 332, step 2. LC-MS (M + H)⁺＝262.2。

Step 2: tert-butyl 6- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -3, 4-dihydro-2H-1, 4-benzoxazine

Prepared in a similar manner to that described in example 332, step 2 from 6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydro-2H-1, 4-benzoxazine and 5-bromo-3-iodo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ]Pyridine the title compound was prepared. LC-MS (M + H)⁺＝486.0。

And step 3: 6- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -3, 4-dihydro-2H-1, 4-benzoxazine

Prepared from 6- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] in a similar manner to that described in step 2 of example 332]Pyridin-3-yl]-3, 4-dihydro-2H-1, 4-benzoxazine and 1-methyl-4- [ 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Piperazine the title compound was prepared. LC-MS (M + H)⁺＝594.3。

And 4, step 4: 6- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] -3, 4-dihydro-2H-1, 4-benzoxazine

Prepared from 6- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] in a similar manner to that in example 369 step 6]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl]-3, 4-dihydro-2H-1, 4-benzoxazine preparation example 503.¹H NMR(400MHz,DMSO-d6)δ11.75(d,J＝2.6Hz,1H),8.48(d,J＝2.1Hz,1H),8.28(d,J＝2.1Hz,1H),7.64(d,J＝2.5Hz,1H),7.55-7.46(m,2H),7.13(d,J＝8.2Hz,1H),6.98(d,J＝2.1Hz,1H),6.87-6.79(m,1H),6.72(d,J＝8.2Hz,1H),5.83(d,J＝2.6Hz,1H),4.18-4.12(m,2H),3.34(s,1H),3.31(s,1H),2.89(t,J＝4.7Hz,4H),2.58-2.52(m,2H),2.51-2.44(m,2H),2.34(s,3H),2.26(s,3H)。LC-MS(M+H)⁺＝440.2。

Example 504: (S) - (3-Hydroxypyrrolidin-1-yl) (4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone (Compound 504)

Step 1: (S) - (4-bromophenyl) (3-hydroxypyrrolidin-1-yl) methanone

The title compound was prepared from 4-bromobenzoic acid and (S) -pyrrolidin-3-ol in a similar manner as in example 304 step 1. 550mg, 81%, brown solid. LC-MS (M + H) ⁺＝270.1。

Step 2: (S) - (3-hydroxypyrrolidin-1-yl) (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) methanone

The title compound was prepared from (S) - (4-bromophenyl) (3-hydroxypyrrolidin-1-yl) methanone and BPD in a similar manner as in example 308, step 2. 570mg, 88%, brown solid. LC-MS (M + H)⁺＝318.1。

And step 3: (S) - (4- (5-bromo-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (3-hydroxypyrrolidin-1-yl) methanone

Prepared in a similar manner to that in step 2 of example 332 from (S) - (3-hydroxypyrrolidin-1-yl) (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) methanone and 5-bromo-3-iodo-1-toluenesulfonyl-1H-pyrrolo [2,3-b ] -c]Pyridine the title compound was prepared. 577mg, 68% brown solid. LC-MS (M + H)⁺＝540.3。

And 4, step 4: (S) - (3-hydroxypyrrolidin-1-yl) (4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone

Prepared from (S) - (4- (5-bromo-1-tosyl-1H-pyrrolo [2, 3-b) in a similar manner to that in step 2 of example 332]Pyridin-3-yl) phenyl) (3-hydroxypyrrolidin-1-yl) methanone and 1-methyl-4- (2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) piperazine the title compound was prepared. 67mg, 18%, brown solid. LC-MS (M + H) ⁺＝650.5。

And 5: (S) - (3-hydroxypyrrolidin-1-yl) (4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone

Prepared in a similar manner to that in example 369, step 6 from (S) - (3-hydroxypyrrolidin-1-yl) (4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1-toluenesulfonyl-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) phenyl) methanone preparation example 504 is given toThe title product (9mg, 11%).¹H NMR(400MHz,DMSO-d6)δ12.06(s,1H),8.53(s,1H),8.42(s,1H),8.01(s,1H),7.89-7.83(m,2H),7.64-7.51(m,4H),7.13(d,J＝8.2Hz,1H),5.06-4.87(m,1H),4.41-4.19(m,1H),3.74-3.51(m,3H),2.92-2.87(m,4H),2.49-2.44(m,4H),2.34(s,3H),2.27(s,3H),2.05-1.77(m,3H)。LC-MS(M+H)⁺＝496.4。

Example 505: n- (2-hydroxy-2-methylpropyl) -N-methyl-4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide (compound 505)

Step 1: 4-bromo-N- (2-hydroxy-2-methylpropyl) benzamide

The title compound (1.10g, 85%) was prepared from 4-bromobenzoic acid and 1-amino-2-methylpropan-2-ol in a similar manner to that in example 304, step 1. LC-MS (M + H)⁺＝272.1。

Step 2: 4-bromo-N- (2- (tert-butyldimethylsilyloxy) -2-methylpropyl)

The title compound was prepared from 4-bromo-N- (2-hydroxy-2-methylpropyl) benzamide and TBDMS-Cl in a similar manner to that in example 490, step 2. 1.36g, 38% white solid. LC-MS (M + H)⁺＝388.1。

And step 3: 4-bromo-N- (2- (tert-butyldimethylsilyloxy) -2-methylpropyl) -N-methylbenzamide

The title compound was prepared from 4-bromo-N- (2- (tert-butyldimethylsilyloxy) -2-methylpropyl) benzamide and MeI in a similar manner to that in example 394 step 1. 1.40g, 96% white solid. LC-MS (M + H)⁺＝400.3。

And 4, step 4: 4-bromo-N- (2-hydroxy-2-methylpropyl) -N-methylbenzamide

The title compound was prepared from 4-bromo-N- (2- (tert-butyldimethylsilyloxy) -2-methylpropyl) -N-methylbenzamide in a similar manner to that in example 490, step 4. 494mg, 49%。LC-MS(M+H)⁺＝287.2。

And 5: n- (2-hydroxy-2-methylpropyl) -N-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide

The title compound was prepared from 4-bromo-N- (2-hydroxy-2-methylpropyl) -N-methylbenzamide and BPD in a similar manner to that in example 308, step 2. 461mg, 80%. LC-MS (M + H)⁺＝334.2。

Step 6: 4- (5-bromo-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (2-hydroxy-2-methylpropyl) -N-methylbenzamide

Prepared in a similar manner to that described in step 2 of example 332 from N- (2-hydroxy-2-methylpropyl) -N-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide and 5-bromo-3-iodo-1-toluenesulfonyl-1H-pyrrolo [2,3-b ] -c ]Pyridine the title compound was prepared. 432mg, 62%, brown solid. LC-MS (M + H)⁺＝557.5。

And 7: n- (2-hydroxy-2-methylpropyl) -N-methyl-4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Prepared in a similar manner to that in step 2 of example 332 from 4- (5-bromo-1-tosyl-1H-pyrrolo [2,3-b ]]Pyridin-3-yl) -N- (2-hydroxy-2-methylpropyl) -N-methylbenzamide and 1-methyl-4- (2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) piperazine the title compound was prepared. 331mg, 64% brown solid. LC-MS (M + H)⁺＝666.3。

And 8: n- (2-hydroxy-2-methylpropyl) -N-methyl-4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Prepared in a similar manner to that in example 369 step 6 from N- (2-hydroxy-2-methylpropyl) -N-methyl-4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1-toluenesulfonyl-1H-pyrrolo [2,3-b]Pyridin-3-yl) benzamide example 505 was prepared to give the title product (20mg, 7%).¹H NMR(400MHz,DMSO-d6)δ12.04(s,1H),8.53(s,1H),8.41(s,1H),7.99(s,1H),7.89-7.82(m,2H),7.60-7.47(m,4H),7.13(d,J＝8.2Hz,1H),4.64-4.60(m,1H),3.51-3.47(m,2H),3.10(s,3H),2.93-2.86(m,4H),2.54-2.47(m,4H),2.34(s,3H),2.26(s,3H),1.23-0.91(m,6H)。LC-MS(M+H)⁺＝512.5。

Example 506: 2-methoxy-N, N-dimethyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide (compound 506)

Step 1: 4-bromo-2-methoxy-N, N-dimethylbenzamide

Prepared from 4-bromo-2-methoxybenzoic acid and Me in a similar manner to that described in step 1 of example 304₂NH the title compound was prepared. LC-MS (M + H)⁺＝258.5。

Step 2: 2-methoxy-N, N-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide

The title compound was prepared from 4-bromo-2-methoxy-N, N-dimethylbenzamide and BPD in a similar manner to that in example 308, step 1. LC-MS (M + H)⁺＝306.2。

And step 3: 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -2-methoxy-N, N-dimethylbenzamide

Prepared in a similar manner to that described in step 2 of example 332 from 2-methoxy-N, N-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide and 5-bromo-3-iodo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyrrole]Pyridine the title compound was prepared. LC-MS (M + H)⁺＝528.1。

And 4, step 4: 2-methoxy-N, N-dimethyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

Prepared from 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] in a similar manner to that described in step 2 of example 332 ]Pyridin-3-yl]-2-methoxy-N, N-dimethylbenzamide and 1-methyl-4- [ 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxo)Heterocyclopentylboran-2-yl) phenyl]Piperazine the title compound was prepared. LC-MS (M + H)⁺＝638.4。

And 5: 2-methoxy-N, N-dimethyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

Prepared in a similar manner to that described in example 369, step 6 from 2-methoxy-N, N-dimethyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl]Benzamide preparation example 506.¹H NMR(400MHz,DMSO-d6)δ12.04(s,1H),8.54(d,J＝1.8Hz,1H),8.40(d,J＝1.8Hz,1H),8.02(d,J＝1.2Hz,1H),7.59-7.50(m,2H),7.43(d,J＝7.9Hz,1H),7.38(s,1H),7.24(d,J＝7.7,1.3Hz,1H),7.13(d,J＝8.2,2.1Hz,1H),3.92(d,J＝1.3Hz,3H),3.00(d,J＝1.4Hz,3H),2.90(d,J＝5.0Hz,4H),2.84(d,J＝1.4Hz,3H),2.51-2.45(m,2H),2.34(s,3H),2.26(d,J＝1.9Hz,3H)。LC-MS(M+H)⁺＝484.4。

Example 507: 2-ethoxy-N, N-dimethyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide (compound 507)

Step 1: 4-bromo-2-ethoxy-N, N-dimethylbenzamide

Prepared from 4-bromo-2-ethoxybenzoic acid and Me in a similar manner to that described in step 1 of example 304₂NH the title compound was prepared. LC-MS (M + H)⁺＝272.0。

Step 2: 2-ethoxy-N, N-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide

The title compound was prepared from 4-bromo-2-ethoxy-N, N-dimethylbenzamide and BPD in a similar manner to that in example 308, step 1. LC-MS (M + H) ⁺＝320.2。

And step 3: 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -2-ethoxy-N, N-dimethylbenzamide

Prepared in a similar manner to that described in step 2 of example 332 from 2-ethoxy-N, N-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide and 5-bromo-3-iodo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyrrole]Pyridine the title compound was prepared. LC-MS (M + H)⁺＝542.0。

And 4, step 4: 2-ethoxy-N, N-dimethyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

Prepared from 4- [ 5-bromo-1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] in a similar manner to that described in step 2 of example 332]Pyridin-3-yl]-2-ethoxy-N, N-dimethylbenzamide and 1-methyl-4- [ 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Piperazine the title compound was prepared. LC-MS (M + H)⁺＝652.4。

And 5: 2-ethoxy-N, N-dimethyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

Prepared in a similar manner to that described in example 369, step 6 from 2-ethoxy-N, N-dimethyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl]Benzamide preparation example 507.¹H NMR(400MHz,DMSO-d6)δ12.03(d,1H),8.53(d,J＝2.0Hz,1H),8.38(d,J＝2.1Hz,1H),8.00(d,J＝2.6Hz,1H),7.59-7.50(m,2H),7.41(d,J＝7.8Hz,1H),7.35(s,1H),7.24(d,J＝7.7Hz,1H),7.13(d,J＝8.3Hz,1H),4.22(q,J＝6.9Hz,2H),3.00(s,3H),2.93-2.87(m,4H),2.85(s,3H),2.50(d,J＝1.8Hz,3H),2.34(s,3H),2.26(s,3H),1.36(t,J＝6.9Hz,3H)。LC-MS(M+H)⁺＝498.4。

Example 508: 2-cyclopropyl-N, N-dimethyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide (compound 508)

Step 1: 4-bromo-2-cyclopropylbenzoic acid

To a solution of 4-bromo-2-fluorobenzoic acid (713mg, 3.253mmol) in THF (10mL) at 0 deg.C was added dropwise magnesium bromo (cyclopropyl) in THF (5mL, 10mmol, 2M). The resulting mixture was stirred at 0 ℃ under a nitrogen atmosphere for 3 h. When the reaction was complete, the reaction was then quenched by addition of HCl (6N). The resulting solution was extracted with ethyl acetate (30mLx 3). The organic phases were combined, washed with brine and over Na₂SO₄And (5) drying. The solution was concentrated under reduced pressure and the residue was applied to a C18 gel column and purified by flash chromatography using MeCN (containing 10mmol/L NH) in water₄HCO₃) A gradient of 30% to 60% over 30min was eluted to give 4-bromo-2-cyclopropylbenzoic acid (128mg, 16%) as a light brown solid. LC-MS (M + H)⁺＝241.0。

Step 2: 4-bromo-2-cyclopropyl-N, N-dimethylbenzamide

Prepared from 4-bromo-2-cyclopropylbenzoic acid and Me in a similar manner to that described in step 1 of example 304 ₂NH the title compound was prepared. LC-MS (M + H)⁺＝268.1。

And step 3: 2-cyclopropyl-N, N-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide

The title compound was prepared from 4-bromo-2-cyclopropyl-N, N-dimethylbenzamide and BPD in a similar manner to that in example 308, step 1. LC-MS (M + H)⁺＝316.2。

And 4, step 4: 2-cyclopropyl-N, N-dimethyl-4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

Prepared in a similar manner to that in step 8 of example B03 from 2-cyclopropyl-N, N-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide and 1- (4- [ 3-iodo-1H-pyrrolo [2,3-B ] pyrrole]Pyridin-5-yl]-2-methylphenyl) -4-methylpiperazine preparation example 508.¹H NMR(400MHz,DMSO-d6)δ12.00(d,J＝2.7Hz,1H),8.52(d,J＝2.1Hz,1H),8.30(d,J＝2.1Hz,1H),7.96(d,J＝2.6Hz,1H),7.62(dd,J＝7.8,1.7Hz,1H),7.55(d,J＝2.3Hz,1H),7.51(dd,J＝8.1,2.4Hz,1H),7.20(d,J＝7.9Hz,2H),7.13(d,J＝8.2Hz,1H),3.05(s,3H),2.88(d,J＝5.5Hz,7H),2.51-2.48(m,4H),2.33(s,3H),2.25(s,3H),1.89-1.78(m,1H),0.96(d,J＝8.4Hz,2H),0.84(s,2H)。LC-MS(M+H)⁺＝494.5。

Example 509: (R) -4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (2-hydroxypropyl) -N, 2-dimethylbenzamide (Compound 509)

Step 1: (R) -4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (2-hydroxypropyl) -N, 2-dimethylbenzamide

Prepared in a similar manner to that in step 2 of example 332 from (R) -4- (5-bromo-1-tosyl-1H-pyrrolo [2, 3-b) ]Pyridin-3-yl) -N- (2-hydroxypropyl) -N, 2-dimethylbenzamide and 1- (2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -4-methylpiperazine the title compound was prepared. 86mg, 47%, yellow solid. LC-MS (M + H)⁺＝680.4。

Step 2: (R) -4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (2-hydroxypropyl) -N, 2-dimethylbenzamide

Prepared in a similar manner to that in example 369, step 6 from (R) -4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1-toluenesulfonyl-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) -N- (2-hydroxypropyl) -N, 2-dimethylbenzamide EXAMPLE 509 was prepared to give the title product (21mg, 22%).¹H NMR(400MHz,DMSO-d6)δ12.00(s,1H),8.50(s,1H),8.37(s,1H),7.97-7.90(m,1H),7.68-7.60(m,2H),7.36(s,2H),7.23(d,J＝8.4Hz,1H),4.85-4.77(m,1H),4.03-3.77(m,1H),3.56-3.35(m,1H),3.14-3.01(m,6H),2.91-2.86(m,2H),2.47-2.40(m,4H),2.37(s,6H),2.33-2.23(m,6H),1.17-0.88(m,3H)。LC-MS(M+H)⁺＝526.3。

Example 510: 4- (2- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -N, N, 2-trimethylbenzamide (compound 510)

Step 1: 4- (2- (2, 5-dimethyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -5-tosyl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -N, N, 2-trimethylbenzamide

Prepared in a similar manner to that in step 2 of example 332 from N, N, 2-trimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide and 2-bromo-7-iodo-5-toluenesulfonyl-5H-pyrrolo [2,3-b ] b ]Pyrazine the title compound was prepared. 600mg, 60%, yellow solid. LCMS (M + H)⁺＝513.2。

Step 2: 4- (2- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -N, 2-trimethylbenzamide

Prepared from 4- (2-bromo-5H-pyrrolo [2,3-b ] in a similar manner to that in example 291, step 4]Pyrazin-7-yl) -N, 2-trimethylbenzamide and 1- (2, 6-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -4-methylpiperazine example 510 was prepared to give the title product (60mg, 63%).¹H NMR(400MHz,DMSO-d6)δ12.00(s,1H),8.50(d,J＝1.9Hz,1H),8.36(d,J＝1.9Hz,1H),7.92(d,J＝2.6Hz,1H),7.65-7.61(m,2H),7.35(s,2H),7.23(s,1H),7.21(s,1H),3.08-3.03(m,4H),3.02(s,3H),2.83(s,3H),2.47-3.41(m,4H),2.36(s,6H),2.27(s,3H),2.25(s,3H)。LCMS(M+H)⁺＝483.0HPLC：254nm，98.9％。

Example 511: (R) - (3-Hydroxypyrrolidin-1-yl) (4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone (Compound 511)

Step 1: (R) - (4-bromophenyl) (3-hydroxypyrrolidin-1-yl) methanone

Prepared from 4-bromobenzoic acid and (R) -pyrrole in a similar manner to that described in step 1 of example 304Alk-3-ol the title compound was prepared. 611mg, 91%, brown solid. LC-MS (M + H)⁺＝270.0。

Step 2: (R) - (3-hydroxypyrrolidin-1-yl) (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) methanone

