HK1229331B - ANALOGUES OF 4H-PYRAZOLO[1,5-α]BENZIMIDAZOLE COMPOUND AS PARP INHIBITORS - Google Patents

Description

Analogs of 4H-pyrazolo[1,5-α]benzimidazole compounds as PARP inhibitors

Technical Field

The present invention relates to a series of analogs of 4H-pyrazolo[1,5-α]benzimidazole compounds as PARP inhibitors. Specifically, the present invention relates to compounds represented by formula (I) or pharmaceutically acceptable salts thereof as PARP inhibitors.

Background Art

PARPs are a family of enzymes that catalyze the addition of ADP-ribose residues to various target proteins. To date, up to 18 isoforms have been identified and characterized. Despite the large number of enzymes in this family, PARP-1 is responsible for over 90% of ADP-ribosylation in cells.

PARP-1 has long been associated with DNA repair and the maintenance of genomic function. Following DNA damage, PARP-1 is transiently activated by binding to DNA breaks. Following this structural change, it begins to use NAD+ to synthesize poly(ADP)-ribose, which serves as a signal for other repair enzymes, such as DNA ligase III and DNA polymerase β. PARP-1 binding and activation, a process known as base excision repair, contributes to the amplification of the repair process, targeting single-stranded DNA breaks (SSBs). SSBs are typically initiated by oxidative damage, which is caused by the cell's own metabolic processes, as well as by exogenous chemotherapeutic agents and radiation. It is well known that many types of anticancer therapies, such as DNA alkylating agents, platinum drugs, topoisomerase inhibitors, and radiation therapy, are associated with DNA damage. The emergence of drug resistance has cast a shadow over these therapies, particularly in DNA repair pathways dominated by PARP-1. Recent studies have demonstrated that selective PARP-1 inhibitors significantly enhance the anti-tumor efficacy of TMZ and cisplatin.

BRCA1 and BRCA2 play an important role in homologous recombination (HR). DNA breaks generated during DNA replication can only be repaired by HR. In 2005, Bryant and Farmer (Nature, 2005, 913 and 917) independently discovered that cell lines lacking BACA1 and BACA2 were very sensitive to PARP-1 inhibitors, which led to cell death. The breast cancer gene BRCA1/2 has long been characterized as a tumor suppressor gene, which plays an indispensable role in the repair of double-strand breaks in DNA. Carriers of BRCA1/2 mutations in ovarian cancer and prostate cancer are also at high risk. Therefore, for tumor types that already lack certain types of DNA repair mechanisms, PARP-1 inhibitors can also be used as a stand-alone therapy.

PARP-1 has been actively explored as an anti-tumor target for 30 years, and Ferraris has comprehensively summarized the progress in this field (J. Med. Chem. 2010, 4561). A series of compounds are in clinical research, both as single agents and as potentiators, such as veliparib (ABT-888), niraparib (MK-4827), BMN-673, CEP-977, BGP-15, E-7016 MP-124 and IND-1022. Recently, some patents have disclosed certain heterocyclic compounds that can effectively treat various cancers, such as WO2014009872(A1), WO2014019468(A1), WO2014023390(A2), WO2013182580, WO2013164061(A1), and EP2656843(A1).

In addition, PARP-1 inhibition has been actively explored as a drug target, with therapeutic areas encompassing stroke, myocardial ischemia, inflammation, and diabetes (Pharmacol. Rev. 2002, 54, 375).

While efforts to develop PARP-1 inhibitors for the treatment of cancer and other diseases continue, satisfactory treatments have not been achieved, and thus there is a need to develop new PARP-1 inhibitors.

Summary of the Invention

The object of the present invention is to provide a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

in,

D is selected from -C( _Rd1 )( _Rd2 )-, -C(=O)N( _Rd3 )-, -N( _Rd4 )-, -C(= _NRd5 )-, -S(=O) _2N ( _Rd6 )-, -S(=O)N( _Rd7 )-, -O-, -S-, -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O)-, or -S(=O) _2- ;

R _1-3 , R _d1 , and R _d2 are each independently selected from H, F, Cl, Br, I, CN, OH, SH, and NH ₂ , or selected from C _1-10 alkyl or heteroalkyl groups optionally substituted with R ₀₁ , C _3-10 cycloalkyl or heterocycloalkyl groups, or C _1-10 alkyl or heteroalkyl groups substituted with C _3-10 cycloalkyl or heterocycloalkyl groups;

R ₀₁ is selected from F, Cl, Br, I, CN, OH, SH, NH ₂ , R ₀₂ ;

R ₀₂ is selected from C _1-10 alkyl, C _1-10 alkylamino, N,N-di(C _1-10 alkyl)amino, C _1-10 alkoxy, C _1-10 alkanoyl, C _1-10 alkoxycarbonyl, C _1-10 alkylsulfonyl, C _1-10 alkylsulfinyl, C _3-10 cycloalkyl, C 3-10 cycloalkylamino, C _3-10 heterocycloalkylamino, C _3-10 cycloalkyloxy, C _3-10 cycloalkylacyl, C _3-10 cycloalkyloxycarbonyl, C _3-10 cycloalkylsulfonyl, C _3-10 cycloalkylsulfinyl _;

The heteroatom or heteroatom group is independently selected from -C(=O)N(R _d3 )-, -N(R _d4 )-, -C(=NR _d5 )-, -S(=O) ₂ N(R _d6 )-, -S(=O)N(R _d7 )-, -O-, -S-, -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O)- and/or -S(=O) ₂ -;

R _d3-d7 are independently selected from H, R ₀₃ ;

R ₀₃ is selected from C _1-10 alkyl, C _1-10 alkylacyl, C _1-10 alkoxycarbonyl, C _1-10 alkylsulfonyl, C _1-10 alkylsulfinyl, C _3-10 cycloalkyl, C _3-10 cycloalkylacyl, C _{3-10 cycloalkyloxycarbonyl, C 3-10 cycloalkylsulfonyl} , C _3-10 cycloalkylsulfinyl;

R ₀₂ and R ₀₃ are optionally substituted by R ₀₀₁ ;

R ₀₀₁ is selected from F, Cl, Br, I, CN, OH, N(CH ₃ ) ₂ , NH(CH ₃ ), NH ₂ , trifluoromethyl, aminomethyl, hydroxymethyl, methyl, methoxy, formyl, methoxycarbonyl, methylsulfonyl, methylsulfinyl;

The number of R ₀₁ , R ₀₀₁ , heteroatoms or heteroatom groups is independently selected from 0, 1, 2 or 3.

In one embodiment of the present invention, D is selected from -NH-, -N(CH ₃ )-, -C(F) ₂ -, -C(H)(F)-, and -C(H)(OH)-.

In one embodiment of the present invention, R _1-3 are independently selected from H, F, Cl, Br, I, CN, OH, SH, NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, benzyloxy, -CH ₂ N(R ₂₁ )(R ₂₂ ),

in,

L and D ₂₁ are each independently selected from -C(R _d1 )(R _d2 )-, -C(═O)N(R _d3 )-, -N(R _d4 )-, -C(═NR _d5 )-, -S(═O) ₂ N(R _d6 )-, -S(═O)N(R _d7 )-, -O-, -S-, -C(═O)-, -C(═O)O-, -C(═S)-, -S(═O)-, or -S(═O) ₂ -;

L can also be a single bond that only serves as a link;

T _21-22 are independently selected from C(R _t ), N;

X is selected from (CH2) _n optionally substituted by _R01 , n is selected from 0, 1, 2 or 3, preferably 0, 1, or 2;

Y is selected from (CH2) _m optionally substituted by _R01 , m is selected from 0, 1, 2 or 3, preferably 1, 2, or 3;

R _21-23 and R _d3-d7 are independently selected from H and R ₀₃ ;

R _24-27 , R _d1 , R _d2 , and R _t are each independently selected from H, F, Cl, Br, I, CN, OH, SH, and NH ₂ , or selected from C _1-10 alkyl or heteroalkyl groups optionally substituted with R ₀₁ , C _3-10 cycloalkyl or heterocycloalkyl groups, or C _1-10 alkyl or heteroalkyl groups substituted with C _3-10 cycloalkyl or heterocycloalkyl groups;

R ₀₁ is selected from F, Cl, Br, I, CN, OH, SH, NH ₂ , R ₀₂ ;

R ₀₂ is selected from C _1-10 alkyl, C _1-10 alkylamino, N,N-di(C _1-10 alkyl)amino, C _1-10 alkoxy, C _1-10 alkanoyl, C _1-10 alkoxycarbonyl, C _1-10 alkylsulfonyl, C _1-10 alkylsulfinyl, C _3-10 cycloalkyl, C 3-10 cycloalkylamino, C _3-10 heterocycloalkylamino, C _3-10 cycloalkyloxy, C _3-10 cycloalkylacyl, C _3-10 cycloalkyloxycarbonyl, C _3-10 cycloalkylsulfonyl, C _3-10 cycloalkylsulfinyl _;

The heteroatom or heteroatom group is independently selected from -C(=O)N(R _d3 )-, -N(R _d4 )-, -C(=NR _d5 )-, -S(=O) ₂ N(R _d6 )-, -S(=O)N(R _d7 )-, -O-, -S-, C(=O)O, -C(=O)-, -C(=S)-, -S(=O)- and/or -S(=O) ₂ -;

R _d3-d7 are independently selected from H, R ₀₃ ;

R ₀₃ is selected from C _1-10 alkyl, C _1-10 alkylacyl, C _1-10 alkoxycarbonyl, C _1-10 alkylsulfonyl, C _1-10 alkylsulfinyl, C _3-10 cycloalkyl, C _3-10 cycloalkylacyl, C _{3-10 cycloalkyloxycarbonyl, C 3-10 cycloalkylsulfonyl} , C _3-10 cycloalkylsulfinyl;

R ₀₂ and R ₀₃ are optionally substituted by R ₀₀₁ ;

R ₀₀₁ is selected from F, Cl, Br, I, CN, OH, N(CH ₃ ) ₂ , NH(CH ₃ ), NH ₂ , trifluoromethyl, aminomethyl, hydroxymethyl, methyl, methoxy, formyl, methoxycarbonyl, methylsulfonyl, methylsulfinyl;

The number of R ₀₁ , R ₀₀₁ , heteroatoms or heteroatom groups is independently selected from 0, 1, 2 or 3.

In one embodiment of the present invention, R ₁ and R ₃ are independently selected from H, F, Cl, Br, I, CN, OH, SH, NH ₂ , C _1-3 alkyl, C _1-3 alkoxy, benzyloxy, or R ₁₀₁ is selected from H, methyl, ethyl, n-propyl, or isopropyl.

In one embodiment of the present invention, the _R1 is selected from H, methyl, methoxy, benzyloxy,

In one embodiment of the present invention, R ₃ is selected from H, F, Cl, Br, CN, and methyl.

In one embodiment of the present invention, R ₂ is selected from -CH ₂ N(R ₂₀₁ )(R ₂₀₂ ), R ₂₀₁ and R ₂₀₂ are independently selected from H, C _1-3 alkyl, C _1-3 alkylacyl, C _3-6 cycloalkylacyl or C _3-6 cycloalkyl;

In one embodiment of the present invention, R ₂₀₁ and R ₂₀₂ are independently selected from H or cyclopropanoyl.

In one embodiment of the present invention, the R ₂ is selected from

In one embodiment of the present invention, R ₂ is selected from R ₂₀₃ , R ₂₀₄ , R ₂₁₇ , and R ₂₁₈ , each independently selected from H, optionally substituted C _1-3 alkyl, cyclopropyl, or cyclopropylmethylene, and the substituent is selected from F, Cl, Br, I, CN, OH, NH ₂ , methyl, or methoxy, and the number of substituents is 0, 1, 2, or 3.

In one embodiment of the present invention, R ₂₀₃ is selected from methyl, ethyl, n-propyl, isopropyl, -CH ₂ C(CH ₃ )(CH ₃ )(OH), and cyclopropylmethylene.

In one embodiment of the present invention, R ₂₀₄ is selected from methyl, ethyl, n-propyl, and isopropyl.

In one embodiment of the present invention, R _217-219 are independently selected from ethyl and methyl.

In one embodiment of the present invention, the R ₂ is selected from

In one embodiment of the present invention, R ₂ is selected from R ₂₀₅ and R ₂₀₆ are independently selected from H, optionally substituted C1-3 alkyl, cyclopropyl or cyclopropylmethylene, and the substituents are selected from F, Cl, Br, I, CN, OH, NH ₂ , methyl or methoxy, and the number of substituents is 0, 1, 2 or 3.

In one embodiment of the present invention, R ₂₀₅ and R ₂₀₆ are each independently preferably H, methyl, ethyl, n-propyl, or isopropyl, and R ₂₀₆ may also be preferably F, Cl, Br, I, CN, OH, or NH ₂ .

In one embodiment of the present invention, the R ₂ is selected from

In one embodiment of the present invention, the R ₂ is selected from

In one embodiment of the present invention, R ₂ is selected from R ₂₀₇ , H, optionally substituted C _1-3 alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclobutylmethylene, oxetanyl or oxetanylmethylene, the substituents are selected from F, Cl, Br, I, CN, OH, NH ₂ , methyl, trifluoromethyl, methoxy, methylsulfonyl, and the number of substituents is 0, 1, 2 or 3.

In one embodiment of the present invention, R ₂₀₇ is selected from H, methyl, ethyl, n-propyl, isopropyl, -CH ₂ CF ₃ , -CH ₂ CH ₂ CF ₃ , -CH ₂ CH ₂ F, -CH ₂ CH ₂ S(=O) ₂ CH ₃ , -CH ₂ CH ₂ CN,

In one embodiment of the present invention, the R ₂ is selected from

In one embodiment of the present invention, R ₂ or R ₂₀₈ is selected from H, optionally substituted C _1-4 alkyl, the substituents are selected from F, Cl, Br, I, CN, OH, NH ₂ , methyl, trifluoromethyl, methoxy, methylsulfonyl, and the number of substituents is 0, 1, 2 or 3.

In one embodiment of the present invention, R ₂₀₈ is selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropylmethylene, and cyclobutyl.

In one embodiment of the present invention, the R ₂ is selected from

In one embodiment of the present invention, R ₂ is selected from R ₂₀₉ selected from -C(R _d1 )(R _d2 )-, -C(＝O)N(R _d3 )-, -N(R _d4 )-, -C(＝NR _d5 )-, -S(＝O) ₂ N(R _d6 )-, -S(＝O)N(R _d7 )-, -O-, -S-, C(＝O)O, -C(＝O)-, -C(＝S)-, -S(＝O)- or -S(＝O) ₂ -, and R _d1-d7 are as defined in claim 1;

In one embodiment of the present invention, R ₂₀₉ is selected from O and S(═O) ₂ .

In one embodiment of the present invention, R ₂ is selected from R ₂₁₀ , which is selected from H, F, Cl, Br, I, CN, OH, NH ₂ , N,N-di(C _1-3 alkyl)amino, and C _1-3 alkylamino.

In one embodiment of the present invention, R ₂₁₀ is selected from dimethylamino, methylamino, H, F, Cl, Br, I, CN, OH, and NH ₂ .

In one embodiment of the present invention, the R ₂ is selected from

R _211-214 is selected from H or C _1-4 alkoxycarbonyl, C _1-4 alkyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkylmethylene or 5-6 membered unsaturated heterocyclic hydrocarbon group optionally substituted by R ₂₁₅ , R _211-213 is further selected from F, Cl, Br, I, CN, OH, NH ₂ ,

The cycloalkyl group or unsaturated heterocyclic hydrocarbon group contains 0, 1 or 2 O, S or NR ₂₁₆ ,

R ₂₁₆ is selected from optionally H, R ₂₁₅ substituted C _1-4 alkyl,

R ₂₁₅ is selected from F, Cl, Br, I, CN, OH, NH ₂ , methyl, ethyl, methoxy, ethoxy, formyl, acetyl, methylsulfonyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, dimethylamino, diethylamino, dimethylaminocarbonyl, diethylaminocarbonyl, oxo, and the number of R ₂₁₅ is 1, 1, 2, or 3.

Optionally, R ₂₁₂ and R ₂₁₃ together form a linking bond -CH ₂ -, -CH ₂ CH ₂ -, or -CH ₂ CH ₂ CH ₂ -;

In one embodiment of the present invention, the

R ₂₁₁ is selected from H, F, Cl, Br, I, CN, OH, NH ₂ , methyl, ethyl, hydroxymethyl, methoxycarbonyl,

R ₂₁₂ is selected from H, F, Cl, Br, I, CN, OH, NH ₂ , methyl,

R ₂₁₃ is selected from H, F, Cl, Br, I, CN, OH, NH ₂ ,

R ₂₁₄ is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CH2C(OH) _{( CH3 ) 2 , -CH2C} (F _{) ( CH3} ) _{2 , -CH2CH2F} , _-CH2CF3 , _{-CH2CH2CF3 ,} -CH2CH2NH2 _{, -CH2CH2OH ,} -CH2CH2CN _{, -CH2CH2OCH3} , _{-CH2CH2CH2OCH3} , _-CH2CH2N ( _{CH3 ) 2} , -S _{( =} O _{) 2CH3 , -CH2CH2S} ( ₌ O _{) 2CH3 , cyclopropyl} , cyclopropylmethylene _,

In one embodiment of the present invention, the R ₂ is selected from

In one embodiment of the present invention, R ₂ is selected from T ₂₂ is selected from N or C (R ₂₂₄ ); R _220-224 are independently selected from H, F, Cl, Br, I, CN, OH, SH, NH ₂ , C _1-3 alkylamino, C _1-3 alkyl,

In one embodiment of the present invention, the C _1-3 alkylamino C _1-3 alkyl group is selected from methylaminomethylene.

In one embodiment of the present invention, the R ₂ is selected from

In one embodiment of the present invention, the compound or a pharmaceutically acceptable salt thereof is selected from:

1) 6-fluoro-3-(piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

2) 3-(1-ethylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

3) 6-fluoro-3-(1-(2-fluoroethyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

4) 3-(1-cyclopropylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

5) 3-(1-(cyclopropylmethyl)piperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

6) 6-fluoro-3-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

7) 6-fluoro-3-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

8) 3-(1-(cyclopropylcarbonyl)piperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

9) 6-fluoro-3-(1-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

10) 6-fluoro-3-(1-isopropylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

11) 6-fluoro-3-(1-(oxetan-3-yl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

12) 6-fluoro-3-(1-propylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

13) 6-fluoro-3-(1-(2-aminoethyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

14) 3-(1-(2-(dimethylamino)ethyl)piperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

15) 6-fluoro-3-(1-(2-methoxyethyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

16) 6-fluoro-3-(1-(2-hydroxyethyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

17) 3-(1-ethylpiperidin-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

18) 3-(1-ethylazepan-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

19) 6-fluoro-3-(1-methylazepan-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

20) 6-fluoro-3-(1-methylpyrrolidin-3-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

21) 3-(1-ethylpyrrolidin-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

22) 6-Fluoro-3-(1-isopropylpyrrolidin-3-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

23) 6-Fluoro-3-(pyrrolidin-2-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

24) 6-Fluoro-3-(1-methylpyrrolidin-2-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

25) 3-(1-ethylpyrrolidin-2-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

26) 3-(1-ethylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

27) 6-fluoro-3-(1-propylpyrrolidin-2-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

28) 6-fluoro-3-(3-methyl-3-azabicyclo[3.1.0]hexan-1-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

29) 3-(3-ethyl-3-azabicyclo[3.1.0]hexan-1-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

30) 3-(3-cyclobutyl-3-azabicyclo[3.1.0]hexan-1-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

31) 3-(3-cyclopropylmethylene-3-azabicyclo[3.1.0]hexan-1-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

32) 6-fluoro-3-(3-isopropyl-3-azabicyclo[3.1.0]hexan-1-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

33) 3-(3-Azabicyclo[3.1.0]hexan-6-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

34) 3-(3-ethyl-3-azabicyclo[3.1.0]hexan-6-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

35) 3-(8-ethyl-8-azabicyclo[3.2.1]octan-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

36) 6-fluoro-3-(4-hydroxypyrrolidin-2-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

37) 3-cyano-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

38) 3-cyano-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

39) 3-aminomethyl-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

40) 3-(cyclopropylcarboxamidomethylene)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

41) 6-Fluoro-3-(4-fluorophenyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

42) 6-fluoro-3-(2-fluoro-4-((methylaminomethylene)phenyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

43) 6-fluoro-3-(4-((methylamino)methyl)phenyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

44) 6-fluoro-3-(2-fluoro-5-((methylamino)methyl)phenyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

45) 6-fluoro-3-(pyridin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

46) 6-fluoro-3-(4-(piperidin-3-yl)phenyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

47) 6-fluoro-3-(tetrahydro-2H-pyran-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

48) 3-(4-(dimethylamino)cyclohexyl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

49) 6-Fluoro-3-(4-methylpiperazine-1-carbonyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

50) 3-(1-(cyclopropylmethyl)piperidin-4-yl)-4,4,6-trifluoro-4H-pyrazolo[1,5-a]indole-8-carboxamide;

51) 3-(1-ethylpiperidin-4-yl)-6-fluoro-4-hydroxy-4H-pyrazolo[1,5-a]indole-8-carboxamide;

52) 3-(1-ethylpiperidin-4-yl)-6-fluoro-4-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

53) 6-fluoro-3-(4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

54) 3-(1-ethyl-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

55) 3-(1-cyclopropyl-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

56) 6-fluoro-3-(1-(2-hydroxy-2-methylpropyl)-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

57) 3-(1-cyclopropylmethylene-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

58) 3-(1-(4,4-difluorocyclohexyl)-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

59) 6-fluoro-3-(4-methyl-1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

60) 6-fluoro-3-(1-(2-fluoroethyl)-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

61) 6-fluoro-3-(4-methyl-1-(2,2,2-trifluoroethyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

62) 6-Fluoro-3-(4-methyl-1-(2,2,2-trifluoropropyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

63) 3-(1-((1-cyanocyclopropyl)methyl)-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

64) 3-(1-((1-cyanocyclobutyl)methyl)-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

65) 6-fluoro-3-(4-methyl-1-(2-(methylsulfonyl)ethyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

66) 6-fluoro-3-(4-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

67) 3-(1-((1-aminocyclopropyl)methyl)-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

68) 6-fluoro-3-(4-methyl-1-(oxetan-3-ylmethyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

69) 6-fluoro-3-(1-(2-methoxyethyl)-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

70) 6-fluoro-3-(1-((1-hydroxycyclopropyl)methyl)-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

71) 6-fluoro-3-(4-methyl-1-((3-methyloxetan-3-yl)methyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

72) 6-fluoro-3-(1-(3-methoxypropyl)-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

73) 6-fluoro-3-(4-methyl-1-((1-(methylsulfonyl)cyclopropyl)methyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

74) 6-fluoro-3-(4-methyl-1-(thiazol-2-ylmethyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

75) 6-fluoro-3-(4-methyl-1-(methylsulfonyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

76) 6-fluoro-3-(1-(3-fluorocyclobutyl)-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

77) 6-fluoro-3-(4-methyl-1-(thien-2-ylmethyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

78) 3-(1-((1-ethylpiperidin-4-yl)methyl)-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

79) 6-fluoro-3-(4-methyl-1-((1-methylazetidin-3-yl)methyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

80) ethyl 2-((4-(8-carbamoyl-6-fluoro-4H-benzo[4,5]imidazo[1,2-B]pyrazol-3-yl)-4-methylpiperidin-1-yl)methyl)cyclopropanecarboxylate;

81) 3-(1-((2-(dimethylaminomethyl)cyclopropyl)methyl)-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

82) 6-Fluoro-3-(1-isobutyl-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

83) 6-fluoro-3-(4-methyl-1-((4-methylthiazol-5-yl)methyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

84) 6-fluoro-3-(4-methyl-1-((1-methyl-1H-imidazol-2-yl)methyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

85) 3-(1-((1,2-dimethyl-1H-imidazol-5-yl)methyl)-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

86) 3-(1′-ethyl-4-methyl-[1,4′-bipiperidinyl]-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

87) 6-fluoro-3-(4-methyl-1-((6-oxo-1,6-dihydropyridazin-3-yl)methyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

88) 3-(1-(2-cyanoethyl)-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

89) 6-chloro-3-(1-ethyl-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

90) 3-(1-ethyl-3-methylpyrrolidin-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

91) 3-(1,3-dimethylpyrrolidin-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

92) 6-Fluoro-3-(1-isopropyl-3-methylpyrrolidin-3-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

93) 3-(1-(cyclopropylmethyl)-3-methylpyrrolidin-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

94) 6-fluoro-3-(3-methyl-1-(oxetan-3-yl)pyrrolidin-3-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

95) 6-fluoro-3-(1-(2-fluoroethyl)-3-methylpyrrolidin-3-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

96) 3-(1-((2,2-difluorocyclopropyl)methyl)-3-methylpyrrolidin-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

97) 6-fluoro-3-(3-methyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

98) 6-fluoro-3-(3-methyl-1-(2-(methylsulfonyl)ethyl)pyrrolidin-3-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

99) 6-fluoro-3-(3-methyl-1-(3,3,3-trifluoropropyl)pyrrolidin-3-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

100) 3-(1-((1-aminocyclopropyl)methyl)-3-methylpyrrolidin-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

101) 3-(1-((1-cyanocyclobutyl)methyl)-3-methylpyrrolidin-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

102) 3-(1-((1-cyanocyclopropyl)methyl)-3-methylpyrrolidin-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

103) 3-(1-(2-cyanoisoyl)-3-methylpyrrolidin-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

104) 3-(1-(cyclopropylmethyl)-3-methylpyrrolidin-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

105) 6-fluoro-3-(1-isopropyl-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

106) 6-fluoro-3-(4-methyl-1,1-dioxo-2H-thiopyran-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

107) 3-(1,4-ethylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

108) 3-(4-cyano-1-(cyclopropylmethyl)piperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

109) 3-(4-hydroxymethyl-1-(cyclopropylmethyl)piperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

110) ethyl 4-(8-formamido-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazol-3-yl)-1-(cyclopropylmethyl)piperidine-4-carboxylate;

111) 3-(1-(cyclopropylmethyl)-4-methylpiperidin-4-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

112) 3-(1-ethyl-4-methylpiperidin-4-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

113) 3-(1-isobutyl-4-methylpiperidin-4-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

114) 3-(1-isopropyl-4-methylpiperidin-4-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

115) 3-(1,4-dimethylpiperidin-4-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

116) 3-(1-(2-hydroxy-2-methylpropyl)-4-methylpiperidin-4-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

117) 3-(1-ethyl-2,4-dimethylpiperidin-4-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

118) 3-(1-ethyl-3-methylpyrrolidin-3-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

119) 3-(1-isopropyl-3-methylpyrrolidin-3-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

120) 3-(1-(cyclopropylmethyl)-3-methylpyrrolidin-3-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

121) 3-(1,3-dimethylazepin-3-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

122) 3-(1-ethyl-3-methylazepin-3-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

123) 3-(1-isopropyl-3-methylazepin-3-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

124) 3-(1-(cyclopropylmethyl)-3-methylazepin-3-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

125) 3-(1-(2-hydroxy-2-methylpropyl)-3-methylazepin-3-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

126) 6-fluoro-3-(1-isopropyl-4-methylpiperidin-4-yl)-2-methoxy-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

127) 2-Benzylmethoxy-6-fluoro-3-(1-isopropyl-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;

128) 6-fluoro-2-(piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; and

129) 2-(1-Ethylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide.