Compound 2 was prepared from (R) - (4-bromophenyl) (3-hydroxypyrrolidin-1-yl) methanone and BPD in analogy to example 308, step 1. 230mg, 97%, yellow solid. LC-MS (M + H) ⁺＝318.2。

And step 3: (R) - (4- (5-bromo-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (3-hydroxypyrrolidin-1-yl) methanone

Prepared in a similar manner to that in step 2 of example 332 from (R) - (3-hydroxypyrrolidin-1-yl) (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) methanone and 5-bromo-3-iodo-1-toluenesulfonyl-1H-pyrrolo [2,3-b ] -c]Pyridine the title compound was prepared. 109mg, 96%, brown solid. LC-MS (M + H)⁺＝540.0。

And 4, step 4: (R) - (3-hydroxypyrrolidin-1-yl) (4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone

Prepared from (R) - (4- (5-bromo-1-tosyl-1H-pyrrolo [2, 3-b) in a similar manner to that in step 2 of example 332]Pyridin-3-yl) phenyl) (3-hydroxypyrrolidin-1-yl) methanone and 1-methyl-4- (2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) piperazine the title compound was prepared. 111mg, 61% grey solid. LC-MS (M + H)⁺＝650.4。

And 5: (R) - (3-hydroxypyrrolidin-1-yl) (4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone

Prepared in a similar manner to that in example 369, step 6 from (R) - (3-hydroxypyrrolidin-1-yl) (4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1-toluenesulfonyl-1H-pyrrolo [2, 3-b) ]Pyridin-3-yl) phenyl) methanone example 511 was prepared and obtained as a white solid (15mg, 27%).¹H NMR(400MHz,DMSO-d6)δ8.52(s,1H),8.41(s,1H),7.98(s,1H),7.88-7.82(m,2H),7.66-7.48(m,4H),7.12(d,J＝8.2Hz,1H),4.37-4.21(m,1H),3.72-3.51(m,3H),3.44-3.26(m,1H),2.92-2.85(m,4H),2.59-2.44(m,4H),2.33(s,3H),2.26(s,3H),2.01-1.78(m,2H)。LC-MS(M+H)⁺＝496.3。

Example 512A/512B: n- ((S) -2-hydroxypropyl) -N-methyl-4- (5- (3-methyl-4- ((R) -1-methylpiperidin-3-yl) phenyl) -1H-pyrrolo [2,3-B ] pyridin-3-yl) benzamide and N- ((S) -2-hydroxypropyl) -N-methyl-4- (5- (3-methyl-4- ((S) -1-methylpiperidin-3-yl) phenyl) -1H-pyrrolo [2,3-B ] pyridin-3-yl) benzamide (compounds 512A/512B)

Step 1: n- ((S) -2-hydroxypropyl) -N-methyl-4- (5- (3-methyl-4- (1-methylpiperidin-3-yl) phenyl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Prepared in a similar manner to that described in step 2 of example 332 from (S) -N- (2-hydroxypropyl) -N-methyl-4- (5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-toluenesulfonyl-1H-pyrrolo [2,3-b ] ne]Pyridin-3-yl) benzamide and 3-methyl-4- (1-methylpiperidin-3-yl) phenyl trifluoromethanesulfonate the title compound was prepared. 82mg, 32%, yellow solid. LC-MS (M + H)⁺＝651.7。

Step 2: n- ((S) -2-hydroxypropyl) -N-methyl-4- (5- (3-methyl-4- ((R) -1-methylpiperidin-3-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide and N- ((S) -2-hydroxypropyl) -N-methyl-4- (5- (3-methyl-4- ((S) -1-methylpiperidin-3-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Example 512A/512B was prepared from N- ((S) -2-hydroxypropyl) -N-methyl-4- (5- (3-methyl-4- (1-methylpiperidin-3-yl) phenyl) -1-tosyl-1H-pyrrolo [2,3-B ] pyridin-3-yl) benzamide in a similar manner to that in example 369 step 6. The 2 isomeric products were obtained by separation on chiral-HPLC under the following conditions: column: CHIRALPAK IG-3, 0.46x50cm, 3 um. Mobile phase: hex (0.1% IPAmine) in (EtOH: DCM ═ 1:1), 70% isocratic within 15 min; a detector: UV 254 nm.

Example 512A: (12mg, 33%)¹H NMR(400MHz,DMSO-d6)δ12.09(s,1H),8.55(s,1H),8.44(s,1H),8.01(s,1H),7.88-7.82(m,2H),7.59-7.46(m,4H),7.33(d,J＝8.0Hz,1H),4.95-4.80(m,1H),4.05-3.82(m,1H),3.51-3.46(m,1H),3.20-3.16(m,1H),3.08-2.96(m,4H),2.87-2.76(m,2H),2.40(s,3H),2.22(s,3H),1.98-1.93(m,2H),1.81-1.60(m,3H),1.52-1.36(m,1H),1.18-0.87(m,3H)。LC-MS(M+H)⁺497.3. chiral-HPLC, tR: 3.472 m.

Example 512B: (11mg, 30%)¹H NMR(400MHz,DMSO-d6)δ12.09(s,1H),8.55(s,1H),8.44(s,1H),8.01(s,1H),7.88-7.82(m,2H),7.59-7.46(m,4H),7.33(d,J＝8.0Hz,1H),4.95-4.80(m,1H),4.05-3.82(m,1H),3.51-3.46(m,1H),3.20-3.16(m,1H),3.08-2.96(m,4H),2.87-2.76(m,2H),2.40(s,3H),2.22(s,3H),1.98-1.93(m,2H),1.81-1.60(m,3H),1.52-1.36(m,1H),1.18-0.87(m,3H)。LC-MS(M+H)⁺497.3. chiral-HPLC, tR: 4.844 m.

Example 513A/513B: (R) - (4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-B ] pyridin-3-yl) phenyl) (1-methylazetidin-3-yl) methanol and (S) - (4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-B ] pyridin-3-yl) phenyl) (1-methylazetidin-3-yl) methanol (Compound 513A/513B)

Example 513A/513B was prepared from (4- (5- (3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-B ] pyridin-3-yl) phenyl) (1-methylazetidin-3-yl) methanone in a similar manner to that in example 377, step 4. The 2 isomeric products were obtained by separation on chiral-HPLC under the following conditions: column: lux cellulose-4, 0.46x10cm, 3 um. Mobile phase: hexane in EtOH (containing 0.2% isopropylamine), 70% isocratic within 15 min; a detector: UV 254 nm.

Example 513A:¹H NMR(400MHz,DMSO-d6)δ11.95(brs,1H),8.50(s,1H),8.34(s,1H),7.87(s,1H),7.75-7.68(m,2H),7.42-7.33(m,4H),5.43(brs,1H),4.66(d,J＝7.8Hz,1H),3.38-3.24(m,3H),3.10-3.04(m,5H),2.67-2.64(m,1H),2.50-2.40(m,4H),2.37(s,6H),2.31(s,3H),2.25(s,3H)。LC-MS(M+H)⁺496.3. chiral-HPLC, tR: 4.389 m.

Example 513B:¹H NMR(400MHz,DMSO-d6)δ11.95(brs,1H),8.50(s,1H),8.34(s,1H),7.87(s,1H),7.75-7.68(m,2H),7.42-7.33(m,4H),5.43(brs,1H),4.66(d,J＝7.8Hz,1H),3.38-3.24(m,3H),3.10-3.04(m,5H),2.67-2.64(m,1H),2.50-2.40(m,4H),2.37(s,6H),2.31(s,3H),2.25(s,3H)。LC-MS(M+H)⁺496.3. chiral-HPLC, tR: 3.357 m.

Example 514A/514B: (S) - (4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-B ] pyridin-3-yl ] phenyl) (1-methylazetidin-3-yl) methanol and (R) - (4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-B ] pyridin-3-yl ] phenyl) (1-methylazetidin-3-yl) methanol (Compound 514A/514B)

Step 1: 1-methyl-4- (2-methyl-4- [3- [4- (1-methylazetidine-3-carbonyl) phenyl ] -1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl ] phenyl) piperazine

Prepared from 3- [4- [ 5-bromo-1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b ] in a similar manner to that described in step 2 of example 332]Pyridin-3-yl]Benzoyl radical]-1-methylazetidine and 1-methyl-4- [ 2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Piperazine the title compound was prepared. LC-MS (M + H)⁺＝634.3。

Step 2: (4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl ] phenyl) (1-methylazetidin-3-yl) methanol

Prepared in a similar manner to that described in step 4 of example 377 from 1-methyl-4- (2-methyl-4- [3- [4- (1-methylazetidine-3-carbonyl) phenyl ]-1- (4-methylbenzenesulfonyl) -1H-pyrrolo [2,3-b]Pyridin-5-yl]Phenyl) piperazine the title compound was prepared. LC-MS (M + H)⁺＝636.7。

And step 3: (S) - (4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] phenyl) (1-methylazetidin-3-yl) methanol and (R) - (4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1H-pyrrolo [2,3-b ] pyridin-3-yl ] phenyl) (1-methylazetidin-3-yl) methanol

Example 514A/514B was prepared from (4- [5- [ 3-methyl-4- (4-methylpiperazin-1-yl) phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-B ] pyridin-3-yl ] phenyl) (1-methylazetidin-3-yl) methanol in a similar manner to that in example 369, step 6. The 2 isomeric products were obtained by separation on chiral-HPLC under the following conditions: column: CHIRALPAK IG-3, 0.46x10cm, 3 um. Mobile phase: hexane in EtOH (containing 0.1% isopropylamine), 70% isocratic within 15 min; a detector: UV254 nm.

Example 514A:¹H NMR(400MHz,DMSO-d6)δ11.92(s,1H),8.51(s,1H),8.35(s,1H),7.86(s,1H),7.75-7.68(m,2H),7.58-7.49(m,2H),7.41-7.34(m,2H),7.13(d,J＝8.2Hz,1H),5.30(s,1H),4.63(d,J＝8.2Hz,1H),3.28-3.25(m,1H),3.11-3.06(m,2H),2.90-2.85(m,5H),2.61-2.51(m,1H),2.50-2.37(m,4H),2.34(s,3H),2.26(s,3H),2.21(s,3H)。LC-MS(M+H)⁺482.3. chiral-HPLC, tR: 4.404 m.

Example 514B:¹H NMR(400MHz,DMSO-d6)δ11.92(s,1H),8.51(s,1H),8.35(s,1H),7.86(s,1H),7.75-7.68(m,2H),7.58-7.48(m,2H),7.41-7.34(m,2H),7.13(d,J＝8.2Hz,1H),5.32(s,1H),4.63(d,J＝8.1Hz,1H),3.30-3.27(m,1H),3.13-3.08(m,2H),2.92-2.88(m,5H),2.62-2.57(m,1H),2.52-2.50(m,4H),2.34(s,3H),2.26(s,3H),2.22(s,3H)。LC-MS(M+H)⁺482.3. chiral-HPLC, tR: 3.180 m.

Example 515A/515B: (R) - (3-hydroxy-3-methylpyrrolidin-1-yl) (4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-B ] pyridin-3-yl) phenyl) methanone and (S) - (3-hydroxy-3-methylpyrrolidin-1-yl) (4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-B ] pyridin-3-yl) phenyl) methanone (Compound 515A/515B)

Step 1: 4- (3-hydroxy-3-methylpyrrolidine-1-carbonyl) phenylboronic acid

The title compound was prepared from 3-methylpyrrolidin-3-ol and 4-boronobenzoic acid in a similar manner to that in example 304, step 1. 864mg, 46%, yellow solid. LC-MS (M + H)⁺＝250.2。

Step 2: (4- (5-bromo-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (3-hydroxy-3-methylpyrrolidin-1-yl) methanone

Prepared from 4- (3-hydroxy-3-methylpyrrolidine-1-carbonyl) phenylboronic acid and 5-bromo-3-iodo-1-toluenesulfonyl-1H-pyrrolo [2,3-b ] in a similar manner to that described in step 2 of example 332]Pyridine the title compound was prepared. 656mg, 51%, brown solid. LC-MS (M + H)⁺＝555.3。

And step 3: (3-hydroxy-3-methylpyrrolidin-1-yl) (4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone

Prepared in a similar manner to that in step 2 of example 332 from (4- (5-bromo-1-tosyl-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) phenyl) (3-hydroxy-3-methylpyrrolidin-1-yl) methanone and 1-methyl-4- (2-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) piperazine the title compounds were prepared. 365mg, 45% brown solid. LC-MS (M + H) ⁺＝664.4。

And 4, step 4: (R) - (3-hydroxy-3-methylpyrrolidin-1-yl) (4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone and (S) - (3-hydroxy-3-methylpyrrolidin-1-yl) (4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone

Example 515A/515B was prepared from (3-hydroxy-3-methylpyrrolidin-1-yl) (4- (5- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) -1-toluenesulfonyl-1H-pyrrolo [2,3-B ] pyridin-3-yl) phenyl) methanone in a similar manner as in example 369, step 6. The 2 isomeric products were obtained by separation on chiral-HPLC under the following conditions: column: CHIRALPAK AD-3, 4.6x10mm, 3 um. Mobile phase: hexane in IPA (containing 0.2% IPAmine), 80% isocratic within 15 min; a detector: UV 254 nm.

Example 515A: (22mg, 8%)¹H NMR(400MHz,DMSO-d6)δ12.06(s,1H),8.53(s,1H),8.42(s,1H),8.00(s,1H),7.85(d,J＝8.1Hz,2H),7.66-7.46(m,4H),7.13(d,J＝8.2Hz,1H),4.89-4.70(m,1H),3.75-3.60(m,1H),3.60-3.42(m,2H),3.40-3.25(m,5H),2.93-2.86(m,4H),2.34(s,3H),2.27(s,3H),1.89-1.77(m,2H),1.39-1.20(m,3H)。LC-MS(M+H)⁺510.4. chiral-HPLC, tR [ hexane in IPA (0.2% IPAmine), 85% isocratic]：8.781m。

Example 515B: (17mg, 6%)¹H NMR(400MHz,DMSO-d6)δ12.06(s,1H),8.53(s,1H),8.42(s,1H),8.03-7.98(m,1H),7.86(d,J＝7.9Hz,2H),7.65-7.49(m,4H),7.13(d,J＝8.2Hz,1H),4.89-4.74(m,1H),3.76-3.61(m,1H),3.59-3.39(m,2H),3.38-3.25(m,5H),2.93-2.86(m,4H),2.34(s,3H),2.27(s,3H),1.89-1.77(m,2H),1.38-1.20(m,3H)。LC-MS(M+H)⁺510.5. chiral-HPLC, tR [ hexane in IPA (0.2% IPAmine), 85% isocratic]：11.546m。

Example 516A/516B: (S) -N, N-dimethyl-4- (5- (3-methyl-4- (1-methylpiperidin-3-yl) phenyl) -1H-pyrrolo [2,3-B ] pyridin-3-yl) benzamide and (R) -N, N-dimethyl-4- (5- (3-methyl-4- (1-methylpiperidin-3-yl) phenyl) -1H-pyrrolo [2,3-B ] pyridin-3-yl) benzamide (compounds 516A/516B)

Step 1: 3- (4-methoxy-2-methylphenyl) pyridine

The title compound was prepared from 1-bromo-4-methoxy-2-methylbenzene and pyridin-3-ylboronic acid in a similar manner to that in example 332, step 2. LC-MS (M + H)⁺＝200.3。

Step 2: 3- (4-methoxy-2-methylphenyl) piperidine

In nitrogenTo a solution of 3- (4-methoxy-2-methylphenyl) pyridine (588mg, 2.951mmol) in AcOH (10mL) under a gas atmosphere was added PtO₂(134mg, 0.590 mmol). The reaction flask was evacuated and flushed with hydrogen. The reaction mixture was then hydrogenated in a pressure pot at 40 ℃ under a hydrogen atmosphere of 60atm for 72 h. When the reaction was complete, the solids were removed by filtration. The filtrate was concentrated to give 3- (4-methoxy-2-methylphenyl) piperidine (140mg, 23%) which was obtained as a yellow solid. LC-MS (M + H)⁺＝206.3。

And step 3: 3- (4-methoxy-2-methylphenyl) -1-methylpiperidine

The title compound was prepared from 3- (4-methoxy-2-methylphenyl) piperidine in a similar manner to that in example 397, step 1. LC-MS (M + H)⁺＝220.1。

And 4, step 4: 3-methyl-4- (1-methylpiperidin-3-yl) phenol

The title compound was prepared from 3- (4-methoxy-2-methylphenyl) -1-methylpiperidine in a similar manner to that in example 343, step 1. LC-MS (M + H) ⁺＝206.1。

And 5: 3-methyl-4- (1-methylpiperidin-3-yl) phenyl trifluoromethanesulfonate

Prepared from 3-methyl-4- (1-methylpiperidin-3-yl) phenol and PhNTf in a similar manner to that in step 3 of example 455₂The title compound was prepared. LC-MS (M + H)⁺＝338.0。

Step 6: n, N-dimethyl-4- [5- [ 3-methyl-4- (1-methylpiperidin-3-yl) phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

Prepared in a similar manner to that described in step 2 of example 332 from N, N-dimethyl-4- [1- (4-methylbenzenesulfonyl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ]]Pyridin-3-yl]Benzamide and 3-methyl-4- (1-methylpiperidin-3-yl) phenyl trifluoromethanesulfonate the title compound was prepared. LC-MS (M + H)⁺＝607.4。

And 7: (S) -N, N-dimethyl-4- (5- (3-methyl-4- (1-methylpiperidin-3-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide and (R) -N, N-dimethyl-4- (5- (3-methyl-4- (1-methylpiperidin-3-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Prepared in a similar manner to that described in example 369, step 6 from N, N-dimethyl-4- [5- [ 3-methyl-4- (1-methylpiperidin-3-yl) phenyl]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl ]Benzamide preparation example 516A/516B. The 2 isomeric products were obtained by separation on chiral-HPLC under the following conditions: column: CHIRALPAK IE-3, 0.46x50cm, 3 um. Mobile phase: hexane in EtOH (0.1% NH)₃) 50% isocratic within 15 min; a detector: UV 254 nm.

Example 516A:¹H NMR(400MHz,DMSO-d6)δ12.08(d,J＝2.7Hz,1H),8.55(d,J＝2.1Hz,1H),8.44(d,J＝2.1Hz,1H),8.01(d,J＝2.7Hz,1H),7.89-7.83(m,2H),7.59-7.52(m,2H),7.52-7.46(m,2H),7.35(d,J＝8.0Hz,1H),3.01(s,7H),2.88-2.76(m,2H),2.41(s,3H),2.23(s,3H),1.99-1.95(m,2H),1.78-1.74(m,2H),1.70-1.62(m,1H),1.52-1.37(m,1H)。LC-MS(M+H)⁺453.2. chiral-HPLC, tR [ hexane in EtOH (0.2% IPAmine), 50% isocratic]：5.340m。

Example 516B:¹H NMR(400MHz,DMSO-d6)δ12.08(d,J＝2.7Hz,1H),8.55(d,J＝2.1Hz,1H),8.44(d,J＝2.1Hz,1H),8.01(d,J＝2.7Hz,1H),7.89-7.83(m,2H),7.59-7.46(m,4H),7.34(d,J＝7.9Hz,1H),3.01(s,7H),2.87-2.75(m,2H),2.41(s,3H),2.22(s,3H),2.01-1.89(m,2H),1.81-1.69(m,2H),1.69-1.62(m,1H),1.51-1.36(m,1H)。LC-MS(M+H)⁺453.2. chiral-HPLC, tR [ hexane in EtOH (0.2% IPAmine), 50% isocratic]：7.631m。

Example 517A/517B: (R) -N, N, 2-trimethyl-4- (5- (3-methyl-4- (1-methylpiperidin-3-yl) phenyl) -1H-pyrrolo [2,3-B ] pyridin-3-yl) benzamide and (S) -N, N, 2-trimethyl-4- (5- (3-methyl-4- (1-methylpiperidin-3-yl) phenyl) -1H-pyrrolo [2,3-B ] pyridin-3-yl) benzamide (Compound 517A/517B)

Step 1: n, N, 2-trimethyl-4- [5- [ 3-methyl-4- (1-methylpiperidin-3-yl) phenyl ] -1- (4-methylbenzenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] benzamide

Prepared in a similar manner to that described in step 2 of example 332 from N, N, 2-trimethyl-4- [1- (4-methylbenzenesulfonyl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ]]Pyridin-3-yl ]Benzamide and 3-methyl-4- (1-methylpiperidin-3-yl) phenyl trifluoromethanesulfonate the title compound was prepared. LC-MS (M + H)⁺＝621.3。

Step 2: (R) -N, N, 2-trimethyl-4- (5- (3-methyl-4- (1-methylpiperidin-3-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide and (S) -N, N, 2-trimethyl-4- (5- (3-methyl-4- (1-methylpiperidin-3-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Prepared in a similar manner to that described in example 369, step 6 from N, N, 2-trimethyl-4- [5- [ 3-methyl-4- (1-methylpiperidin-3-yl) phenyl]-1- (4-Methylbenzenesulfonyl) pyrrolo [2,3-b]Pyridin-3-yl]Benzamide preparation example 517A/517B. The 2 isomeric products were obtained by separation on chiral-HPLC under the following conditions: column: CHIRALPAK IE-3, 0.46x50cm, 3 um. Mobile phase: hexane in EtOH (0.1% NH)₃) 50% isocratic within 15 min; a detector: UV 254 nm.

Example 517A:¹H NMR(400MHz,DMSO-d6)δ12.02(d,J＝2.7Hz,1H),8.53(d,J＝2.0Hz,1H),8.41(d,J＝2.1Hz,1H),7.94(d,J＝2.6Hz,1H),7.68-7.61(m,2H),7.57-7.49(m,2H),7.34(d,J＝7.9Hz,1H),7.22(d,J＝7.8Hz,1H),3.03(s,4H),2.84(s,5H),2.40(s,3H),2.28(s,3H),2.21(s,3H),1.99-1.87(m,2H),1.80-1.58(m,3H),1.48-1.36(m,1H)。LC-MS(M+H)⁺467.2. chiral-HPLC, tR [ hexane in EtOH (0.2% IPAmine), 50% isocratic]：4.438m。

Example 517B:¹H NMR(400MHz,DMSO-d6)δ12.02(d,J＝2.7Hz,1H),8.53(d,J＝2.0Hz,1H),8.41(d,J＝2.1Hz,1H),7.94(d,J＝2.6Hz,1H),7.68-7.61(m,2H),7.58-7.49(m,2H),7.34(d,J＝7.9Hz,1H),7.22(d,J＝7.8Hz,1H),3.03(s,3H),2.99(t,J＝11.2Hz,1H),2.86-2.74(m,5H),2.41(s,3H),2.28(s,3H),2.21(s,3H),2.00-1.88(m,2H),1.81-1.70(m,2H),1.69-1.61(m,1H),1.51-1.36(m,1H)。LC-MS(M+H)⁺467.2. Hand (W.E.)sex-HPLC, tR [ hexane in EtOH (0.2% IPAmine), 50% isocratic]：5.422m。

Example 518A/518B: n- ((R) -2-hydroxypropyl) -N-methyl-4- (5- (3-methyl-4- ((R) -1-methylpiperidin-3-yl) phenyl) -1H-pyrrolo [2,3-B ] pyridin-3-yl) benzamide and N- ((R) -2-hydroxypropyl) -N-methyl-4- (5- (3-methyl-4- ((S) -1-methylpiperidin-3-yl) phenyl) -1H-pyrrolo [2,3-B ] pyridin-3-yl) benzamide (compounds 518A/518B)

Step 1: n- ((R) -2-hydroxypropyl) -N-methyl-4- (5- (3-methyl-4- (1-methylpiperidin-3-yl) phenyl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Prepared in a similar manner to that described in step 2 of example 332 from (R) -N- (2-hydroxypropyl) -N-methyl-4- (5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-toluenesulfonyl-1H-pyrrolo [2,3-b ] ne]Pyridin-3-yl) benzamide and 3-methyl-4- (1-methylpiperidin-3-yl) phenyl trifluoromethanesulfonate the title compound was prepared and obtained as a brown solid (211mg, 84%). LC-MS (M + H)⁺＝651.4。

Step 2: n- ((R) -2-hydroxypropyl) -N-methyl-4- (5- (3-methyl-4- ((R) -1-methylpiperidin-3-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide and N- ((R) -2-hydroxypropyl) -N-methyl-4- (5- (3-methyl-4- ((S) -1-methylpiperidin-3-yl) phenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) benzamide

Example 518A/518B was prepared from N- ((R) -2-hydroxypropyl) -N-methyl-4- (5- (3-methyl-4- (1-methylpiperidin-3-yl) phenyl) -1-tosyl-1H-pyrrolo [2,3-B ] pyridin-3-yl) benzamide in a similar manner to that in example 369 step 6. The 2 isomeric products were obtained by separation on chiral-HPLC under the following conditions: column: CHIRALPAK IG-3, 0.46x50cm, 3 um. Mobile phase: (Hex: DCM ═ 3:1) (0.2% IPAmine) in EtOH, 85% isocratic within 15 min; a detector: UV 254 nm.

Example 518A: (19mg, 23%)¹H NMR(400MHz,DMSO-d6)δ12.06(s,1H),8.55(s,1H),8.44(s,1H),8.00(s,1H),7.90-7.81(m,2H),7.59-7.46(m,4H),7.34(d,J＝8.0Hz,1H),4.89-4.80(m,1H),4.06-3.83(m,1H),3.51-3.46(m,1H),3.21-3.16(m,1H),3.10-2.93(m,4H),2.87-2.75(m,2H),2.41(s,3H),2.22(s,3H),2.03-1.85(m,2H),1.83-1.61(m,3H),1.51-1.37(m,1H),1.19-0.85(m,3H)。LC-MS(M+H)⁺497.3. chiral-HPLC, tR [ Hex (0.2% IPAmine) in (EtOH: DCM ═ 1:1), 70% isocratic]：3.742m。

Example 518B: (18mg, 22%)¹H NMR(400MHz,DMSO-d6)δ12.06(s,1H),8.55(s,1H),8.44(s,1H),8.00(s,1H),7.90-7.81(m,2H),7.59-7.46(m,4H),7.34(d,J＝8.0Hz,1H),4.89-4.80(m,1H),4.06-3.83(m,1H),3.51-3.46(m,1H),3.21-3.16(m,1H),3.10-2.93(m,4H),2.87-2.75(m,2H),2.41(s,3H),2.22(s,3H),2.03-1.85(m,2H),1.83-1.61(m,3H),1.51-1.37(m,1H),1.19-0.85(m,3H)。LC-MS(M+H)⁺497.3. chiral-HPLC, tR [ Hex (0.2% IPAmine) in (EtOH: DCM ═ 1:1), 70% isocratic]：4.844m。

Example B

Example B01: 5- (4-methoxyphenyl) -3- [4- (4-methylpiperazin-1-yl) phenyl ] -1H,4H, 5H-pyrazolo [3,4-d ] pyrimidin-4-one

Step 1: 5- (4-methoxyphenyl) -1H,4H, 5H-pyrazolo [3,4-d ] pyrimidin-4-one

1H,4H, 5H-pyrazolo [3,4-d ] in a 100mL round-bottom flask at room temperature]To a mixture of pyrimidin-4-one (1g, 6.98mmol, 1 equiv.), 4-methoxyaniline (1.4g, 10.47mmol, 1.5 equiv.), HATU (5.5g, 13.74mmol, 1.97 equiv.) in toluene (30mL) was slowly added DBU (1.4g, 8.74mmol, 1.25 equiv.). The resulting mixture was stirred at 80 ℃ for 48h, and then cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with EtOAc/MeOH (10:1) to give 500mg of crude product, which was purified by preparative HPLC using the following conditions: column: XBridge prep C18 OBD column, 19x150mm, 5 um; mobile phase: water (containing)10mmol/L NH₄HCO₃And 0.1% NH₃.H₂O) and ACN (10% phase B, up to 30% in 8 min); a detector: and (6) UV. This gave 5- (4-methoxyphenyl) -1H,4H, 5H-pyrazolo [3,4-d as a white solid ]Pyrimidin-4-one (130mg, 7.30%).¹H NMR(400MHz,DMSO-d6)δ13.88(s,1H),8.25(d,J＝3.3Hz,2H),7.48-7.35(m,2H),7.14-7.03(m,2H),3.83(s,3H)。

Step 2: 3-iodo-5- (4-methoxyphenyl) -1H,4H, 5H-pyrazolo [3,4-d ] pyrimidin-4-one

To 5- (4-methoxyphenyl) -1H,4H, 5H-pyrazolo [3,4-d ] in a 50mL round-bottomed flask at room temperature]To a mixture of pyrimidin-4-one (120mg, 0.47mmol, 1 eq) in DMF (10mL) was added NIS (200mg, 0.84mmol, 1.79 eq). The resulting mixture was stirred at 60 ℃ for 24 h. The mixture was allowed to cool to room temperature and extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with water and dried over anhydrous Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (2:3) to give 3-iodo-5- (4-methoxyphenyl) -1H,4H, 5H-pyrazolo [3,4-d as a pale yellow solid]Pyrimidin-4-one (100mg, 54.83%). LCMS (M + H)⁺＝369.0。

And step 3: 5- (4-methoxyphenyl) -3- [4- (4-methylpiperazin-1-yl) phenyl ] -1H,4H, 5H-pyrazolo [3,4-d ] pyrimidin-4-one

To 3-iodo-5- (4-methoxyphenyl) -1H,4H, 5H-pyrazolo [3,4-d ] under a nitrogen atmosphere]Pyrimidin-4-one (80mg, 0.21mmol, 1.31 equiv.) and 1-methyl-4- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]To a solution of piperazine (50mg, 0.16mmol, 1 eq) in 2-propanol (4mL) and water (1mL) was added K ₃PO₄(40mg, 0.18mmol, 1.14 equiv.) and Pd AMPHOS (15mg, 0.02mmol, 0.13 equiv.). The reaction mixture was irradiated with microwaves at 80 ℃ for 1h under a nitrogen atmosphere. Insoluble solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with EtOAc/MeOH (1: 2). The crude product obtained (20mg) was purified by preparative HPLC using the following conditions: column: XBridge prep OBD C18 column, 30x150mm, 5 um; mobile phase: water (containing 10mmol/L NH)₄HCO₃And 0.1% NH₃.H₂O) and ACN (21% phase B, up to 51% in 8 min); a detector: and (6) UV. This gives 5- (4-methoxyphenyl) -3- [4- (4-methylpiperazin-1-yl) phenyl]-1H,4H, 5H-pyrazolo [3,4-d]Pyrimidin-4-one (1.6mg, 2.33%). HPLC: 254nm, 99.9%; rt 1.049 min. LCMS (M + H)⁺＝337.0.0；¹H NMR(300MHz,DMSO-d6)δ8.24(s,1H),8.7(d,J＝8.7Hz,2H),7.41(d,J＝6.6Hz,2H),7.08(d J＝6.9Hz,2H),6.98(d,J＝9.0Hz,2H),3.83(s,3H),3.44-3.20(m,4H),2.51-2.44(m,4H),2.27(s,3H)。

Example B02: 3-fluoro-5- (3- (2-methoxyphenyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) -N, N-dimethyl-2- (4-methylpiperazin-1-yl) benzamide

Step 1: 5-bromo-3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridine

Reacting 5-bromo-3-iodo-1H-pyrrolo [2,3-b ]]Pyridine (4.8g,14.86mmol) was dissolved in DMF (50 mL). NaH (892mg, 22.30mmol) was added at 0 ℃ and stirred at 0 ℃ for 30 min. SEMCl (3.72g, 22.30mmol) was added dropwise and stirred at room temperature for 4 hours. Water (100mL) was added at 0 ℃ and extracted with ethyl acetate. The combined organic layers were washed with brine and over Na ₂SO₄And (5) drying. The product was received by column chromatography on silica gel (4.05g, 60%). LCMS (M + H)⁺＝453.0。

Step 2: 5-bromo-3- (2-methoxyphenyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridine

Reacting 5-bromo-3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b]Pyridine (4.05g, 8.94mmol), (2-methoxyphenyl) boronic acid (1.358g, 8.94mmol), Pd (dppf) Cl₂(327mg, 0.447mmol) and Na₂CO₃(3.32g, 31.3mmol) was dissolved in 1, 4-dioxane (40mL) and water (20mL) and in N₂Heat to 60 ℃ overnight. The product was received by chromatography on silica gel (3).27g，84％)。LCMS(M+H)⁺＝433.0。

And step 3: 3- (2-methoxyphenyl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridine

Reacting 5-bromo-3- (2-methoxyphenyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b]Pyridine (3.27g, 7.545mmol), 4,4,4 ', 4 ', 5,5,5 ', 5 ' -octamethyl-2, 2 ' -bis (1,3, 2-dioxaborolan) (3.83g, 15.1mmol), KOAc (2.22g, 22.6mmol) and Pd (dppf) Cl₂(276 mg, 0.377mmol) was dissolved in 1, 4-dioxane (60mL) and washed with N₂Heat to 90 ℃ overnight. The solvent was removed under vacuum and the product was received by column chromatography on silica gel (3.5g, 97%). LCMS (M + H) ⁺＝481.0。

And 4, step 4: 2, 3-difluoro-5-iodo-N, N-dimethylbenzamide

2, 3-difluoro-5-iodobenzoic acid (6.79g, 23.9mmol), HATU (10.9g, 28.7mmol), DIPEA (10.8g, 83.7mmol) and dimethylamine hydrochloride (2.92g, 35.85mmol) were dissolved in DMF (100mL) and stirred at room temperature overnight. Water (200mL) was added and extracted with DCM. The combined organic layers were washed with brine and over Na₂SO₄And (5) drying.

The product was received by column chromatography on silica gel (7.4g, 99%). LCMS (M + H)⁺＝312.0。

And 5: 3-fluoro-5-iodo-N, N-dimethyl-2- (4-methylpiperazin-1-yl) benzamide

2, 3-difluoro-5-iodo-N, N-dimethylbenzamide (7.4g, 23.9mmol) was dissolved in 1-methylpiperazine (25ml) and heated to 110 ℃ for 4 h. The 1-methylpiperazine was removed in vacuo. Water (50mL) was added and extracted with ethyl acetate. The combined organic layers were washed with brine and over Na₂SO₄And (5) drying. The product was received (9.31g, 100%). LCMS (M + H)⁺＝392.0。

Step 6: 3-fluoro-5- (3- (2-methoxyphenyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) -N, N-dimethyl-2- (4-methylpiperazin-1-yl) benzamide

Reacting 3- (2-methoxyphenyl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] ]Pyridine (1g, 2.08mmol), 3-fluoro-5-iodo-N, N-dimethyl-2- (4-methylpiperazin-1-yl) benzamide (0.977g, 2.50mmol), Na₂CO₃(441.2mg, 4.162mmol) and Pd (dppf) Cl₂(327mg, 0.447mmol) was dissolved in 1, 4-dioxane (15mL) and water (10mL) then N₂Heat to 85 ℃ overnight. The solvent was removed under vacuum and extracted with DCM. The combined organic layers were washed with brine and over Na₂SO₄And (5) drying. The product was received by column chromatography on silica gel (792mg, 62%). LCMS (M + H)⁺＝618.0。

And 7: 3-fluoro-5- (3- (2-methoxyphenyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) -N, N-dimethyl-2- (4-methylpiperazin-1-yl) benzamide

Reacting 3-fluoro-5- (3- (2-methoxyphenyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b)]Pyridin-5-yl) -N, N-dimethyl-2- (4-methylpiperazin-1-yl) benzamide (792mg, 1.28mmol) was dissolved in DCM (10 mL). TFA (10mL) was added and stirred at room temperature for 15 h. The solvent was removed under vacuum and water (10mL) was added. With Na₂CO₃The pH was adjusted to 8-9 (aq) and extracted with DCM. The combined organic layers were washed with brine and over Na₂SO₄And (5) drying. The product was received by column chromatography on silica gel (150mg, 24%). LCMS (M + H) ⁺＝488.0。¹H NMR(400MHz,DMSO-d6)δ11.93(s,1H),8.55(s,1H),8.19(s,1H),7.74(s,1H),7.62(t,J＝8.5Hz,2H),7.33(s,1H),7.29(d,J＝7.5Hz,1H),7.13(d,J＝8.2Hz,1H),7.06(t,J＝7.2Hz,1H),3.82(s,3H),3.14(s,2H),3.01(s,5H),2.82(s,3H),2.36(s,4H),2.20(s,3H)。

Example B03: n, N-dimethyl-4- [3- [4- (4-methylpiperazin-1-yl) phenyl ] -4-oxo-1H, 4H, 5H-pyrazolo [4,3-c ] pyridin-5-yl ] benzamide

Step 1: 4- (3-oxobutanamido) benzoic acid methyl ester

To a solution of methyl 4-aminobenzoate (5.70g, 37.71mmol) in toluene (24mL) was added 4-methyleneoxetan-2-one (3.42g, 40.72mmol) at room temperature. The resulting mixture was stirred at 65 ℃ for 3 h. When the reaction was complete, the solid precipitated out of the reaction mixture was collected by filtration, washed with toluene (6mLx3) and then dried under high vacuum to give methyl 4- (3-oxobutanamido) benzoate (5.91g, 67%) as an off-white solid. LCMS (M + H)⁺＝236.0。