Definitions:

_C1-10 is selected from the group consisting of _C1 , C2, _C3 , _C4 , _C5 , _C6 , _{C7 , C8 , C9} and _C10 ; _C3-10 is selected from the group consisting of _C3 , _C4 , _C5 , _C6 , _C7 , _C8 , _C9 and _C10 .

C _1-10 alkyl or heteroalkyl, C _3-10 cyclyl or heterocycloalkyl, C _1-10 alkyl or heteroalkyl substituted by C _3-10 cyclyl or heterocycloalkyl include, but are not limited to:

C _1-10 alkyl, C _1-10 alkylamino, N,N-di(C _1-10 alkyl)amino, C _1-10 alkoxy, C 1-10 alkanoyl, C _1-10 alkoxycarbonyl, C _1-10 alkylsulfonyl, C _1-10 alkylsulfinyl, C _3-10 cycloalkyl, C _3-10 cycloalkylamino, C _3-10 heterocycloalkylamino, C _3-10 cycloalkyloxy, C _3-10 cycloalkylacyl, C _3-10 cycloalkyloxycarbonyl, C _3-10 cycloalkylsulfonyl, C _3-10 cycloalkylsulfinyl _;

methyl, ethyl, n-propyl, isopropyl, -CH2C(CH3)(CH3)(OH), cyclopropyl, cyclobutyl, propylmethylene, cyclopropanoyl, benzyloxy, trifluoromethyl, aminomethyl, hydroxymethyl, methoxy, formyl, methoxycarbonyl, methylsulfonyl, methylsulfinyl, ethoxy, acetyl, ethylsulfonyl, ethoxycarbonyl, dimethylamino, diethylamino, dimethylaminocarbonyl, diethylaminocarbonyl;

N(CH ₃ ) ₂ , NH(CH ₃ ), -CH ₂ CF ₃ , -CH2CH ₂ CF ₃ , -CH ₂ CH ₂ F, -CH ₂ CH ₂ S(=O) ₂ CH ₃ , -CH ₂ CH ₂ CN, -CH ₂ CH(OH)(CH3) ₂ , -CH ₂ CH(F)(CH ₃ ) ₂ , -CH ₂ CH ₂ F, -CH ₂ CF ₃ , -CH ₂ CH ₂ CF ₃ , -CH ₂ CH ₂ NH ₂ , -CH ₂ CH ₂ OH, -CH ₂ CH ₂ OCH ₃ , -CH ₂ CH ₂ CH ₂ OCH ₃ , -CH ₂ CH ₂ N(CH ₃ ) ₂ , -S(=O) ₂ CH ₃ , -CH ₂ CH ₂ S(=O) ₂ CH ₃ , and

phenyl, thiazolyl, biphenyl, naphthyl, cyclopentyl, furanyl, 3-pyrrolinyl, pyrrolidinyl, 1,3-oxopentacyclyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, imidazolyl, oxazolyl, thiazolyl, 1,2,3-oxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-thiadiazolyl, 4H-pyranyl, pyridyl, piperidyl, 1,4-dioxanyl, morpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3,5-trithianyl, 1,3,5-triazinyl, benzofuranyl, benzothiophenyl, indolyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, or quinoxalinyl;

The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared by reacting the compounds of the present invention with relatively nontoxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts, or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, bisulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and salts of amino acids such as arginine, and organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the present invention contain both basic and acidic functional groups and can be converted into either base or acid addition salts.

Preferably, the neutral form of the compound is regenerated by contacting the salt with a base or acid in a conventional manner and isolating the parent compound. The parent form of the compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.

As used herein, "pharmaceutically acceptable salts" are derivatives of the compounds of the present invention wherein the parent compound is modified by acid or base salt formation. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid radicals such as carboxylic acids, and the like. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound, such as salts formed with non-toxic inorganic or organic acids. Conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodide, hydroxy, hydroxynaphthalene, isethionic acid, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, sulfamic acid, p-aminobenzenesulfonic acid, sulfuric acid, tannin, tartaric acid, and p-toluenesulfonic acid.

The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent, or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.

In addition to the form of salts, the compounds provided by the present invention also exist in prodrug form. The prodrugs of the compounds described herein easily undergo chemical changes under physiological conditions to be converted into the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.

Some compounds of the present invention may exist in unsolvated or solvated forms, including hydrate forms. Generally speaking, solvated forms are comparable to unsolvated forms and are included within the scope of the present invention. Some compounds of the present invention may exist in polycrystalline or amorphous forms.

Certain compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all within the scope of the present invention.

The diagrammatic representations of racemic, ambiscalemic, scalemic, or enantiomerically pure compounds herein are adapted from Maehr, J. Chem. Ed. 1985, 62:114-120. Unless otherwise indicated, wedge-shaped and dashed bonds are used to represent the absolute configuration at a stereocenter. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they are intended to include both E and Z geometric isomers unless otherwise specified. Likewise, all tautomeric forms are intended to be encompassed within the scope of this invention.

The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are encompassed within the scope of the present invention.

Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by fractional crystallization or chromatography as is known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished by using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms comprising the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( ³ H), iodine-125 ( ¹²⁵ I), or C-14 ( ¹⁴ C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient. Representative carriers include water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, viscosity increasing agents, transdermal enhancers, etc. Their preparations are well known to those skilled in the art of cosmetics or topical medicine. For additional information on carriers, reference can be made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

The term "excipient" generally refers to a carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.

With respect to a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a non-toxic amount of the drug or agent sufficient to achieve the intended effect. For the oral dosage forms of the present invention, an "effective amount" of an active substance in the composition means the amount required to achieve the intended effect when used in combination with another active substance in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.

The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is a keto group (i.e., =0), it means that two hydrogen atoms are replaced. Keto substitution does not occur on aromatic groups. The term "optionally substituted" means that it may be substituted or unsubstituted, and unless otherwise specified, the type and number of substituents can be any chemically feasible basis.

When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and/or their variants are permissible only if such combinations result in stable compounds.

When a substituent's bond crosses two atoms in a ring, such substituent may be bonded to any atom in the ring. When a substituent is listed without specifying the atom through which it is bonded to a compound included in the general chemical formula but not specifically mentioned, such substituent may be bonded to any atom therein. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

Substituents for alkyl and heteroalkyl radicals (including those groups commonly referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) are generally referred to as "alkyl substituents" and may be selected from, but are not limited to, one or more of the following groups: -R', -OR', =O, =NR', =N-OR', -NR'R", -SR', halogen, -SiR'R"R"', OC(O)R', -C(O)R', _-CO2R ', -CONR'R", -OC(O)NR'R", -NR"C(O)R', NR'C(O)NR"R"', -NR"C(O) _2R ', -NR""', -C(NR'R"R"')=NR"", NR""C(NR'R")=NR"', -S(O)R', -S(O) _2R ', -S(O) ₂ NR'R", NR" _SO2R ', -CN, _-NO2 , _-N3 , -CH(Ph) ₂ and fluoro( _C1 - _C4 )alkyl, the number of substituents being 0 to (2m'+1), where m' is the total number of carbon atoms in such radicals. R', R", R"', R"" and R""' are each independently preferably hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1 to 3 halogens), substituted or unsubstituted alkyl, alkoxy, thioalkoxy or aralkyl. When a compound of the present invention includes more than one R group, for example, each R group is independently selected, as are each of these groups when more than one R', R", R"', R"" and R""' group is present. When R' and R" are attached to the same nitrogen atom, they may be combined with the nitrogen atom to form a 5-, 6- or 7-membered ring. For example, -NR'R" is intended to include but is not limited to 1-pyrrolidinyl and 4-morpholinyl. Based on the above discussion of substituents, those skilled in the art will understand that the term "alkyl" is intended to include groups consisting of a carbon atom bonded to _a non-hydrogen group, such as haloalkyl (e.g., _-CF3 , _-CH2CF3 ) and acyl (e.g., -C(O) _CH3 , -C(O) _CF3 , -C(O) _CH2OCH3 , _etc. ).

Similar to the substituents described for alkyl radicals, aryl and heteroaryl substituents are generally referred to as "aryl substituents" and are selected from, for example, -R', -OR', -NR'R", -SR', -halogen, -SiR'R"R"', OC(O)R', -C(O)R', -C02R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', NR'C(O)NR"R"', -NR"C(O)2R', -NR""'-C(NR'R"R"')＝NR"", NR""C(NR'R")＝NR"', -S(O)R', -S(O) _2R ', -S(O) _2NR'R ", NR" _SO2R ', -CN, _-NO2 , _-N3 , -CH(Ph) ₂ , fluoro( _C1 - _C4) )alkoxy and fluoro(C ₁ -C ₄ )alkyl, and the like, with the number of substituents ranging from 0 to the total number of open valences on the aromatic ring; wherein R', R", R'", R"" and R""' are independently preferably selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. When a compound of the present invention includes more than one R group, for example, each R group is independently selected, as are each of these groups when more than one R', R", R'", R"" and R""' group is present.

Two substituents on adjacent atoms of an aryl or heteroaryl ring may be optionally substituted with substituents of the formula -TC(O)-(CRR')qU-, wherein T and U are independently selected from -NR-, -O-, CRR'-, or a single bond, and q is an integer from 0 to 3. Alternatively, two substituents on adjacent atoms of an aryl or heteroaryl ring may be optionally substituted with substituents of the formula -A(CH2)rB-, wherein A and B are independently selected from -CRR'-, -O-, -NR-, -S-, -S(O)-, S(O) _2- , -S(O) _2NR'- , or a single bond, and r is an integer from 1 to 4. Optionally, one single bond in the new ring thus formed may be replaced with a double bond. Alternatively, two substituents on adjacent atoms of an aryl or heteroaryl ring may be optionally substituted with substituents of the formula -A(CH2)rB-, wherein s and d are independently selected from integers from 0 to 3, and X is -O-, -NR', -S-, -S(O)-, -S(O) _2- , or -S(O) _2NR'- . The substituents R, R', R", and R'" are independently selected from hydrogen and substituted or unsubstituted ( _C1 - _C6 )alkyl.

Unless otherwise specified, the term "hydrocarbyl" or its subordinate concepts (such as alkyl, alkenyl, alkynyl, phenyl, etc.) by itself or as part of another substituent represents a linear, branched or cyclic hydrocarbon radical or a combination thereof, which may be fully saturated, mono- or polyunsaturated, mono-, di- or poly-substituted, and may include divalent or polyvalent radicals, and have a specified number of carbon atoms (such as _C1 - _C10 represents 1 to 10 carbons). "Hydrocarbyl" includes but is not limited to aliphatic and aromatic hydrocarbon radicals, the aliphatic hydrocarbon radicals including chain and cyclic ones, specifically including but not limited to alkyl, alkenyl, and alkynyl, and the aromatic hydrocarbon radicals including but not limited to 6-12 membered aromatic hydrocarbon radicals, such as benzene, naphthalene, etc. In some embodiments, the term "alkyl" represents a linear or branched radical or a combination thereof, which may be fully saturated, mono- or polyunsaturated, and may include divalent and polyvalent radicals. Examples of saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, and homologues or isomers of radicals such as n-pentyl, n-hexyl, n-heptyl, and n-octyl. Unsaturated alkyl radicals have one or more double or triple bonds, and examples thereof include, but are not limited to, vinyl, 2-propenyl, butenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologues and isomers.

Unless otherwise specified, the term "heteroalkyl" or its subordinate concepts (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.) by itself or in combination with another term means a stable linear, branched or cyclic hydrocarbon radical or combination thereof, consisting of a certain number of carbon atoms and at least one heteroatom. In some embodiments, the term "heteroalkyl" by itself or in combination with another term means a stable linear, branched or cyclic hydrocarbon radical or combination thereof, consisting of a certain number of carbon atoms and at least one heteroatom. In a typical embodiment, the heteroatom is selected from B, O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. The heteroatoms B, O, N and S may be located at any interior position of the heteroalkyl group (except the position at which the alkyl group is attached to the rest of the molecule). Examples include, but are not limited to, _-CH2 - _CH2 -O- _CH3 , _-CH2 - _CH2 -NH- _CH3 , _{-CH2 -CH2} -N( _CH3 ) _-CH3 , -CH2 _- S- _CH2 - _CH3 , -CH2 _{- CH2} , -S(O) _-CH3 , _-CH2- CH2 _- S(O) _{2- CH3} , -CH=CH-O- _CH3 , _-CH2 -CH=N- _OCH3 , and -CH=CH-N( _CH3 ) _-CH3 . Up to two heteroatoms may be consecutive, for example, _-CH2- NH- _OCH3 .

The terms "alkoxy," "alkylamino," and "alkylthio" (or thioalkoxy) are conventional expressions referring to those alkyl groups that are attached to the remainder of the molecule through an oxygen, amino, or sulfur atom, respectively.

Unless otherwise specified, the terms "cycloalkyl," "heterocycloalkyl," "cycloalkylheteroalkyl," or their sub-groups (e.g., aryl, heteroaryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkylheteroalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, cycloalkynylheteroalkyl, etc.), by themselves or in combination with other terms, refer to a cyclized "alkyl," "heteroalkyl," or "alkylheteroalkyl," respectively. Furthermore, in the case of heteroalkyl or heterocycloalkyl (e.g., heteroalkyl, heterocycloalkyl), a heteroatom may occupy the position at which the heterocycle is attached to the rest of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Non-limiting examples of heterocyclic groups include 1-(1,2,5,6-tetrahydropyridinyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuranindol-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, and 2-piperazinyl.

Unless otherwise specified, the term "halo" or "halogen," by itself or as part of another substituent, means a fluorine, chlorine, bromine, or iodine atom. Additionally, the term "haloalkyl" is intended to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C ₁ -C ₄ )alkyl" is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, and 3-bromopropyl, among others.

Unless otherwise specified, the term "aryl" represents a polyunsaturated aromatic hydrocarbon substituent, which can be monosubstituted, disubstituted or polysubstituted, and can be monocyclic or polycyclic (preferably 1 to 3 rings), which are fused together or covalently linked. The term "heteroaryl" refers to an aryl group (or ring) containing one to four heteroatoms. In an exemplary embodiment, the heteroatoms are selected from B, N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. The heteroaryl group can be connected to the rest of the molecule through the heteroatoms. Non-limiting examples of aryl or heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolyl. Substituents for any of the above aryl and heteroaryl ring systems are selected from the group consisting of acceptable substituents described below.

For simplicity, aryl when used in conjunction with other terms (e.g., aryloxy, arylthio, arylalkyl) includes both aryl and heteroaryl rings as defined above. Thus, the term "arylalkyl" is intended to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, etc.), including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom, such as phenoxymethyl, 2-pyridyloxymethyl-3-(1-naphthyloxy)propyl, etc.

"Ring" means a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. The so-called ring includes a fused ring. The number of atoms in the ring is usually defined as the number of ring members, for example, "5- to 7-membered ring" means 5 to 7 atoms arranged around it. Unless otherwise specified, the ring optionally contains 1 to 3 heteroatoms. Therefore, "5- to 7-membered ring" includes, for example, phenylpyridine and piperidinyl; on the other hand, the term "5- to 7-membered heterocycloalkyl ring" includes pyridinyl and piperidinyl, but does not include phenyl. The term "ring" also includes a ring system containing at least one ring, each of which "rings" independently meets the above definition.

The term "heteroatom" as used herein includes atoms other than carbon (C) and hydrogen (H), for example, oxygen (O), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Al) and boron (B).

The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (e.g., an affine substitution reaction). For example, representative leaving groups include trifluoromethanesulfonate; chloro, bromo, iodo; sulfonate groups such as methanesulfonate, toluenesulfonate, p-bromobenzenesulfonate, p-toluenesulfonate, etc.; acyloxy groups such as acetoxy and trifluoroacetoxy, etc.

The term "protecting group" includes, but is not limited to, an "amino protecting group," a "hydroxy protecting group," or a "thiol protecting group." The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl, such as tert-butyloxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-bis-(4'-methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like. The term "hydroxy protecting group" refers to a protecting group suitable for preventing side reactions at the hydroxyl group. Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (e.g., acetyl); arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like.

Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. "Alkoxy" represents an alkyl group as described above with the specified number of carbon atoms attached through an oxygen bridge. _C1-6 alkoxy groups include _C1 , _C2 , _C3 , _C4 , _C5 , and _C6 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, and S-pentoxy. "Cycloalkyl" includes saturated cyclic groups such as cyclopropyl, cyclobutyl, or cyclopentyl. C3-7 cycloalkyl includes _C3 , _C4 , _C5 , _C6 , and _C7 cycloalkyl groups. "Alkenyl" includes hydrocarbon chains in a straight or branched configuration with one or more carbon-carbon double bonds present at any stable position along the chain, such as ethenyl and propenyl. The term "halogen" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

The term "heterocycle" or "heterocyclyl" means a stable monocyclic or bicyclic heterocycle, which may be saturated, partially unsaturated, or unsaturated (aromatic), and which comprises carbon atoms and 1, 2, 3, or 4 ring heteroatoms independently selected from N, O, and S, wherein any of the above heterocycles may be fused to a benzene ring to form a bicyclic ring. The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)p). The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or other substituents as defined herein). The heterocycle may be attached to any heteroatom or carbon atom pendant group that forms a stable structure. The heterocycles described herein may be substituted at the carbon or nitrogen positions if the resulting compound is stable. The nitrogen atoms in the heterocycle may be quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, the heteroatoms are not adjacent to each other. Another preferred embodiment is that the total number of S and O atoms in the heterocycle does not exceed 1. As used herein, the term "aromatic heterocyclic group" or "heteroaryl" refers to a stable 5-, 6-, or 7-membered monocyclic or bicyclic or 7-, 8-, 9-, or 10-membered bicyclic heterocyclic aromatic ring comprising carbon atoms and 1, 2, 3, or 4 ring heteroatoms independently selected from N, O, and S. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or other substituents as defined herein). The nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O)p). It is noted that the total number of S and O atoms in the aromatic heterocyclic ring does not exceed 1. Bridged rings are also included in the definition of heterocycle. A bridged ring is formed when one or more atoms (i.e., C, O, N, or S) link two non-adjacent carbon atoms or nitrogen atoms. Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. In bridged rings, substituents on the ring may also appear on the bridge.

Examples of heterocyclic compounds include, but are not limited to, acridinyl, azcinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromene, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuranyl, furanyl, furazanyl, alkyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolene, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, pyran, isoindolyl, isoindolyl, isoindolyl, indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidine oxazolyl, isoxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazine, phenothiazine, benzoxanthinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, pyrazolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxaline The present invention also includes 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, 1,3-dinitro-1,4-dinitro-2,4-dinitro-3,4-dinitro-4, 1,4-dinitro-5, 1,2,5-triazolyl, 1,3,4-triazolyl, 1,4-dinitro-1,4-dinitro-2,4-dinitro-3, 1,2,5-triazolyl, 1,3,4-triazolyl, ...3,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, 1,3,4

The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.

All solvents used in the present invention are commercially available and can be used without further purification. Reactions are generally carried out in anhydrous solvents under inert nitrogen. Proton nuclear magnetic resonance data were recorded on a Bruker Avance III 400 (400 MHz) spectrometer, and chemical shifts were expressed in ppm at low field from tetramethylsilane. Mass spectra were measured on an Agilent 1200 series plus 6110 (&1956A). LC/MS or Shimadzu MS includes a DAD: SPD-M20A (LC) and a Shimadzu Micromass 2020 detector. The mass spectrometer is equipped with an electrospray ionization source (ESI) operating in positive or negative mode.

The present invention uses the following abbreviations: aq represents water; HATU represents (7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate; EDC represents N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride; m-CPBA represents 3-chloroperoxybenzoic acid; eq represents equivalent; CDI represents carbonyldiimidazole; DCM represents dichloromethane; PE represents petroleum ether; DIAD represents diisopropyl azodicarboxylate; DMF represents N,N-dimethylformamide; DMSO represents dimethyl sulfoxide; EtOAc represents ethyl acetate; EtOH represents ethanol; MeOH represents methanol; CBz represents benzyloxycarbonyl, which is an amine protecting group; BOC represents tert-butylcarbonyl, which is an amine protecting group; HOAc represents acetic acid; NaCNBH ₃ represents sodium cyanoborohydride; rt represents room temperature; O/N represents overnight; THF represents tetrahydrofuran; Boc ₂ represents methyl benzoate; O represents di-tert-butyl dicarbonate; TFA represents trifluoroacetic acid; DIPEA represents diisopropylethylamine; SOCl ₂ represents thionyl chloride; CS ₂ represents carbon disulfide; TsOH represents p-toluenesulfonic acid; NFSI represents N-fluoro-N-(phenylsulfonyl)benzenesulfonamide; NCS represents 1-chloropyrrolidine-2,5-dione; n-Bu ₄ NF represents tetrabutylammonium fluoride; iPrOH represents 2-propanol; mp represents melting point.

The compounds were named manually or by software, and commercially available compounds used the supplier's catalog names.

High-performance liquid chromatography (HPLC) analyses were performed on a Shimadzu LC20AB system equipped with a Shimadzu SIL-20A autosampler and a Shimadzu DAD:SPD-M20A detector. An Xtimate C18 column (3 μm packing, 2.1 x 300 mm dimensions) was used. The 0-60AB 6-minute method involved a linear gradient starting with 100% A (0.0675% TFA in water) and ending with 60% B (0.0625% TFA in MeCN) over 4.2 minutes, followed by 1 minute of 60% B. The column was then equilibrated for 0.8 minutes to a 100:0 ratio, for a total run time of 6 minutes. 10-80AB_6 minute method: A linear gradient was applied, starting with 90% A (0.0675% TFA in water) and ending with 80% B (0.0625% TFA in acetonitrile) over 4.2 minutes, followed by 1 minute of 80% B. The column was re-equilibrated for 0.8 minutes to a 90:10 ratio, for a total run time of 6 minutes. The column temperature was 50°C, and the flow rate was 0.8 mL/min. The diode array detector scanned from 200 to 400 nm.

Thin layer chromatography (TLC) was performed on silica gel GF254 from Sanpont-group. Spots were usually detected using UV illumination. In some cases, other methods were used to visualize the spots. In these cases, the plates were developed with iodine (prepared by adding approximately 1 g of iodine to 10 g of silica gel and mixing thoroughly), vanillin (prepared by dissolving approximately 1 g of vanillin in 100 mL _of 10% _H2SO4 ), ninhydrin (purchased from Aldrich), or _a special color developer (prepared by thoroughly mixing ( _NH4 ) _6Mo7O24 · _4H2O , ₅ g of ( _NH4 ) _2Ce (IV)( _NO3 ) ₆ , 450 mL _{of H2O} , and 50 mL of concentrated H2SO4 ₎ to visualize the compounds. Flash column chromatography was performed on Silicycle 40-63 μm (230-400 mesh) silica gel using a method similar to the techniques disclosed in Still, W.C.; Kahn, M.; and Mitra, M. Journal of Organic Chemistry, 1978, 43, 2923-2925. Common solvents for flash column chromatography or thin layer chromatography are mixtures of dichloromethane/methanol, ethyl acetate/methanol, and hexane/ethyl acetate.

Preparative chromatography was performed on a Gilson-281 Prep LC 322 system using a Gilson UV/VIS-156 detector. The columns used were: Agella Venusil ASB Prep C18, 5 m, 150 x 21.2 mm; Phenomenex Gemini C18, 5 m, 150 x 30 mm; Boston Symmetrix C18, 5 m, 150 x 30 mm; or Phenomenex Synergi C18, 4 m, 150 x 30 mm. Compounds were eluted with a low gradient of acetonitrile/water containing either 0.05% HCl, 0.25% HCOOH, or 0.5% _NH₃ · _H₂O at a flow rate of approximately 25 mL/min, with a total run time of 8–15 minutes.

SFC analysis was performed using an Agilent 1260 Infinity SFC system equipped with an Agilent 1260 autosampler and an Agilent DAD:1260 detector. The chromatographic columns used were a Chiralcel OD-H 250 x 4.6 mm ID, 5 µm, a Chiralpak AS-H 250 x 4.6 mm ID, 5 µm, or a Chiralpak AD-H 250 x 4.6 mm ID, 5 µm. Chromatographic conditions for the OD-H_5_40_2.35ML were: a Chiralcel OD-H column (250 x 4.6 mm ID, µm packing), a mobile phase of 40% ethanol (0.05% DEA) _-CO2 , a flow rate of 2.35 mL/min, and detection at 220 nm. Chromatographic conditions for AS-H_3_40_2.35ML: Chiralpak AS-H column (250 x 4.6 mm ID, 5 µm packing); mobile phase: 40% methanol (0.05% DEA) _-CO2 ; flow rate: 2.35 mL/min; detection wavelength: 220 nm. Chromatographic conditions for OD-H_3_40_2.35M: Chiralcel OD-H column (250 x 4.6 mm ID, 5 µm packing); mobile phase: 40% methanol (0.05% DEA) _-CO2 ; flow rate: 2.35 mL/min; detection wavelength: 220 nm. AD-H_2_50_2.35ML Chromatographic conditions: Chiralpak AD-H column (specifications: 250x4.6 mm ID, 5 mm filler), mobile phase: 50% methanol (0.1% MEA)-CO ₂ , flow rate: 2.35 mL/min, detection wavelength: 220 nm.

Preparative SFC analyses were performed on a Waters Thar 80 Pre-SFC system with a Gilson UV detector using either Chiralcel OD-H (250 x 4.6 mm ID, 5 μm packing) or Chiralpak AD-H (250 x 4.6 mm ID, 5 μm packing) columns. Compounds were eluted with a slow gradient of ethanol-CO2 or methanol-CO2 containing 0.05% _NH3 · _H2O , 0.05% DEA, or 0.1% MEA at a flow rate of approximately 40-80 mL/min, with a total run time of 20-30 minutes.

The PARP-1 inhibitors provided by the present invention can be used to treat a wide range of diseases, including cancer, stroke, myocardial ischemia, inflammation, and diabetes. PARP-1 inhibitors can be used as a single agent or in combination with other chemotherapeutic agents to enhance the effects of these standard chemotherapeutic agents.

Cancers that can be treated with PARP-1 inhibitors include but are not limited to breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, clonal cancer, and leukemia.