Step 2: 4- [2- [ (dimethylamino) methylene ] -3-oxobutanamido ] benzoate

To a solution of methyl 4- (3-oxobutanamido) benzoate (5.91g, 25.14mmol) in DMF (10mL) at room temperature was added K₂CO₃(3.61g, 26.14mmol), DMF-DMA (6.27g, 52.29 mmol). The resulting mixture was stirred at 60 ℃ for 15 h. After completion of the reaction, the reaction mixture was filtered and the obtained solid was redissolved in DCM (500 mL). The resulting mixture was washed with brine (500mLx2) and over anhydrous Na ₂SO₄And (5) drying. The solvent was removed under reduced pressure and the residue was purified by flash chromatography, eluting with EtOAc in hexanes (gradient 0% to 100%) to give 4- [2- [ (dimethylamino) methylene group as a red solid]-3-oxobutanamido group]Benzoate (4.20g, 58%). LCMS (M + H)⁺＝291.0。

And step 3: 4- (4-chloro-3-formyl-2-oxo-1, 2-dihydropyridin-1-yl) benzoic acid methyl ester

At 0 deg.C, to 4- [2- [ (dimethylamino) methylene]-3-oxobutanamido group]Methyl benzoate (4.20g, 14.47mmol) in DMF (50mL) was added POCl dropwise at room temperature₃(7.98g, 51.79 mmol). The resulting mixture was stirred at 80 ℃ for an additional 0.5 h. When the reaction was complete, it was quenched with ice water (50mL) and the resulting mixture was adjusted to pH 8 with NaOH solution (2M). The precipitated solid was removed by filtration and washed with water (50mLx 2). The filtrate was concentrated and the residue was purified by flash chromatography with DCM in hexane (0% to 2)Gradient of 0%) to yield methyl 4- (4-chloro-3-formyl-2-oxo-1, 2-dihydropyridin-1-yl) benzoate (2.98g, 70%) as a pale yellow solid. LCMS (M + H)⁺＝291.9。

And 4, step 4: 4- [ 4-chloro-3- [ (hydroxyimino) methyl ] -2-oxo-1, 2-dihydropyridin-1-yl ] benzoic acid methyl ester

To a solution of methyl 4- (4-chloro-3-formyl-2-oxo-1, 2-dihydropyridin-1-yl) benzoate (1.96g, 6.70mmol) in EtOH (40mL) at room temperature was added NH₂OH.HCl (760mg, 10.94mmol) and NaOAc (1.90g, 23.16 mmol). The resulting mixture was stirred at 70 ℃ for 2 h. When the reaction was complete, the solid precipitated from the reaction mixture was collected by filtration, washed with ethanol (15mLx2) and then dried under high vacuum to give 4- [ 4-chloro-3- [ (hydroxyimino) methyl group as a yellow solid]-2-oxo-1, 2-dihydropyridin-1-yl]Methyl benzoate (1.64g, 80%). LCMS (M + H)⁺＝306.9。

And 5: 4- [ 4-chloro-3- [ (1E) - (hydroxyimino) methyl ] -2-oxo-1, 2-dihydropyridin-1-yl ] benzoic acid methyl ester

At 0 deg.C, at room temperature to 4- [ 4-chloro-3- [ (hydroxyimino) methyl group]-2-oxo-1, 2-dihydropyridin-1-yl]Methyl benzoate (1.64g, 5.34mmol) in acetonitrile was added dropwise POCl₃(1.71g, 11.15 mmol). The resulting mixture was stirred at 90 ℃ for 2 h. When the reaction was complete, the precipitated solid was collected by filtration, rinsed with acetonitrile (8mL x3) and then dried under high vacuum to give methyl 4- (4-chloro-3-cyano-2-oxo-1, 2-dihydropyridin-1-yl) benzoate (0.95g, 62%) as a yellow solid. LCMS (M + H) ⁺＝289.0。

Step 6: 4- [ 3-amino-4-oxo-1H, 4H, 5H-pyrazolo [4,3-c ] pyridin-5-yl ] benzoic acid methyl ester

To a solution of methyl 4- (4-chloro-3-cyano-2-oxo-1, 2-dihydropyridin-1-yl) benzoate (850mg, 2.944mmol) in EtOH (20mL) at room temperature was added NH₂NH₂.H₂O (440mg, 8.789 mmol). The resulting mixture was stirred at 90 ℃ for 15 h. The mixture was allowed to cool to room temperature. The precipitated solid was collected by filtration and washed with ethanol (3 × 3mL)And then dried under high vacuum to give 4- [ 3-amino-4-oxo-1H, 4H, 5H-pyrazolo [4,3-c ] as a yellow solid]Pyridin-5-yl]Methyl benzoate (755mg, 90%). LCMS (M + H)⁺＝285.1。

And 7: 4- [ 3-iodo-4-oxo-1H, 4H, 5H-pyrazolo [4,3-c ] pyridin-5-yl ] benzoic acid methyl ester

4- [ 3-amino-4-oxo-1H, 4H, 5H-pyrazolo [4,3-c ] over a period of 30min at 0 DEG C]Pyridin-5-yl]Methyl benzoate (695mg, 2.435mmol) in H₂SO₄(30mL) to the solution NaNO was added dropwise₂(1.14g, 16.523mmol) in H₂Solution in O (30 mL). The resulting mixture was stirred for 3H and then added dropwise to KI (4.75g, 28.614mmol) and CuI (565mg, 2.968mmol) in H at 0 ℃ over a period of 15min₂O (10 mL). The reaction mixture was then stirred at 55 ℃ for 2 h. The mixture was allowed to cool to room temperature and saturated Na ₂CO₃The solution adjusted its pH to about 8. The resulting mixture was extracted with ethyl acetate (350mLx 3). The organic phases were combined, washed with brine and over Na₂SO₄And (5) drying. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC under the following conditions: column: XBridge prep C18 OBD column, 150x19mm, 5 um; mobile phase: acetonitrile in water (containing 10mmol/L NH)₄HCO₃) Gradient 25% to 42% over 7 min; a detector: UV 254 nm. 4- [ 3-iodo-4-oxo-1H, 4H, 5H-pyrazolo [4,3-c ] is obtained as a white solid]Pyridin-5-yl]Methyl benzoate (123mg, 13%). LCMS (M + H)⁺＝396.1。

And 8: 4- [3- [4- (4-methylpiperazin-1-yl) phenyl ] -4-oxo-1H, 4H, 5H-pyrazolo [4,3-c ] pyridin-5-yl ] benzoic acid methyl ester

4- [ 3-iodo-4-oxo-1H, 4H, 5H-pyrazolo [4,3-c ] in a 50mL microwave tube under a nitrogen atmosphere]Pyridin-5-yl]To a solution of methyl benzoate (123mg, 0.313mmol) in i-PrOH (10mL) was added 1-methyl-4- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Piperazine (105mg, 0.346mmol), K₃PO₄(81mg, 0.380mmol) in H₂A solution in O (2mL), and Pd amps hos (30mg,0.043 mmol). The reaction mixture was irradiated with microwaves at 80 ℃ for 3h under a nitrogen atmosphere. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography, eluting with MeOH in EtOAc (gradient 0% to 50%) to give 4- [3- [4- (4-methylpiperazin-1-yl) phenyl as a pale yellow solid ]-4-oxo-1H, 4H, 5H-pyrazolo [4,3-c]Pyridin-5-yl]Methyl benzoate (28mg, 20%). LCMS (M + H)⁺＝444.3。

And step 9: n, N-dimethyl-4- [3- [4- (4-methylpiperazin-1-yl) phenyl ] -4-oxo-1H, 4H, 5H-pyrazolo [4,3-c ] pyridin-5-yl ] benzamide

4- [3- [4- (4-methylpiperazin-1-yl) phenyl ] in a 25mL microwave tube]-4-oxo-1H, 4H, 5H-pyrazolo [4,3-c]Pyridin-5-yl]To a solution of methyl benzoate (23mg, 0.052mmol) in THF (4mL) were added dimethylamine hydrogen chloride (48mg, 0.583mmol) and AlMe₃Solution (2M in toluene, 0.15mL, 0.3 mmol). The reaction mixture was irradiated with microwaves at 140 ℃ for 30min under a nitrogen atmosphere. 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, 150x30mm, 5 um; mobile phase: acetonitrile in water (containing 10mmol/L NH)₄HCO₃) Gradient from 10% to 50% over 7 min; a detector: UV 254 nm. N, N-dimethyl-4- [3- [4- (4-methylpiperazin-1-yl) phenyl ] as a white solid]-4-oxo-1H, 4H, 5H-pyrazolo [4,3-c]Pyridin-5-yl]Benzamide (7mg, 30%).¹H NMR(400MHz,DMSO-d6)δ13.51-13.48(m,1H),8.12(d,J＝8.4Hz,2H),7.57-7.44(m,5H),7.01-6.91(m,2H),6.61(d,J＝7.4Hz,1H),3.25-3.15(m,4H),3.05-2.95(m,6H),2.50-2.40(m,4H),2.23(s,3H)。LC-MS(M+H)⁺＝457.2。

Biological assay

HPK1 kinase binding assay

The compounds disclosed herein were tested for inhibition of HPK1 kinase (aa1-346, Life Technologies) in a combined assay based on a time-resolved fluorescence resonance energy transfer method. Recombinant HPK1(5nM) was combined with a compound disclosed herein or DMSO at room temperature in a medium containing 50mM HEPES pH 7.5, 10mM MgCl ₂1mM EGTA, 0.01% Brij-35 for 1 hour. And then Tracer222(Life Technologies) and Eu-Anti-GST antibody (cisbio) were added to the plate and further incubated at room temperature for 1 h. TR-FRET signals (ex337nm, em 620nm/665nm) were read on a BMG PHERAStar FS instrument. Inhibition of HPK1 in the presence of increasing concentrations of compound was calculated based on the ratio of fluorescence at 665nm to fluorescence at 620 nm. IC for each compound was derived by fitting the data to a four parameter logistic equation using Graphpad Prism software₅₀. The compounds disclosed herein showed enzyme binding values as shown in table 1.

Measurement of HPK kinase Activity at 1mM ATP

The compounds disclosed herein were tested for inhibition of HPK1 kinase (aa1-346, Life Technologies) activity in assays based on the time-resolved fluorescence resonance energy transfer (TR-FRET) method. In 384 well low volume black plates containing 50mM HEPES, 0.01% BSA, 0.1mM orthovanadate, 10mM MgCl₂Assay was performed in a reaction mixture containing HPK1 kinase (40nM), 1mM ATP, 0.5 μ M STK1 substrate and 0-10 μ M compound in a buffer of 1mM DTT, pH 7.0, 0.005% Tween-20. The kinase was incubated with the compound disclosed herein or DMSO for 60 minutes at room temperature and the reaction was initiated by the addition of ATP and STK1 substrate. After 120 minutes of reaction at room temperature, an equal volume of stop/detection solution was added according to the manufacturer's instructions (CisBio). The stop/detection solution contained STK antibody-Cryptate (Cryptate) and XL 665-conjugated streptavidin in detection buffer. The TR-FRET signal (ratio of fluorescence emission at 665nm to emission at 620nm with excitation at 337nm wavelength) was recorded on a PHERAStar FS plate reader (BMG Labtech). Phosphorylation of the STK1 substrate results in binding of STK antibody-cryptate to biotinylated STK1 substrate, which will be the fluorescence donor (Eu) ³⁺Cryptate) is placed in close proximity to the receptor (streptavidin-XL 665), resulting in a high degree of fluorescence resonance energy transfer. Inhibition of HPK1 in the presence of increasing concentrations of compound was calculated based on the ratio of fluorescence at 665nm to fluorescence at 620 nm. Data were fitted to four by Graphpad Prism softwareObtaining IC of each compound by parameter logistic equation₅₀. The compounds disclosed herein showed enzymatic activity values as shown in table 1.

TABLE 1 enzyme binding IC of Compounds disclosed herein₅₀(nM) or enzyme Activity IC₅₀(nM)

Indicates no data is available.

It will be understood that, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms part of the common general knowledge in the art in any country.

The disclosures of all publications, patents, patent applications, and published patent applications referred to herein by an identifying citation are hereby incorporated by reference in their entirety.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be apparent to those skilled in the art that certain minor changes and modifications may be practiced. Therefore, the description and examples should not be construed as limiting the scope of the invention.

Claims (188)

1. A compound of formula (AIII):

or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

wherein

X¹Is C or N;

R¹is hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^1a、-SO₂R^1a、-COR^1a、-CO₂R^1a、-CONR^1aR^1b、-C(＝NR^1a)NR^1bR^1c、-NR^1aR^1b、-NR^1aCOR^1b、-NR^1aCONR^1bR^1c、-NR^1aCO₂R^1b、-NR^1aSONR^1bR^1c、-NR^1aSO₂NR^1bR^1cor-NR^1aSO₂R^1bsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally substituted with halogen, hydroxy, -C_1-8Alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; provided that X is¹In the case of N, R is absent¹；

R^1a、R^1bAnd R^1cEach independently is hydrogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^1dSubstitution; or

(R^1aAnd R^1b)、(R^1bAnd R^1c) Or (R)^1cAnd R^1a) Together with the atom or atoms to which they are attached form a 3 to 9 membered ring containing 0, 1 or 2 further heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulphur as one or more ring members, said ring being optionally substituted with at least one substituent R^1eSubstitution;

wherein R is^1dAnd R ^1eEach independently is hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^1f、-SO₂R^1f、-COR^1f、-CO₂R^1f、-CONR^1fR^1g、-C(＝NR^1f)NR^1gR^1h、-NR^1fR^1g、-NR^1fCOR^1g、-NR^1fCONR^1gR^1h、-NR^1fCO₂R^1g、-NR^1fSONR^1gR^1h、-NR^1fSO₂NR^1gR^1hor-NR^1fSO₂R^1gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR¹ⁱ、-NR¹ⁱR^1jCycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^1f、R^1g、R^1h、R¹ⁱand R^1jEach independently is hydrogen, -C_1-8Alkyl radical, C_1-8alkoxy-C_1-8Alkyl-, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, arylOr heteroaryl;

R²and R³Each independently is hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^2a、-SO₂R^2a、-COR^2a、-CO₂R^2a、-CONR^2aR^2b、-C(＝NR^2a)NR^2bR^2c、-NR^2aR^2b、-NR^2aCOR^2b、-NR^2aCONR^2bR^2c、-NR^2aCO₂R^2b、-NR^2aSONR^2bR^2c、-NR^2aSO₂NR^2bR^2cor-NR^2aSO₂R^2bsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally substituted with halogen, hydroxy, -C_1-8Alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^2a、R^2band R^2cEach independently is hydrogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

L¹is a single bond, alkylene, cycloalkylene¹-O-alkylene-a ¹、*¹-alkylene-O-)¹、*¹-NH-alkylene-a¹、*¹-alkylene-NH-x¹、*¹-NHC(O)-**¹、*¹-C(O)NH-**¹Alkenylene, or alkynylene;

wherein¹Refers to the position of attachment with Cy1, and¹refers to a position of attachment to the backbone;

L²is a single bond, alkylene, cycloalkylene²-O-alkylene-a²、*²-alkylene-O-)²、*²-NH-alkylene-a²、*²-alkylene-NH-x²、*²-NHC(O)-**²、*²-C(O)NH-**²Alkenylene, or alkynylene;

wherein²Refers to a position attached to a phenyl group, and²refers to a position of attachment to the backbone; cy1 is cycloalkyl, phenyl, 5-or 6-membered heterocyclyl, 5-or 6-membered heteroaryl, or 7-to 12-membered bicyclic fused heteroaryl or heterocyclyl, each of which is substituted with one R⁴Substituted and optionally substituted by R⁵Substitution;

n is 0, 1 or 2;

R⁴and R⁵At each occurrence thereof, is independently halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^4a、-SO₂R^4a、-SO₂NR^4aR^4b、-COR^4a、-CO₂R^4a、-CONR^4aR^4b、-C(＝NR^4a)NR^4bR^4c、-NR^4aR^4b、-NR^4aCOR^4b、-NR^4aCONR^4bR^4c、-NR^4aCO₂R^4b、-NR^4aSONR^4bR^4c、-NR^4aSO₂NR^4bR^4cor-NR^4aSO₂R^4bsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^4dSubstitution;

R^4a、R^4band R^4cEach independently is hydrogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said-C_1-8Alkyl, -C_2-8Alkenyl, -C _2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^4eSubstitution; or

(R^4aAnd R^4b)、(R^4bAnd R^4c) Or (R)^4cAnd R^4a) Together with the atom or atoms to which they are attached form a 3 to 12 membered ring containing 0, 1 or 2 further heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulphur as one or more ring members, said ring being optionally substituted with at least one substituent R^4eSubstitution;

R^4dand R^4eEach independently is hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^4f、-SO₂R^4f、-SO₂NR^4fR^4g、-COR^4f、-CO₂R^4f、-CONR^4fR^4g、-C(＝NR^4f)NR^4gR^4h、-NR^4fR^4g、-NR^4fCOR^4g、-NR^4fCONR^4gR^4h、-NR^4fCO₂R^4f、-NR^4fSONR^4fR^4g、-NR^4fSO₂NR^4gR^4hor-NR^4fSO₂R^4gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁴ⁱ、-NR⁴ⁱR^4jCycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^4f、R^4g、R^4h、R⁴ⁱand R^4jEach independently is hydrogen, -C_1-8Alkyl radical, C_1-8alkoxy-C_1-8Alkyl-, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R⁶is halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^6a、-SO₂R^6a、-SO₂NR^6aR^6b、-COR^6a、-CO₂R^6a、-CONR^6aR^6b、-C(＝NR^6a)NR^6bR^6c、-NR^6aR^6b、-NR^6aCOR^6b、-NR^6aCONR^6bR^6c、-NR^6aCO₂R^6b、-NR^6aSONR^6bR^6c、-NR^6aSO₂NR^6bR^6cor-NR ^6aSO₂R^6bsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^6dSubstitution;

R^6a、R^6band R^6cEach independently is hydrogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, alkyl, heterocyclyl, aryl, or heteroaryl, said-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^6eSubstitution;