DETAILED DESCRIPTION

In order to illustrate the present invention in more detail, the following examples are given, but the scope of the present invention is not limited thereto.

Process A

Example 1

6-Fluoro-3-(piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

Example 1A

tert-Butyl 4-(p-toluenesulfonyloxymethyl)piperidine-1-carboxylate

To a solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (10 g, 46.5 mmol), triethylamine (5.64 g, 55.8 mmol), and DMAP (1.13 g, 9.3 mmol) in dichloromethane (100 mL) at 0°C under nitrogen was added portionwise TosCl (9.73 g, 51.2 mmol). After stirring at 17°C for 2 hours, the mixture was quenched by addition of water (100 mL). The aqueous layer was extracted with dichloromethane (100 mL x 2). The combined organic layers were dried over sodium sulfate, filtered, and evaporated. The residue was purified by column chromatography to yield the title compound (white solid, 17 g, 99% yield). LCMS (ESI) m/z: 370 (M+1).

Example 1B

tert-Butyl 4-(cyanomethyl)piperidine-1-carboxylate

A mixture of Example 1A (19 g, 55.7 mmol) and sodium cyanide (8.19 g, 167 mmol) in dimethyl sulfoxide (100 ml) was reacted at 100°C for 16 hours. After cooling to room temperature, the mixture was diluted with water (200 ml), and the aqueous layer was extracted with ethyl acetate (100 ml x 3). The combined organic layers were washed with water (50 ml) and brine (50 mL), dried over sodium sulfate, filtered, and evaporated to provide the title compound (11 g), which was used directly in the next step without further purification. LCMS (ESI) m/z: 225 (M+1)

Example 1C

tert-Butyl 4-(1-cyano-2-oxoethyl)piperidine-1-carboxylate

To a mixture of Example 1B (11 g, 49 mmol) and potassium tert-butoxide (32.9 g, 294 mmol) in DMF (80 mL) was added dropwise a solution of ethyl formate (21.7 g, 294 mmol) in DMF (50 mL) under nitrogen at -10°C. After the addition was complete, the mixture was stirred at 17°C for 16 hours, neutralized with 1N hydrochloric acid, and the aqueous layer was extracted with ethyl acetate (100 mL x 4). The combined organic layers were dried over sodium sulfate, filtered, and evaporated to provide the title compound (11 g, 89%), which was used directly in the next step without further purification. LCMS (ESI) m/z: 253 (M+1)

Example 1D

(2,6-Dibromo-4-fluorophenyl)hydrazine

To a solution of 2,6-dibromo-4-fluoroaniline (5 g, 18.6 mmol) in 35 mL of 20% aqueous hydrochloric acid was added dropwise sodium nitrite (1.41 g, 20.45 mmol) in water (40 mL) at -5°C. The addition rate was maintained to maintain the internal temperature below 5°C. After 0.5 hour, the above solution was added dropwise to a solution of stannous chloride (10.49 g, 46 mmol) in concentrated hydrochloric acid (40 mL) at -15°C. After the addition was complete, the mixture was heated to 35°C and stirred for 12 hours. The mixture was then cooled to 0°C and adjusted to pH = 9 with concentrated aqueous ammonia. The aqueous layer was extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with water (100 mL), dried over sodium sulfate, filtered, and evaporated. The residue was purified by column chromatography to give the title compound (4 g, yield: 76%). ¹ H NMR (400MHz, CDCl3-d): δppm 3.91 (br.s., 1H), 5.37 (br.s., 1H), 7.31 (d, J=7.37Hz, 2H).

Example 1E

tert-Butyl 4-(1-cyano-2-(2-(2,6-dibromo-4-fluorophenyl)hydrazono)ethyl)piperidine-1-carboxylate

A mixture of Example 1C (3.5 g, 13.87 mmol) and Example 1D (3.94 g, 13.87 mmol) in ethanol (30 mL) was stirred at 80°C for 0.5 hours. After the solvent was removed in vacuo, the residue was purified by column chromatography to afford the title compound as a white solid (3.8 g, 53%). LCMS (ESI) m/z: 519 (M+1).

Example 1F

tert-Butyl 4-(5-amino-1-(2,6-dibromo-4-fluorophenyl)-1H-pyrazol-4-yl)piperidine-1-carboxylate

A mixture of Example 1E (3.8 g, 7.33 mmol) and triethylamine (1.48 g, 14.67 mmol) in ethanol (30 mL) was stirred at 80° C. for 16 hours. The solvent was removed in vacuo to afford the title compound (3.8 g, 100%) which was used in the next step without further purification.

Example 1G

tert-Butyl 4-(8-bromo-6-fluoro-4H-benzo[4,5]imidazo[1,2-B]pyrazol-3-yl)piperidine-1-carboxylate

Under nitrogen, a mixture of Example 1F (2.4 g, 4.63 mmol), N1,N2-dimethylethane-1,2-diamine (40.83 mg, 0.463 mmol), cuprous iodide (88 mg, 0.463 mmol), and potassium phosphate (983 mg, 4.63 mmol) in DMF (30 mL) was heated in a microwave at 60°C for 1 hour. After cooling to room temperature, the mixture was filtered through celite. The solvent was removed in vacuo, and the residue was purified by column chromatography to provide the title compound as a white solid (0.4 g, 15%). LCMS (ESI) m/z: 437, 439 (M, M+2).

Example 1H

3-(1-(tert-Butyloxycarbonyl)piperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxylic acid methyl ester

A mixture of Example 1G (200 mg, 0.457 mmol), palladium acetate (10.27 mg, 0.0457 mmol), Pd(dppf)Cl2 (33.46 mg, 0.0457 mmol), Xantphos (53 mg, 0.0914 mmol), DPPP (38 mg, 0.0914 mmol), triphenylphosphine (24 mg, 0.0914 mmol), and triethylamine (232 mg, 2.29 mmol) in DMF (40 mL) and methanol (20 mL) was stirred at 120°C under a carbon monoxide atmosphere (3 MPa) for 12 hours. After cooling to room temperature, the mixture was filtered through a pad of Celite, the filtrate was evaporated, and the residue was purified by column chromatography to yield the title compound as a white solid (100 mg, 52%). LCMS (ESI) m/z: 417 (M+1).

Example II

tert-Butyl 4-(8-carbamoyl-6-fluoro-4H-benzo[4,5]imidazo[1,2-B]pyrazol-3-yl)piperidine-1-carboxylate

A mixture of Example 1H (100 mg, 0.24 mmol) and ammonia/methanol (30 mL) in DMF (100 mL) was reacted in a sealed container at 120°C for 16 hours. After cooling, the solvent was removed in vacuo, and the residue was purified by column chromatography to afford the title compound as a white solid (70 mg, 73%). LCMS (ESI) m/z: 402 (M+1).

Example 1J

6-Fluoro-3-(piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

A solution of Example II (70 mg, 0.174 mmol) in dichloromethane (3 mL) and trifluoroacetic acid (1 mL) was stirred at 15°C for 1 hour. The solvent was removed in vacuo, and the residue was purified by preparative HPLC to yield the title compound (25 mg, 49%). ^1H NMR (400 MHz, METHANOL-d4) ppm: 1.93-1.96 (m, 2H), 2.37-2.36 (d, 2H), 3.09-3.22 (m, 3H), 3.31-3.53 (t, 2H), 7.37-7.39 (m, 1H), 7.68-7.74 (m, 2H). LCMS (ESI) m/z: 302 (M+1).

Example 2

3-(1-ethylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

A mixture of Example 1J (750 mg, 2.49 mmol) and acetaldehyde (1.1 g, 24.9 mmol) in methanol (15 mL) was stirred at 50° C. for 0.5 h, followed by the addition of sodium cyanoborohydride (3.13 g, 49.8 mmol). The resulting mixture was stirred at 50° C. for 16 h. After the solvent was removed in vacuo, the residue was purified by column chromatography to afford the title compound as a white solid (563.1 g, 69%). ^1H NMR (400MHz, METHANOL-d4) ppm 1.31-1.34(t, 3H), 1.94-1.97(m, 2H), 2.27-2.31(d, 2H), 2.82(t, 2H), 2.97-3.02(m, 3 H), 3.47-3.48 (d, 2H), 7.34-7.37 (m, 1H), 7.67-7.72 (m, 2H). LCMS (ESI) m/z: 330 (M+1).

Example 3

6-Fluoro-3-(1-(2-fluoroethyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

A mixture of Example 1J (112 mg, 0.372 mmol), 1-bromo-2-methoxyethane (71 mg, 0.558 mmol) and potassium carbonate (154 mg, 1.116 mmol) in acetonitrile (20 mL) was stirred at 40° C. for 16 hours. The mixture was cooled and filtered, the solvent was removed in vacuo, and the residue was purified by preparative HPLC to give the title compound (4.6 mg, 3.6%). ^1H NMR(400MHz, METHANOL-d ₄ )ppm 1.94-2.15(m, 2H), 2.17-2.37(m, 2H), 2.86-3.07(m, 3H), 3.27-3.32(m, 1H), 3.35-3.39(m, 1H), 3.46-3.61(m, 2H), 4. 71-4.80 (m, 1H), 4.89 (br.s., 1H), 7.28-7.41 (m, 1H), 7.60-7.76 (m, 2H), 8.24-8.69 (m, 1H). LCMS (ESI) m/z: 348 (M+1).

Example 4

3-(1-cyclopropylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

A mixture of (1-ethoxycyclopropyloxy)trimethylsilane (115 mg, 0.663 mmol), Example 1J (40 mg, 0.133 mmol), acetic acid (79 mg, 1.33 mmol) and sodium cyanoborohydride (83 mg, 1.33 mmol) in methanol (10 mL) was stirred at 66° C. for 7 hours. After cooling and removing the solvent in vacuo, the residue was purified by preparative HPLC to give the title compound (19.6 mg, 43%). ^1H NMR (400MHz, METHANOL-d4) ppm 0.70-0.79(m, 4H), 1.84-1.92(m, 2H), 2.18-2.28(t, 3H), 2.85-2.94(m, 3H), 3.42-3.45 (d, 2H), 7.33-7.35 (m, 1H), 7.65-7.68 (m, 2H), 8.395 (s, 1H). LCMS (ESI) m/z: 342 (M+1).

Example 5

3-(1-(Cyclopropylmethyl)piperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

A mixture of Example 1J (12 mg, 0.04 mmol), cyclopropanecarboxaldehyde (5.58 mg, 0.08 mmol), sodium cyanoborohydride (50 mg, 0.8 mmol) in methanol (2 mL) was stirred at 10° C. for 16 hours, and then tetraisopropoxytitanium (17 mg, 0.06 mmol) was added and stirring was continued for 1 hour. After the solvent was removed in vacuo, the residue was purified by preparative HPLC to provide the title compound (5.2 mg, 37%). ^1H NMR (400MHz, METHANOL-d4) ppm 0.40-0.44(m, 2H), 0.75-0.79(m, 1H), 1.12-1.13(m, 1H), 2.04(s, 2H), 2.32-2.36(d, 2H), 2.9-3.12 (m, 5H), 3.68 (s, 2H), 7.36-7.39 (m, 1H), 7.68-7.73 (m, 2H), 8.50 (s, 1H). LCMS (ESI) m/z: 356 (M+1).

Example 6

6-Fluoro-3-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

Example 6A

tert-Butyl 4-(4-benzyl-8-carbamoyl-6-fluoro-4H-benzo[4,5]imidazo[1,2-B]pyrazol-3-yl)piperidine-1-carboxylate

A mixture of Example II (100 mg, 0.25 mmol), benzyl bromide (127 mg, 0.748 mmol), and potassium carbonate (103 mg, 0.748 mmol) in acetonitrile (4 mL) was stirred at 60°C for 4 hours. After cooling and filtration, the solvent was removed in vacuo, and the residue was purified by silica gel chromatography to yield the title compound (112.6 mg, 91.8%). LCMS (ESI) m/z: 492 (M+1).

Example 6B

4-Benzyl-6-fluoro-3-(piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

A solution of Example 6A (112.6 mg, 0.229 mmol) in dichloromethane (10 mL) and trifluoroacetic acid (3 mL) was stirred at 12°C for 2 hours. Removal of the solvent in vacuo afforded the title compound (115 mg, 100%) as a yellow solid, which was used in the next step without further purification. LCMS (ESI) M/Z: 392 (M+1).

Example 6C

4-Benzyl-6-fluoro-3-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

A mixture of Example 6B (115 mg, 0.229 mmol), 2,2-dimethyloxirane (50 mg, 0.690 mmol), and triethylamine (116 mg, 1.15 mmol) in ethanol (5 mL) was heated in a microwave at 120°C for 1 hour. After cooling and removing the solvent in vacuo, the residue was purified by silica gel chromatography to provide the title compound. LCMS (ESI) m/z: 464 (M+1).

Example 6D

6-Fluoro-3-(1-2-hydroxy-2-methylpropyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

A mixture of Example 6C (32 mg, 0.069 mmol) and Pd/C (25 mg) in methanol (30 mL) was hydrogenated at 50°C for 4 hours (1 atm). After cooling and filtration, the solvent was removed in vacuo, and the residue was purified by preparative HPLC to give the title compound (8.2 mg, 32.2%). ^1H NMR (400 MHz, METHANOL-d ₄ ) ppm: 1.38 (s, 6H), 2.10-2.30 (m, 4H), 3.12 (s, 5H), 3.57-3.73 (m, 2H), 7.29-7.39 (m, 1H), 7.61-7.69 (m, 1H), 7.69-7.75 (m, 1H), 8.54 (br. s., 1H). LCMS (ESI) m/z: 374 (M+1).

Example 7

6-Fluoro-3-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

Example 7A

4-Benzyl-6-fluoro-3-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

To a solution of Example 6C (32 mg, 0.069 mmol) in dichloromethane (10 mL) was added dropwise a solution of DAST (33 mg, 0.207 mmol) in dichloromethane (2 mL) under nitrogen at 0°C. After the addition was complete, the mixture was stirred at 17°C for 16 hours and then quenched with saturated sodium bicarbonate solution (10 mL). The aqueous layer was extracted with ethyl acetate (10 mL x 2). The combined organic layers were dried over sodium sulfate, filtered, and evaporated. The residue was purified by silica gel chromatography to yield the title compound (27 mg, 84.4%). LCMS (ESI) m/z: 466 (M+1).

Example 7B

6-Fluoro-3-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

A mixture of Example 7A (27 mg, 0.058 mmol) and Pd/C (30 mg) in methanol (20 mL) was hydrogenated at 45° C. for 16 h (1 atm). The mixture was cooled and filtered, the filtrate was evaporated, and the residue was purified by preparative HPLC to give the title compound (2.1 mg, 10%). ^1H NMR(400MHz, METHANOL-d ₄ )ppm 1.42(s, 3H), 1.48(s, 3H), 1.90-2.03(m, 2H), 2.04-2.16(m, 2H), 2.51-2.67(m, 2H), 2.72-2.90(m, 3H) , 3.23-3.31 (m, 2H), 7.32-7.41 (m, 1H), 7.63-7.75 (m, 2H), 8.27-8.59 (m, 1H). LCMS (ESI) m/z: 376 (M+1)

Example 8

3-(1-(cyclopropylcarbonyl)piperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

A mixture of Example 1J (52 mg, 0.125 mmol), cyclopropanecarboxylic acid (13 mg, 0.150 mmol), triethylamine (50.5 mg, 0.5 mmol) and HATU (47.5 mg, 0.125 mmol) in acetonitrile (5 mL) was stirred at 50° C. for 3 hours. After cooling and removing the solvent in vacuo, the residue was purified by preparative HPLC to give the title compound (12.7 mg, 27.3%). LCMS: 370[M+1]. ¹ H NMR (400MHz, DMSO-d ₆ )ppm 0.72(d, J=7.53Hz, 4H), 1.42-1.69(m, 2H), 1.88-2.07(m, 3H), 2.65-2.77(m, 1H), 2.86-2.98(m, 1H), 3.14-3 .29 (m, 1H), 4.26-4.50 (m, 2H), 7.43-7.50 (m, 1H), 7.51-7.59 (m, 1H), 7.76 (s, 1H). LCMS (ESI) m/z: 370 (M+1).

Example 9

6-Fluoro-3-(1-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 2. ¹ H NMR (400 MHz, METHANOL-d4) ppm 1.98-2.01 (d, 2H), 2.29-2.31 (d, 2H), 2.83 (s, 1H), 3.01-3.04 (d, 2H), 3.48 (d, 2H), 7.36-7.39 (m, 1H), 7.68-7.73 (m, 2H), 8.49 (s, 1H). LCMS (ESI) m/z: 316 (M+1).

Example 10

6-Fluoro-3-(1-isopropylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 2. ¹ H NMR (400 MHz, METHANOL-d4) ppm 1.38-1.40 (d, 6H), 2.02-2.05 (d, 2H), 2.36-2.40 (d, 2H), 3.06 (m, 1H), 3.19-3.22 (t, 2H), 3.51-3.55 (m, 3H), 7.35-7.38 (m, 1H), 7.66-7.72 (m, 2H), 8.51 (s, 1H). LCMS (ESI) m/z: 344 (M+1).

Example 11

6-Fluoro-3-(1-(oxetan-3-yl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 2. ¹ H NMR (400 MHz, DMSO-d ₆ ) ppm 1.66-1.79 (m, 2H), 1.82-1.99 (m, 4H), 2.58-2.69 (m, 1H), 2.70-2.81 (m, 2H), 3.36-3.45 (m, 1H), 4.45 (s, 2H), 4.51-4.58 (m, 2H), 7.36-7.44 (m, 1H), 7.45-7.53 (m, 1H), 7.65-7.75 (m, 1H). LCMS (ESI) m/z: 358 (M+1).

Example 12

6-Fluoro-3-(1-propylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 2. ¹ H-NMR (400 MHz, METHANOL-d4) ppm 1.02-1.06 (t, 3H), 1.76-1.82 (m, 2H), 2.00-2.03 (d, 2H), 2.31-2.34 (d, 2H), 3.01-3.05 (m, 5H), 3.57-3.58 (d, 2H), 7.36-7.39 (m, 1H), 7.68-7.73 (m, 2H), 8.51 (s, 1H). LCMS (ESI) m/z: 344 (M+1).

Example 13

6-Fluoro-3-(1-(2-aminoethyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 2. ¹ H NMR (400 MHz, METHANOL-d ₄ ) ppm 1.80-1.98 (m, 2H), 2.06-2.17 (m, 2H), 2.30-2.46 (m, 2H), 2.68-2.85 (m, 3H), 3.05-3.19 (m, 4H), 7.30-7.38 (m, 1H), 7.69 (br. s., 2H), 8.28-8.67 (m, 1H). LCMS (ESI) m/z: 345 (M+1).

Example 14

3-(1-(2-(dimethylamino)ethyl)piperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 2. ¹ H NMR (400 MHz, METHANOL-d ₄ ) ppm 1.83-1.98 (m, 2H), 2.05-2.18 (m, 2H), 2.36-2.48 (m, 2H), 2.68 (s, 6H), 2.80 (t, J=6.46 Hz, 3H), 2.97-3.07 (m, 2H), 3.11-3.25 (m, 2H), 7.25-7.40 (m, 1H), 7.57-7.75 (m, 2H). LCMS (ESI) m/z: 373 (M+1).

Example 15

6-Fluoro-3-(1-(2-methoxyethyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 3. ¹ H NMR (400 MHz, METHANOL-d4) ppm 2.00-2.18 (m, 2H), 2.22-2.38 (m, 2H), 2.94-3.08 (m, 1H), 3.08-3.22 (m, 2H), 3.33-3.38 (m, 2H), 3.44 (s, 3H), 3.56-3.70 (m, 2H), 3.71-3.82 (m, 2H), 7.19-7.38 (m, 1H), 7.53-7.64 (m, 1H), 7.68 (s, 1H), 8.42-8.66 (m, 1H). LCMS (ESI) m/z: 360 (M+1).

Example 16

6-Fluoro-3-(1-(2-hydroxyethyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 3. ¹ H NMR (400 MHz, METHANOL-d ₄ ) ppm: 2.04-2.20 (m, 2H), 2.25-2.37 (m, 2H), 2.98-3.10 (m, 1H), 3.12-3.24 (m, 2H), 3.25-3.31 (m, 2H), 3.62-3.75 (m, 2H), 3.89-3.99 (m, 2H), 7.25-7.38 (m, 1H), 7.57-7.66 (m, 1H), 7.69 (s, 1H), 8.50-8.62 (m, 1H). LCMS (ESI) m/z: 346 (M+1).

Example 17

3-(1-ethylpiperidin-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

In this example, the product was prepared as described in Examples 1 and 2, substituting tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate for tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate. ^H -NMR (MeOD, 400 MHz) δ: 1.38 (t, 3H), 1.85-2.00 (m, 2H), 2.13-2.26 (m, 2H), 2.94-3.03 (m, 2H), 3.21-3.24 (m, 3H), 3.59-3.73 (m, 2H), 7.37-7.39 (dd, 1H), 7.66-7.69 (dd, 1H), 7.76 (s, 1H), 8.52 (bs, 1H). LCMS (ESI) m/z: 331 (M+1).

Example 18

3-(1-ethylazepan-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

Example 18A

1-tert-Butyl-4-ethyl-5-oxoazepane-1,4-dicarboxylic acid diester

To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (50 g, 251 mmol) and boron trifluoride etherate (49.86 g, 351 mmol) in THF (500 mL) was added dropwise ethyl-2-diazonium chloride (40.09 g, 351 mmol) at -40°C under nitrogen. After the addition was complete, the mixture was stirred at -40°C for 2 hours, then warmed to 15°C and stirred for 16 hours. Upon completion, the reaction was quenched with aqueous potassium carbonate (500 mL). The aqueous layer was extracted with ethyl acetate (500 mL x 2). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was purified by silica gel column chromatography to yield the title compound (45 g, 63% yield). LCMS (ESI) m/z: 286 (M+1).

Example 18B

1-tert-Butyl-4-ethyl-5-hydroxyazepine-1,4-dicarboxylic acid diester

To a solution of Example 18A (45 g, 157.7 mmol) in methanol (420 mL) was added sodium borohydride (7.16 g, 189 mmol) portionwise at 0°C. After stirring at 0°C for 1 hour, the resulting mixture was quenched with water (400 mL), and the aqueous phase was extracted with ethyl acetate (400 mL x 2). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was purified by silica gel column chromatography to provide the title compound (22.3 g, yield: 49%). LCMS (ESI) m/z: 288 (M+1).

Example 18C

1-tert-Butyl-4-ethyl 2,3,6,7-tetrahydro-1H-azepine-1,4-dicarboxylate

To a solution of Example 18B (21 g, 73 mmol) and DBU (22 g, 146 mmol) in toluene (200 mL) was added dropwise MsCl (14.56 g, 128 mmol) at room temperature. After the addition was complete, the mixture was stirred at 110°C for 2 hours. After cooling to room temperature, the mixture was quenched with water (200 mL). The aqueous layer was extracted with ethyl acetate (200 mL x 2). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was purified by silica gel column chromatography to provide the title compound (13 g, 66% yield). LCMS (ESI) m/z: 270 (M+1).

Example 18D

1-tert-Butyl-4-methylazepane-1,4-dicarboxylic acid diester

A mixture of Example 18C (13 g, 48.27 mmol) and Pd/C (1 g) in methanol (130 mL) was hydrogenated at 15°C for 16 hours (1 atm). The mixture was filtered, and the filtrate was evaporated to give the title compound (10.7 g, 82% yield), which was used directly in the next step without purification. LCMS (ESI) m/z: 258 (M+1).

Example 18E

tert-Butyl 4-(hydroxymethyl)azepane-1-carboxylate

To a solution of Example 18D (10.7 g, 39 mmol) in THF (200 mL) at 0°C was added lithium aluminum tetrahydride (1.48 g, 39 mmol) portionwise. After stirring at 0°C for 30 minutes, the resulting mixture was quenched with water (10 mL), 15% aqueous NaOH (10 mL), and water (30 mL). The mixture was filtered, the filtrate evaporated, and the residue purified by silica gel column chromatography to afford the title compound (7 g, yield: 77%). LCMS (ESI) m/z: 230 (M+1).

Example 18F

3-(1-ethylazepan-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

In this example, the compound was prepared as described in Examples 1 and 2, substituting tert-butyl 4-(hydroxymethyl)azepane-1-carboxylate for tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate. ¹ H-NMR (MeOD, 400MHz) δ: 1.38-1.42 (t, 3H), 1.93-1.96 (m, 2H), 1.99-2.12 (m, 2H), 2.32-2.34 (m, 2H), 3.15-3.30 (m, 1H), 3.32- 3.33 (m, 2H), 3.33-3.53 (m, 4H), 7.38-7.40 (dd, 1H), 7.69-7.73 (dd, 1H), 7.74 (s, 1H), 8.50 (bs, 1H). LCMS (ESI) m/z: 344 (M+1).

Example 19

6-Fluoro-3-(1-methylazepan-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 18. ¹ H-NMR (MeOD, 400 MHz) δ: 1.95-2.10 (m, 3H), 2.26-2.35 (m, 3H), 2.96 (s, 1H), 3.14-3.17 (m, 1H), 3.36-3.49 (m, 4H), 7.38-7.40 (dd, 1H), 7.69-7.72 (dd, 1H), 7.74 (s, 1H), 8.47 (bs, 1H). LCMS (ESI) m/z: 330 (M+1).

Example 20

6-Fluoro-3-(1-methylpyrrolidin-3-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

In this example, the product was prepared as described in Examples 1 and 2, substituting tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate for tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate. ^H -NMR (MeOD, 400 MHz) δ: 2.29-2.35 (m, 1H), 2.59-2.62 (m, 1H), 2.99 (s, 3H), 3.32-3.36 (m, 1H), 3.53-3.55 (m, 2H), 3.76-3.81 (m, 2H), 7.40-7.42 (dd, 1H), 7.70-7.73 (dd, 1H), 7.80 (s, 1H), 8.50 (bs, 1H). LCMS (ESI) m/z: 302 (M+1).

Example 21

3-(1-ethylpyrrolidin-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 20, substituting tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate for tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate. ^H -NMR (MeOD, 400 MHz) δ: 2.29-2.35 (m, 1H), 2.59-2.62 (m, 1H), 2.99 (s, 3H), 3.32-3.36 (m, 1H), 3.53-3.55 (m, 2H), 3.76-3.81 (m, 2H), 7.40-7.42 (dd, 1H), 7.70-7.73 (dd, 1H), 7.80 (s, 1H), 8.50 (bs, 1H). LCMS (ESI) m/z: 316 (M+1).