R^6dand R^6eEach independently is hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^6f、-SO₂R^6f、-SO₂NR^6fR^6g、-COR^6f、-CO₂R^6f、-CONR^6fR^6g、-C(＝NR^6f)NR^6gR^6h、-NR^6fR^6g、-NR^6fCOR^6g、-NR^6fCONR^6gR^6h、-NR^6fCO₂R^6f、-NR^6fSONR^6fR^6g、-NR^6fSO₂NR^6gR^6hor-NR^6fSO₂R^6gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁶ⁱ、-NR⁶ⁱR^6jCycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^6f、R^6g、R^6h、R⁶ⁱand R^6jEach independently is hydrogen, -C_1-8Alkyl radical, C_1-8alkoxy-C_1-8Alkyl-, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

m is 0, 1, 2, 3 or 4, provided that valency theory is satisfied;

L³is a single bond or C_1-8An alkylene group;

X²and X³Each independently is CH or N, provided that X ²And X³Are not all CH;

t is 0, 1, 2, or 3;

s is 0, 1, 2, or 3;

R⁷and R⁸Each independently is halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^7a、-SO₂R^7a、-SO₂NR^7aR^7b、-COR^7a、-CO₂R^7a、-CONR^7aR^7b、-C(＝NR^7a)NR^7bR^7c、-NR^7aR^7b、-NR^7aCOR^7b、-NR^7aCONR^7bR^7c、-NR^7aCO₂R^7b、-NR^7aSONR^7bR^7c、-NR^7aSO₂NR^7bR^7cor-NR^7aSO₂R^7bsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^7dSubstitution;

R^7a、R^7band R^7cEach independently is hydrogen, -C_1-8Alkyl, -C_2-8An alkenyl group,-C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^7eSubstitution;

R^7dand R^7eEach independently is hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^7f、-SO₂R^7f、-SO₂NR^7fR^7g、-COR^7f、-CO₂R^7f、-CONR^7fR^7g、-C(＝NR^7f)NR^7gR^7h、-NR^7fR^7g、-NR^7fCOR^7g、-NR^7fCONR^7gR^7h、-NR^7fCO₂R^7f、-NR^7fSONR^7fR^7g、-NR^7fSO₂NR^7gR^7hor-NR^7fSO₂R^7gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁷ⁱ、-NR⁷ⁱR^7jCycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^7f、R^7g、R^7h、R⁷ⁱand R^7jEach independently is hydrogen, -C_1-8Alkyl radical, C_1-8alkoxy-C _1-8Alkyl-, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

p is 0, 1, 2 or 3, provided that the valence theory is satisfied, and

with the proviso that the compound is not 5- (4- (4-hydroxymethylpiperidin-1-ylmethyl) -3-hydroxyphenyl) -3- (2-methoxyphenyl) -1H-pyrrolo [2,3-b ] pyridine; 5- (4- (4-methyl-1, 4-diazepan-1-ylmethyl) -3-hydroxyphenyl) -3- (2-methoxyphenyl) -1H-pyrrolo [2,3-b ] pyridine; 5- (4- (4-hydroxypiperidin-1-yl) -3-fluoro-5-dimethylcarbamoylphenyl) -3- (2-methoxyphenyl) -1H-pyrrolo [2,3-b ] pyridine; or 5- (4- (4-methylpiperazin-1-yl) -3-fluoro-5-dimethylcarbamoylphenyl) -3- (2-methoxyphenyl) -1H-pyrrolo [2,3-b ] pyridine.

2. A compound according to claim 1, which is a compound of formula (III)

Or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

wherein

X¹Is C or N;

R¹is hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^1a、-SO₂R^1a、-COR^1a、-CO₂R^1a、-CONR^1aR^1b、-C(＝NR^1a)NR^1bR^1c、-NR^1aR^1b、-NR^1aCOR^1b、-NR^1aCONR^1bR^1c、-NR^1aCO₂R^1b、-NR^1aSONR^1bR^1c、-NR^1aSO₂NR^1bR^1cor-NR^1aSO₂R^1bsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally substituted with halogen, hydroxy, -C _1-8Alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; provided that X is¹In the case of N, R is absent¹；

R^1a、R^1bAnd R^1cEach independently is hydrogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^1dSubstitution; or

(R^1aAnd R^1b)、(R^1bAnd R^1c) Or (R)^1cAnd R^1a) Together with the atom or atoms to which they are attached form a 3 to 9 membered ring containing 0, 1 or 2 further heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulphur as one or more ring members, said ring being optionally substituted with at least one substituent R^1eSubstitution;

wherein R is^1dAnd R^1eEach independently is hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^1f、-SO₂R^1f、-COR^1f、-CO₂R^1f、-CONR^1fR^1g、-C(＝NR^1f)NR^1gR^1h、-NR^1fR^1g、-NR^1fCOR^1g、-NR^1fCONR^1gR^1h、-NR^1fCO₂R^1g、-NR^1fSONR^1gR^1h、-NR^1fSO₂NR^1gR^1hor-NR^1fSO₂R^1gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR¹ⁱ、-NR¹ⁱR^1jCycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^1f、R^1g、R^1h、R¹ⁱand R ^1jEach independently is hydrogen, -C_1-8Alkyl radical, C_1-8alkoxy-C_1-8Alkyl-, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroAn aryl group;

R²and R³Each independently is hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^2a、-SO₂R^2a、-COR^2a、-CO₂R^2a、-CONR^2aR^2b、-C(＝NR^2a)NR^2bR^2c、-NR^2aR^2b、-NR^2aCOR^2b、-NR^2aCONR^2bR^2c、-NR^2aCO₂R^2b、-NR^2aSONR^2bR^2c、-NR^2aSO₂NR^2bR^2cor-NR^2aSO₂R^2bsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally substituted with halogen, hydroxy, -C_1-8Alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^2a、R^2band R^2cEach independently is hydrogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

L¹is a single bond, alkylene, cycloalkylene¹-O-alkylene-a¹、*¹-alkylene-O-)¹、*¹-NH-alkylene-a¹、*¹-alkylene-NH-x¹、*¹-NHC(O)-**¹、*¹-C(O)NH-**¹Alkenylene, or alkynylene;

wherein¹Refers to the position of attachment with Cy1, and¹refers to a position of attachment to the backbone;

L²is a single bond, alkylene, cycloalkylene²-O-alkylene-a²、*²-alkylene-O-)²、*²-NH-alkylene-a²、*²-alkylene-NH-x²、*²-NHC(O)-**²、*²-C(O)NH-**²Alkenylene, or alkynylene;

wherein²Refers to a position attached to a phenyl group, and²refers to a position of attachment to the backbone; cy1 is cycloalkyl, phenyl, 5-or 6-membered heterocyclyl, 5-or 6-membered heteroaryl, or 7-to 12-membered bicyclic fused heteroaryl or heterocyclyl, each of which is substituted with one R ⁴Substituted and optionally substituted by R⁵Substitution;

n is 0, 1 or 2;

R⁴and R⁵At each occurrence thereof, is independently halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^4a、-SO₂R^4a、-SO₂NR^4aR^4b、-COR^4a、-CO₂R^4a、-CONR^4aR^4b、-C(＝NR^4a)NR^4bR^4c、-NR^4aR^4b、-NR^4aCOR^4b、-NR^4aCONR^4bR^4c、-NR^4aCO₂R^4b、-NR^4aSONR^4bR^4c、-NR^4aSO₂NR^4bR^4cor-NR^4aSO₂R^4bsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^4dSubstitution;

R^4a、R^4band R^4cEach independently is hydrogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^4eSubstitution; or

(R^4aAnd R^4b)、(R^4bAnd R^4c) Or (R)^4cAnd R^4a) With itOne or more of the atoms to which they are attached together form a 3 to 12 membered ring containing 0, 1 or 2 further heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulphur as one or more ring members, optionally substituted with at least one substituent R^4eSubstitution;

R^4dand R^4eEach independently is hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO ₂、-OR^4f、-SO₂R^4f、-SO₂NR^4fR^4g、-COR^4f、-CO₂R^4f、-CONR^4fR^4g、-C(＝NR^4f)NR^4gR^4h、-NR^4fR^4g、-NR^4fCOR^4g、-NR^4fCONR^4gR^4h、-NR^4fCO₂R^4f、-NR^4fSONR^4fR^4g、-NR^4fSO₂NR^4gR^4hor-NR^4fSO₂R^4gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁴ⁱ、-NR⁴ⁱR^4jCycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^4f、R^4g、R^4h、R⁴ⁱand R^4jEach independently is hydrogen, -C_1-8Alkyl radical, C_1-8alkoxy-C_1-8Alkyl-, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R⁶is halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^6a、-SO₂R^6a、-SO₂NR^6aR^6b、-COR^6a、-CO₂R^6a、-CONR^6aR^6b、-C(＝NR^6a)NR^6bR^6c、-NR^6aR^6b、-NR^6aCOR^6b、-NR^6aCONR^6bR^6c、-NR^6aCO₂R^6b、-NR^6aSONR^6bR^6c、-NR^6aSO₂NR^6bR^6cor-NR^6aSO₂R^6bsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^6dSubstitution;

R^6a、R^6band R^6cEach independently is hydrogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^6eSubstitution;

R^6dand R^6eEach independently is hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO ₂、-OR^6f、-SO₂R^6f、-SO₂NR^6fR^6g、-COR^6f、-CO₂R^6f、-CONR^6fR^6g、-C(＝NR^6f)NR^6gR^6h、-NR^6fR^6g、-NR^6fCOR^6g、-NR^6fCONR^6gR^6h、-NR^6fCO₂R^6f、-NR^6fSONR^6fR^6g、-NR^6fSO₂NR^6gR^6hor-NR^6fSO₂R^6gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁶ⁱ、-NR⁶ⁱR^6jCycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^6f、R^6g、R^6h、R⁶ⁱand R^6jEach independently is hydrogen, -C_1-8Alkyl radical, C_1-8alkoxy-C_1-8Alkyl-, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

m is 0, 1, 2, 3 or 4, provided that valency theory is satisfied;

L³is a single bond or C_1-8An alkylene group;

X²and X³Each independently is CH or N, provided that X²And X³Are not all CH;

t is 0, 1, 2, or 3;

R⁷and R⁸Each independently is halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^7a、-SO₂R^7a、-SO₂NR^7aR^7b、-COR^7a、-CO₂R^7a、-CONR^7aR^7b、-C(＝NR^7a)NR^7bR^7c、-NR^7aR^7b、-NR^7aCOR^7b、-NR^7aCONR^7bR^7c、-NR^7aCO₂R^7b、-NR^7aSONR^7bR^7c、-NR^7aSO₂NR^7bR^7cor-NR^7aSO₂R^7bsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^7dSubstitution;

R^7a、R^7band R^7cEach independently is hydrogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroAryl of the formula_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R ^7eSubstitution;

R^7dand R^7eEach independently is hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^7f、-SO₂R^7f、-SO₂NR^7fR^7g、-COR^7f、-CO₂R^7f、-CONR^7fR^7g、-C(＝NR^7f)NR^7gR^7h、-NR^7fR^7g、-NR^7fCOR^7g、-NR^7fCONR^7gR^7h、-NR^7fCO₂R^7f、-NR^7fSONR^7fR^7g、-NR^7fSO₂NR^7gR^7hor-NR^7fSO₂R^7gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁷ⁱ、-NR⁷ⁱR^7jCycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^7f、R^7g、R^7h、R⁷ⁱand R^7jEach independently is hydrogen, -C_1-8Alkyl radical, C_1-8alkoxy-C_1-8Alkyl-, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

p is 0, 1, 2 or 3, provided that the valence theory is satisfied, and

with the proviso that the compound is not 5- (4- (4-hydroxymethylpiperidin-1-ylmethyl) -3-hydroxyphenyl) -3- (2-methoxyphenyl) -1H-pyrrolo [2,3-b ] pyridine; 5- (4- (4-methyl-1, 4-diazepan-1-ylmethyl) -3-hydroxyphenyl) -3- (2-methoxyphenyl) -1H-pyrrolo [2,3-b ] pyridine; 5- (4- (4-hydroxypiperidin-1-yl) -3-fluoro-5-dimethylcarbamoylphenyl) -3- (2-methoxyphenyl) -1H-pyrrolo [2,3-b ] pyridine; or 5- (4- (4-methylpiperazin-1-yl) -3-fluoro-5-dimethylcarbamoylphenyl) -3- (2-methoxyphenyl) -1H-pyrrolo [2,3-b ] pyridine.

3. A compound according to claim 1 or 2, wherein R²And R³Each independently is hydrogen, halogen or cyano.

4. A compound according to claim 1 or 2, wherein R²And R³Each is hydrogen.

5. The compound according to any one of claims 1-4, wherein L¹Is a single bond, alkylene¹-O-alkylene-a¹、*¹-NH-alkylene-a¹、*¹-NHC(O)-**¹Or¹-C(O)NH-**¹(ii) a And L is²Is a single bond, alkylene, alkenylene, or alkynylene.

6. A compound according to claim 5, wherein L¹Is a single bond, -CH₂-、-(CH₂)₂-、-CH(CH₃)-、-C≡C-、*¹-O-CH(CH₃)-**¹、*¹-O-CH₂-**¹、*¹-NH-CH₂-**¹、*¹-NH-CH(CH₃)-**¹Or¹-NHC(O)-**¹And L is²Is a single bond, -C ≡ C-, or-CH ═ CH-.

7. A compound according to claim 5, wherein L¹And L²Each is a single bond.

8. A compound according to any one of claims 1 to 7, wherein R¹Is hydrogen, -OR^1aor-NR^1aR^1bWherein R is^1aAnd R^1bAs defined for formula (III).

9. A compound according to claim 8, wherein R¹Is hydrogen.

10. A compound according to claim 8, wherein R¹is-OR^1aWherein R is^1aIs hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl.

11. A compound according to claim 8, wherein R¹is-NR^1aR^1bWherein R is^1aAnd R^1bEach independently is hydrogen or-C_1-8Alkyl radical of formula (I), said_1-8Alkyl optionally substituted by at least one substituent R^1dAnd (4) substitution.

12. A compound according to claim 11, wherein R ^1dIs heterocyclyl, aryl, or-NR^1fR^1gWherein said heterocyclyl or aryl is optionally substituted with halogen, -C_1-8Alkyl, -OR¹ⁱor-NR¹ⁱR^1jIs substituted in which R^1f、R^1g、R¹ⁱAnd R^1jEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl.

13. A compound according to claim 12, wherein said aryl is phenyl.

14. A compound according to claim 12, wherein said heterocyclyl is a 4-, 5-, 6-or 7-membered ring comprising as ring members a heteroatom selected from nitrogen, oxygen or optionally oxidised sulfur, preferably tetrahydropyranyl or piperidinyl.

15. A compound according to claim 8, wherein R¹is-NR^1aR^1bWherein R is^1aAnd R^1bTogether with the heteroatom to which they are attached form a 3-to 6-membered ring, said ring containing as further heteroatoms 0, 1 or 2 independently selected from nitrogen, oxygen or optionally oxidized sulfurOne or more ring members, said ring being optionally substituted with at least one substituent R^1eIs substituted in which R^1eAs defined for formula (III).

16. A compound according to claim 15, wherein R¹is-NR^1aR^1bWherein R is^1aAnd R^1bTogether with the heteroatom to which they are attached form a 4-, 5-or 6-membered ring, which ring comprises 0 or 1 further heteroatom independently selected from nitrogen, oxygen or optionally oxidised sulphur as one or more ring members, which ring is optionally substituted with at least one substituent R ^1eAnd (4) substitution.

17. A compound according to claim 15 or 16, wherein R^1eis-OR^1f、-CONR^1fR^1gor-NR^1fR^1gWherein R is^1fAnd R^1gEach independently is hydrogen, or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl.

18. A compound according to any one of claims 1-17, wherein Cy1 is a 5 or 6 membered heterocyclyl containing one or two heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as one or more ring members, said heterocyclyl being substituted with one R⁴Substituted and optionally substituted by R⁵Substituted, and R is in case the heterocycle is 6-membered⁴Relative to the attachment point L¹Para (or 4) to the heterocyclic group, or Cy1 is a 7-to 10-membered bicyclic fused heterocyclic group containing one, two or three heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, optionally substituted with R⁵Is substituted in which R⁵Is halogen, -C_1-8Alkyl, oxo, or aryl.

19. The compound according to claim 18, wherein said 6-membered heterocyclyl is piperidinyl, tetrahydropyridinyl, or piperazinyl or said 7 to 10-membered bicyclic fused heterocyclyl is dihydropyridinooxazine (preferably 2, 3-dihydro-1H-pyrido [2,3-b ] [1,4] oxazine), dihydrobenzoxazepinyl (preferably 5-oxo-3, 4-dihydrobenzo [ f ] [1,4] oxoazepinyl), isoindolinyl (preferably 1-oxo-2-methylisoindoline-5-yl), dihydroisoquinolinyl (preferably 1-oxo-2-methyl-3, 4-dihydroisoquinolin-6-yl), tetrahydroisoquinolinyl (preferably 2-methyl-1-oxo-1, 2,3, 4-tetrahydroisoquinolin-6-yl), benzoazepine (preferably 2,3,4, 5-tetrahydro-1-oxo-2-benzazepin-6-yl), benzoxaazepine (preferably 5-oxo-2, 3,4, 5-tetrahydro-1, 4-benzoxazin-8-yl), dihydrobenzoxazine (preferably 3, 4-dihydro-2H-1, 4-benzoxazin-6-yl).

20. The compound according to claim 19, wherein said 6-membered heterocyclyl is

And n is 0, 1 or 2.

21. The compound according to any one of claims 1-17, wherein Cy1 is a 5 or 6 membered heteroaryl group comprising one or two heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as one or more ring members, said heteroaryl group being substituted with one R⁴Substituted and optionally substituted by R⁵Substituted, and R is in the case that the heteroaryl is 6-membered⁴Relative to the attachment point L¹At the para (or 4) position of the heteroaryl group.

22. The compound according to claim 21, wherein the 5 or 6 membered heteroaryl is pyrazolyl, oxazolyl, pyridinyl, or pyrimidinyl.

23. The compound according to claim 22, wherein said 5-membered heteroaryl is

Or said 6-membered heteroaryl is

And n is 0, 1 or 2.

24. The compound according to any one of claims 1-17, wherein Cy1 is in a relative relationship to L¹By an R in position 4 of the attached position⁴Is substituted and substituted by R⁵Substituted phenyl, and n is 0, 1 or 2.

25. The compound according to any one of claims 18-24, wherein Cy1 is substituted by one R in the 4-position where Cy1 is 6-membered⁴Substituted and n is 0.

26. The compound according to any one of claims 18-25, wherein Cy1 is substituted by one R in the 4-position where Cy1 is 6-membered ⁴Is substituted and substituted by R⁵And n is 1; and said R is⁵Is halogen or-C_1-8An alkyl group.

27. A compound according to claim 25 or 26, wherein R⁴Is a halogen.

28. The compound according to any one of claims 18-25, wherein R⁴is-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^4dAnd (4) substitution.

29. The method of claim 28Compound (I) wherein R^4dIs hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^4f、-SO₂R^4f、-SO₂NR^4fR^4g、-COR^4f、-CO₂R^4f、-CONR^4fR^4g、-C(＝NR^4f)NR^4gR^4h、-NR^4fR^4g、-NR^4fCOR^4g、-NR^4fCONR^4gR^4h、-NR^4fCO₂R^4f、-NR^4fSONR^4fR^4g、-NR^4fSO₂NR^4gR^4hor-NR^4fSO₂R^4gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁴ⁱor-NR⁴ⁱR^4jWherein R is^4f、R^4g、R^4h、R⁴ⁱAnd R^4jEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

30. A compound according to claim 28 or 29, wherein R⁴Is optionally substituted by cycloalkyl, aryl, heterocyclyl, -OR^4f、-CONR^4fR^4g、-NR^4fR^4gor-NR^4fSO₂R^4gsubstituted-C_1-8Alkyl, preferably-C _1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl, wherein said cycloalkyl, aryl or heterocyclyl is optionally substituted by halogen, -C_1-8Alkyl, OR-OR⁴ⁱIs substituted in which R^4f、R^4gAnd R⁴ⁱEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

31. A compound according to claim 30, wherein said heterocyclyl is optionally substituted by-C_1-8Alkyl or-C_1-8Alkoxy-substituted 4 to 7 membered rings comprising one or two heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulfur, preferably 4, 5, 6 or 7 membered saturated rings comprising one nitrogen or oxygen atom as a ring member.

32. The compound according to claim 30, wherein R⁴Is a methyl group, an ethyl group,

33. A compound according to claim 28 or 29, wherein R⁴Is optionally halogen, -C_1-8Alkyl, -OR^4for-NR^4fR^4gSubstituted aryl radicals, in which R is^4fAnd R^4gEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

34. The compound according to claim 33, wherein said aryl is phenyl.

35. A compound according to claim 33, wherein R⁴Is that

36. A compound according to claim 28 or 29, wherein R⁴Is optionally substituted by halogen, oxo, -C _1-8Alkyl, -OR^4for-NR^4fR^4gSubstituted heteroaryl, wherein R^4fAnd R^4gEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

37. The compound according to claim 36, wherein said heteroaryl is a 5-, 6-or 7-membered heteroaryl comprising one or two or three heteroatoms independently selected from oxygen, nitrogen or sulfur.

38. The compound according to claim 35 or 37, said heteroaryl being pyrrolyl, pyridyl, pyrimidinyl, pyrazolyl, oxazolyl, or triazolyl.

39. A compound according to claim 36, wherein R⁴Is that

40. A compound according to claim 28 or 29, wherein R⁴Is optionally substituted by halogen, oxo, -C_1-8Alkyl, -OR^4for-NR^4fR^4gSubstituted heterocyclic radical, wherein R^4fAnd R^4gEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

41. A compound according to claim 40, wherein said heterocyclyl is a 4 to 7 membered ring comprising one or two heteroatoms independently selected from nitrogen, oxygen or sulfur, preferably a 4, 5, 6 or 7 membered saturated ring comprising one nitrogen or oxygen atom as a ring member.

42. A compound according to claim 51, wherein said heterocyclyl is piperidinyl, pyrrolidinyl, or azepanyl.

43. The compound according to any one of claims 40-42, wherein R⁴Is that

44. A compound according to claim 28 or 29, wherein R⁴Is optionally substituted by halogen, oxo, -C_1-8Alkyl, -OR^4for-NR^4fR^4gSubstituted cycloalkyl, wherein R^4fAnd R^4gEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

45. A compound according to claim 44, wherein R⁴Is optionally substituted by-C_1-8Alkyl (preferably methyl), -OR^4for-NR^4fR^4gSubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, wherein R is^4fAnd R^4gEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

46. A compound according to claim 44 or 45, wherein R⁴Is that

47. A compound according to any one of claims 18 to 25, wherein

R⁴is-CONR^4aR^4b，

Wherein R is^4aAnd R^4bEach independently is hydrogen, -C_1-8Alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said-C_1-8Each of the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is optionally substituted with at least one substituent R^4eSubstitution;

R^4eis hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO ₂、-OR^4f、-SO₂R^4f、-SO₂NR^4fR^4g、-COR^4f、-CO₂R^4f、-CONR^4fR^4g、-C(＝NR^4f)NR^4gR^4h、-NR^4fR^4g、-NR^4fCOR^4g、-NR^4fCONR^4gR^4h、-NR^4fCO₂R^4f、-NR^4fSONR^4fR^4g、-NR^4fSO₂NR^4gR^4hor-NR^4fSO₂R^4gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁴ⁱ、-NR⁴ⁱR^4jCycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^4f、R^4g、R^4h、R⁴ⁱand R^4jEach independently is hydrogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

48. A compound according to claim 47, wherein

R⁴is-CONR^4aR^4bWherein

R^4aIs hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl; and is

R^4bIs optionally substituted by at least one substituent R^4esubstituted-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl, ethyl or propyl;

R^4eis hydrogen, halogen, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^4f、-SO₂R^4f、-SO₂NR^4fR^4g、-COR^4f、-CO₂R^4f、-CONR^4fR^4g、-C(＝NR^4f)NR^4gR^4h、-NR^4fR^4g、-NR^4fCOR^4g、-NR^4fCONR^4gR^4h、-NR^4fCO₂R^4f、-NR^4fSONR^4fR^4g、-NR^4fSO₂NR^4gR^4hor-NR^4fSO₂R^4gEach of said cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one substituent selected from the group consisting of halogen, -C_1-8Alkyl, -OR⁴ⁱor-NR⁴ⁱR^4jSubstituted with the substituent(s); and is

R^4f、R^4g、R^4h、R⁴ⁱAnd R^4jEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

49. A compound according to claim 48, wherein R^4eIs optionally substituted by-C_1-8Alkyl, hydroxy, or-C_1-8Alkoxy, preferably methyl, substituted 4 to 7 membered ring containing one or two heteroatoms independently selected from nitrogen, oxygen or sulfur, preferably a 4, 5, 6, or 7 membered saturated ring containing one nitrogen or oxygen atom as a ring member, or a 4, 5, 6, or 7 membered heteroaryl ring containing one or two heteroatoms selected from nitrogen and oxygen as a ring member.

50. A compound according to claim 49, wherein R^4eIs azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholino, piperazinyl, or pyrazolyl, each of which is optionally substituted with methyl, ethyl, hydroxy, methoxy, amino, or halogen.

51. A compound according to claim 48, wherein R^4eIs optionally substituted by at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁴ⁱor-NR⁴ⁱR^4jPhenyl substituted with the substituent of (1); wherein R is⁴ⁱAnd R^4jEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

52. A compound according to claim 48, wherein R^4eis-OR^4fWherein R is^4fIs hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

53. A compound according to claim 48, wherein R^4eis-NR^4fR^4gWherein R is^4fAnd R^4gEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

54. The compound according to any one of claims 47-53, wherein R⁴Is that

55. A compound according to claim 47, wherein

R⁴is-CONR^4aR^4bWherein

R^4aIs hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl; and is

R^4bIs cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with at least one substituent R ^4eSubstitution;

R^4eis hydrogen, halogen, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^4f、-SO₂R^4f、-SO₂NR^4fR^4g、-COR^4f、-CO₂R^4f、-CONR^4fR^4g、-C(＝NR^4f)NR^4gR^4h、-NR^4fR^4g、-NR^4fCOR^4g、-NR^4fCONR^4gR^4h、-NR^4fCO₂R^4f、-NR^4fSONR^4fR^4g、-NR^4fSO₂NR^4gR^4hor-NR^4fSO₂R^4gEach of said cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one substituent selected from the group consisting of halogen, -C_1-8Alkyl, -OR⁴ⁱor-NR⁴ⁱR^4jSubstituted with the substituent(s); and is

R^4f、R^4g、R^4h、R⁴ⁱAnd R^4jEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

56. A compound according to claim 55, wherein R^4bIs optionally substituted by at least one substituent R^4eSubstituted monocyclic ring C_3-8Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl), R^4eIs halogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl), -OR⁴ⁱor-NR⁴ⁱR^4jWherein R is⁴ⁱAnd R^4jEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

57. A compound according to claim 55, wherein R^4bIs optionally substituted by at least one substituent R^4eSubstituted heterocyclic group, said R^4eIs halogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl), -OR⁴ⁱor-NR⁴ⁱR^4jWherein R is⁴ⁱAnd R^4jEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

58. A compound according to claim 57, wherein R ^4bIs a 4 to 7 membered ring containing one or two heteroatoms independently selected from nitrogen, oxygen or sulfur, preferably a 4, 5, 6 or 7 membered saturated ring containing one nitrogen or oxygen atom as a ring member.

59. A compound according to claim 58, wherein R^4bIs azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, tetrahydrofuranyl, tetrahydropyranyl, or morpholino.

60. A compound according to claim 55, wherein R⁴Is that

61. The compound according to any one of claims 18-25, wherein R⁴is-CONR^4aR^4b，R^4aAnd R^4bTogether with the nitrogen atom to which they are attached form a 3-to 12-membered ring, which ring comprises as one or more ring members 0, 1 or 2 further heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulfur, which ring is optionally substituted with at least one substituent R^4eSubstitution;

R^4eis hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^4f、-SO₂R^4f、-SO₂NR^4fR^4g、-COR^4f、-CO₂R^4f、-CONR^4fR^4g、-C(＝NR^4f)NR^4gR^4h、-NR^4fR^4g、-NR^4fCOR^4g、-NR^4fCONR^4gR^4h、-NR^4fCO₂R^4f、-NR^4fSONR^4fR^4g、-NR^4fSO₂NR^4gR^4hor-NR^4fSO₂R^4gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁴ⁱ、-NR⁴ⁱR^4jCycloalkyl, heterocyclyl, aryl, or heteroaryl; and is

R^4f、R^4g、R^4h、R⁴ⁱAnd R^4jEach independently is hydrogen, -C_1-8Alkyl, or C_1-8alkoxy-C_1-8An alkyl group-.

62. The compound according to claim 61, wherein R is^4aAnd R^4bThe ring formed with the nitrogen atom to which they are attached is a monocyclic 3 to 8 membered ring comprising as one or more ring members 0, 1 or 2 further heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulfur, the ring being optionally substituted with at least one substituent R^4eAnd (4) substitution.

63. The compound according to claim 62, wherein R is^4aAnd R^4bThe ring formed with the nitrogen atom to which they are attached is a 4-, 5-, 6-or 7-membered ring containing 0 additional heteroatoms (e.g., azetidinyl, pyrrolidinyl, piperidinyl, and azepanyl), optionally substituted with at least one substituent R^4eAnd (4) substitution.

64. The compound according to claim 62, wherein R is^4aAnd R^4bThe ring formed with the nitrogen atom to which they are attached is 1 additionalA 4-, 5-, 6-or 7-membered ring containing the nitrogen or oxygen heteroatom as a ring member (e.g. morpholino or piperazinyl), said ring being optionally substituted by at least one substituent R^4eAnd (4) substitution.

65. The compound according to any one of claims 62-64, wherein R^4eis-C_1-8Alkyl (preferably-C) _1-6Alkyl, more preferably methyl OR ethyl), -OR^4f、-NR^4fR^4gsaid-C_1-8Alkyl is optionally substituted by at least one substituent selected from halogen, -NR⁴ⁱR^4jOr cycloalkyl, wherein R is^4f、R^4g、R⁴ⁱAnd R^4jEach independently is hydrogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl), or C_1-8alkoxy-C_1-8Alkyl- (preferably methoxy-C)_1-6Alkyl-, more preferably methoxy-ethyl-).

66. The compound according to claim 65, wherein R^4eIs methoxy, methoxy-ethoxy-, -NH₂、-N(CH₃)₂、NH(CH₃) Hydroxy, methyl, ethyl, N (CH)₃)₂-(CH₂)₂-, or cyclopropyl-CH₂-。

67. The compound according to any one of claims 62-66, wherein R⁴Is that

68. The compound according to claim 61, wherein said ring is a bicyclic 7 to 12 membered ring comprising as one or more ring members 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur, said ring optionally substituted with at least one substituent R^4eAnd (4) substitution.

69. The compound according to claim 61, wherein R^4eis-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl or ethyl) or cycloalkyl (preferably C)_3-8Cycloalkyl, more preferably cyclopropyl).

70. The compound according to claim 68 or 69, wherein said ring is a bicyclic spiro 7-to 12-membered ring.

71. A compound according to claim 70, wherein said ring is azaspiro [3.3] heptane, azaspiro [3.5] nonane, azaspiro [3.4] octane, azaspiro [5.5] undecane, or azaspiro [4.5] decane, each containing 0 or 1 additional nitrogen or oxygen atoms as ring members.

72. A compound according to claim 68 or 69, wherein R⁴Is that

73. The compound according to any one of claims 18-25, wherein R⁴is-SO₂R^4a、-SO₂NR^4aR^4b、-NR^4aSO₂R^4b、-NR^4aCOR^4b、-CO₂R^4a、-COR^4a、-NR^4aR^4bor-NR^4aCONR^4bR^4cWherein

R^4a、R^4bAnd R^4cEach independently is hydrogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl or ethyl), cycloalkyl (preferably monocyclic-C)_3-8Cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), heterocyclyl, aryl (preferably phenyl), or heteroarylsaid-C_1-8Each of the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is optionally substituted with at least one substituent R^4eSubstitution;

R^4eis hydrogen, halogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl or ethyl), cycloalkyl (preferably monocyclic-C)_3-8Cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl OR cyclohexyl), heterocyclyl, aryl, heteroaryl, -OR^4f、-CO₂R^4for-NR^4fR^4g；

R^4fAnd R^4gEach independently is hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl or ethyl).

74. A compound according to claim 73, wherein R⁴is-SO₂R^4aWherein R is^4ais-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl or ethyl) or cycloalkyl (preferably monocyclic-C)_3-8Cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), said-C_1-8Alkyl and cycloalkyl are each optionally substituted by at least one substituent R as defined in claim 1 ^4eAnd (4) substitution.

75. A compound according to claim 74, wherein R⁴Is that

76. A compound according to claim 73, wherein R⁴is-SO₂NR^4aR^4bWherein R is^4aAnd R^4bEach independently is hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl or ethyl).

77. A compound according to claim 76, wherein R⁴Is that

78. A compound according to claim 73, wherein R⁴is-NR^4aSO₂R^4bWherein

R^4aAnd R^4bEach independently is hydrogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl or ethyl), cycloalkyl (preferably monocyclic-C)_3-8Cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), or aryl, preferably phenyl, said-C_1-8Each of the alkyl, cycloalkyl, or aryl groups being optionally substituted with at least one substituent R^4eSubstitution;

R^4eis-OR^4fAnd R is^4fIs hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl or ethyl.

79. A compound according to claim 78, wherein R⁴Is that

80. A compound according to claim 73, wherein R⁴is-NR^4aCOR^4bWherein R is^4aAnd R^4bEach independently is hydrogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl group) of said-C_1-8Alkyl is optionally substituted by R^4eSubstituted, said R^4eIs cycloalkyl (preferably monocyclic-C)_3-8Cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl OR cyclohexyl), heterocyclyl (preferably a monocyclic 4-, 5-OR 6-membered ring containing one nitrogen OR oxygen atom as a ring member), -OR ^4for-NR^4fR^4g(ii) a Wherein R is^4fAnd R^4gEach independently is hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl or ethyl).

81. A compound according to claim 80, wherein R⁴Is that

82. A compound according to claim 73, wherein R⁴is-NR^4aCONR^4bR^4cWherein R is^4a、R^4bAnd R^4cEach independently is hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl or ethyl), said-C_1-8Alkyl is optionally substituted by R^4eSubstitution; wherein R is^4eis-NR^4fR^4g；R^4fAnd R^4gEach independently is hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl or ethyl).

83. A compound according to claim 82, wherein R⁴Is that

84. A compound according to claim 73, wherein R⁴is-COR^4aWherein R is^4ais-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl or ethyl) or a heterocyclyl (preferably a monocyclic 4-, 5-or 6-membered ring containing as ring members one nitrogen or oxygen atom), optionally substituted with one R^4eSubstituted, R^4eis-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl or ethyl).

85. The compound according to claim 84, wherein R⁴Is that

86. The compound according to any one of claims 18-25, wherein R⁴is-OR^4a，R^4ais-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl or ethyl or propyl) or heterocyclyl (preferably selected from tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl), said-C _1-8Alkyl or heterocyclyl being optionally substituted by at least one substituent R^4eSubstitution; r^4eIs hydrogen, halogen, cycloalkyl, aryl, -CONR^4fR^4g、-CO₂R^4f、-C(＝NR^4f)NR^4gR^4hor-NR^4fR^4g；R^4f、R^4gAnd R^4hEach independently is hydrogen, or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl).

87. The compound according to claim 86, wherein R⁴Is a methoxy group, an ethoxy group,

88. The compound according to any one of claims 1-17, wherein Cy1 is substituted with one R in the 4-position⁴Substituted phenyl and n is 0, wherein R⁴is-CONR as defined in any one of claims 46 to 71^4aR^4b。

89. The compound according to any one of claims 1-88, wherein m is 0, 1 or 2, R⁶Is as defined in formula (III).

90. According to the rightThe compound of claim 89 wherein m is 2, one R⁶At a position opposite to the attachment point L²At position 3 of (3), another R⁶At a position opposite to the attachment point L²At position 5.

91. The compound according to claim 89, wherein m is 1, R⁶At a position opposite to the attachment point L²At position 3 or 5.

92. The compound according to any one of claims 89-91, wherein

R⁶Is halogen, -C_1-8Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, nitro, -OR^6a、-COR^6a、-CO₂R^6a、-CONR^6aR^6bor-NR^6aR^6bsaid-C_1-8Each of the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is optionally substituted with at least one substituent R ^6dSubstitution;

R^6aand R^6bEach independently is hydrogen, -C_1-8Alkyl, cycloalkyl, or heterocyclyl, said-C_1-8Each of the alkyl, cycloalkyl, or heterocyclyl is optionally substituted with at least one substituent R^6eSubstitution;

R^6dand R^6eEach independently is hydrogen, halogen, -C_1-8Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR^6f、-CONR^6fR^6gor-NR^6fR^6gsaid-C_1-8Each of alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one substituent selected from the group consisting of halogen, -C_1-8Alkyl, -OR⁶ⁱor-NR⁶ⁱR^6jSubstituted with the substituent(s);

R^6f、R^6g、R⁶ⁱand R^6jEach independently is hydrogen, or-C_1-8An alkyl group.