Example 22

6-Fluoro-3-(1-isopropylpyrrolidin-3-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 20, substituting tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate for tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate. ^H -NMR (MeOD, 400 MHz) δ: 1.42-1.44 (d, 6H), 2.25-2.31 (m, 1H), 2.57-2.60 (m, 1H), 3.32-3.33 (m, 1H), 3.44-3.55 (m, 3H), 3.68-3.71 (m, 1H), 7.41-7.43 (dd, 1H), 7.71-7.74 (dd, 1H), 7.82 (s, 1H), 8.55 (bs, 1H). LCMS (ESI) m/z: 330 (M+1).

Example 23

6-Fluoro-3-(pyrrolidin-2-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

In this example, the compound was prepared as described in Example 1, substituting tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate for tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate. ^1H -NMR (400 MHz, MethanoL-d ₄ ) δ ppm: 2.17-2.31 (m, 1H), 2.33-2.51 (m, 2H), 2.52-2.67 (m, 1H), 3.48 (t, J = 7.28 Hz, 2H), 7.40 (dd, J = 8.03, 2.26 Hz, 1H), 7.65 (dd, J = 10.79, 2.26 Hz, 1H), 7.94 (s, 1H), 8.55 (br. s., 1H). LCMS (ESI) m/z: 288 (M+1).

Example 24

6-Fluoro-3-(1-propylpyrrolidin-2-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 2, substituting tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate for tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate. ¹ H-NMR (400MHz, MethanoL-d ₄ ) δppm 0.93 (t, J=7.34Hz, 3H), 1.54-1.79 (m, 2H), 2.23 (d, J=5.02Hz, 2H), 2.37-2.53 (m, 2H), 2.76 (br.s., 1H), 3.05 (br.s., 2H), 3.65 (br.s., 1H) , 4.31 (br.s., 1H), 7.44 (dd, J=8.09, 2.32Hz, 1H), 7.73 (dd, J=10.92, 2.38Hz, 1H), 7.94 (s, 1H), 8.54 (br.s., 1H). LCMS (ESI) m/z: 330 (M+1).

Example 25

6-Fluoro-3-(1-methylpyrrolidin-2-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 2, substituting tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate for tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate. ¹ H-NMR (400MHz, MethanoL-d ₄ ) δppm 2.25-2.41(m, 2H), 2.47-2.67(m, 2H), 2.82(s, 3H), 3.23-3.30(m, 1H), 3.66-3.79(m, 1H), 4.50-4.58(m, 1H), 7.43(dd , J=8.16, 2.51Hz, 1H), 7.64 (dd, J=10.73, 2.57Hz, 1H), 7.95-8.02 (m, 1H), 8.52 (br.s., 1H). LCMS (ESI) m/z: 302 (M+1).

Example 26

3-(1-ethylpyrrolidin-2-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 2, substituting tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate for tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate. ¹ H-NMR (400MHz, MethanoL-d ₄ ) δppm 1.30 (t, J=7.28Hz, 3H), 2.26-2.37 (m, 2H), 2.46-2.61 (m, 2H), 2.98-3.09 (m, 1H), 3.25 (d, J=10.29Hz, 2H), 3.68-3.80 (m, 1H), 4.55 (t, J =8.78Hz, 1H), 7.42 (dd, J=8.16, 2.26Hz, 1H), 7.64 (dd, J=10.73, 2.32Hz, 1H), 7.97 (s, 1H), 8.54 (br.s., 1H). LCMS (ESI) m/z: 316 (M+1).

Example 27

3-(1-ethylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 1, substituting 2,6-dibromophenylhydrazine for 2,6-dibromo-4-fluorophenylhydrazine. 1H-NMR (400 MHz, METHANOL-d4) ppm 1.16-1.20 (t, 3H), 1.84-1.87 (m, 2H), 2.07-2.11 (d, 2H), 2.16-2.19 (d, 2H), 2.51-2.56 (q, 2H), 2.70-2.75 (m, 1H), 3.11-3.13 (d, 2H), 7.40-7.44 (t, 1H), 7.61-7.63 (m, 1H), 7.70 (s, 1H), 7.99-8.02 (m, 1H). LCMS (ESI) m/z: 312 (M+1).

Example 28

6-Fluoro-3-(3-methyl-3-azabicyclo [3.1.0]hexan-1- yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

Example 28A

1-Benzyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid ethyl ester

To a solution of N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (4.5 g, 61 mmol) and ethyl propiolate (5.0 g, 51 mmol) in dichloromethane (150 mL) was added triethylamine (0.4 mL, 5.2 mmol) dropwise at 0°C. After the addition was complete, the mixture was stirred at 0°C for 1 hour, then warmed to 20°C and stirred for 24 hours. The reaction mixture was quenched with saturated NaHCO₃ (100 mL), and the aqueous phase was extracted with dichloromethane (250 mL x 2). The combined organic layers were washed with brine (150 mL x 2) and dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was purified by column chromatography to provide the title compound (10 g, yield: 80%) as a yellow oil. LCMS (ESI) m/z: 232 (M+1).

Example 28B

3-Benzyl-3-azabicyclo[3.1.0]hexane-1-carboxylic acid ethyl ester

To a mixture of (CH3)3SOI (21.5 g, 97.7 mmol) in DMSO (150 mL) at 0°C-5°C under nitrogen was added 60% sodium hydride (3.5 g, 87.5 mmol) portionwise. After stirring at 19°C for 2 hours, Example 28A (9 g, 38.9 mmol) was added portionwise at 0°C-5°C. The reaction mixture was stirred at 19°C for 15 hours, then quenched with saturated sodium bicarbonate (300 mL). The aqueous phase was extracted with dichloromethane (500 mL x 2). The combined organic layers were washed with brine (200 mL x 2) and dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was purified by column chromatography to provide the title compound (5.4 g, yield: 32%) as a yellow oil. LCMS (ESI) m/z: 246 (M+1).

Example 28C

3-tert-Butyl-1-ethyl-3-azabicyclo[3.1.0]hexane-1,3-dicarboxylic acid diester

A mixture of Example 28B (5.4 g, 22 mmol), BOC2O (10 g, 46 mmol), and 10% Pd/C (600 mg) in methanol (100 mL) was hydrogenated at 19°C for 15 hours (1 atm). The mixture was filtered, the filtrate evaporated, and the residue purified by column chromatography to give the title compound (5.3 g, yield: 94%) as a colorless oil. ¹ H-NMR (400 MHz, _CDCl3 ) δ ppm 0.83(t, J＝4.96Hz, 1H), 1.25(t, J＝7.15Hz, 3H), 1.39-1.48(m, 9H), 1.56( dd, J=8.34, 4.58Hz, 1H), 1.79 (s, 1H), 1.94-2.10 (m, 1H), 3.41 (dd, J=10. 73, 3.45Hz, 1H), 3.50-3.82 (m, 3H), 4.07-4.19 (m, 2H), 4.25 (d, J=7.15Hz , 1H), 5.05 (s, 1H), 6.61 (t, J=1.88Hz, 1H), 7.14 (s, 1H), 7.28-7.38 (m, 1H)

Example 28D

tert-Butyl 1-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

A mixture of Example 28C (5.3 g, 20.7 mmol) and 1N lithium hydroxide (50 mL, 50 mmol) in tetrahydrofuran (25 mL) and methanol (50 mL) was stirred at 60°C for 2 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with water (50 mL x 2) and brine (50 mL x 2), dried over anhydrous sodium sulfate, and evaporated to obtain a residue which was dissolved in tetrahydrofuran (100 mL). 10 M borane dimethyl sulfide (10 mL, 100 mmol) was added dropwise at 0°C under nitrogen. After the addition was complete, the mixture was stirred at 19°C for 15 hours. After completion of the reaction, the mixture was quenched with methanol (100 mL). The solution was evaporated in vacuo, and the residue was purified by column chromatography to give the title compound (3.5 g, yield: 89%) as a colorless oil. ¹ H-NMR (400MHz, CDCl ₃ ) δ ppm 0.51 (br.s., 1H, 0.78 (dd, J=8.09, 5.08Hz, 1H), 1.37-1.47 (m, 10H), 3.42 (d, J=10.29Hz, 2H, 3.48-3.78 (m, 4H).

Example 28E

tert-Butyl 1-(chloromethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a mixture of Example 28D (3.5 g, 16.43 mmol), DMAP (200 mg, 1.6 mmol), and triethylamine (5 mL, 36.14 mmol) in dichloromethane (100 mL) at 0°C was added TosCl (3.7 g, 19.47 mmol) portionwise. The mixture was stirred at 24°C for 15 hours and then quenched with water (100 mL). The aqueous layer was extracted with dichloromethane (250 mL x 2), and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated. The residue was purified by column chromatography to give the title compound (2.6 g, yield: 68%) as a colorless oil. ¹ H-NMR (400MHz, CDCl ₃ ) δppm 0.68 (t, J=4.64Hz, 1H), 0.90 (dd, J=8.16, 5.27Hz, 1H), 1.39-1.55 (m, 10H), 3.36-3.46 (m, 2H), 3.48-3.77 (m, 4H).

Example 28F

tert-Butyl 1-(cyanomethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

A mixture of Example 28E (2.6 g, 11 mmol), sodium cyanide (1.57 g, 32 mmol) and potassium iodide (1.87 g, 11 mmol) in DMSO (40 mL) was stirred at 100-120° C. for 2 hours. After cooling to room temperature, the mixture was dispersed in ethyl acetate (200 mL) and aqueous sodium carbonate solution (120 mL). The aqueous layer was extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography to give the title compound (2.4 g, yield: 96%) as a colorless oil. ¹ H-NMR (400MHz, CDCl ₃ ) δppm 0.47-0.72(m, 1H), 0.81-0.96(m, 1H), 1.34-1.55(m, 10H), 2.53-2.80(m, 2 H), 3.30 (d, J=10.54Hz, 1H), 3.38-3.84 (m, 1H). LCMS (ESI) m/z: 167 (M-55).

Example 28G

tert-Butyl 1-(1-cyano-2-(dimethylamino)vinyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

A mixture of 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (3.8 g, 21.8 mmol) and Example 28F (2.4 g, 10.8 mmol) in DMF (20 mL) was stirred at 70° C. for about 10 hours. After cooling to room temperature, the solvent was removed in vacuo to provide the title compound, which was used directly in the next step without further purification.

Example 28H

tert-Butyl 1-(1-cyano-2-hydroxyvinyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

Example 28G (3.0 g, crude, 10.8 mmol) was stirred in a mixture of tetrahydrofuran/acetic acid/water (1/1/1) (45 mL) at 24°C for 5 hours. After the solvent was removed in vacuo, the residue was divided between saturated sodium bicarbonate (100 mL) and ethyl acetate (100 mL). The aqueous phase was extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with water (100 mL x 2) and brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was purified by column chromatography to give the title compound (1.4 g, yield: 52%) as a yellow oil. LCMS (ESI) m/z: 195 (M-55).

Example 28I

3-(3-Azabicyclo[3.1.0]hexan-1-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Examples 1E-1J.

Example 28J

6-Fluoro-3-(3-methyl-3-azabicyclo[3.1.0]hexan-1-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 2. ¹ H-NMR (400 MHz, MethanoL-d ₄ )δppm1.32 (d, J=6.40Hz, 2H), 2.05 (td, J=6.37, 3.95Hz, 1H), 2.93 (s, 3H), 3.47 (d, J=11.04Hz, 1H), 3.59 (dd, J=11.11, 3.83Hz, 1H), 3.67-3.76 (m, 1H), 3.85 (d, J=11.04Hz, 1H), 7.32 (dd, J=8.16, 2.51Hz, 1H), 7.58 (dd, J=10.79, 2.51Hz, 1H), 7.77 (s, 1H), 8.52 (s, 1H). LCMS (ESI) m/z: 314 (M+1).

Example 29

3-(3-ethyl-3-azabicyclo[3.1.0]hexan-1-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 28. ¹ H-NMR (400 MHz, MethanoL-d ₄ ) δ ppm: 1.27-1.37 (m, 5H), 1.95-2.11 (m, 1H), 3.22 (q, J = 7.19 Hz, 2H), 3.41 (d, J = 10.92 Hz, 1H), 3.48-3.57 (m, 1H), 3.69 (s, 1H), 3.86 (d, J = 10.92 Hz, 1H), 7.33 (dd, J = 8.16, 2.51 Hz, 1H), 7.64 (dd, J = 10.85, 2.57 Hz, 1H), 7.79 (s, 1H), 8.51 (s, 1H). LCMS (ESI) m/z: 328 (M+1).

Example 30

3-(3-cyclobutyl-3-azabicyclo[3.1.0]hexan-1-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

In this example, the compound was prepared as described in Example 28. ¹ H-NMR (400 MHz, DMSO-d ₆ + D ₂ O) 0.77 (dd, J=7.91, 4.14 Hz, 1H), 1.22 (t, J=4.14 Hz, 1H), 1.51-1.68 (m, 3H), 1.77-1.96 (m, 4H), 2.47 (br. s., 2H), 2.88 (d, J=8.78 Hz, 1H), 2.98-3.13 (m, 2H), 7.44 (dd, J=8.41, 2.51 Hz, 1H), 7.52 (dd, J=10.98, 2.57 Hz, 1H), 7.71 (s, 1H). LCMS (ESI) m/z: 354 (M+1).

Example 31

3-(3-Cyclopropylmethylene-3-azabicyclo[3.1.0]hexan-1-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 28. ¹ H NMR (400MHz, METHANOL-d4)ppm0.32-0.35(m, 2H), 0.65-0.68(m, 2H), 1.06(m , 1H), 1.16-1.19(m, 1H), 1.39-1.42(t, 1H), 1.92-1.94(m, 1H), 2.84-2.85(d, 2H), 3.18-3.21(m, 1H), 3.56-3.59(d, 2H), 3.73-3.75(d, 2H), 7.35-7.39(dd, 1H), 7.68-7.71 (dd, 1H), 7.78 (s, 1H), 8.55 (s, 1H). LCMS (ESI) m/z: 354 (M+1).

Example 32

6-Fluoro-3-(3-isopropyl-3-azabicyclo[3.1.0]hexan-1-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 28. ¹ H-NMR (400 MHz, MethanoL-d ₄ ) 1.25-1.43 (m, 8H), 2.00-2.15 (m, 1H), 3.39 (s, 1H), 3.49 (d, J=11.04 Hz, 1H), 3.62 (d, J=3.89 Hz, 1H), 3.71 (s, 1H), 3.90 (d, J=10.92 Hz, 1H), 7.29-7.40 (m, 1H), 7.64 (dd, J=10.85, 2.57 Hz, 1H), 7.79 (s, 1H), 8.52 (br. s., 1H). LCMS (ESI) m/z: 342 (M+1).

Example 33

3-(3-Azabicyclo[3.1.0]hexan-6-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

Example 33A

5-Benzyl-4,6-dioxo-1,4,5,6,6a-hexahydro[3,4-c]pyrazole-3-carboxylic acid ethyl ester

A mixture of 1-benzyl-1H-pyrrole-2,5-dione (5.0 g, 26.7 mmol) and 2-propionyldiazenecarbaldehyde (2.9 mL, 28.0 mmol) in toluene (30 mL) was stirred at 30°C for 5 h. After removing the solvent in vacuo, the residue was purified by silica gel chromatography to provide the title compound (7.67 g, 95.4% yield). LCMS (ESI) m/z: 302 (M+1).

Example 33B

3-Benzyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester

Example 33A (7.67 g, 25.5 mmol) was heated to 190°C for 1 hour. The residue was purified by chromatography to give the title compound (5.353 g, 76.9%) as a white solid. LCMS (ESI) m/z: 274 (M+1).

Example 33C

(3-Benzyl-3-azabicyclo[3.1.0]hexan-6-yl)methanol

To a suspension of lithium aluminum tetrahydride (3.055 g, 80.4 mmol) in tetrahydrofuran (50 mL) was added dropwise a solution of Example 33B (5.353 g, 19.6 mmol) in tetrahydrofuran (30 mL) at 0°C under nitrogen. After reflux for 16 hours, the reaction mixture was quenched with saturated aqueous sodium sulfate (5 mL). The organic layer was dried over sodium sulfate, filtered, and evaporated to afford a residue which was purified by chromatography to yield the title compound (1.42 g, 35.8%). LCMS (ESI) m/z: 204 (M+1).

Example 33D

tert-Butyl 6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

A mixture of Example 33C (1.42 g, 7.0 mmol), Boc2O (1.81 g, 8.4 mmol), and 10% Pd/C (200 mg) in methanol (80 mL) was hydrogenated at 25°C for 16 hours (1 atm). The mixture was filtered, and the filtrate was evaporated to give a residue which was purified by chromatography to afford the title compound 4 (1.14 g, 76%). LCMS (ESI) m/z: 214 (M+1).

Example 33E

3-(3-Azabicyclo[3.1.0]hexan-6-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Examples 1E-1J. ¹ H NMR (400 MHz, METHANOL-d4) ppm 1.86-1.95 (m, 1H), 2.12-2.22 (m, 2H), 3.49-3.65 (m, 4H), 7.34-7.42 (m, 1H), 7.64-7.74 (m, 2H), 8.42-8.61 (m, 1H). LCMS (ESI) m/z: 300 (M+1).

Example 34

3-(3-ethyl-3-azabicyclo[3.1.0]hexan-6-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 28. ¹ H NMR (400 MHz, METHANOL-d ₄ ) ppm 1.26 (s, 3H), 1.95-2.02 (m, 2H), 2.11-2.18 (m, 1H), 2.85-2.95 (m, 2H), 2.96-3.08 (m, 2H), 3.42-3.58 (m, 2H), 7.30-7.38 (m, 1H), 7.60-7.65 (m, 1H), 7.65-7.70 (m, 1H). LCMS (ESI) m/z: 328 (M+1).

Example 35

3-(8-ethyl-8-azabicyclo[3.2.1]octan-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

Example 35A

tert-Butyl 3-cyano-8-azabicyclo[3.2.1]octane-8-carboxylate

To a mixture of tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (10 g, 44.389 mmol) in dimethylethylene glycol (300 mL) and ethanol (6.7 mL) at 0°C under nitrogen was added potassium tert-butoxide (20 g, 177.557 mmol) and TOSMIC (17.33 g, 88.778 mmol) portionwise. After stirring at 60°C for 16 hours, the mixture was quenched with water (100 mL). The aqueous layer was extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was purified by column chromatography to yield the title compound (6.08 g, yield: 57.96%) as a white solid. LCMS (ESI) m/z: 327 (M+1).

Example 35B

8-(tert-Butoxycarbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid

A mixed solution of Example 35A (6.58 g, 27.845 mmol) and potassium hydroxide (9.36 g, 167.069 mmol) in ethanol/water (1:1, 200 mL) was stirred at 80° C. for 4 hours. The resulting mixture was diluted with water (100 mL), and the aqueous phase was adjusted to pH 3-4 with 2N hydrochloric acid and extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and evaporated to afford the title compound (6.01 g, yield: 84.53%) as a white solid, which was used directly in the next step without further purification.

Example 35C

tert-Butyl 3-(hydroxymethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate

To a solution of Example 35B (6 g, 23.529 mmol) in tetrahydrofuran (60 mL) at 0°C under nitrogen was added borane dimethyl sulfide. After stirring at 25°C for 16 hours, the mixture was quenched by addition of methanol (100 mL). The resulting mixture was evaporated, and the residue was purified by column chromatography to afford the title compound (5.2 g, yield: 92.69%). LCMS (ESI) m/z: 242 (M+1).

Example 35D

3-(8-ethyl-8-azabicyclo[3.2.1]octan-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Examples 1E-1J & 2. ^1H -NMR (MeOD, 400 MHz) δ: 1.42-1.45 (t, 3H), 2.18-2.36 (m, 8H), 3.16-3.18 (m, 2H), 3.36-3.42 (m, 1H), 4.13 (s, 2H), 7.36-7.37 (dd, 1H), 7.61-7.66 (dd, 1H), 7.68 (s, 1H), 8.62 (bs, 1H). LCMS (ESI) m/z: 356 (M+1).

Example 36

6-Fluoro-3-(4-hydroxypyrrolidin-2-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

Example 36A

1-(tert-Butyl)-2-methyl 4-((tert-butyldiphenylsilyl)oxy)pyrrolidine-1,2-dicarboxylate

To a mixture of 1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (2 g, 8.13 mmol) and imidazole (1.1 g, 16.26 mmol) in anhydrous dichloromethane (50 mL) was added TBDPSCl (2.68 g, 9.76 mmol) in portions under nitrogen at 0°C. After stirring at 15°C for 4 hours, the reaction solution was washed with water (10 mL x 2), dried over anhydrous sodium sulfate, filtered and evaporated to provide the title compound (3.9 g, yield: 99%) as a colorless oil, which was used directly without further purification.

Example 36B

1-(tert-Butoxycarbonyl)-4-((tert-butyldiphenylsilyl)oxy)pyrrolidine-2-carboxylic acid

A mixed solution of Example 36A (3.9 g, 8.1 mmol) and lithium hydroxide (1 g, 24.2 mmol) in water (20 mL), methanol (5 mL) and tetrahydrofuran (20 mL) was stirred at 15° C. for 16 hours. The mixture was diluted with water (50 mL) and adjusted to pH 4-5 with 1N hydrochloric acid. The aqueous layer was extracted with ethyl acetate (50 mL×3), and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated to provide the title compound (3.7 g, yield: 97%), which was used directly in the next step without further purification.

Example 36C

tert-Butyl 4-((tert-Butyldiphenylsilyl)oxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate

To a mixed solution of Example 36B (3.7 g, 7.89 mmol) and triethylamine (2.2 g, 15.8 mmol) in tetrahydrofuran (100 mL) at 0°C under nitrogen was added isopropylcarbonyl chloride (1.2 g, 9.5 mmol). After stirring at 15°C for 4 hours, the temperature was lowered to 0°C, sodium borohydride (1.2 g, 31.56 mmol) was added, and the reaction mixture was stirred at 15°C for 64 hours. After the solvent was removed in vacuo, the residue was divided into water (50 mL) and dichloromethane (50 mL). The aqueous layer was extracted with dichloromethane (50 mL x 2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated. The residue was purified by column chromatography to yield the title compound (3.5 g, yield: 100%). LCMS (ESI) m/z: 456 (M+1).

Example 36D

tert-Butyl 4-((tert-Butyldiphenylsilyl)oxy)-2-(8-carboxamido-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazol-3-yl)-1-pyrrolidinecarboxylate

This example was prepared as described in Examples 1E-1J. LCMS (ESI) m/z: 642 (M+1).

Example 36E

6-Fluoro-3-(4-hydroxypyrrolidin-2-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

A mixture of Example 36D (50 mg, 0.078 mmol) in hydrogen bromide/acetic acid (0.5 mL) was stirred at 15° C. for 6 hours. The resulting mixture was evaporated and the residue was purified by preparative HPLC to give the title compound (10 mg, yield: 43%). ¹ H NMR (400MHz, DMSO-d ₆ )=8.36 (br.s., 1H), 8.06-7.86 (m, 1H), 7.53 (d, J=9.9Hz, 2H), 4.91 (dd, J=6.1, 11.5Hz, 1H), 4.56 (br.s., 1H), 3.45 ( d, J=8.8Hz, 1H), 3.06 (d, J=12.7Hz, 1H), 2.48-2.41 (m, 1H), 2.21 (dd, J=5.8, 13.0Hz, 1H). LCMS (ESI) m/z: 304 (M+1).

Example 37

3-Cyano-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

Example 37A

5-Amino-1-(2,6-dibromo-4-fluorophenyl)-1H-pyrazole-4-carbonitrile

A mixture of Example 1D (4 g, 14 mmol) and 2-ethoxymethylenemalononitrile (2.24 g, 18.31 mmol) in ethanol (30 mL) was stirred at 80° C. for 1.5 hours. The mixture was evaporated in vacuo to provide the title compound which was used directly in the next step without further purification (2.8 g, 56%).

Example 37B

8-Bromo-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-3-carbonitrile

Under nitrogen, a mixture of Example 37A (2.8 g, 7.78 mmol), N1,N2-dimethylethane-1,2-diamine (68 mg, 0.777 mmol), cuprous iodide (148 mg, 0.777 mmol) and potassium phosphate (1.65 g, 7.78 mmol) in DMF (30 mL) was stirred at 60° C. for 24 hours. After cooling to room temperature, the mixture was filtered and the filtrate was evaporated to give a residue which was washed with methanol and water and dried in vacuo to provide the title compound which was used directly in the next step without further purification (1.7 g, 78%).

Example 37C

Ethyl 3-cyano-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxylate

A solution of Example 37B (1 g, 3.58 mmol), palladium acetate (161 mg, 0.72 mmol), Pd(dppf) _Cl2 (526 mg, 0.72 mmol), Xantphos (420 mg, 0.72 mmol), DPPP (296 mg, 0.72 mmol), triphenylphosphine (188 mg, 0.72 mmol) and triethylamine (1.8 g, 18 mmol) in DMF (30 mL) and methanol (10 mL) was stirred at 120°C for 12 hours under a CO atmosphere (3 MPa). After cooling to room temperature, the mixture was filtered and the filtrate was evaporated to give a residue which was washed with dichloromethane and dried. The title compound was used in the next step without further purification (0.5 g, 54%).

Example 37D

3-Cyano-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

A mixture of Example 37C (20 mg, 0.077 mmol), aqueous ammonia (5 mL) in DMF (1 mL) and methanol (1 mL) was stirred at 120°C for 4 hours. After the solvent was removed in vacuo, the resulting residue was purified by preparative HPLC to give the title compound (2.99 mg, 16%). ^1H -NMR (400 MHz, MeOD-d4) δ ppm: 7.52 (dd, J = 7.91 Hz, 1H), 7.80 (dd, J = 10.67 Hz, 1H), 8.19 (s, 1H). LCMS (ESI) m/z: 244 (M+1).

Example 38

3-Cyano-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 37. ¹ H NMR (400 MHz, D2O) ppm 7.54-7.58 (t, 1H), 7.75-7.77 (d, 1H), 8.10-8.12 (d, 1H), 8.23 (s, 1H). LCMS (ESI) m/z: 226 (M+1).

Example 39

3-(Aminomethyl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

To a mixture of Example 37D (100 mg, 0.4 mmol) in dichloromethane (20 mL) and methanol (50 mL) at 0°C were added nickel chloride hexahydrate (200 mg, 0.8 mmol) and sodium borohydride (47 mg, 1.2 mmol) portionwise. After stirring at 0°C for 5 minutes, the reaction mixture was evaporated to give a residue which was purified by preparative HPLC to afford the title compound (45 mg, 45%). ^1H NMR (400 MHz, D2O) ppm 4.2 (s, 2H), 7.269-7.318 (t, 2H), 7.796 (s, 1H), 8.399 (s, 1H). LCMS (ESI) m/z: 248 (M+1).

Example 40

3-(Cyclopropylcarboxamidomethylene)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

A mixture of Example 39 (20 mg, 0.081 mmol), cyclopropanecarboxylic acid (8.36 mg, 0.098 mmol), HOBT (13.12 mg, 0.0979 mmol), EDCI (18.61 mg, 0.097 mmol) and triethylamine (25 mg, 0.242 mmol) in DMF (5 mL) was stirred at 30° C. for 6 hours. After removing the solvent in vacuo, the residue was purified by preparative HPLC to provide the title compound (11.9 mg, 48%). ^1H NMR(400MHz, DMSO-d6)ppm 0.64-0.72(m, 4H), 1.52-1.57(m, 1H), 4.25-2.50(d, 2H), 7.57-7.61(m, 2H), 7.82(s, 1H) , 8.13 (s, 1H), 8.44-8.46 (t, 1H), 10.46 (s, 1H), 11.93 (br, 1H). LCMS (ESI) m/z: 316 (M+1).

Process B

Example 41

6-Fluoro-3-(4-fluorophenyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

Example 41A

5-Amino-1-(2,6-dibromo-4-fluorophenyl)-1H-pyrazole-4-carboxylic acid ethyl ester

A mixture of Example 1D (5 g, 17.61 mmol) and ethyl 2-cyano-3-ethoxyacrylate (2.98 g, 17.61 mmol) in ethanol (100 mL) was stirred at 78° C. for 16 hours. After the solvent was removed in vacuo, the residue was purified by column chromatography to give the title compound (2.7 g, yield: 38%), which was used directly in the next step without further purification.

Example 41B

8-Bromo-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-3-carboxylic acid ethyl ester

Under nitrogen, a mixture of Example 41A (2.7 g, 6.63 mmol), cuprous iodide (252 mg, 1.33 mmol), N1,N2-dimethylethane-1,2-diamine (233.9 mg, 2.65 mmol) and potassium phosphate (4.22 g, 19.9 mmol) in DMF (60 mL) was stirred at 70° C. for 16 hours. After cooling to room temperature, the mixture was filtered and the solvent was evaporated in vacuo. The residue was used in the next step without further purification (2.16 g).

Example 41C

8-Bromo-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-3-carboxylic acid

To a mixture of Example 41B (2.16 g, 6.62 mmol) and sodium hydroxide (1.06 g, 26.49 mmol) in methanol (40 mL) and water (10 mL) was stirred at 70° C. for 16 hours. The solvent was removed in vacuo and the residue was used in the next step without further purification.

Example 41D

8-Bromo-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole

A solution of Example 41C (1.97 g, 6.61 mmol) in concentrated hydrochloric acid (20 mL) and water (20 mL) was stirred at 80° C. for 16 hours. After neutralization with concentrated aqueous ammonia, the resulting mixture was filtered, and the filter cake was washed with methanol and dried under vacuum. The resulting solid (1.58 g) was used directly in the next step without further purification.

Example 41E

8-Bromo-6-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole

To a solution of NaH (0.746 g, 18.66 mmol) in tetrahydrofuran (10 mL) at 0°C under nitrogen was added dropwise a solution of Example 41D (1.58 g, 6.22 mmol) in tetrahydrofuran (20 mL). After stirring at 0°C for 0.5 hours, SEMCl (1.56 g, 9.33 mmol) was added dropwise. The mixture was stirred at 0°C for an additional hour and then quenched with water (20 mL). The aqueous layer was extracted with dichloromethane (20 mL x 3). The combined organic layers were dried over sodium sulfate, filtered, and evaporated. The residue was purified by column chromatography to yield the title compound (0.43 g, 17% yield over four steps). LCMS (ESI) m/z: 384, 386 (M, M+2).

Example 41F

6-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxylic acid methyl ester

A solution of Example 41E (0.43 g, 1.12 mmol), palladium acetate (50 mg, 0.233 mmol), Pd(dppf) _Cl₂ (164 mg, 0.233 mmol), Xantphos (194 mg, 0.335 mmol), DPPP (138 mg, 0.335 mmol), triphenylphosphine (88 mg, 0.335 mmol), and triethylamine (566 mg, 5.59 mmol) in DMF (10 mL) and methanol (10 mL) was stirred at 80°C under a carbon monoxide atmosphere (3 atm) for 24 hours. After cooling to room temperature, the mixture was filtered, the filtrate was evaporated, and the residue was purified by column chromatography to give the title compound (0.265 g, 63% yield). LCMS (ESI) m/z: 364 (M+1).

Example 41G

3-Bromo-6-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxylic acid methyl ester

A mixture of Example 41F (0.265 g, 729 mmol) and NBS (117 mg, 656 mmol) in dichloromethane (20 mL) was stirred at 10°C for 20 minutes. After the solvent was removed in vacuo, the residue was purified by column chromatography to give the title compound (75% yield, 0.24 g). LCMS (ESI) m/z: 442, 444 (M, M+2).

Example 41H

3-Bromo-6-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxylic acid

A mixture of Example 41G (240 mg, 0.542 mmol) and sodium hydroxide (108 mg, 2.71 mmol) in methanol (6 mL) and water (1.5 mL) was stirred at 60°C for 0.5 hours. After cooling to room temperature, the pH of the mixture was adjusted to 4 with 1N hydrochloric acid, and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and evaporated to afford the title compound (196 mg, 84% yield), which was used directly in the next step without further purification.

Example 41I

3-Bromo-6-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

Under nitrogen, a mixture of Example 41H (0.196 g, 0.46 mmol), HATU (0.226 mg, 0.595 mmol), ammonium carbonate (0.439 g, 4.6 mmol), and triethylamine (0.138 g, 1.37 mmol) in DMF (8 mL) was stirred at 40°C for 16 hours. After the solvent was removed in vacuo, the residue was diluted with water (10 mL), and the aqueous layer was extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography to give the title compound (0.125 g, yield: 64%). LCMS (ESI) m/z: 427, 429 (M, M+2).

Example 41J

6-Fluoro-3-(4-fluorophenyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

Under nitrogen, a mixture of Example 41I (50 mg, 0.117 mmol), Pd(dppf) _Cl₂ (17 mg, 0.023 mmol), sodium carbonate (31 mg, 0.292 mmol), and (4-fluorophenyl)boronic acid (24 mg, 0.175 mmol) in DMF (3 mL) and water (0.5 mL) was stirred at 100°C for 16 hours. After the solvent was removed in vacuo, the residue was diluted with water (10 mL), and the aqueous layer was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated. The residue was purified by preparative TLC to give the title compound (40 mg, 77% yield). LCMS (ESI) m/z: 443 (M+1).

Example 41K

6-Fluoro-3-(4-fluorophenyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

A mixture of Example 41J (40 mg, 0.090 mmol) in trifluoroacetic acid (0.5 mL) and dichloromethane (0.5 mL) was stirred at 10°C for 5 hours. After the solvent was removed in vacuo, methanol (3 mL) and potassium carbonate (0.037 g, 0.271 mmol) were added to the residue and stirred at 10°C for 2 hours. The mixture was filtered, and the solvent was evaporated in vacuo. The residue was purified by preparative HPLC to give the title compound (6.3 mg, yield: 24%). ^1H NMR (400 MHz, DMSO-d6) δ: 8.32 (s, 1H), 7.67-7.71 (m, 2H), 7.59-7.61 (d, 1H), 7.55-7.57 (d, 1H), 7.22-7.27 (t, 2H). LCMS (ESI) m/z: 313 (M+1).

Example 42

6-Fluoro-3-(2-fluoro-4-((methylaminomethylene)phenyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

Example 42A

1-(4-Bromo-3-fluorophenyl)-N-methylmethanamine

A mixture of 4-bromo-3-fluorobenzaldehyde (2 g, 9.8 mmol) and methylamine (30%-40% in EtOH) (10 mL, 16.7 mmol) in ethanol (10 mL) was stirred at 75°C for 15 hours. After cooling to room temperature, sodium borohydride (745 mg, 19.6 mmol) was added in one portion and stirred for an additional 30 minutes. After removing the solvent in vacuo, the residue was diluted with saturated sodium bicarbonate (20 mL), and the aqueous layer was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over sodium sulfate, filtered, and evaporated. The residue was purified by column chromatography to provide the title compound (1.47 g, yield: 74%). LCMS (ESI) m/z: 218, 220 (M, M+2).

Example 42B

tert-Butyl (4-bromo-3-fluorobenzyl)(methyl)carbamate

A mixture of Example 42A (1.47 g, 6.77 mmol), BocO (1.77 g, 8.12 mmol), and triethylamine (1.37 g, 13.54 mmol) in dichloromethane (15 mL) was stirred at 18°C for 2 hours. After removing the solvent in vacuo, the residue was purified by column chromatography to provide the title compound (85% yield, 1.83 g). LCMS (ESI) m/z: 319 (M+1).

Example 42C

tert-Butyl (3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)(methyl)carbamate

Under N2 protection, a mixture of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (1.76 g, 6.92 mmol), Example 42B (1.83 g, 5.77 mmol), potassium acetate (1.13 g, 11.54 mmol) and Pd(dppf) _Cl2 (422 mg, 0.577 mmol) in DMSO (15 mL) was stirred at 80°C for 15 hours. After cooling to room temperature, the mixture was filtered, the filtrate was diluted with water (20 mL), and the aqueous layer was extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by column chromatography to afford the title compound (2 g, yield: 95%) as a colorless oil.

Example 42D

tert-Butyl (4-(8-formamido-6-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazol-3-yl)-3-fluoromethylphenyl)(methyl)carbamate

Under nitrogen, a mixture of Example 41I (100 mg, 0.23 mmol), Example 42C (85.7 mg, 0.23 mmol), sodium carbonate (50 mg, 0.47 mmol), and Pd(dppf) _Cl₂ (17.1 mg, 0.023 mmol) in DMF (5 mL) and water (1 mL) was stirred at 80°C for 15 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was diluted with water (20 mL). The aqueous layer was extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to afford the residue, which was purified by preparative TLC to provide the title compound (110 mg, 97% yield). LCMS (ESI) m/z: 586 (M+1).

Example 42E

6-Fluoro-3-(2-fluoro-4-((methylaminomethylene)phenyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

A mixture of trifluoroacetic acid (5 mL) and dichloromethane (5 mL) in Example 42D (110 mg, 0.19 mmol) was stirred at 10 ° C for 15 hours. After the solution was removed in vacuo, methanol (15 mL) and potassium carbonate (53 mg, 0.38 mmol) were added to the residue. The mixture was stirred at 18 ° C for 15 hours. The mixture was filtered, the filtrate was evaporated, and the residue was dispersed between water (10 mL) and ethyl acetate (10 mL). The aqueous layer was extracted with ethyl acetate/tetrahydrofuran = 3/1 (20 mL × 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and evaporated to give the residue which was purified by preparative HPLC to give the title compound (22.45 mg, yield: 34%) as a white solid. ^1H NMR(400MHz, METHANOL-d ₄ )ppm 2.79 (s, 3H), 4.24 (s, 2H), 4.48-5.29 (m, 27H), 7.37-7.43 (m, 2H), 7.52 (d, J=7.78Hz, 1H), 7.72 (d , J=9.79Hz, 1H), 7.78 (t, J=7.78Hz, 1H), 8.23 (s, 1H), 8.49 (br.s., 1H). LCMS (ESI) m/z: 356 (M+1).

Example 43

6-Fluoro-3-(4-((methylamino)methyl)phenyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 42. ¹ H-NMR (400 MHz, MethanoL-d ₄ + D ₂ O) 2.77 (s, 3H), 4.21 (s, 2H), 7.46-7.62 (m, 3H), 7.75 (d, J=8.16 Hz, 3H), 8.26 (s, 1H), 8.53 (br. s., 1H). LCMS (ESI) m/z: 338 (M+1).

Example 44

6-Fluoro-3-(2-fluoro-5-((methylamino)methyl)phenyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 42. ¹ H-NMR (400 MHz, DMSO-d ₆ + D ₂ O) 2.59 (br. s., 3H), 4.13 (br. s., 2H), 7.15-7.41 (m, 2H), 7.47-7.68 (m, 2H), 7.95-8.09 (m, 1H), 8.16-8.27 (m, 1H), 8.36 (br. s., 1H). LCMS (ESI) m/z: 356 (M+1).

Example 45

6-Fluoro-3-(pyridin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 42. ¹ H-NMR (MeOD, 400 MHz) δ: 7.55-7.63 (m, 2H), 7.73-7.79 (m, 1H), 8.11-8.14 (m, 1H), 8.15-8.19 (m, 1H), 8.48-8.54 (m, 2H), 8.55-8.59 (m, 1H), 10.28-10.36 (m, 1H). LCMS (ESI) m/z: 296 (M+1).

Example 46

6-Fluoro-3-(4-(piperidin-3-yl)phenyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

Example 46A

tert-Butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxylate

Under N protection, a mixture of tert-butyl 3-(4-aminophenyl)piperidine-1-carboxylate (0.1 g, 0.362 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (0.101 g, 0.398 mmol), BPO (1.75 g, 0.00724 mmol) and t-BuONO (0.056 g, 0.542 mmol) in acetonitrile (3 mL) was stirred at 10° C. for 16 hours. The solvent was evaporated in vacuo, and the residue was purified by preparative TLC to give the title compound (0.095 g, yield: 68%).

Example 46B

6-Fluoro-3-(4-(piperidin-3-yl)phenyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 42. ¹ H NMR (300 MHz, METHANOL-d4) ppm: 1.189 (m, 2H), 2.10-2.01 (m, 2H), 3.03-3.14 (m, 3H), 3.45-3.49 (m, 2H), 7.37-7.40 (d, 2H), 7.44-7.47 (dd, 1H), 7.66-7.68 (d, 2H), 7.74-7.79 (dd, 1H), 8.22 (s, 1H), 8.53 (s, 1H). LCMS (ESI) m/z: 378 (M+1).

Example 47

6-Fluoro-3-(tetrahydro-2H-pyran-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

Example 47A

3,6-Dihydro-2H-pyran-4-yl trifluoromethanesulfonate

To a solution of dihydro-2H-pyran-4(3H)-one (1.8 g, 18.0 mol) in tetrahydrofuran (20 mL) at -78°C under nitrogen was added dropwise LiHMDS (1 M, 21.6 mL, 21.6 mmol). After stirring at -78°C for 1 hour, (CF3SO2)2NPh (6.4 g, 18.0 mmol) was added portionwise. The mixture was stirred at 15°C for 16 hours and then quenched with aqueous ammonium chloride (20 mL). The aqueous layer was extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with water and brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by column chromatography to afford the title compound as a colorless oil (1.5 g, yield: 35.7%). LCMS (ESI) m/z: 233 (M+1).

Example 47B

2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

This example was prepared as described in Example 42C.

Example 47C

6-Fluoro-3-(tetrahydro-2H-pyran-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This compound was prepared as described in Example 46B. ^1H -NMR (MeOD, 400 MHz) δ: 1.82-2.03 (m, 4H), 2.93-3.04 (m, 1H), 3.62 (td, J=11.70, 2.45 Hz, 2H), 4.04-4.11 (m, 2H), 7.32-7.39 (m, 1H), 7.66-7.75 (m, 2H), 8.51-8.55 (m, 1H). LCMS (ESI) m/z: 303 (M+1).

Example 48

3-(4-(Dimethylamino)cyclohexyl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

Example 48A

4-((tert-Butoxycarbonyl)amino)cyclohex-1-en-1-yl trifluoromethanesulfonate

To a solution of tert-butyl (4-oxocyclohexyl)carbamate (1 g, 4.689 mol) in tetrahydrofuran (20 mL) was added dropwise LiHMDS (1 M, 9.4 mL, 9.378 mmol) at -78°C under nitrogen. After stirring at -78°C for 1 hour, a solution of (CF3SO2)2NPh (1.84 g, 5.158 mmol) in tetrahydrofuran (5 mL) was added dropwise. The mixture was stirred at 15°C for 16 hours and then quenched with aqueous ammonium chloride (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was purified by silica gel column chromatography to afford the title compound as a white solid (1.16 g, yield: 71.60%). LCMS (ESI) m/z: 347 (M+1).

Example 48B

tert-Butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)carbamate

In this example, the method described in Example 47B was used to prepare the present invention.

Example 48C

3-(4-(Dimethylamino)cyclohexyl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared according to the methods described in Example 47C and Example 2. ¹ H-NMR (MeOD, 400 MHz) δ: 1.63-1.87 (m, 3H), 1.91-2.10 (m, 2H), 2.20-2.46 (m, 3H), 2.81 (s, 4H), 2.90 (s, 3H), 3.19-3.30 (m, 1H), 7.34-7.44 (m, 1H), 7.64-7.75 (m, 2H), 7.78-7.85 (m, 1H), 8.38-8.73 (m, 3H). LCMS (ESI) m/z: 344 (M+1).

Example 49

6-Fluoro-3-(4-methylpiperazine-1-carbonyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

Example 49A

8-Bromo-6-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-3-carboxylic acid ethyl ester

To a solution of Example 41B (3.2 g, 9.812 mol) in tetrahydrofuran (50 mL) at 0°C under nitrogen was added NaH (785 mg, 19.625 mmol) portionwise. After stirring at 15°C for 0.5 hours, the mixture was cooled to 0°C and SEMCl (3.3 g, 19.625 mmol) was added dropwise. The mixture was stirred at 15°C for 16 hours and then quenched with saturated aqueous ammonium chloride (30 mL). The aqueous layer was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by column chromatography to provide the title compound as a yellow solid (2.16 g, yield: 48.21%). LCMS (ESI) m/z: 456, 458 (M, M+2).

Example 49B

8-Bromo-6-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-3-carboxylic acid

A mixture of Example 49A (2.16 g, 4.726 mmol) and sodium hydroxide (950 mg, 23.632 mmol) in methanol/water (2:1) (30 mL) was stirred at 80°C for 16 hours. The resulting mixture was adjusted to pH 3-4 with 1N hydrochloric acid, and the aqueous layer was extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and evaporated to give the title compound (1.73 g, yield: 85.22%), which was used in the next step without further purification.

Example 49C

tert-Butyl 4-(8-bromo-6-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-3-carbonyl)piperazine-1-carboxylate

Under N2 protection, a mixture of tert-butyl piperazine-1-carboxylate (415 mg, 2.241 mmol), Example 49B (800 mg, 1.868 mmol), HATU (1.42 g, 3.735 mmol), and triethylamine (567 mg, 5.603 mmol) in DMF (15 mL) was stirred at 15°C for 16 hours. The mixture was quenched with water (10 mL), and the aqueous layer was extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by column chromatography to give the title compound (1 g, yield: 90%). LCMS (ESI) m/z: 596, 598 (M, M+2).

Example 49D

tert-Butyl 4-(8-cyano-6-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-3-carbonyl)piperazine-1-carboxylate

Under nitrogen, a mixture of Example 49C (400 mg, 0.671 mmol), zinc (87 mg, 1.341 mmol), zinc cyanide (158 mg, 1.341 mmol), DPPF (75 mg, 0.134 mmol), and Pd(DBA) (61 mg, 0.0671 mmol) in DMF (10 mL) was stirred at 120°C for 10 hours. After cooling to room temperature, the resulting mixture was diluted with water (20 mL), and the aqueous layer was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was purified by column chromatography to give the title compound (350 mg, yield: 96.15%). LCMS (ESI) m/z: 543 (M+1).

Example 49E

tert-Butyl 4-(8-carbamoyl-6-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-3-carbonyl)piperazine-1-carboxylate

To a mixture of Example 49D (400 mg, 0.737 mmol) and potassium carbonate (510 mg, 3.685 mmol) in DMSO (10 mL) was added dropwise hydrogen peroxide (5 mL) at 0-5°C. After stirring at 15°C for 1 hour, the mixture was quenched with aqueous sodium sulfite (20 mL). The aqueous layer was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by column chromatography to give the title compound (400 mg, 96.85% yield). LCMS (ESI) m/z: 561 (M+1).

Example 49F

6-Fluoro-3-(piperazine-1-carbonyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

A mixture of Example 49E (100 mg, 0.178 mmol) in trifluoroacetic acid (1 ml) and dichloromethane (1 ml) was stirred at 15° C. for 16 hours. After the solvent was removed in vacuo, potassium carbonate (123 mg, 0.892 mmol) and methanol (2 ml) were added to the residue, and the mixture was stirred at 15° C. for 2 hours. The mixture was filtered and the filtrate was evaporated to give the title compound which was used directly in the next step without further purification.

Example 49G

6-Fluoro-3-(4-methylpiperazine-1-carbonyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

A mixture of Example 49F (59 mg, 0.179 mmol), formaldehyde (40 mg, 0.358 mmol), and sodium cyanoborohydride (56 mg, 0.894 mmol) in methanol (2 mL) was stirred at 15° C. for 16 hours. The solvent was evaporated in vacuo, and the residue was purified by preparative HPLC to give the title compound (8.14 mg, yield: 13.23%) as a white solid. ¹ H-NMR (MeOD, 400MHz) δ: 2.68 (s, 3H), 2.99 (d, J=4.64Hz, 4H), 4.00 (br.s., 4H), 7.46-7.54 ( m, 1H), 7.74-7.84 (m, 1H), 8.12-8.20 (m, 1H), 8.24-8.35 (m, 2H). LCMS (ESI) m/z: 345 (M+1).

Example 50

3-(1-(Cyclopropylmethyl)piperidin-4-yl)-4,4,6-trifluoro-4H-pyrazolo[1,5-a]indole-8-carboxamide

Example 50A

(E)-4-(Dimethylamino)-2-oxobut-3-enoic acid ethyl ester

A solution of ethyl 2-oxopropanoate (5.0 g, 43.1 mmol) in DMF-DMA (5.0 g, 42.0 mmol) was stirred at 20° C. for 16 h. The resulting mixture was evaporated to give the title compound (7.0 g, crude) as a brown oil which was used in the next step without further purification.

Example 50B

1-(2,6-Dibromo-4-fluorophenyl)-1H-pyrazole-5-carboxylic acid ethyl ester

A mixture of Example 1D (5.0 g, 17.6 mmol) and Example 50A (6.0 g, 35.2 mmol) in ethanol (100 mL) and concentrated hydrochloric acid (2.4 mL) was stirred at 80° C. for 16 hours. After the solvent was removed in vacuo, the residue was purified by column chromatography to provide the title compound (3.6 g, yield: 46.8%) as a yellow solid.

Example 50C

1-(2,6-Dibromo-4-fluorophenyl)-1H-pyrazole-5-carboxylic acid

A mixture of Example 50B (3.6 g, 9.18 mmol) and sodium hydroxide (2.2 g, 55.1 mmol) in methanol (20 mL) and water (2 mL) was stirred at 20° C. for 1 hour. After the solvent was removed in vacuo, the residue was diluted with water (50 mL) and the pH was adjusted to 3 with 2N hydrochloric acid. The aqueous layer was extracted with dichloromethane (50 mL×3), and the combined organic layers were dried over sodium sulfate, filtered and evaporated to provide the title compound which was used directly in the next step without further purification (3.2 g, 97.0%).

Example 50D

1-(2,6-Dibromo-4-fluorophenyl)-N-methoxy-N-methyl-1H-pyrazole-5-carboxamide

Under nitrogen, a mixture of Example 50C (3.2 g, 8.82 mmol), O,N-dimethylhydroxylamine (1.7 g, 17.6 mmol), HATU (4.0 g, 10.6 mmol) and triethylamine (3.6 g, 35.3 mmol) in anhydrous DMF (2 mL) was stirred at 20° C. for 16 hours. After removing the solvent in vacuo, the residue was purified by column chromatography to give the title compound (3.4 g, yield: 94.4%) as a yellow solid.

Example 50E

8-Bromo-6-fluoro-4H-pyrazolo[1,5-a]indol-4-one

To a mixture of Example 50D (3.2 g, 7.90 mmol) in anhydrous tetrahydrofuran (5 mL) at -78°C under nitrogen was added n-butyllithium (2.8 mL, 7.11 mmol) dropwise. After stirring at -78°C for 0.5 hour, the mixture was quenched with saturated aqueous ammonium chloride (30 mL). The aqueous layer was extracted with dichloromethane (50 mL x 2). The combined organic layers were evaporated, and the residue was washed with methanol (30 mL) to obtain the title compound as a bright yellow solid (1.5 g, yield: 71.4%). LCMS (ESI) m/z: 267, 269 (M, M+2).

Example 50F

6-Fluoro-4-oxo-4H-pyrazolo[1,5-a]indole-8-carboxylic acid methyl ester

A mixture of Example 50E (1.3 g, 4.89 mmol), Pd(dppf) _Cl₂ (0.71 g, 0.98 mmol), palladium acetate (0.22 g, 0.98 mmol), DPPP (0.81 g, 1.96 mmol), triphenylphosphine (0.51 g, 1.96 mmol), Xantphos (1.13 g, 1.96 mmol), and triethylamine (3 mL) in methanol (20 mL) and DMF (60 mL) was stirred at 80°C under a carbon monoxide atmosphere (3 atm) for 16 hours. After cooling to 20°C, the mixture was filtered, the filtrate evaporated, and the residue purified by column chromatography to give the title compound (0.9 g, yield: 75.0%) as a yellow solid. LCMS (ESI) m/z: 247 (M+1).

Example 50G

Methyl 6-fluorospiro[pyrazolo[1,5-a]indole-4,2′-[1,3]dithiolane]-8-carboxylate

Under nitrogen, a mixture of Example 50F (0.9 g, 3.66 mmol), 2-ethanedithiol (0.69 g, 7.32 mmol), and boron trifluoride etherate (1.0 g, 7.32 mmol) in dry dichloromethane (30 mL) was stirred at 50°C for 24 hours. After cooling to room temperature, the mixture was diluted with dichloromethane (30 mL). The combined organic layers were washed with water and 10% sodium hydroxide (30 mL), dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was purified by silica gel column chromatography to give the title compound (0.5 g, yield: 42.4%) as a yellow solid. LCMS (ESI) m/z: 323 (M+1).

Example 50H

Methyl 3-bromo-6-fluorospiro[pyrazolo[1,5-a]indole-4,2′-[1,3]dithiolane]-8-carboxylate

A mixture of Example 50G (500 mg, 1.55 mmol) and NBS (276 mg, 1.55 mmol) in tetrahydrofuran (20 mL) was stirred at 40°C for 16 hours. After cooling to 20°C, the mixture was evaporated, and the residue was purified by column chromatography to provide the title compound (470 mg, yield: 75.7%) as a light yellow solid. LCMS (ESI) m/z: 401, 403 (M, M+2).