93. The compound according to claim 92, wherein R⁶is-C optionally substituted by halogen (preferably fluorine) or heteroaryl_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl).

94. The compound according to claim 92, wherein R⁶Is cycloalkyl (preferably C)_3-8Cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).

95. The compound according to claim 92, wherein R⁶is-OR^6aWherein R is^6aIs hydrogen or is optionally substituted by at least one substituent R^6esubstituted-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), R^6eIs cycloalkyl (preferably C)_3-8Cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl, OR cyclohexyl), optionally substituted by-OR ⁶ⁱSubstituted aryl, heteroaryl (preferably 6-membered heteroaryl containing one or two nitrogen atoms as one or more ring members), -CONR^6fR^6gAnd R is^6f、R^6gAnd R⁶ⁱEach independently is hydrogen, or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl).

96. The compound according to claim 95, wherein R⁶Is methoxy, ethoxy, isopropoxy,

97. The compound according to claim 92, wherein R⁶is-OR^6aWherein R is^6aIs cycloalkyl (preferably C)_3-8Cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).

98. The compound according to claim 92, wherein R⁶is-NR^6aR^6bAnd R is^6aAnd R^6bEach independently is hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), heterocyclyl, benzyl, cycloalkyl (preferably cyclopropyl), or alkoxyalkyl.

99. The compound according to claim 92, wherein R⁶is-COOR^6aAnd R is^6aIs hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

100. The compound according to claim 92, wherein R⁶is-COR^6aAnd R is^6aIs hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl) or heterocyclyl (preferably monocyclic 5-or 6-membered heterocyclyl comprising one or two heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulphur, more preferably morpholino).

101. The compound according to claim 92, wherein R⁶Is optionally substituted by at least one substituent R^6dSubstituted heteroaryl (preferably monocyclic 5 or 6 membered heteroaryl comprising one or two heteroatoms independently selected from nitrogen or oxygen).

102. The compound according to claim 101, wherein R^6dis-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl) or phenyl, optionally substituted by-C_1-8Alkyl, -OR⁶ⁱor-NR⁶ⁱR^6jIs substituted in which R⁶ⁱAnd R^6jEach independently is hydrogen, or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

103. The compound according to claim 101 or 102, wherein R⁶Is that

104. The compound according to claim 92, wherein R⁶Is optionally substituted by at least one R^6dA substituted heterocyclic group.

105. The compound according to claim 92, wherein R⁶Is a monocyclic 3-to 8-membered heterocyclic group containing as one or more ring members 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur.

106. The compound according to claim 92, wherein R⁶Are 4-, 5-, 6-, or 7-membered heterocyclic groups containing one nitrogen as a ring member (e.g., azetidinyl, pyrrolidinyl, piperidinyl, and azepanyl).

107. A compound according to claim 93, wherein R⁶Is a 4-, 5-, 6-or 7-membered heterocyclyl group (e.g., morpholino or piperazinyl) containing one nitrogen and 1 additional nitrogen or oxygen heteroatom as ring members.

108. The compound according to claim 92, wherein R⁶Is a bicyclic 5-to 12-membered heterocyclyl comprising as one or more ring members 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulfur.

109. The compound according to claim 108, wherein R⁶Is a bicyclic spiro 7-to 12-membered heterocyclyl.

110. The compound according to claim 109, wherein R⁶Is azaspiro [3.3]Heptane, azaspiro [3.5 ]]Nonane, azaspiro [3.4 ]]Octane, azaspiro [5.5 ]]Undecane, or azaspiro [4.5 ]]Decanes, each containing 0 or 1 further nitrogen or oxygen atoms.

111. Root of herbaceous plantA compound according to claim 109, wherein R⁶Is 2-oxa-6-azaspiro [3.3]Heptane.

112. The compound according to claim 92, wherein R⁶is-CONR^6aR^6bWherein R is^6aAnd R^6bEach independently is-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), aryl or heteroaryl, each optionally substituted with at least one R^6eSubstituted, R^6eis-OR^6f、-NR^6fR^6gAryl, or heteroaryl, and R ^6fAnd R^6gEach independently is hydrogen, or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

113. The compound according to claim 112, wherein R⁶Is that

114. The compound according to any one of claims 1-113, wherein L³Is a single bond or C_1-3Alkylene (e.g., -CH)₂-、-CH₂CH₂-or-CH (CH)₃)-)。

115. The compound according to claim 114, wherein L³Is a single bond.

116. The compound according to any one of claims 1-115, wherein said

Is partially

117. The compound according to any of claims 1-116, wherein said

Is partially

118. The compound according to claim 116 or 117, wherein p is 0 or 1.

119. The compound as claimed in any one of claims 117-118, wherein

R⁷is-C_1-8Alkyl, heterocyclyl, -NR^7aR^7bOR-OR^7asaid-C_1-8Alkyl or heterocyclyl is optionally substituted by one R^7dThe substitution is carried out by the following steps,

wherein R is^7dis-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), cycloalkyl (preferably C)_3-6Cycloalkyl, more preferably cyclopropyl) OR-OR^7fsaid-C_1-8Alkyl, OR cycloalkyl optionally substituted by at least one substituent selected from halogen, -OR⁷ⁱor-NR⁷ⁱR^7jSubstituted with the substituent(s);

R^7aor R^7bIs hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl);

Wherein R is^7f、R⁷ⁱAnd R^7jEach independently is hydrogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

120. The compound as claimed in any one of claims 117-119, wherein p is 0 and R is⁷is-OR^7aWherein R is^7aIs hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

121. The compound as claimed in any one of claims 117-119, wherein p is 0 and R is⁷Is optionally substituted by one R^7dsubstituted-C_1-8Alkyl radical, wherein R^7dis-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), cycloalkyl (preferably C)_3-6Cycloalkyl, more preferably cyclopropyl) OR-OR^7fWherein R is^7fIs hydrogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

122. The compound according to claim 120, wherein p is 0, and R is⁷Is methyl, cyclopropylmethyl, or hydroxyethyl.

123. The compound as claimed in any one of claims 117-119, wherein p is 0 and R is⁷Is a heterocyclic group optionally substituted by one R^7dThe substitution is carried out by the following steps,

wherein R is^7dis-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), said-C_1-8Alkyl is optionally substituted by at least one substituent selected from halogen, -OR ⁷ⁱor-NR⁷ⁱR^7jWherein R is⁷ⁱAnd R^7jEach independently is hydrogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl).

124. A compound according to claim 123, wherein said heterocyclyl is a monocyclic 5-or 6-membered heterocyclyl containing as one or more ring members one or two heteroatoms selected from nitrogen, oxygen or optionally oxidised sulfur.

125. A compound according to claim 124, wherein said heterocyclyl is a monocyclic 6-membered heterocyclyl containing one nitrogen or oxygen as a ring member.

126. A compound according to claim 124, wherein said heterocyclyl is piperidinyl (preferably piperidin-4-yl) or tetrahydropyranyl.

127. The compound as claimed in any one of claims 117-119, wherein p is 1, and

R⁸is-C_1-8Alkyl, -CN, -OR^7aor-CONR^7aR^7b，

Wherein R is^7aAnd R^7bEach independently is hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), said-C_1-8Alkyl optionally substituted by at least one substituent R^7eThe substitution is carried out by the following steps,

R^7eis phenyl, heteroaryl, heterocyclyl, each of which is optionally substituted with at least one substituent selected from the group consisting of halogen, -C_1-8Alkyl, -OR⁷ⁱor-NR⁷ⁱR^7jThe substituent (b) of (a) is substituted,

R⁷ⁱand R^7jEach independently is hydrogen or-C _1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

128. The compound according to claim 127, wherein p is 1, and

R⁸is-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

129. The compound according to claim 127, wherein p is 1, and

R⁸is-OR^7aWherein R is^7aIs hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

130. The compound according to claim 127, wherein p is 1, and

R⁸is-CONR^7aR^7b，

Wherein R is^7aIs hydrogen, and R^7bIs optionally substituted by at least one substituent R^7esubstituted-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

R^7eIs phenyl, heteroaryl (preferably a 5 or 6 membered heteroaryl comprising one or two nitrogens as one or more ring members, more preferably pyridinyl or pyrimidinyl), heterocyclyl (preferably a monocyclic 4, 5, 6, or 7 membered heterocyclyl or a bicyclic 7 to 12 membered heterocyclyl, each comprising one or two heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulphur, more preferably piperidinyl or piperazinyl), each of said heterocyclyl, phenyl or heteroaryl being optionally substituted with at least one substituent selected from halogen, -C _1-8Alkyl, -OR⁷ⁱor-NR⁷ⁱR^7jThe substituent (b) of (a) is substituted,

R⁷ⁱand R^7jEach independently is hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

131. The compound as claimed in any one of claims 117-119, wherein p is 1 and R is⁷is-OR^7aWherein R is^7aIs hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), and R⁸As defined in any one of claims 125-128.

132. The compound as claimed in any one of claims 117-119, wherein p is 1 and R is⁷Is optionally substituted by one R^7dsubstituted-C_1-8Alkyl radical, wherein R^7dis-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), cycloalkyl (preferably C)_3-6Cycloalkyl, more preferably cyclopropyl) OR-OR^7fWherein R is^7fIs hydrogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), and R⁸As defined in any one of claims 125-128.

133. The compound according to claim 132, wherein p is 1, and R is⁷Is methyl, cyclopropylmethyl, or hydroxyethyl.

134. The compound as claimed in any one of claims 117-119, wherein p is 1 and R is⁷Is a heterocyclic group optionally substituted by one R ^7dThe substitution is carried out by the following steps,

wherein R is^7dis-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), said-C_1-8Alkyl is optionally substituted by at least one substituent selected from halogen, -OR⁷ⁱor-NR⁷ⁱR^7jWherein R is⁷ⁱAnd R^7jEach independently is hydrogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl), and

R⁸as defined in any one of claims 125-128.

135. A compound according to claim 135, wherein said heterocyclyl is a monocyclic 5-or 6-membered heterocyclyl containing as one or more ring members one or two heteroatoms selected from nitrogen, oxygen or optionally oxidised sulfur.

136. A compound according to claim 135, wherein said heterocyclyl is a monocyclic 6-membered heterocyclyl containing one nitrogen or oxygen as a ring member.

137. A compound according to claim 134, wherein said heterocyclyl is piperidinyl or tetrahydropyranyl.

138. The compound as claimed in any one of claims 117-137, wherein the compound is

Is partially

139. The compound as claimed in any one of claims 117-137, wherein the compound is

Is partially

140. A compound of formula (AIV):

or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

wherein

X¹Is C or N;

R¹is hydrogen, halogen, or-C _1-8An alkyl group; provided that X is¹In the case of N, R is absent¹；

Cy1 is cycloalkyl, phenyl, 5-or 6-membered heterocyclyl, 5-or 6-membered heteroaryl, or 7-to 12-membered bicyclic fused heteroaryl or heterocyclyl, each of which is substituted with one R⁴Substituted and optionally substituted by R⁵Substitution;

n is 0, 1 or 2;

R⁵at each occurrence thereof, is independently halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^4a、-SO₂R^4a、-SO₂NR^4aR^4b、-COR^4a、-CO₂R^4a、-CONR^4aR^4b、-C(＝NR^4a)NR^4bR^4c、-NR^4aR^4b、-NR^4aCOR^4b、-NR^4aCONR^4bR^4c、-NR^4aCO₂R^4b、-NR^4aSONR^4bR^4c、-NR^4aSO₂NR^4bR^4cor-NR^4aSO₂R^4bsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^4dSubstitution;

R^4a、R^4band R^4cEach independently is hydrogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^4eSubstitution; or

(R^4aAnd R^4b)、(R^4bAnd R^4c) Or (R)^4cAnd R^4a) Together with the atom or atoms to which they are attached form a 3 to 12 membered ring containing 0, 1 or 2 further heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulphur as one or more ring members, said ring being optionally substituted with at least one substituent R ^4eSubstitution;

R^4dand R^4eEach independently is hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^4f、-SO₂R^4f、-SO₂NR^4fR^4g、-COR^4f、-CO₂R^4f、-CONR^4fR^4g、-C(＝NR^4f)NR^4gR^4h、-NR^4fR^4g、-NR^4fCOR^4g、-NR^4fCONR^4gR^4h、-NR^4fCO₂R^4f、-NR^4fSONR^4fR^4g、-NR^4fSO₂NR^4gR^4hor-NR^4fSO₂R^4gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁴ⁱ、-NR⁴ⁱR^4jCycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^4f、R^4g、R^4h、R⁴ⁱand R^4jEach independently is hydrogen, -C_1-8Alkyl radical, C_1-8alkoxy-C_1-8Alkyl-, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R⁶is halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^6a、-SO₂R^6a、-SO₂NR^6aR^6b、-COR^6a、-CO₂R^6a、-CONR^6aR^6b、-C(＝NR^6a)NR^6bR^6c、-NR^6aR^6b、-NR^6aCOR^6b、-NR^6aCONR^6bR^6c、-NR^6aCO₂R^6b、-NR^6aSONR^6bR^6c、-NR^6aSO₂NR^6bR^6cor-NR^6aSO₂R^6bsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^6dSubstitution;

R^6a、R^6band R^6cEach independently is hydrogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R ^6eSubstitution;

R^6dand R^6eEach independently is hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^6f、-SO₂R^6f、-SO₂NR^6fR^6g、-COR^6f、-CO₂R^6f、-CONR^6fR^6g、-C(＝NR^6f)NR^6gR^6h、-NR^6fR^6g、-NR^6fCOR^6g、-NR^6fCONR^6gR^6h、-NR^6fCO₂R^6f、-NR^6fSONR^6fR^6g、-NR^6fSO₂NR^6gR^6hor-NR^6fSO₂R^6gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁶ⁱ、-NR⁶ⁱR^6jCycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^6f、R^6g、R^6h、R⁶ⁱand R^6jEach independently is hydrogen, -C_1-8Alkyl radical, C_1-8alkoxy-C_1-8Alkyl-, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

m is 0, 1, 2, 3 or 4, provided that valency theory is satisfied;

X²and X³Each independently is CH or N, provided that X²And X³Are not all CH;

t is 0, 1, 2, or 3;

s is 0, 1, 2, or 3;

R⁷and R⁸Each independently is halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^7a、-SO₂R^7a、-SO₂NR^7aR^7b、-COR^7a、-CO₂R^7a、-CONR^7aR^7b、-C(＝NR^7a)NR^7bR^7c、-NR^7aR^7b、-NR^7aCOR^7b、-NR^7aCONR^7bR^7c、-NR^7aCO₂R^7b、-NR^7aSONR^7bR^7c、-NR^7aSO₂NR^7bR^7cor-NR^7aSO₂R^7bsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^7dSubstitution;

R^7a、R^7band R^7cEach independently is hydrogen, -C_1-8Alkyl, -C _2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^7eSubstitution;

R^7dand R^7eEach independently is hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^7f、-SO₂R^7f、-SO₂NR^7fR^7g、-COR^7f、-CO₂R^7f、-CONR^7fR^7g、-C(＝NR^7f)NR^7gR^7h、-NR^7fR^7g、-NR^7fCOR^7g、-NR^7fCONR^7gR^7h、-NR^7fCO₂R^7f、-NR^7fSONR^7fR^7g、-NR^7fSO₂NR^7gR^7hor-NR^7fSO₂R^7gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁷ⁱ、-NR⁷ⁱR^7jCycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^7f、R^7g、R^7h、R⁷ⁱand R^7jEach independently is hydrogen, -C_1-8Alkyl radical, C_1-8alkoxy-C_1-8Alkyl-, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

p is 0, 1, 2 or 3, provided that the valence theory is satisfied.

141. A compound of formula (IV)

Or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

wherein

X¹Is C or N;

R¹is hydrogen, halogen, or-C_1-8An alkyl group; provided that X is¹In the case of N, R is absent¹；

Cy1 is cycloalkyl, phenyl, 5-or 6-membered heterocyclyl, 5-or 6-membered heteroaryl, or 7-to 12-membered bicyclic fused heteroaryl or heterocyclyl, each of which is substituted with one R ⁴Substituted and optionally substituted by R⁵Substitution;

n is 0, 1 or 2;

R⁵at each occurrence thereof, is independently halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^4a、-SO₂R^4a、-SO₂NR^4aR^4b、-COR^4a、-CO₂R^4a、-CONR^4aR^4b、-C(＝NR^4a)NR^4bR^4c、-NR^4aR^4b、-NR^4aCOR^4b、-NR^4aCONR^4bR^4c、-NR^4aCO₂R^4b、-NR^4aSONR^4bR^4c、-NR^4aSO₂NR^4bR^4cor-NR^4aSO₂R^4bsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^4dSubstitution;

R^4a、R^4band R^4cEach independently is hydrogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^4eSubstitution; or

(R^4aAnd R^4b)、(R^4bAnd R^4c) Or (R)^4cAnd R^4a) Together with the atom or atoms to which they are attached form a 3 to 12 membered ring containing 0, 1 or 2 further heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulphur as one or more ring members, said ring being optionally substituted with at least one substituent R^4eSubstitution;

R^4dand R^4eEach independently is hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO ₂、-OR^4f、-SO₂R^4f、-SO₂NR^4fR^4g、-COR^4f、-CO₂R^4f、-CONR^4fR^4g、-C(＝NR^4f)NR^4gR^4h、-NR^4fR^4g、-NR^4fCOR^4g、-NR^4fCONR^4gR^4h、-NR^4fCO₂R^4f、-NR^4fSONR^4fR^4g、-NR^4fSO₂NR^4gR^4hor-NR^4fSO₂R^4gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁴ⁱ、-NR⁴ⁱR^4jCycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^4f、R^4g、R^4h、R⁴ⁱand R^4jEach independently is hydrogen, -C_1-8Alkyl radical, C_1-8alkoxy-C_1-8Alkyl-, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R⁶is halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^6a、-SO₂R^6a、-SO₂NR^6aR^6b、-COR^6a、-CO₂R^6a、-CONR^6aR^6b、-C(＝NR^6a)NR^6bR^6c、-NR^6aR^6b、-NR^6aCOR^6b、-NR^6aCONR^6bR^6c、-NR^6aCO₂R^6b、-NR^6aSONR^6bR^6c、-NR^6aSO₂NR^6bR^6cor-NR^6aSO₂R^6bsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^6dSubstitution;

R^6a、R^6band R^6cEach independently is hydrogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^6eSubstitution;

R^6dand R^6eEach independently is hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO ₂、-OR^6f、-SO₂R^6f、-SO₂NR^6fR^6g、-COR^6f、-CO₂R^6f、-CONR^6fR^6g、-C(＝NR^6f)NR^6gR^6h、-NR^6fR^6g、-NR^6fCOR^6g、-NR^6fCONR^6gR^6h、-NR^6fCO₂R^6f、-NR^6fSONR^6fR^6g、-NR^6fSO₂NR^6gR^6hor-NR^6fSO₂R^6gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁶ⁱ、-NR⁶ⁱR^6jCycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^6f、R^6g、R^6h、R⁶ⁱand R^6jEach independently is hydrogen, -C_1-8Alkyl radical, C_1-8alkoxy-C_1-8Alkyl-, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

m is 0, 1, 2, 3 or 4, provided that valency theory is satisfied;

X²and X³Each independently of the otherGround is CH or N, provided that X²And X³Are not all CH;

t is 0, 1, 2, or 3;

R⁷and R⁸Each independently is halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^7a、-SO₂R^7a、-SO₂NR^7aR^7b、-COR^7a、-CO₂R^7a、-CONR^7aR^7b、-C(＝NR^7a)NR^7bR^7c、-NR^7aR^7b、-NR^7aCOR^7b、-NR^7aCONR^7bR^7c、-NR^7aCO₂R^7b、-NR^7aSONR^7bR^7c、-NR^7aSO₂NR^7bR^7cor-NR^7aSO₂R^7bsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R^7dSubstitution;

R^7a、R^7band R^7cEach independently is hydrogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R ^7eSubstitution;

R^7dand R^7eEach independently is hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^7f、-SO₂R^7f、-SO₂NR^7fR^7g、-COR^7f、-CO₂R^7f、-CONR^7fR^7g、-C(＝NR^7f)NR^7gR^7h、-NR^7fR^7g、-NR^7fCOR^7g、-NR^7fCONR^7gR^7h、-NR^7fCO₂R^7f、-NR^7fSONR^7fR^7g、-NR^7fSO₂NR^7gR^7hor-NR^7fSO₂R^7gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁷ⁱ、-NR⁷ⁱR^7jCycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^7f、R^7g、R^7h、R⁷ⁱand R^7jEach independently is hydrogen, -C_1-8Alkyl radical, C_1-8alkoxy-C_1-8Alkyl-, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

p is 0, 1, 2 or 3, provided that the valence theory is satisfied.