Example 50I

3-Bromo-4,4,6-trifluoro-4H-pyrazolo[1,5-a]indole-8-carboxylic acid methyl ester

3-Bromo-6-fluoro-4-oxo-4H-pyrazolo[1,5-a]indole-8-carboxylic acid methyl ester

To a solution of NIS (2.1 g, 9.38 mmol) in DCM (20 mL) was added HF.Py (3.5 mL) dropwise under nitrogen at -78°C. After stirring at -78°C for 10 minutes, Example 50H (470 mg, 1.17 mmol) was added. The resulting mixture was stirred at -78°C for 16 hours, then quenched with saturated aqueous sodium bicarbonate (30 mL). The aqueous layer was extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with saturated aqueous sodium sulfite (30 mL). The solvent was evaporated under vacuum, and the residue was purified by column chromatography to provide Example 50IA as a yellow solid (250 mg, yield: 61.6%) and Example 50IB (110 mg, yield: 27.2%) as a white solid.

Example 50J

tert-Butyl 4-(8-formyl-4,4,6-trifluoro-4H-pyrazolo[1,5-a]indol-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate

Under N₂ protection, a mixture of Example 50IA (200 mg, 0.499 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (185 mg, 0.598 mmol), Pd(DPPF)Cl₂ (37 mg, 0.050 mmol), and potassium carbonate (138 mg, 0.997 mmol) in DMF (9 mL) and water (3 mL) was stirred at 90°C for 16 hours. After cooling to room temperature, the mixture was concentrated in vacuo, and the residue was dissolved in water (20 mL) and the pH was adjusted to 3 with 1N HCl. The aqueous layer was extracted with dichloromethane (50 mL x 3), and the combined organic layers were dried over sodium sulfate, filtered, and evaporated to provide the title compound (220 mg, crude product) without further purification.

Example 50K

tert-Butyl 4-(8-carbamoyl-4,4,6-trifluoro-4H-pyrazolo[1,5-a]indol-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate

A mixture of Example 50J (220 mg, 0.51 mmol), ammonium carbonate (97 mg, 1.01 mmol), triethylamine (0.2 mL, 1.53 mmol), and HATU (252 mg, 0.66 mmol) in DMF (8 mL) was stirred at 20°C for 16 hours. The mixture was concentrated in vacuo, and the residue was purified by column chromatography to afford the title compound as a yellow solid (70 mg, yield: 32.0%). LCMS (ESI) m/z: 435 (M+1).

Example 50L

tert-Butyl 4-(8-carbamoyl-4,4,6-trifluoro-4H-pyrazolo[1,5-a]indol-3-yl)piperidine-1-carboxylate

A mixture of Example 50K (35 mg, 0.08 mmol) and 10% Pd/C (20 mg) in dry dichloromethane (20 mL) and methanol (10 mL) was hydrogenated at 50°C for 16 hours (1 atm). The mixture was filtered, and the filtrate was evaporated to give the title compound (30 mg, 85.7% yield), which was used directly in the next step without further purification. LCMS (ESI) m/z: 437 (M+1).

Example 50M

4,4,6-Trifluoro-3-(piperidin-4-yl)-4H-pyrazolo[1,5-a]indole-8-carboxamide

A mixture of Example 50L (200 mg, 0.466 mmol) in trifluoroacetic acid (2 mL) and dichloromethane (6 mL) was stirred at 20° C. for 2 hours. The resulting mixture was evaporated to afford the title compound which was used in the next step without further purification (30 mg, crude).

Example 50N

3-(1-(Cyclopropylmethyl)piperidin-4-yl)-4,4,6-trifluoro-4H-pyrazolo[1,5-a]indole-8-carboxamide

Under N2 protection, a mixture of Example 50M (30 mg, 0.069 mmol), cyclopropane (10 mg, 0.138 mmol), tetraisopropyloxytitanium (39 mg, 0.138 mmol) and sodium cyanoborocyanide (13 mg, 0.207 mmol) in methanol (8 mL) was stirred at 60°C for 16 hours. The reaction was quenched with water (10 mL), and the aqueous layer was extracted with dichloromethane (20 mL x 3). The combined organic layers were evaporated, and the residue was purified by preparative HPLC to give the title compound as a white solid (5 mg, yield: 18.5%). ^1H -NMR (400MHz, MethanoL-d ₄ )ppm 0.41 (d, J=4.89Hz, 2H), 0.72-0.81 (m, 2H), 1.13 (br.s., 1H), 1.93-2.13 (m, 2H), 2.31 (d, J=13.93Hz, 2H), 2.87-3.12 (m, 5H), 3 .66 (d, J=11.17Hz, 2H), 7.78-7.82 (m, 1H), 7.85 (s, 1H), 7.97 (dd, J=9.91, 2.64Hz, 1H), 8.07 (s, 1H). LCMS (ESI) m/z: 391 (M+1).

Example 51

3-(1-ethylpiperidin-4-yl)-6-fluoro-4-hydroxy-4H-pyrazolo[1,5-a]indole-8-carboxamide

Example 51A

tert-Butyl 4-(8-carbamoyl-6-fluoro-4-oxo-4H-pyrazolo[1,5-a]indol-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate

This example was prepared as described in Example 50K. LCMS (ESI) m/z: 413 (M+1).

Example 51B

tert-Butyl 4-(8-carbamoyl-6-fluoro-4-hydroxy-4H-pyrazolo[1,5-a]indol-3-yl)piperidine-1-carboxylate

A mixture of Example 51A (50 mg, 0.121 mmol) and 10% Pd/C (10 mg) in anhydrous methanol (10 mL) was hydrogenated at 50°C for 16 hours (1 atm). The mixture was filtered, and the filtrate was evaporated to give the title compound (40 mg, 80.0% yield), which was used directly in the next step without further purification. LCMS (ESI) m/z: 417 (M+1).

Example 51C

6-Fluoro-4-hydroxy-3-(piperidin-4-yl)-4H-pyrazolo[1,5-a]indole-8-carboxamide

This example was prepared as described in Example 50M.

Example 51D

3-(1-ethylpiperidin-4-yl)-6-fluoro-4-hydroxy-4H-pyrazolo[1,5-a]indole-8-carboxamide

A mixture of Example 51C (25 mg, 0.079 mmol), 40% acetaldehyde (0.1 ml) and sodium cyanoborocyanide (20 mg, 0.316 mmol) in methanol (5 ml) was stirred at 10° C. for 16 hours. The resulting mixture was diluted with water (10 mL), the aqueous layer was extracted with dichloromethane (20 ml×3), and the combined organic layers were evaporated to give a residue which was purified by preparative HPLC to give the title compound (9.40 mg, yield: 34.8%) as a white solid. ^1H -NMR (400MHz, MethanoL-d ₄ )ppm 1.11-1.18 (m, 3H), 1.77-1.96 (m, 2H), 2.01-2.16 (m, 2H), 2.61 (br.s., 2H), 2.81 (br.s., 3H), 3.27 (br.s., 2H), 5.72 (s, 1H), 7.59 (dd, J=7 .22, 2.45Hz, 1H), 7.70 (d, J=10.42Hz, 1H), 7.76 (s, 1H), 7.99 (br.s., 1H), 8.32 (br.s., 1H), 10.09 (br.s., 1H). LCMS (ESI) m/z: 345 (M+1).

Example 52

3-(1-ethylpiperidin-4-yl)-6-fluoro-4-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

Example 52A

tert-Butyl 4-(8-carbamoyl-6-fluoro-4-methyl-4H-benzo[4,5]imidazo[1,2-B]pyrazol-3-yl)piperidine-1-carboxylate

A mixture of Example 1I (30 mg, 0.075 mmol), potassium carbonate (31 mg, 0.224 mmol), and iodomethane (32 mg, 0.224 mmol) in DMF (3 mL) was stirred at 10°C for 1 hour. The reaction was quenched with water (10 mL), and the aqueous layer was extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried over sodium sulfate, filtered, and evaporated to provide the title compound, which was used directly in the next step without further purification.

Example 52B

6-Fluoro-4-methyl-3-(piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

A mixture of Example 52A (31 mg, 0.074 mmol) in dichloromethane (1 mL) and trifluoroacetic acid (0.2 mL) was stirred at 10°C for 2 hours. The mixture was evaporated to provide the title compound which was used directly in the next step without further purification.

Example 52C

3-(1-ethylpiperidin-4-yl)-6-fluoro-4-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This compound was prepared as described in Example 51D. ^1H -NMR (400 MHz, METHANOL-d4) ppm: 1.23-1.26 (t, 3H), 1.91-1.97 (m, 2H), 2.11-2.14 (d, 2H), 2.55 (t, 2H), 2.78-2.80 (m, 2H), 3.04-3.07 (m, 2H), 3.32 (2H), 3.87 (s, 2H), 7.48-8.50 (m, 1H), 7.64-7.67 (m, 1H), 7.73 (s, 1H), 8.54 (s, 1H). LCMS (ESI) m/z: 344 (M+1).

Process C

Example 53

6-Fluoro-3-(4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

Example 53A

1-(tert-Butyl)-4-methyl-4-methylpiperidine-1,4-dicarboxylic acid dimethyl ester

Under N₂ protection, LiHMDS (1 M, 300 mL) was added dropwise to a solution of 1-tert-butyl-4-methylpiperidine-1,4-dicarboxylate (36.5 g, 0.15 mol) in anhydrous tetrahydrofuran (400 mL) at -78°C. After stirring at -78°C for 30 minutes, a solution of iodomethane (42.6 g, 0.3 mol) in tetrahydrofuran (100 mL) was added dropwise. The reaction mixture was stirred at -78°C for 2 hours, then warmed to 15°C and stirred for an additional 20 hours. After completion, the reaction was quenched with saturated aqueous ammonium chloride (500 mL). The aqueous layer was extracted with ethyl acetate (500 mL x 3). The combined organic layers were dried over sodium sulfate, filtered, and evaporated. The residue was purified by column chromatography to yield the title compound (30 g, yield: 78%). LCMS (ESI) m/z: 258 (M+1).

Example 53B

tert-Butyl 4-(hydroxymethyl)-4-methylpiperidine-1-carboxylate

To a solution of lithium aluminum tetrahydride (3.7 g, 97.5 mmol) in anhydrous tetrahydrofuran (40 mL) was added dropwise a solution of Example 53A (10 g, 39 mmol) in anhydrous tetrahydrofuran (80 mL) at 0° C. under nitrogen. After the addition was complete and the mixture was stirred at 0° C. for 2.5 hours, the reaction mixture was quenched with water (4 mL), 15% aqueous sodium hydroxide solution (4 mL) and water (12 mL). The mixture was stirred at 0° C. for another 20 minutes and then filtered. The solid was washed with ethyl acetate (50 ml×4). The combined organic layers were dried over sodium sulfate, filtered and evaporated to provide the title compound (9 g, crude product) which was used directly in the next step without further purification.

Example 53C

tert-Butyl 4-(hydroxymethyl)-4-methylpiperidine-1-carboxylate

This example was prepared as described in Examples 1A-1B.

Example 53D

6-Fluoro-3-(4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Examples 1E-1J. ^1H NMR (400 MHz, MeOD) δ: 8.51 (s, 1H), 7.81 (s, 1H), 7.69 (dd, J = 2.4 Hz / J = 10.2 Hz, 1H), 7.45 (dd, J = 2.4 Hz / J = 8.0 Hz, 1H), 3.33-3.39 (m, 2H), 3.12-3.32 (m, 2H), 2.42-2.46 (m, 2H), 2.03-2.08 (m, 2H), 1.46 (s, 3H). LCMS (ESI) m/z: 316 (M+1).

Example 54

3-(1-ethyl-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 52C (10 mg, 38% yield). ^1H NMR (400 MHz, DMSO) δ: 10.58 (s, 1H), 8.28 (s, 1H), 8.13 (s, 1H), 7.80 (s, 1H), 7.61 (dd, J = 2.8 Hz/J = 7.2 Hz, 1H), 7.49 (t, J = 2.4 Hz, 1H), 2.75-2.78 (m, 2H), 2.50-2.54 (m, 4H), 2.18-2.20 (m, 2H), 1.73-1.78 (m, 2H), 1.30 (s, 3H), 1.05 (t, J = 7.2 Hz, 3H). LCMS (ESI) m/z: 344 (M+1).

Example 55

3-(1-cyclopropyl-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 4. ¹ H-NMR (400 MHz, MethanoL-d ₄ ) 0.77 (d, J = 5.40 Hz, 4H), 1.41-1.45 (m, 3H), 1.90-2.01 (m, 2H), 2.28-2.44 (m, 3H), 3.03 (br. s., 2H), 3.27 (br. s., 2H), 7.39 (dd, J = 8.16, 2.51 Hz, 1H), 7.73 (dd, J = 10.92, 2.38 Hz, 1H), 7.79 (s, 1H), 8.41 (br. s., 1H). LCMS (ESI) m/z: 356 (M+1).

Example 56

6-Fluoro-3-(1-(2-hydroxy-2-methylpropyl)-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This compound was prepared as described in Example 6. ¹ H-NMR (400 MHz, DMSO-d ₄ ) δ ppm: 1.13 (s, 6H), 1.28 (s, 3H), 1.86 (t, J=10.23 Hz, 2H), 2.20 (d, J=15.43 Hz, 2H), 2.62 (s, 2H), 2.76 (br. s., 2H), 3.04 (d, J=4.02 Hz, 2H), 7.48 (dd, J=8.34, 2.57 Hz, 1H), 7.56 (dd, J=10.92, 2.64 Hz, 1H), 7.79 (s, 1H), 8.31 (s, 1H). LCMS (ESI) m/z: 388 (M+1).

Example 57

3-(1-cyclopropylmethylene-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 5. ¹ H-NMR (400 MHz, MethanoL-d ₄ )δppm0.37 (d, J=3.89Hz, 2H), 0.73 (d, J=7.53Hz, 2H), 1.02-1.14 (m, 1H), 1.4 4(br.s., 3H), 2.08(d, J=11.29Hz, 2H), 2.37-2.66(m, 2H), 2.94(br.s., 3H), 3.34-3.63 (m, 3H), 7.38 (dd, J=8.09, 2.57Hz, 1H), 7.71 (dd, J=10.92, 2.51Hz , 1H), 7.79 (s, 1H), 7.77-7.81 (m, 1H), 8.51 (s, 1H). LCMS (ESI) m/z: 370 (M+1).

Example 58

3-(1-4,4-difluorocyclohexyl)-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 5. ¹ H-NMR (400 MHz, DMSO-d ₄ ) δ ppm 1.22 (s, 3H), 1.33-1.49 (m, 1H), 1.70 (br. s., 6H), 1.92-2.12 (m, 1H), 2.31-2.38 (m, 1H), 2.59-2.64 (m, 1H), 7.40-7.62 (m, 2H), 7.74 (s, 1H). LCMS (ESI) m/z: 434 (M+1).

Example 59

6-Fluoro-3-(4-methyl-1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 5. ¹ H NMR (400 MHz, METHANOL-d ₄ ) 1.05 (t, J=7.22 Hz, 1H), 1.36 (s, 3H), 1.50-1.60 (m, 1H), 1.82 (d, J=11.92 Hz, 3H), 2.21-2.27 (m, 1H), 2.44-2.56 (m, 1H), 2.79 (br. s., 2H), 3.35-3.42 (m, 1H), 3.90-4.05 (m, 1H), 7.32-7.38 (m, 1H), 7.71 (s, 1H). LCMS (ESI) m/z: 400 (M+1).

Example 60

6-fluoro-3-(1-2-fluoroethyl)-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 3. ¹ H NMR (400 MHz, METHANOL-d ₄ ) ppm 1.45 (s, 3H), 2.01-2.05 (m, 2H), 2.24-2.47 (m, 2H), 3.05 (m, 2H), 3.24-3.25 (m, 1H), 3.26-3.27 (m, 1H), 3.33-3.34 (m, 1H), 4.70-4.72 (m, 1H), 4.82-4.93 (m, 1H), 7.37-7.39 (m, 1H), 7.68-7.79 (d, 1H), 7.81 (s, 1H), 8.45 (br. s., 1H). LCMS (ESI) m/z: 362 (M+1).

Example 61

6-Fluoro-3-(4-methyl-1-(2,2,2-trifluoroethyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 3. ¹ H NMR (400 MHz, METHANOL-d ₄ ) ppm 1.37 (s, 3H), 1.79-1.91 (m, 2H), 2.16-2.27 (m, 2H), 2.58-2.69 (m, 2H), 2.79-2.89 (m, 2H), 2.98-3.10 (m, 2H), 7.33-7.39 (m, 1H), 7.66-7.75 (m, 2H). LCMS (ESI) m/z: 398 (M+1).

Example 62

6-Fluoro-3-(4-methyl-1-(2,2,2-trifluoropropyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 3. ¹ H NMR (400 MHz, METHANOL-d ₄ ) 1.42 (s, 3H), 1.92-2.05 (m, 2H), 2.38 (d, J=14.93 Hz, 2H), 2.54-2.71 (m, 2H), 2.86 (d, J=9.79 Hz, 2H), 2.93-3.07 (m, 2H), 3.14 (d, J=11.17 Hz, 2H), 7.37 (dd, J=8.16, 2.51 Hz, 1H), 7.70 (dd, J=10.92, 2.51 Hz, 1H), 7.76 (s, 1H), 8.37 (br. s., 1H). LCMS (ESI) m/z: 412 (M+1).

Example 63

3-(1-((1-cyanocyclopropyl)methyl)-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 3. ¹ H NMR (400 MHz, METHANOL-d ₄ ) ppm 1.05 (d, J = 2.26 Hz, 2H), 1.32-1.38 (m, 2H), 1.40 (s, 3H), 1.89-2.05 (m, 2H), 2.33 (d, J = 15.69 Hz, 2H), 2.69 (s, 4H), 3.02 (br. s., 2H), 7.38 (dd, J = 8.09, 2.57 Hz, 1H), 7.68-7.83 (m, 2H), 8.28 (br. s., 1H). LCMS (ESI) m/z: 395 (M+1).

Example 64

3-(1-((1-cyanocyclobutyl)methyl)-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 3. ¹ H NMR (400 MHz, METHANOL-d ₄ ) 1.38 (s, 3H), 1.85-1.94 (m, 2H), 2.00-2.09 (m, 1H), 2.18-2.31 (m, 5H), 2.42-2.52 (m, 2H), 2.63 (t, J=9.22 Hz, 2H), 2.81 (s, 2H), 2.88 (d, J=5.65 Hz, 2H), 7.36 (dd, J=8.03, 2.26 Hz, 1H), 7.69 (d, J=2.26 Hz, 1H), 7.73 (s, 1H), 8.30 (br. s., 1H). LCMS (ESI) m/z: 409 (M+1).

Example 65

6-Fluoro-3-(4-methyl-1-(2-(methylsulfonyl)ethyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 3. ¹ H NMR (400 MHz, METHANOL-d ₄ ) ppm 1.40 (s, 3H), 1.87-1.98 (m, 2H), 2.28-2.38 (m, 2H), 2.63-2.80 (m, 2H), 2.95-3.05 (m, 2H), 3.07 (s, 3H), 3.07-3.14 (m, 2H), 3.38-3.47 (m, 2H), 7.33-7.40 (m, 1H), 7.66-7.73 (m, 1H), 7.73-7.77 (m, 1H), 8.20-8.37 (m, 1H). LCMS (ESI) m/z: 422 (M+1).

Example 66

6-Fluoro-3-(4-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 3. ¹ H NMR (400 MHz, METHANOL-d ₄ )1.25-1.33(m, 2H), 1.37(s, 3H), 1.70(d, J=13.30Hz, 2H), 1.80-1.89(m, 3 H), 2.22(br.s., 2H), 2.23(br.s., 2H), 2.38(br.s., 2H), 2.67(br.s., 2H), 3.40-3.47 (m, 2H), 3.94 (dd, J=11.67, 2.89Hz, 2H), 7.36 (dd, J=8.16, 2.51H z, 1H), 7.69 (d, J=2.51Hz, 1H), 7.72 (br.s., 1H). LCMS (ESI) m/z: 414 (M+1).

Example 67

3-(1-((1-aminocyclopropyl)methyl)-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 3. ¹ H NMR (400 MHz, METHANOL-d ₄ ) ppm: 0.72-0.82 (m, 2H), 0.93-1.00 (m, 2H), 1.40 (s, 3H), 1.91-2.03 (m, 2H), 2.26-2.37 (m, 2H), 2.66 (s, 4H), 2.94-3.06 (m, 2H), 7.33-7.41 (m, 1H), 7.67-7.73 (m, 1H), 7.73-7.77 (m, 1H), 8.22-8.48 (m, 2H). LCMS (ESI) m/z: 385 (M+1).

Example 68

6-Fluoro-3-(4-methyl-1-(oxetan-3-ylmethyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 3. ¹ H NMR (400 MHz, CHLOROFORM-d) ppm 1.36 (s, 3H), 1.78-1.88 (m, 2H), 2.17-2.25 (m, 2H), 2.36 (br. s., 2H), 2.57-2.68 (m, 2H), 2.72 (d, J=7.03 Hz, 2H), 4.38-4.47 (m, 2H), 4.60-4.63 (m, 1H), 4.80-4.82 (m, 2H), 7.33-7.39 (m, 1H), 7.68-7.76 (m, 2H). LCMS (ESI) m/z: 386 (M+1).

Example 69

6-Fluoro-3-(1-(2-methoxyethyl)-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 3. ¹ H NMR (400 MHz, METHANOL-d ₄ ) 1.45 (s, 3H), 2.07 (ddd, J=14.68, 10.85, 3.58 Hz, 2H), 2.46 (d, J=14.81 Hz, 2H), 3.12 (br. s., 2H), 3.23 (t, J=4.83 Hz, 2H), 3.41 (s, 5H), 3.66-3.73 (m, 2H), 7.39 (dd, J=8.16, 2.51 Hz, 1H), 7.71 (dd, J=10.92, 2.51 Hz, 1H), 7.80 (s, 1H), 8.52 (s, 1H). LCMS (ESI) m/z: 374 (M+1).

Example 70

6-Fluoro-3-(1-((1-hydroxycyclopropyl)methyl)-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 3. ¹ H NMR (400 MHz, METHANOL-d ₄ ) ppm: 0.64-0.74 (m, 2H), 0.84-0.93 (m, 2H), 1.46 (s, 3H), 2.04-2.18 (m, 2H), 2.50 (d, J=15.18 Hz, 2H), 3.16 (br. s., 4H), 3.47-3.68 (m, 2H), 7.36-7.43 (m, 1H), 7.68-7.75 (m, 1H), 7.79-7.84 (m, 1H), 8.48-8.65 (m, 1H). LCMS (ESI) m/z: 386 (M+1).

Example 71

6-Fluoro-3-(4-methyl-1-((3-methyloxetan-3-yl)methyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 3. ¹ H NMR (400 MHz, METHANOL-d ₄ ) ppm: 1.38 (s, 3H), 1.46 (s, 3H), 1.81-1.93 (m, 2H), 2.18-2.29 (m, 2H), 2.33-2.54 (m, 2H), 2.54-2.84 (m, 4H), 4.31-4.35 (m, 2H), 4.49-4.54 (m, 2H), 7.34-7.39 (m, 1H), 7.68-7.75 (m, 2H). LCMS (ESI) m/z: 400 (M+1).

Example 72

6-Fluoro-3-(1-(3-methoxypropyl)-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 3. ¹ H NMR (400 MHz, METHANOL-d ₄ ) 1.45 (s, 3H), 1.94-2.01 (m, 2H), 2.02-2.12 (m, 2H), 2.47 (d, J=13.05 Hz, 2H), 2.89-3.20 (m, 4H), 3.34 (s, 3H), 3.39 (br. s., 2H), 3.45-3.52 (m, 2H), 7.38 (dd, J=8.09, 2.57 Hz, 1H), 7.71 (dd, J=10.92, 2.51 Hz, 1H), 7.79 (s, 1H), 8.55 (s, 1H). LCMS (ESI) m/z: 434 (M+1).

Example 73

6-Fluoro-3-(4-methyl-1-((1-(methylsulfonyl)cyclopropyl)methyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 3. ¹ H NMR (400 MHz, METHANOL-d ₄ ) 0.95-1.01 (m, 2H), 1.38 (s, 3H), 1.41-1.49 (m, 2H), 1.83-1.96 (m, 2H), 2.27 (d, J=13.30 Hz, 2H), 2.55 (br. s., 2H), 2.86 (s, 2H), 2.92 (br. s., 2H), 3.24 (s, 3H), 7.36 (dd, J=8.16, 2.51 Hz, 1H), 7.67-7.78 (m, 2H). LCMS (ESI) m/z: 448 (M+1).

Example 74

6-Fluoro-3-(4-methyl-1-(thiazol-2-ylmethyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 3. ¹ H NMR (400 MHz, METHANOL-d ₄ ) ppm: 1.36-1.42 (m, 3H), 1.86-1.97 (m, 2H), 2.23-2.33 (m, 2H), 2.63-2.73 (m, 2H), 2.89-2.98 (m, 2H), 4.02-4.07 (m, 2H), 7.32-7.40 (m, 1H), 7.58-7.63 (m, 1H), 7.68-7.73 (m, 1H), 7.74 (s, 1H), 7.75-7.79 (m, 1H), 8.25-8.35 (m, 1H). LCMS (ESI) m/z: 413 (M+1).

Example 75

6-Fluoro-3-(4-methyl-1-(methylsulfonyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 3. ¹ H-NMR (MeOD, 400 MHz) δ: 1.38-1.46 (m, 3H), 1.88 (ddd, J = 13.68, 9.66, 3.76 Hz, 2H), 2.32 (d, J = 15.06 Hz, 2H), 2.78 (s, 3H), 3.00-3.17 (m, 2H), 3.46-3.53 (m, 2H), 7.35-7.41 (m, 1H), 7.69-7.75 (m, 1H), 7.77-7.79 (m, 1H), 8.46-8.53 (m, 1H). LCMS (ESI) m/z: 394 (M+1).

Example 76

6-Fluoro-3-(1-(3-fluorocyclobutyl)-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 2. ¹ H-NMR (400 MHz, MethanoL-d ₄ ) δ ppm: 1.45 (s, 3H), 1.96-2.18 (m, 2H), 2.38-2.74 (m, 6H), 2.94 (br. s., 4H), 3.74-3.93 (m, 1H), 5.12-5.32 (m, 1H), 7.41 (dd, J=8.16, 2.38 Hz, 1H), 7.67 (dd, J=10.79, 2.26 Hz, 1H), 7.79 (s, 1H), 8.52 (br. s., 1H). LCMS (ESI) m/z: 388 (M+1).

Example 77

6-Fluoro-3-(4-methyl-1-(thien-2-ylmethyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 2. ¹ H NMR (400 MHz, METHANOL-d ₄ ) 1.34 (s, 3H), 1.82 (ddd, J=13.36, 9.41, 3.45 Hz, 2H), 2.13-2.27 (m, 1H), 2.32-2.53 (m, 1H), 2.69 (br. s., 2H), 3.72 (s, 2H), 6.87-7.01 (m, 2H), 7.25-7.39 (m, 2H), 7.62-7.75 (m, 2H). LCMS (ESI) m/z: 412 (M+1).

Example 78

3-(1-((1-ethylpiperidin-4-yl)methyl)-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 2. ¹ H-NMR (400MHz, METHANOL-d4)ppm1.32-1.35 (t, 3H), 1.42 (s, 3H), 1.47-1. 51(d,2H),1.99-2.08(m,5H),2.35-2.38(d,2H),2.64-2.65(d,2H),2.89(m , 2H), 3.06 (t, 2H), 3.11-3.15 (m, 4H), 3.51-3.54 (d, 2H), 7.37-7.39 (m, 1H ), 7.70-7.74 (m, 1H), 7.77 (s, 1H), 8.446 (s, 2H). LCMS (ESI) m/z: 441 (M+1).

Example 79

6-Fluoro-3-(4-methyl-1-((1-methylazetidin-3-yl)methyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 2. ¹ H-NMR (400 MHz, METHANOL-d4) ppm: 1.32 (s, 3H), 1.89-1.95 (m, 2H), 2.29-2.33 (d, 2H), 2.60 (d, 2H), 2.86-2.91, 2.64-2.65 (m, 7H), 3.18 (m, 1H), 3.84-3.88 (t, 2H), 4.15-4.20 (t, 2H), 7.36-7.39 (m, 1H), 7.70-7.73 (m, 1H), 7.77 (s, 1H), 8.41 (s, 2H). LCMS (ESI) m/z: 399 (M+1).

Example 80

Ethyl 2-((4-(8-carbamoyl-6-fluoro-4H-benzo[4,5]imidazo[1,2-B]pyrazol-3-yl)-4-methylpiperidin-1-yl)methyl)cyclopropanecarboxylate

This example was prepared as described in Example 2. ¹ H NMR (400 MHz, METHANOL-d ₄ ) 0.86-1.34 (m, 6H), 1.35-1.49 (m, 2H), 1.57-2.01 (m, 4H), 2.09-2.28 (m, 2H), 2.44-2.70 (m, 2H), 2.99-3.27 (m, 2H), 3.36-3.47 (m, 2H), 3.53-3.75 (m, 2H), 4.06-4.26 (m, 3H), 7.50-7.65 (m, 1H), 7.74-7.85 (m, 1H), 8.05 (br. s., 1H). LCMS (ESI) m/z: 442 (M+1).

Example 81

3-(1-((2-(dimethylaminomethyl)cyclopropyl)methyl)-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 2. ¹ H NMR (400 MHz, METHANOL-d ₄ )0.97-1.29(m, 2H), 1.47(s, 2H), 1.65(s, 1H), 2.08-2.30(m, 3H), 2.63(d, J=15.3Hz, 1H), 2.85 (s, 1H), 2.92-3.01 (m, 3H), 3.01-3.12 (m, 2H), 3.12-3. 27(m, 2H), 3.29(s, 2H), 3.34-3.47(m, 2H), 3.55-3.77(m, 2H), 7.56-7.70( m, 1H), 7.78-7.85 (m, 1H), 8.12 (d, J=6.5Hz, 1H). LCMS (ESI) m/z: 441 (M+1).

Example 82

6-Fluoro-3-(1-isobutyl-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 2. ¹ H-NMR (MeOD, 400 MHz) δ: 1.00-1.02 (d, 6H), 1.43 (s, 3H), 2.03-2.07 (m, 3H), 2.10-2.11 (d, 2H), 2.81-2.83 (d, 2H), 3.03 (bs, 2H), 3.31 (bs, 2H), 7.35-7.38 (dd, 1H), 7.67-7.71 (s, 1H), 7.77 (s, 1H), 8.53 (bs, 1H). LCMS (ESI) m/z: 372 (M+1).

Example 83

6-Fluoro-3-(4-methyl-1-((4-methylthiazol-5-yl)methyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 2. ¹ H NMR (400 MHz, METHANOL-d4) ppm: 1.41 (s, 3H), 1.89-2.01 (m, 2H), 2.30-2.39 (m, 2H), 2.43 (s, 3H), 2.73-2.86 (m, 2H), 2.97-3.15 (m, 2H), 4.01-4.20 (m, 2H), 7.30-7.47 (m, 1H), 7.65-7.86 (m, 2H), 8.90-9.04 (m, 1H). LCMS (ESI) m/z: 427 (M+1).

Example 84

6-Fluoro-3-(4-methyl-1-((1-methyl-1H-imidazol-2-yl)methyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 2. ¹ H NMR (400 MHz, METHANOL-d ₄ ) ppm: 1.32-1.44 (m, 3H), 1.78-1.96 (m, 2H), 2.18-2.33 (m, 2H), 2.46-2.62 (m, 2H), 2.71-2.88 (m, 2H), 3.73-3.77 (m, 2H), 3.81 (s, 3H), 7.01-7.11 (m, 1H), 7.18-7.23 (m, 1H), 7.33-7.40 (m, 1H), 7.73 (s, 2H), 8.28-8.44 (m, 1H). LCMS (ESI) m/z: 410 (M+1).

Example 85

3-(1-((1,2-dimethyl-1H-imidazol-5-yl)methyl)-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 2. ¹ H NMR (400 MHz, METHANOL-d ₄ ) ppm 1.38 (s, 3H), 1.83-1.92 (m, 2H), 2.27 (d, J=13.80 Hz, 2H), 2.54 (s, 5H), 2.86 (d, J=10.92 Hz, 2H), 3.70 (s, 2H), 3.75 (s, 3H), 7.17 (s, 1H), 7.36 (dd, J=8.16, 2.51 Hz, 1H), 7.66-7.80 (m, 2H), 8.38 (br. s., 1H). LCMS (ESI) m/z: 424 (M+1).

Example 86

3-(1′-ethyl-4-methyl-[1,4′-bipiperidinyl]-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 2. ¹ H-NMR (400 MHz, MethanoL-d ₄ )1.09(t, J=7.09Hz, 3H), 1.27(s, 3H), 1.50-1.70(m, 2H), 1.72-1.85(m, 2 H), 1.92 (d, J=11.54Hz, 2H), 2.34 (br.s., 2H), 2.75 (d, J=7.40Hz, 7H), 2.8 6 (br.s., 2H), 3.23 (d, J=10.42Hz, 2H), 7.49 (d, J=8.41Hz, 1H), 7.58 (dd, J =10.85, 2.20Hz, 1H), 7.79 (s, 1H), 8.28 (s, 2H). LCMS (ESI) m/z: 427 (M+1).

Example 87

6-Fluoro-3-(4-methyl-1-((6-oxo-1,6-dihydropyridazin-3-yl)methyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 2. ¹ H NMR (400 MHz, MeOD) δ: 8.35 (s, 1H), 7.70-7.74 (m, 2H), 7.57-7.60 (d, 1H), 7.36-7.38 (t, 1H), 6.98-7.00 (d, 1H), 3.63 (s, 2H), 2.86 (m, 2H), 2.61-2.63 (m, 2H), 2.26-2.30 (d, 2H), 1.87-1.94 (m, 2H), 1.39 (s, 3H). LCMS (ESI) m/z: 424 (M+1).

Example 88

3-(1-(2-cyanoethyl)-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

A mixture of Example 53D (52 mg, 0.125 mmol), acrylonitrile (66 mg, 1.25 mmol), and potassium carbonate (172 mg, 1.25 mmol) in DMF (18 mL) was stirred at 28° C. for 1 hour. After completion of the reaction, the mixture was quenched with water (10 mL), and the aqueous layer was extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over sodium sulfate, filtered, and evaporated. The residue was purified by preparative HPLC to give the title compound (31 mg, 66.0% yield). ¹ H NMR (400MHz, METHANOL-d ₄ )ppm1.39(s, 3H), 1.86-1.97(m, 2H), 2.25-2.36(m, 2H), 2.60-2.70(m, 2H), 2.74(s, 2H), 2.84-2.98(m , 4H), 7.33-7.41 (m, 1H), 7.68-7.73 (m, 1H), 7.74 (s, 1H), 8.21-8.32 (m, 1H). LCMS (ESI) m/z: 369 (M+1).

Example 89

6-Chloro-3-(1-ethyl-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 53, using 2,6-dibromo-4-chlorophenylhydrazine in place of 2,6-dibromo-4-fluorophenylhydrazine. ^1H -NMR (MeOD, 400 MHz) δ: 1.32-1.39 (t, 3H), 1.46 (m, 1H), 2.52-2.55 (s, 3H), 2.06-2.08 (m, 2H), 2.47-2.48 (m, 2H), 3.09-3.11 (m, 3H), 3.34-3.41 (m, 3H), 7.63 (s, 1H), 7.83 (s, 1H), 7.97-7.97 (d, 1H), 8.54 (bs, 1H). LCMS (ESI) m/z: 360 (M+1).

Example 90

3-(1-ethyl-3-methylpyrrolidin-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

In this example, the compound was prepared as described in Example 53, substituting tert-butyl 3-(hydroxymethyl)-3-methylpyrrolidine-1-carboxylate for tert-butyl 4-(hydroxymethyl)-4-methylpiperidine-1-carboxylate. ^1H NMR(400MHz, METHANOL-d ₄ )ppm 1.38(s, 3H), 1.64(s, 3H), 2.25-2.42(m, 1H), 2.59-2.76(m, 1H), 3.27-3.32(m, 2H), 3.39-3.53(m, 1H), 3.54-3.71(m, 2H), 3.71-3.88 (m, 1H), 7.33-7.39 (m, 1H), 7.57-7.70 (m, 1H), 7.76-7.90 (m, 1H), 8.28-8.80 (m, 1H). LCMS (ESI) m/z: 330 (M+1).

Example 91

3-(1,3-Dimethylpyrrolidin-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 90. ¹ H-NMR (400 MHz, MethanoL-d ₄ ) δ ppm 8.52 (br. s., 1H), 7.84 (s, 1H), 7.67 (dd, J=2.5, 10.9 Hz, 1H), 7.38 (dd, J=2.5, 8.0 Hz, 1H), 3.74 (d, J=11.3 Hz, 1H), 3.67-3.49 (m, 2H), 3.40 (d, J=11.3 Hz, 1H), 2.96 (s, 3H), 2.73-2.60 (m, 1H), 2.34 (td, J=7.8, 13.4 Hz, 1H), 1.64 (s, 3H). LCMS (ESI) m/z: 316 (M+1).

Example 92

6-Fluoro-3-(1-isopropyl-3-methylpyrrolidin-3-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 90. ¹ H NMR (400 MHz, METHANOL-d ₄ ) ppm 1.38-1.52 (m, 6H), 1.71 (d, J=2.26 Hz, 3H), 2.32-2.46 (m, 1H), 2.63-2.82 (m, 1H), 3.38-3.70 (m, 3H), 3.76-4.11 (m, 2H), 7.58-7.70 (m, 1H), 7.76-7.86 (m, 1H), 8.15-8.29 (m, 1H). LCMS (ESI) m/z: 344 (M+1).

Example 93

3-(1-(Cyclopropylmethyl)-3-methylpyrrolidin-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 5. ¹ H NMR (400 MHz, METHANOL-d ₄ )ppm0.41-0.52(m, 2H), 0.70-0.82(m, 2H), 1.10-1.26(m, 1H), 1.66(s, 3H) , 2.27-2.39 (m, 1H), 2.63-2.75 (m, 1H), 3.17 (d, J=7.15Hz, 2H), 3.44-3.58 (m, 1H), 3.59-3.78 (m, 2H), 3.79-3.94 (m, 1H), 7.27-7.40 (m, 1H), 7.55-7. 67 (m, 1H), 7.77-7.89 (m, 1H), 8.43-8.69 (m, 1H). LCMS (ESI) m/z: 356 (M+1).

Example 94

6-Fluoro-3-(3-methyl-1-(oxetan-3-yl)pyrrolidin-3-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 5. ^1H NMR(400MHz, METHANOL-d ₄ )ppm 1.58(s, 3H), 2.01-2.10(m, 1H), 2.26-2.35(m, 1H), 2.68-2.74(m, 1H), 2.79-2.87(m, 1H), 2.87-2.96(m, 1H), 2.96-3.03(m, 1H), 3.78- 3.85 (m, 1H), 4.62-4.72 (m, 1H), 4.74-4.81 (m, 1H), 7.31-7.40 (m, 1H), 7.64-7.71 (m, 1H), 7.72-7.77 (m, 1H). LCMS (ESI) m/z: 358 (M+1).

Example 95

6-Fluoro-3-(1-(2-fluoroethyl)-3-methylpyrrolidin-3-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 3. ¹ H-NMR (MeOD, 400MHz) δ: 1.635 (s, 1H), 2.243-2.263 (m, 1H), 2.522-2.554 (m, 1H), 3.288-3.321(d, 1H), 3.325(s, 2H), 3.329-3.337(m, 1H), 3.391-3.414( m, 1H), 3.632-3.659 (d, 1H), 4.730-4.860 (dt, 2H), 7.291-7.317 (dd, 1H), 7. 586-7.619 (dd, 1H), 7.788 (s, 1H), 8.445 (bs, 1H), LCMS (ESI) m/z: 348 (M+1).

Example 96

3-(1-((2,2-difluorocyclopropyl)methyl)-3-methylpyrrolidin-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 3. ¹ H NMR (400 MHz, METHANOL-d ₄ )ppm1.34-1.46(m,1H)1.64(s,3H)1.67-1.79(m,1H)2.03-2.11(m,1H)2. 20-2.31(m,1H)2.52-2.63(m,1H)3.13-3.24(m,1H)3.24-3.31(m,2H)3.37 -3.48(m,1H)3.48-3.58(m,1H)3.59-3.67(m,1H)7.29-7.39(m,1H)7.57- 7.67 (m, 1H) 7.76-7.84 (m, 1H) 8.35-8.54 (m, 1H) LCMS (ESI) m/z: 392 (M+1).

Example 97

6-Fluoro-3-(3-methyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 3. ¹ H NMR (400 MHz, METHANOL-d ₄ ) ppm 1.74 (s, 3H), 2.39-2.54 (m, 1H), 2.74-2.88 (m, 1H), 3.69-3.82 (m, 1H), 3.82-3.95 (m, 2H), 3.97-4.14 (m, 1H), 4.36-4.50 (m, 2H), 7.55-7.64 (m, 1H), 7.73-7.83 (m, 1H), 8.12-8.20 (m, 1H). LCMS (ESI) m/z: 384 (M+1).

Example 98

6-Fluoro-3-(3-methyl-1-(2-(methylsulfonyl)ethyl)pyrrolidin-3-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 3. ¹ H NMR (400 MHz, METHANOL-d ₄ ) ppm 1.60(s, 3H), 2.05-2.15(m, 1H), 2.18-2.28(m, 1H), 2.63-2.69(m, 1H), 2 .69-2.78(m, 1H), 3.01-3.10(m, 1H), 3.11(s, 3H), 3.26-3.31(m, 1H), 3.3 4-3.41(m, 2H), 3.41-3.50(m, 1H), 3.50-3.60(m, 1H), 7.35-7.45(m, 1H) , 7.63-7.70 (m, 1H), 7.72 (s, 1H), 8.22 (s, 1H). LCMS (ESI) m/z: 408 (M+1).

Example 99

6-Fluoro-3-(3-methyl-1-(3,3,3-trifluoropropyl)pyrrolidin-3-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 3. ¹ H NMR (400 MHz, METHANOL-d ₄ ) ppm 1.62 (s, 3H), 2.16-2.25 (m, 1H), 2.43-2.53 (m, 1H), 2.58-2.72 (m, 1H), 3.08-3.14 (m, 1H), 3.16-3.29 (m, 1H), 3.34-3.39 (m, 1H), 3.41-3.47 (m, 1H), 7.32-7.41 (m, 1H), 7.63-7.71 (m, 1H), 7.74-7.83 (m, 1H), 8.24-8.34 (m, 1H). LCMS (ESI) m/z: 398 (M+1).

Example 100

3-(1-((1-aminocyclopropyl)methyl)-3-methylpyrrolidin-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 3. ¹ H NMR (400 MHz, METHANOL-d ₄ ) ppm 0.85(s, 1H), 1.00(s, 1H), 1.62(s, 3H), 2.07-2.17(m, 1H), 2.34-2.44(m, 1H), 2.85 (s, 1H), 2.94-3.01 (m, 1H), 3.04-3.12 (m, 1H), 3.20 (d, J=9.41Hz , 1H), 7.33-7.39 (m, 1H), 7.64-7.70 (m, 1H), 7.75-7.80 (m, 1H), 7.83-7.8 5 (m, 1H), 8.02-8.05 (m, 1H), 8.34-8.47 (m, 1H). LCMS (ESI) m/z: 371 (M+1).

Example 101

3-(1-((1-cyanocyclobutyl)methyl)-3-methylpyrrolidin-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 3. ¹ H NMR (400 MHz, METHANOL-d ₄ )1.60(s, 3H), 2.00-2.11(m, 2H), 2.13-2.23(m, 1H), 2.25-2.40(m, 3H), 2.45-2.58(m, 2H), 2.65-2.70(m, 1H), 2.72-2.80(m, 1H), 2.93(s, 1H), 2. 99-3.06 (m, 1H), 3.14-3.23 (m, 2H), 7.38-7.44 (m, 1H), 7.69 (dd, J=10.85, 2.57Hz, 1H), 7.74 (s, 1H), 8.33 (br.s., 1H). LCMS (ESI) m/z: 395 (M+1).

Example 102

3-(1-((1-cyanocyclopropyl)methyl)-3-methylpyrrolidin-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This compound was prepared as described in Example 3. ¹ H NMR (400 MHz, DMSO-d ₆ ) ppm 0.92 (d, J=2.26 Hz, 2H), 1.16-1.24 (m, 2H), 1.48 (s, 3H), 1.87-1.97 (m, 1H), 2.05 (s, 1H), 2.55 (d, J=7.53 Hz, 4H), 2.91 (s, 2H), 7.43-7.50 (m, 1H), 7.51-7.61 (m, 1H), 7.79 (s, 1H). LCMS (ESI) m/z: 381 (M+1).

Example 103

3-(1-(2-cyanoisoyl)-3-methylpyrrolidin-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 88. ¹ H NMR (400 MHz, METHANOL-d ₄ ) ppm 1.61 (s, 3H), 2.06-2.16 (m, 1H), 2.23-2.33 (m, 1H), 2.80 (d, J=6.40 Hz, 1H), 2.83-2.91 (m, 1H), 2.93-3.02 (m, 1H), 3.03-3.12 (m, 1H), 3.27 (d, J=9.29 Hz, 2H), 7.37-7.44 (m, 1H), 7.64-7.72 (m, 1H), 7.76 (s, 1H), 8.14-8.26 (m, 1H). LCMS (ESI) m/z: 355 (M+1).

Example 104

3-(1-(Cyclopropylmethyl)-3-methylpyrrolidin-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 93. ¹ H NMR (400 MHz, MeOD) δ: 8.51 (s, 1H), 7.96 (s, 1H), 7.70-7.73 (dd, 1H), 7.39-7.41 (dd, 1H), 4.39-4.32 (d, 2H), 4.23-4.26 (d, 2H), 3.15-3.17 (d, 2H), 1.87 (s, 3H), 1.06-1.08 (m, 1H), 0.69-0.74 (m, 2H), 0.42-0.46 (m, 2H). LCMS (ESI) m/z: 342 (M+1).

Process D

Example 105

6-Fluoro-3-(1-isopropyl-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

Example 105A

tert-Butyl 4-(1-cyano-2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate

tert-Butyl 4-oxopiperidine-1-carboxylate (100 grams, 0.5 mole), ethyl-2-cyanoacetate (56.5 grams, 0.5 mole), a mixture of toluene (1 liter) of ammonium acetate (19.2 grams, 0.25 mole) and acetic acid (15 grams, 0.25 mole) was stirred at 120°C for 5-6 hours, using a Dean-Stark water separator to remove water. After removing the solvent under vacuum, the residue was dissolved in ethyl acetate (500 mL) and water (500 mL), and the aqueous layer was extracted with ethyl acetate (500 milliliters × 3). The organic layers were washed with brine (500 milliliters), dried over sodium sulfate, filtered, and evaporated. The residue was purified by slurrying with petroleum ether/ethyl acetate=10/1 (300 mL). The white solid was collected by filtration to give the title compound (90 grams, 61% yield). ¹ H NMR (400MHz, CHLOROFORM-d) δppm 1.38 (t, J=7.15Hz, 3H), 1.50 (s, 9H), 2.79 (t, J=5.90Hz, 2H), 3.15 (t, J=5.83Hz, 2H), 3.56 ( t, J=5.71Hz, 2H), 3.63 (t, J=5.83Hz, 2H), 4.31 (q, J=7.15Hz, 2H). LCMS (ESI) m/z: 295 (M+1).

Example 105B

tert-Butyl 4-(1-cyano-2-ethoxy-2-oxoethyl)-4-methylpiperidine-1-carboxylate

To a mixture of cuprous iodide (86.3 g, 0.454 mol) in anhydrous tetrahydrofuran (1.7 L) at -60-70°C under nitrogen was added 3 M methylmagnesium bromide (378 mL, 1.13 mol) dropwise. After stirring at -10-0°C for 1 hour, the mixture was cooled to -60-70°C and a solution of Example 105A (133.5 g, 0.454 mol) in tetrahydrofuran (300 mL) was added dropwise. The mixture was stirred at 20°C for 15 hours, cooled to 0°C and quenched with saturated aqueous ammonium chloride (1.2 L). After filtration through celite, the aqueous layer was extracted with ethyl acetate (600 mL x 3). The combined organic layers were washed with brine (500 mL), dried over sodium sulfate, filtered, and evaporated to give the crude title compound (142 g) as a yellow oil, which was used directly in the next step without further purification.

Example 105C

2-(1-(tert-Butoxycarbonyl)-4-methylpiperidin-4-yl)-2-cyanoacetic acid

To a solution of Example 105B (142 g, crude, 0.458 mol) in tetrahydrofuran/methanol (10:1) (1.2 L) was added dropwise a solution of sodium hydroxide (73.3 g, 1.82 mol) in water (320 mL) at 0°C. After stirring at 20°C for 2 hours, the mixture was diluted with water (320 mL). The aqueous layer was extracted with ethyl acetate (500 mL x 3), and the combined organic layers were washed with water (200 mL x 2). The combined aqueous layers were adjusted to pH 3-4 with 1N hydrochloric acid and extracted with dichloromethane/methanol (10:1) (300 mL x 6). The combined dichloromethane/methanol organic layers were washed with brine (800 mL), dried over sodium sulfate, filtered, and evaporated to yield the crude title compound (111.5 g) in a yellowish color, which was used directly in the next step without further purification.

Example 105D

tert-Butyl 4-(cyanomethyl)-4-methylpiperidine-1-carboxylate

A mixture of Example 105C (111.5 g, crude, 0.395 mol) and cuprous oxide (11.4 g, 79.08 mmol) in acetonitrile (900 mL) was stirred at 80°C for 2 hours. After cooling to room temperature, the mixture was evaporated, the residue was dissolved in ethyl acetate (1 L), and the insoluble material was removed by filtration through celite. The filter residue was washed with ethyl acetate (250 mL x 2), and tetrahydrofuran (150 mL) was added to the filtrate to dissolve the precipitate. The organic layer was washed with water, water/brine = 1:1 (300 mL), dried over sodium sulfate, filtered, and evaporated. The residue was purified by slurrying with petroleum ether/ethyl acetate = 10/1 (300 mL). A white solid was collected by filtration to give the title compound (98 g). LCMS (ESI) m/z: 239 (M+1).

Example 105E

tert-Butyl 4-(1-cyano-2-oxoethyl)-4-methylpiperidine-1-carboxylate

To a mixture of Example 105D (50 g, 0.21 mol) in tetrahydrofuran (400 mL) was added 2 M LDA (160 mL, 0.32 mol) dropwise at -60-70°C under nitrogen. After stirring at -60-70°C for 1 hour, ethyl formate (32 g, 0.43 mol) was added dropwise. After the addition was complete, the temperature was slowly raised to 15°C and stirred for an additional 4 hours. After completion, the reaction was quenched with aqueous ammonium chloride (500 mL). The aqueous layer was extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with water (200 mL), 1N hydrochloric acid (300 mL x 3), and brine (200 mL), dried over sodium sulfate, filtered, and evaporated. The residue was purified by slurrying with petroleum ether/ethyl acetate = 10/1 (200 mL). The white solid was collected by filtration to give the title compound (45 g, 80% yield). LCMS (ESI) m/z: 267 (M+1).

Example 105F

(2,6-Dibromo-4-fluorophenyl)hydrazine hydrochloride

To a solution of 2,6-dibromo-4-fluoroaniline (50 g, 0.186 mol) in concentrated hydrochloric acid (190 ml) was added dropwise a solution of sodium nitrite (14.1 g, 0.205 mol) in water (70 ml) at -5-0°C. After stirring at -5-0°C for 40 minutes, a solution of stannous chloride dihydrate (62.95 g, 0.279 mol) in concentrated hydrochloric acid (240 ml) was added dropwise to the reaction mixture at -5-0°C. The resulting mixture was slowly warmed to about 20°C and stirred for 12 hours. The solid was collected by filtration, washed with isopropyl alcohol (200 ml) and dried in vacuo to give the title compound (47 g, 78% yield) which was used in the next step without further purification. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 2.37-2.68 (m, 1H), 6.94-7.28 (m, 1H), 7.80 (d, J=8.03Hz, 2H), 10.13 (br.s., 3H).

Example 105G

tert-Butyl 4-(5-amino-1-(2,6-dibromo-4-fluorophenyl)-1H-pyrazol-4-yl)-4-methylpiperidine-1-carboxylate

Example 105E (50 grams, 187.73 mmol), potassium acetate (27.64 grams, 281.73 mmol) and Example 105F (72.17 grams, 225.28 mmol) in ethanol (500 ml) was stirred at 60 ° C for 5 hours. After the reaction was completed, NaHCO (31.57 grams, 375.78 mmol) was added to the mixture and stirred for another 15 hours at 80 ° C. After cooling to room temperature, the resulting mixture was evaporated, and the residue was dissolved in ethyl acetate (200 ml) and water (200 mL). The aqueous layer was extracted with ethyl acetate (200 milliliters × 3). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered and evaporated, and the residue was purified by slurrying with petroleum ether/ethyl acetate=10/1 (200 mL). The white solid was collected by filtration to provide the title compound (75 grams, 75% yield) which can be used in the next step without further purification.