142. The compound as claimed in any of claims 140-141, wherein n is 1; and R is⁵Is halogen or-C_1-8An alkyl group.

143. The compound as claimed in any one of claims 140-142, wherein-CONR in formulae (AIV) and (IV)^4aR^4bIn the section (a) above, the section (b),

R^4aand R^4bEach independently is hydrogen, -C_1-8Alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said-C_1-8Each of the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is optionally substituted with at least one substituent R^4eSubstitution;

R^4eis hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C _2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^4f、-SO₂R^4f、-SO₂NR^4fR^4g、-COR^4f、-CO₂R^4f、-CONR^4fR^4g、-C(＝NR^4f)NR^4gR^4h、-NR^4fR^4g、-NR^4fCOR^4g、-NR^4fCONR^4gR^4h、-NR^4fCO₂R^4f、-NR^4fSONR^4fR^4g、-NR^4fSO₂NR^4gR^4hor-NR^4fSO₂R^4gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁴ⁱ、-NR⁴ⁱR^4jCycloalkyl, heterocyclyl, aryl, or heteroaryl;

R^4f、R^4g、R^4h、R⁴ⁱand R^4jEach independently is hydrogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

144. The compound according to claim 143, wherein-CONR in formulae (AIV) and (IV)^4aR^4bIn the section (a) above, the section (b),

R^4ais hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl; and is

R^4bIs optionally substituted by at least one substituent R^4esubstituted-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl, ethyl or propyl;

R^4eis hydrogen, halogen, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^4f、-SO₂R^4f、-SO₂NR^4fR^4g、-COR^4f、-CO₂R^4f、-CONR^4fR^4g、-C(＝NR^4f)NR^4gR^4h、-NR^4fR^4g、-NR^4fCOR^4g、-NR^4fCONR^4gR^4h、-NR^4fCO₂R^4f、-NR^4fSONR^4fR^4g、-NR^4fSO₂NR^4gR^4hor-NR^4fSO₂R^4gEach of said cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one substituent selected from the group consisting of halogen, -C_1-8Alkyl, -OR⁴ⁱor-NR⁴ⁱR^4jSubstituted with the substituent(s); and is

R^4f、R^4g、R^4h、R⁴ⁱAnd R^4jEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

145. The compound according to claim 144, wherein R^4eIs optionally substituted by-C_1-8Alkyl, hydroxy, or-C_1-8Alkoxy, preferably methyl, substituted 4 to 7 membered ring containing one or two heteroatoms independently selected from nitrogen, oxygen or sulfur, preferably a 4, 5, 6, or 7 membered saturated ring containing one nitrogen or oxygen atom as a ring member, or a 4, 5, 6, or 7 membered heteroaryl ring containing one or two heteroatoms selected from nitrogen and oxygen as a ring member.

146. A compound according to claim 145, wherein R^4eIs azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholino, piperazinyl, or pyrazolyl, each of which is optionally substituted with methyl, ethyl, hydroxy, methoxy, amino, or halogen.

147. The compound according to claim 144, wherein R^4eIs optionally substituted by at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁴ⁱor-NR⁴ⁱR^4jPhenyl substituted with the substituent of (1); wherein R is⁴ⁱAnd R^4jEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethylAnd (4) a base.

148. The compound according to claim 144, wherein R^4eis-OR^4fWherein R is^4fIs hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

149. The compound according to claim 144, wherein R^4eis-NR^4fR^4gWherein R is^4fAnd R^4gEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

150. The compound according to claim 143, wherein-CONR in formulae (AIV) and (IV)^4aR^4bIn the section (a) above, the section (b),

R^4ais hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl; and is

R^4bIs cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with at least one substituent R^4eSubstitution;

R^4eis hydrogen, halogen, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^4f、-SO₂R^4f、-SO₂NR^4fR^4g、-COR^4f、-CO₂R^4f、-CONR^4fR^4g、-C(＝NR^4f)NR^4gR^4h、-NR^4fR^4g、-NR^4fCOR^4g、-NR^4fCONR^4gR^4h、-NR^4fCO₂R^4f、-NR^4fSONR^4fR^4g、-NR^4fSO₂NR^4gR^4hor-NR^4fSO₂R^4gEach of said cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one substituent selected from the group consisting of halogen, -C_1-8Alkyl, -OR⁴ⁱor-NR⁴ⁱR^4jSubstituted with the substituent(s); and is

R^4f、R^4g、R^4h、R⁴ⁱAnd R^4jEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

151. A compound according to claim 150, wherein R^4bIs optionally substituted by at least one substituent R^4eSubstituted monocyclic ring C_3-8Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl), R^4eIs halogen, -C_1-8Alkyl (preferably-C) _1-6Alkyl, more preferably methyl), -OR⁴ⁱor-NR⁴ⁱR^4jWherein R is⁴ⁱAnd R^4jEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

152. A compound according to claim 150, wherein R^4bIs optionally substituted by at least one substituent R^4eSubstituted heterocyclic group, said R^4eIs halogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl), -OR⁴ⁱor-NR⁴ⁱR^4jWherein R is⁴ⁱAnd R^4jEach independently is hydrogen or-C_1-8Alkyl, preferably-C_1-6Alkyl, more preferably methyl or ethyl.

153. The compound according to claim 152, wherein R^4bIs a 4 to 7 membered ring containing one or two heteroatoms independently selected from nitrogen, oxygen or sulfur, preferably a 4, 5, 6 or 7 membered saturated ring containing one nitrogen or oxygen atom as a ring member.

154. The compound according to claim 153, wherein R^4bIs azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, tetrahydrofuranyl, tetrahydropyranyl, or morpholino.

155. The compound as claimed in any one of claims 140-142, wherein-CONR in formulae (AIV) and (IV)^4aR^4bIn the section (a) above, the section (b),

R^4aand R^4bTogether with the nitrogen atom to which they are attached form a 3-to 12-membered ring, which ring comprises as one or more ring members 0, 1 or 2 further heteroatoms independently selected from nitrogen, oxygen or optionally oxidised sulfur, which ring is optionally substituted with at least one substituent R ^4eSubstitution;

R^4eis hydrogen, halogen, -C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO₂、-OR^4f、-SO₂R^4f、-SO₂NR^4fR^4g、-COR^4f、-CO₂R^4f、-CONR^4fR^4g、-C(＝NR^4f)NR^4gR^4h、-NR^4fR^4g、-NR^4fCOR^4g、-NR^4fCONR^4gR^4h、-NR^4fCO₂R^4f、-NR^4fSONR^4fR^4g、-NR^4fSO₂NR^4gR^4hor-NR^4fSO₂R^4gsaid-C_1-8Alkyl, -C_2-8Alkenyl, -C_2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C_1-8Alkyl, -OR⁴ⁱ、-NR⁴ⁱR^4jCycloalkyl, heterocyclyl, aryl, or heteroaryl; and is

R^4f、R^4g、R^4h、R⁴ⁱAnd R^4jEach independently is hydrogen, -C_1-8Alkyl, or C_1-8alkoxy-C_1-8An alkyl group-.

156. The compound according to claim 155, wherein R is substituted with R^4aAnd R^4bThe ring formed with the nitrogen atom to which they are attached is a ring containing 0, 1 or 2 independently selectedA monocyclic 3-to 8-membered ring which is substituted by one or more ring members and is optionally substituted by at least one substituent R^4eAnd (4) substitution.

157. The compound according to claim 156, wherein R is selected from^4aAnd R^4bThe ring formed with the nitrogen atom to which they are attached is a 4-, 5-, 6-or 7-membered ring containing 0 additional heteroatoms (e.g., azetidinyl, pyrrolidinyl, piperidinyl, and azepanyl), optionally substituted with at least one substituent R ^4eAnd (4) substitution.

158. The compound according to claim 156, wherein R is selected from^4aAnd R^4bThe ring formed with the nitrogen atom to which they are attached is a 4-, 5-, 6-or 7-membered ring containing 1 additional nitrogen or oxygen heteroatom as a ring member (e.g. morpholino or piperazinyl), optionally substituted with at least one substituent R^4eAnd (4) substitution.

159. The compound as recited in any one of claims 156-158, wherein R^4eis-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl OR ethyl), -OR^4f、-NR^4fR^4gsaid-C_1-8Alkyl is optionally substituted by at least one substituent selected from halogen, -NR⁴ⁱR^4jOr cycloalkyl, wherein R is^4f、R^4g、R⁴ⁱAnd R^4jEach independently is hydrogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl), or C_1-8alkoxy-C_1-8Alkyl- (preferably methoxy-C)_1-6Alkyl-, more preferably methoxy-ethyl-).

160. The compound according to claim 159, wherein R^4eIs methoxy, methoxy-ethoxy-, -NH₂、-N(CH₃)₂、NH(CH₃) Hydroxy, methyl, ethyl, N (CH)₃)₂-(CH₂)₂-, or cyclopropyl-CH₂-。

161. The compound according to claim 155, wherein said ring is a bicyclic 7-to 12-membered ring comprising as one or more ring members 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring optionally substituted with at least one substituent R ^4eAnd (4) substitution.

162. The compound according to claim 155, wherein R^4eis-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl or ethyl) or cycloalkyl (preferably C)_3-8Cycloalkyl, more preferably cyclopropyl).

163. The compound according to claim 161 or 162, wherein said ring is a bicyclic spiro 7-to 12-membered ring.

164. A compound according to claim 163, wherein the ring is azaspiro [3.3] heptane, azaspiro [3.5] nonane, azaspiro [3.4] octane, azaspiro [5.5] undecane, or azaspiro [4.5] decane, each containing 0 or 1 additional nitrogen or oxygen atoms as ring members.

165. The compound as claimed in any of claims 143-164, wherein-CONR in formulae (AIV) and (IV)^4aR^4bIs partially

e)

f)

g)

Or

h)

166. The compound as defined in claim 140-165, wherein the compound has the formula

167. The compound as claimed in any one of claims 140-166, wherein

R⁶Is halogen, -C_1-8Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, nitro, -OR^6a、-COR^6a、-CO₂R^6a、-CONR^6aR^6bor-NR^6aR^6bsaid-C_1-8Each of the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is optionally substituted with at least one substituent R^6dSubstitution;

R^6aand R^6bEach independently is hydrogen, -C_1-8Alkyl, cycloalkyl, or heterocyclyl, said-C _1-8Each of the alkyl, cycloalkyl, or heterocyclyl is optionally substituted with at least one substituent R^6eSubstitution;

R^6dand R^6eEach independently is hydrogen, halogen, -C_1-8Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR^6f、-CONR^6fR^6gor-NR^6fR^6gsaid-C_1-8Each of alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one substituent selected from the group consisting of halogen, -C_1-8Alkyl, -OR⁶ⁱor-NR⁶ⁱR^6jSubstituted with the substituent(s);

R^6f、R^6g、R⁶ⁱand R^6jEach independently is hydrogen, or-C_1-8An alkyl group.

168. A compound according to claim 167, wherein R⁶Is that

h) -C optionally substituted by halogen (preferably fluorine) or heteroaryl_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl); or

i) Cycloalkyl (preferably C)_3-8Cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl);

j)-OR^6awherein R is^6aIs hydrogen or is optionally substituted by at least one substituent R^6esubstituted-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), R^6eIs cycloalkyl (preferably C)_3-8Cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl, OR cyclohexyl), optionally substituted by-OR⁶ⁱSubstituted aryl, heteroaryl (preferably 6-membered heteroaryl containing one or two nitrogen atoms as one or more ring members), -CONR ^6fR^6gAnd R is^6f、R^6gAnd R⁶ⁱEach independently is hydrogen, or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl); or

k)-OR^6aWherein R is^6aIs cycloalkyl (preferably C)_3-8Cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl); or

l)-NR^6aR^6bAnd R is^6aAnd R^6bEach independently is hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), heterocyclyl, benzyl, cycloalkyl (preferably cyclopropyl), or alkoxyalkyl; or

m) is optionally substituted by at least one substituent R^6dSubstituted heteroaryl (preferably monocyclic 5 or 6 membered heteroaryl comprising one or two heteroatoms independently selected from nitrogen or oxygen), wherein R is^6dis-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl) or phenyl, optionally substituted by-C_1-8Alkyl, -OR⁶ⁱor-NR⁶ⁱR^6jIs substituted in which R⁶ⁱAnd R^6jEach independently is hydrogen, or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl);

n) is optionally substituted by at least one R^6dA substituted heterocyclic group.

169. A compound according to claim 168, wherein R⁶Is a monocyclic 3-to 8-membered heterocyclic group containing as one or more ring members 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur.

170. A compound according to claim 168, wherein R⁶Are 4-, 5-, 6-, or 7-membered heterocyclic groups containing one nitrogen as a ring member (e.g., azetidinyl, pyrrolidinyl, piperidinyl, and azepanyl).

171. A compound according to claim 168, wherein R⁶Is a 4-, 5-, 6-or 7-membered heterocyclyl group (e.g., morpholino or piperazinyl) containing one nitrogen and 1 additional nitrogen or oxygen heteroatom as ring members.

172. The compound according to claim 112, wherein R⁶Is that

h) Halogen; CN; a nitro group;

i) methyl, trifluoromethyl;

j) methoxy, ethoxy, isopropoxy, trifluoromethoxy, hydroxy, oxetan-3-yloxy, oxetanyl, and the like,

k)

l) cyclopropyl;

m) methylamino, ethylamino, benzylamino, (2-methoxyethyl) (methyl) amino, isopropylamino, propylamino, cyclopropylamino, ((tetrahydrofuran-2-yl) methyl) amino; or

n) (R) -3-hydroxypyrrolidin-1-yl, (S) -3-hydroxypyrrolidin-1-yl, (1-methyl-1H-pyrazol-4-yl) methyl, 1H-pyrazol-4-yl, 5-oxopyrrolidin-3-yl, or tetrahydrofuran-3-yl.

173. The compound as claimed in any one of claims 140-172, wherein the compound is

Is partially

174. The compound as claimed in any one of claims 141-172, wherein the compound is

Is partially

175. The compound according to claim 173 or 174, wherein p is 0 or 1.

176. The compound as claimed in any one of claims 173-175, wherein p is 0 and R is⁷Is optionally substituted by one R^7dsubstituted-C_1-8Alkyl radical, wherein R^7dis-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), cycloalkyl (preferably C)_3-6Cycloalkyl, more preferably cyclopropyl) OR-OR^7fWherein R is^7fIs hydrogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

177. The compound according to claim 176, wherein p is 0, and R is⁷Is methyl, cyclopropylmethyl, or hydroxyethyl.

178. The compound as claimed in any one of claims 173-175, wherein p is 0 and R is⁷Is a heterocyclic group optionally substituted by one R^7dThe substitution is carried out by the following steps,

wherein R is^7dis-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), said-C_1-8Alkyl is optionally substituted by at least one substituent selected from halogen, -OR⁷ⁱor-NR⁷ⁱR^7jWherein R is⁷ⁱAnd R^7jEach independently is hydrogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl).

179. A compound according to claim 178, wherein said heterocyclyl is a monocyclic 5-or 6-membered heterocyclyl containing as one or more ring members one or two heteroatoms selected from nitrogen, oxygen or optionally oxidised sulfur.

180. A compound according to claim 179, wherein said heterocyclyl is a monocyclic 6-membered heterocyclyl containing one nitrogen or oxygen as a ring member.

181. A compound according to claim 179, wherein said heterocyclyl is piperidinyl (preferably piperidin-4-yl) or tetrahydropyranyl.

182. The compound according to claim 127, wherein p is 1, and

R⁸is-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl) or R⁸is-OR^7aWherein R is^7aIs hydrogen or-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

183. The compound as claimed in any one of claims 117-119, wherein p is 1 and R is⁷Is optionally substituted by one R^7dsubstituted-C_1-8Alkyl radical, wherein R^7dis-C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), cycloalkyl (preferably C)_3-6Cycloalkyl, more preferably cyclopropyl) OR-OR^7fWherein R is^7fIs hydrogen, -C_1-8Alkyl (preferably-C)_1-6Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), and R⁸As defined in any one of claims 125-128.

184. The compound according to claim 183, wherein p is 1, and R is⁷Is methyl, cyclopropylmethyl, or hydroxyethyl.

185. The compound as claimed in any one of claims 173-184, wherein the compound is

Is partially

186. A compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, selected from

187. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-186, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

188. A method for treating or preventing a disorder or disease responsive to inhibition of HPK1 activity in a subject, comprising administering to the subject a compound of any one of claims 1 to 188, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, as an inhibitor of HPK1 kinase.