Example 105H

tert-Butyl 4-(8-bromo-6-fluoro-4H-benzo[4,5]imidazo[1,2-B]pyrazol-3-yl)-4-methylpiperidine-1-carboxylate

Under nitrogen, a mixture of Example 105G (35 g, 65.78 mmol), PD2(DBA)3 (6.02 g, 6.57 mmol), Xantphos (7.61 g, 13.16 mmol), and cesium carbonate (42.77 g, 131.58 mmol) in DMF (300 mL) was stirred at 130°C for 9 hours. After cooling to room temperature, the resulting mixture was filtered, and the filtrate was evaporated. The residue was dissolved in ethyl acetate (500 mL), washed with water (200 mL x 2), brine (200 mL x 2), dried over sodium sulfate, filtered, and evaporated to provide the crude title compound as a brown oil, which was used in the next step without further purification. LCMS (ESI) m/z: 451, 453 (M, M+2).

Example 105I

tert-Butyl 4-(8-cyano-6-fluoro-4H-benzo[4,5]imidazo[1,2-B]pyrazol-3-yl)-4-methylpiperidine-1-carboxylate

Under nitrogen, a mixture of Example 105H (29.7 g, 65.8 mmol), zinc cyanide (15.4 g, 131.71 mmol), PD2(DBA)3 (6.02 g, 6.58 mmol), DPPF (7.30 g, 13.17 mmol), and zinc (8.65 g, 131.71 mmol) in DMF (300 mL) was stirred at 120°C for 5 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was evaporated to give a residue which was purified by column chromatography to give the crude title compound (35 g, crude) as a yellow foam. LCMS (ESI) m/z: 398 (M+1).

Example 105J

tert-Butyl 4-(8-carbamoyl-6-fluoro-4H-benzo[4,5]imidazo[1,2-B]pyrazol-3-yl)-4-methylpiperidine-1-carboxylate

To a solution of Example 105I (35 g, crude, 88.17 mmol) in 1N sodium hydroxide (140 mL, 140 mmol) and DMSO (100 mL) was added dropwise 30% hydrogen peroxide (40 mL) at 0°C. After the addition was complete, the mixture was heated to 40-50°C and stirred for 2 hours. The reaction mixture was then diluted with water (200 mL) and extracted with ethyl acetate/tetrahydrofuran (3/1) (200 mL x 2). The combined organic layers were washed with water (150 mL x 2) and brine (150 mL x 2), dried over sodium sulfate, filtered, and evaporated. The residue was purified by column chromatography to afford the title compound (12.2 g, 45% yield) as a yellow solid. LCMS (ESI) m/z: 416 (M+1).

Example 105K

6-Fluoro-3-(4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

A solution of Example 105J (5 g, 12 mmol) in dichloromethane/trifluoroacetic acid (50 mL/10 mL) was stirred for 2 hours at 20° C. The resulting mixture was evaporated to provide the title compound as a yellow oil which was used in the next step without further purification.

Example 105L

6-Fluoro-3-(1-isopropyl-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

A mixture of Example 105K (3.8 g, crude, 12 mmol), sodium cyanoborocyanide (2.8 g, 60 mmol) in acetone (2.0 g, 34 mmol) and methanol (50 mL) was stirred at 25°C for 3 hours. After the solvent was removed in vacuo, the residue was dissolved in ethyl acetate/tetrahydrofuran = 5/1 (200 mL). The organic layer was washed with water (50 mL x 2) and brine (50 mL), dried over sodium sulfate, filtered, and evaporated. The residue was purified by column chromatography to provide the title compound (4 g, yield: 90%). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.11-1.61 (m, 9H), 1.89-2.29 (m, 2H), 2.47 (br.s., 1H), 2.55 (br.s., 1H), 2.77 (d, J=12.05Hz, 1H), 3.09-3.66 (m, 4H), 7.53 (dd, J=8.28, 2.51Hz , 1H), 7.63 (dt, J=10.92, 2.26Hz, 1H), 7.79-7.99 (m, 1H), 8.17 (br.s., 1 H), 10.23-10.75 (m, 2H), 12.49-12.93 (m, 1H). LCMS (ESI) m/z: 358 (M+1).

Example 106

6-Fluoro-3-(4-methyl-1,1-dioxo-2H-thiopyran-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

Example 106A

8-Bromo-6-fluoro-3-(4-methyltetrahydro-2H-thiopyran-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole

This example was prepared as described in Examples 105A-105H, substituting dihydro-2H-thiopyran-4(3H)-one for tert-butyl 4-oxopiperidine-1-carboxylate. LCMS (ESI) m/z: 368, 370 (M, M+2).

Example 106B

4-(8-Bromo-6-fluoro-4H-benzo[4,5]imidazo[1,2-B]pyrazol-3-yl)-4-methyltetrahydro-2H-thiopyran 1,1-dioxide

A mixture of Example 106A (0.1 g, 0.271 mmol) and mCPBA (0.94 g, 0.542 mmol) in dichloromethane (15 mL) and tetrahydrofuran (3 mL) was stirred at 25° C. for 3 hours. The mixture was quenched with saturated aqueous sodium sulfite solution (20 mL), the aqueous layer was extracted with dichloromethane (15 mL×3), and the combined organic layers were washed with saturated aqueous sodium bicarbonate solution (20 mL), brine (15 mL), dried over sodium sulfate, filtered and evaporated to provide the title compound, which was used directly in the next step without further purification.

Example 106C

6-Fluoro-3-(4-methyl-1,1-dioxo-2H-thiopyran-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Examples 105I and 105J. ^1H NMR (400 MHz, MeOD) δ: 7.8798 (s, 1H), 7.56-7.59 (d, 1H), 7.46-7.48 (d, 1H), 3.11 (m, 2H), 2.95-3.01 (m, 2H), 2.52 (m, 2H), 2.13-2.19 (m, 2H), 1.35 (s, 3H). LCMS (ESI) m/z: 365 (M+1).

Example 107

3-(1,4-ethylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

Example 107A

tert-Butyl 4-(1-cyano-2-ethoxy-2-oxoethyl)-4-ethylpiperidine-1-carboxylate

To a mixture of Example 105A (1.0 g, 3.4 mmol) in tetrahydrofuran (20 mL) was added ethylmagnesium bromide (2.83 mL, 8.49 mmol) dropwise under nitrogen at -78°C. After stirring at -78°C for 1 hour, the mixture was warmed to 32°C and stirred for 15 hours. The mixture was quenched with saturated aqueous ammonium chloride (100 mL). The aqueous layer was extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered, and evaporated. The residue was purified by column chromatography to afford the title compound (0.8 g, yield: 73%) as a colorless oil. LCMS (ESI) m/z: 325 (M+1).

Example 107B

3-(1,4-ethylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 105. ¹ H-NMR (400MHz, MethanoL-d ₄ ) δppm 0.80 (t, J=7.47Hz, 3H), 1.28 (t, J=7.34Hz, 3H), 1.72 (d, J=7.40Hz, 1H), 1.89-2.14 (m, 1H), 2.41-2.61 (m, 1H), 3.06 (d, J=7.28Hz, 3H), 3.37-3.58 (m, 1H), 7.35 (dd, J=8.16, 2.51Hz, 1H), 7.69 (dd, J=10.92, 2.64Hz, 1H), 7.76 (s, 1H), 8.52 (s, 1H). LCMS (ESI) m/z: 358 (M+1).

Example 108

3-(4-cyano-1-(cyclopropylmethyl)piperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

Example 108A

tert-Butyl 4-cyano-4-(cyanomethyl)piperidine-1-carboxylate

A mixture of Example 105A (2.0 g, 6.8 mmol) and potassium cyanide (1.71 g, 26.3 mmol) in ethanol (20 mL)/water (4 mL) was stirred at 70-80°C for 15 hours. The solvent was removed in vacuo, and the residue was dissolved in water (100 mL). The aqueous phase was extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered, and evaporated. The residue was purified by column chromatography to afford the title compound (1.3 g, 79% yield) as a white solid. LCMS (ESI) m/z: 250 (M+1).

Example 108B

tert-Butyl 4-(5-amino-1-(2,6-dibromo-4-fluorophenyl)-1H-pyrazol-4-yl)-4-cyanopiperidine-1-carboxylate

This example was prepared as described in Examples 105E-105G.

Example 108C

tert-Butyl 4-(8-bromo-6-fluoro-4H-benzo[4,5]imidazo[1,2-B]pyrazol-3-yl)-4-cyanopiperidine-1-carboxylate

Under nitrogen, a mixture of Example 108B (660 mg, 1.22 mmol), cuprous iodide (70 mg, 0.37 mmol), N1,N2-dimethylethane-1,2-diamine (65 mg, 0.74 mmol), and potassium phosphate (780 mg, 3.68 mmol) in DMF (15 mL) was stirred at 70°C for 10 hours. After cooling to room temperature, the resulting mixture was filtered through Celite, the filtrate evaporated, and the residue purified by column chromatography to afford the title compound (470 mg, yield: 78%) as a white solid. LCMS (ESI) m/z: 462, 464 (M, M+2).

Example 108D

3-(4-cyanopiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Examples 1G-1J. LCMS (ESI) m/z: 327 (M+1).

Example 108E

3-(4-cyano-1-(cyclopropylmethyl)piperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 5. ¹ H-NMR (400 MHz, MethanoL-d ₄ )δppm0.34 (d, J=5.90Hz, 2H), 0.67-0.75 (m, 2H), 0.99-1.13 (m, 1H), 2.37 (br.s., 2H), 2.58 (br.s., 2H), 2.75 (d, J=6.90Hz, 2H), 2.89-3.07 (m, 2 H), 3.39-3.61 (m, 2H), 7.44 (dd, J=8.09, 2.57Hz, 1H), 7.75 (dd, J=10.85, 2.57Hz, 1H), 7.90 (s, 1H), 8.34-8.47 (m, 1H). LCMS (ESI) m/z: 381 (M+1).

Example 109

3-(4-Hydroxymethyl-1-(cyclopropylmethyl)piperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

Example 109A

4-(8-Bromo-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazol-3-yl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid

A mixture of Example 108C (800 mg, 1.73 mmol) and 40% aqueous sodium hydroxide solution (5 mL) in ethanol (25 mL) was stirred at 80-90°C for 15 hours. After cooling to room temperature, the mixture was acidified to pH 3-4 with 1N HCl and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with water (50 mL x 2), brine (50 mL x 2), dried over sodium sulfate, filtered, and evaporated to provide the title compound (850 mg, purity: 79%, yield: 98%) as a yellow solid. LCMS (ESI) m/z: 481, 483 (M, M+2).

Example 109B

tert-Butyl 4-(8-bromo-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazol-3-yl)-4-(hydroxymethyl)piperidine-1-carboxylate

To a mixture of Example 109A (800 mg, 1.56 mmol) in tetrahydrofuran (15 mL) at 0°C under nitrogen was added dropwise 101 M borane dimethyl sulfide (1 mL, 10 mmol). After stirring at 0°C for 2 hours, the mixture was quenched with methanol (20 mL). The solvent was evaporated in vacuo, and the residue was purified by column chromatography to afford the title compound as a white solid (508 mg, 70% yield). LCMS (ESI) m/z: 467, 469 (M, M+2).

Example 109C

tert-Butyl 4-(8-cyano-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazol-3-yl)-4-(hydroxymethyl)piperidine-1-carboxylate

Under nitrogen, a mixture of Example 109B (450 mg, 0.96 mmol), zinc cyanide (225 mg, 1.92 mmol), PD2(DBA)3 (176 mg, 0.19 mmol), DPPF (215 mg, 0.38 mmol), and Zn (125 mg, 1.92 mmol) in DMF (5 mL) was stirred at 120°C for 15 hours. After cooling to room temperature, the resulting mixture was filtered, the filtrate was concentrated in vacuo, and the residue was purified by column chromatography to afford the title compound as a brown solid (387 mg, 87% yield). LCMS (ESI) m/z: 414 (M+1).

Example 109D

tert-Butyl 4-(8-formamido-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazol-3-yl)-4-(hydroxymethyl)piperidine-1-carboxylate

To a mixture of Example 109C (350 mg, 0.85 mmol) and potassium carbonate (600 mg, 4.34 mmol) in DMSO (10 mL) was added dropwise 30% H₂O₂ (10 mL) at 0°C. After stirring at 25°C for 10 hours, the mixture was diluted with water (50 mL). The aqueous layer was extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with water (50 mL x 2) and brine (50 mL x 2), dried over sodium sulfate, filtered, and evaporated. The residue was purified by column chromatography to afford the title compound as a yellow solid (270 mg, yield: 68%). LCMS (ESI) m/z: 432 (M+1).

Example 109E

6-Fluoro-3-(4-(hydroxymethyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

A mixture of Example 109D (100 mg, 0.23 mmol) in dichloromethane (10 mL) and trifluoroacetic acid (3 mL) was stirred at 25°C for 3 hours. The resulting mixture was evaporated to afford the title compound as a yellow oil, which was used in the next step without further purification. LCMS (ESI) m/z: 332 (M+1).

Example 109F

3-(4-Hydroxymethyl-1-(cyclopropylmethyl)piperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared according to the method described in Example 108E. ¹ H-NMR (400 MHz, DMSO-d ₆ + D ₂ O) δ ppm 0.06-0.35 (m, 2H), 0.44-0.70 (m, 2H), 0.81-1.14 (m, 1H), 1.57-2.01 (m, 1H), 2.05-2.47 (m, 1H), 2.57-2.98 (m, 1H), 3.08-3.28 (m, 1H), 3.32-3.52 (m, 1H), 7.38-7.69 (m, 2H), 7.80 (s, 1H), 8.34 (s, 1H). LCMS (ESI) m/z: 386 (M+1).

Example 110

4-(8-Formylamino-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazol-3-yl)-1-(cyclopropylmethyl)piperidine-4-carboxylic acid ethyl ester

Example 110A

1-(tert-Butyl)-4-methyl-4-(8-bromo-6-fluoro-4H-benzo[4,5]imidazo[1,2-B]pyrazol-3-yl)piperidine-1,4-dicarboxylic acid dimethyl ester

To a solution of Example 109A (250 mg, 0.52 mmol) in a 10/1 methanol/dichloromethane (1 ml) mixture at 0°C under nitrogen was added dropwise TMSCH2N2 (0.52 ml, 1.04 mmol). After stirring at 0°C for 5 minutes, the mixture was quenched with acetic acid/water (1/10) (20 ml). The aqueous layer was extracted with dichloromethane (50 ml x 2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated. The residue was purified by column chromatography to give the title compound (200 mg, yield: 78%). LCMS (ESI) m/z: 495, 497 (M, M+2).

Example 110B

4-(8-Formylamino-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazol-3-yl)-1-(cyclopropylmethyl)piperidine-4-carboxylic acid ethyl ester

This example was prepared according to the method described in Examples 109C-109F. (11 mg, yield: 37%). LCMS (ESI) m/z: 414 (M+1). ¹ H-NMR (400 MHz, MethanoL-d4) δ ppm 0.34 (d, J=5.90Hz, 2H), 0.67-0.75 (m, 2H), 0.99-1.13 (m, 1H), 2.37 (br.s., 2H), 2.58 (br.s., 2H), 2.75 (d, J=6.90Hz, 2H), 2.89-3.07 (m, 2H), 3.39-3.61 (m, 2H), 7.44 (dd, J=8.09, 2.57Hz, 1H), 7.75 (dd, J=10.85, 2.57Hz, 1H), 7.90 (s, 1H), 8.34-8.47 (m, 1H). LCMS (ESI) m/z: 414 (M+1).

Process E

Example 111

3-(1-(Cyclopropylmethyl)-4-methylpiperidin-4-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

Example 111A

tert-Butyl 4-(1-cyano-2-oxopropyl)-4-methylpiperidine-1-carboxylate

To a solution of Example 53C (5.0 g, 21.0 mmol) in anhydrous tetrahydrofuran (60 mL) at -78°C under nitrogen was added LDA (26 mL, 52.0 mmol) dropwise. After stirring at -78°C for 1 hour, acetic anhydride (5.4 g, 52.0 mmol) was added dropwise. The resulting mixture was slowly warmed to room temperature and stirred for 30 minutes. The mixture was quenched with saturated aqueous ammonium chloride (30 mL), and the aqueous layer was extracted with ethyl acetate (30 mL x 2). The combined organic layers were evaporated, and the residue was purified by column chromatography to afford the title compound (4.5 g, yield: 76.5%) as a yellow oil. LCMS (ESI) m/z: 281 (M+1).

Example 111B

tert-Butyl 4-(1-cyano-2-(2-(2,6-dibromo-4-fluorophenyl)hydrazono)propyl)-4-methylpiperidine-1-carboxylate

A mixture of Example 111A (2.0 g, 7.14 mmol), acetic acid (0.2 mL) and Example 1D (2.4 g, 8.57 mmol) in ethanol (30 mL) was stirred at 70° C. for 16 hours. After the solvent was removed in vacuo, the residue was purified by column chromatography to provide the title compound (2.1 g, yield: 53.8%) as a light yellow solid:

Example 111C

tert-Butyl 4-(5-amino-1-(2,6-dibromo-4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl)-4-methylpiperidine-1-carboxylate

A mixture of Example 111B (2.1 g, 3.84 mmol) and potassium carbonate (2.1 g, 15.4 mmol) in ethanol (30 mL) was heated to 80° C. and stirred for 4 hours. After the solvent was removed in vacuo, the residue was purified by column chromatography to provide the title compound (0.8 g, yield: 54.4%) as a light red solid.

Example 111D

tert-Butyl 4-(8-bromo-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-B]pyrazol-3-yl)-4-methylpiperidine-1-carboxylate

Under nitrogen, a mixture of Example 111C (700 mg, 1.28 mmol), cuprous iodide (73 mg, 0.38 mmol), potassium phosphate (814 mg, 3.84 mmol), and N,N-dimethyl-1,2-ethane-1,2-diamine (68 mg, 0.76 mmol) in DMF (15 mL) was stirred at 70°C for 5 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography to give the title compound (400 mg, yield: 67.0%) as a yellow solid. LCMS (ESI) m/z: 465, 467 (M, M+2).

Example 111E

tert-Butyl 4-(8-cyano-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-B]pyrazol-3-yl)-4-methylpiperidine-1-carboxylate

Under N₂ protection, a mixture of Example 111D (650 mg, 1.39 mmol), zinc cyanide (326 mg, 2.78 mmol), PD₂(DBA)₃ (254 mg, 0.28 mmol), DPPF (309 mg, 0.56 mmol), and Zn (181 mg, 2.78 mmol) in DMF (8 mL) was stirred at 120°C for 3 hours. After cooling to room temperature, the resulting mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography to afford the title compound (450 mg, yield: 78.5%) as a yellow solid. LCMS (ESI) m/z: 412 (M+1).

Example 111F

tert-Butyl 4-(8-formamido-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-B]pyrazol-3-yl)-4-methylpiperidine-1-carboxylate

To a mixture of Example 111E (450 mg, 1.09 mmol) and potassium carbonate (906 mg, 6.56 mmol) in DMSO (10 mL) was added dropwise 30% H₂O₂ (6 mL) at 0°C. After stirring at 25°C for 16 hours, the mixture was diluted with water (50 mL) and the aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated sodium sulfite solution (50 mL x 2) and brine (100 mL), dried over sodium sulfate, filtered, and evaporated. The residue was purified by column chromatography to afford the title compound (450 mg, 95.7% yield) as a white solid. LCMS (ESI) m/z: 430 (M+1).

Example 111G

3-(1-(Cyclopropylmethyl)-4-methylpiperidin-4-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Examples 109E and 109F. (50mg, yield: 56.2%). ¹ H-NMR (400MHz, MethanoL-d ₄ )ppm 0.41 (d, J=4.52Hz, 2H), 0.64-0.83 (m, 2H), 1.12 (br.s., 1H), 1.47 (br.s., 3H), 2.09 (br.s., 2H), 2.50 (s, 3H), 2.54-2.71 (m, 2H ), 2.84-3.29 (m, 4H), 3.52 (br.s., 2H), 7.28 (d, J=8.03Hz, 1H), 7.48-7.69 (m, 1H), 8.63 (br.s., 1H). LCMS (ESI) m/z: 384 (M+1).

Example 112

3-(1-ethyl-4-methylpiperidin-4-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 111. ¹ H-NMR (400 MHz, MethanoL-d ₄ ) ppm: 1.20-1.61 (m, 6H), 2.09 (br. s., 2H), 2.49 (s, 3H), 2.52-2.77 (m, 2H), 3.17 (br. s., 4H), 3.49 (br. s., 2H), 7.16-7.34 (m, 1H), 7.46-7.63 (m, 1H), 8.46 (s, 1H). LCMS (ESI) m/z: 358 (M+1).

Example 113

3-(1-Isobutyl-4-methylpiperidin-4-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 111. ¹ H NMR (400 MHz, DMSO-d ₆ ) 0.84 (d, J = 6.5 Hz, 7H), 1.26 (s, 3H), 1.76 (d, J = 6.8 Hz, 3H), 2.00 (d, J = 7.3 Hz, 2H), 2.13-2.29 (m, 3H), 2.34 (s, 1H), 2.41 (s, 3H), 2.68 (s, 1H), 7.36 (dd, J = 2.5, 8.3 Hz, 1H), 7.55 (dd, J = 2.5, 11.0 Hz, 1H), 8.04 (s, 1H), 8.29 (br, s, 1H), 10.63 (s, 1H). LCMS (ESI) m/z: 386 (M+1).

Example 114

3-(1-Isopropyl-4-methylpiperidin-4-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 111. ¹ H-NMR (400 MHz, MethanoL-d ₄ ) d ppm 1.34 (d, J = 5.52 Hz, 6H), 1.47 (br. s., 3H), 2.11 (br. s., 2H), 2.51 (s, 3H), 2.53-2.72 (m, 2H), 3.11 (br. s., 2H), 3.44 (br. s., 3H), 7.20-7.38 (m, 1H), 7.59 (dd, J = 10.92, 2.64 Hz, 1H), 8.66 (br. s., 1H). LCMS (ESI) m/z: 372 (M+1).

Example 115

3-(1,4-dimethylpiperidin-4-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 111. ¹ H-NMR (400 MHz, MethanoL-d ₄ ) ppm: 1.46 (s, 3H), 2.05 (br. s., 2H), 2.50 (s, 3H), 2.56 (d, J = 11.67 Hz, 2H), 2.79 (s, 3H), 3.09 (br. s., 2H), 3.34-3.41 (m, 2H), 7.31 (dd, J = 8.09, 2.32 Hz, 1H), 7.63 (dd, J = 10.98, 2.20 Hz, 1H), 8.55 (s, 1H). LCMS (ESI) m/z: 344 (M+1).

Example 116

3-(1-(2-hydroxy-2-methylpropyl)-4-methylpiperidin-4-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 111. ¹ H NMR (400 MHz, DMSO-d ₆ ) 1.02-1.14 (m, 6H), 1.26 (s, 3H), 1.69-1.81 (m, 2H), 2.11-2.24 (m, 4H), 2.32-2.44 (m, 6H), 2.68 (br, s, 2H), 7.37 (dd, J=2.5, 8.3 Hz, 1H), 7.56 (dd, J=2.5, 11.0 Hz, 1H), 8.06 (s, 1H), 8.28 (s, 1H), 10.65 (s, 1H). LCMS (ESI) m/z: 402 (M+1).

Example 117

3-(1-ethyl-2,4-dimethylpiperidin-4-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

In this example, the compound was prepared as described in Example 111. ¹ H NMR (400 MHz, DMSO-d ₆ ) 1.07 (t, J=7.0 Hz, 3H), 1.13 (d, J=6.0 Hz, 3H), 1.41 (s, 3H), 1.84-1.72 (m, 1H), 1.97 (d, J=10.8 Hz, 2H), 2.05-2.16 (m, 1H), 2.44 (s, 3H), 2.54-2.70 (m, 2H), 2.7 7 (br, s, 1H), 2.90-3.03 (m, 2H), 7.41 (dd, J=2.4, 8.4Hz, 1H), 7.55 (dd, J=2.5, 1 1.0Hz, 1H), 8.05 (s, 1H), 8.33 (s, 1H), 10.63 (s, 1H). LCMS (ESI) m/z: 372 (M+1).

Example 118

3-(1-ethyl-3-methylpyrrolidin-3-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 111. ¹ H-NMR (MeOD, 400 MHz) δ: 1.37-1.41 (t, 3H), 1.58 (s, 3H), 2.47-2.49 (m, 1H), 2.51 (s, 3H), 2.67-2.74 (m, 1H), 3.29-3.30 (m, 2H), 3.34-3.67 (m, 4H), 7.33-7.35 (d, 1H), 7.66-7.69 (d, 1H), 8.52 (bs, 1H). LCMS (ESI) m/z: 344 (M+1).

Example 119

3-(1-Isopropyl-3-methylpyrrolidin-3-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 111. ¹ H-NMR (MeOD, 400 MHz) δ: 1.36-1.45 (m, 6H), 1.52-1.59 (m, 3H), 2.48 (s, 4H), 2.61-2.73 (m, 1H), 3.45-3.53 (m, 1H), 3.55-3.82 (m, 4H), 7.24-7.33 (m, 1H), 7.56-7.68 (m, 1H), 8.40-8.55 (bs, 1H). LCMS (ESI) m/z: 358 (M+1).

Example 120

3-(1-(Cyclopropylmethyl)-3-methylpyrrolidin-3-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 111. ¹ H-NMR (MeOD, 400 MHz) δ: 0.59 (d, 2H), 0.96-1.06 (m, 1H), 1.53 (s, 3H), 2.12-2.22 (m, 1H), 2.48 (s, 5H), 2.83-2.94 (m, 1H), 2.98-3.08 (m, 2H), 3.11-3.20 (m, 1H), 7.33-7.36 (m, 1H), 7.61-7.74 (m, 1H). LCMS (ESI) m/z: 370 (M+1).

Example 121

3-(1,3-Dimethylazepin-3-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This compound was prepared as described in Example 111. ¹ H-NMR (400 MHz, MethanoL-d ₄ ) ppm: 1.74 (s, 3H), 2.37 (s, 3H), 2.94 (s, 3H), 4.27 (d, J = 9.79 Hz, 2H), 4.43 (d, J = 9.29 Hz, 2H), 7.29 (d, J = 8.28 Hz, 1H), 7.62 (d, J = 10.92 Hz, 1H), 8.51 (br. s., 1H). LCMS (ESI) m/z: 316 (M+1).

Example 122

3-(1-ethyl-3-methylazepin-3-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 111. ¹ H-NMR (MeOD, 400 MHz) δ: 1.01-1.08 (m, 3H), 1.65-1.70 (m, 3H), 2.34 (s, 3H), 2.55-2.65 (m, 2H), 3.47-3.53 (m, 2H), 3.59-3.66 (m, 2H), 7.28-7.36 (dd, 1H), 7.63-7.73 (dd, 1H). LCMS (ESI) m/z: 330 (M+1).

Example 123

3-(1-Isopropyl-3-methylazepin-3-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 111. ¹ H-NMR (MeOD, 400 MHz) δ: 1.26 (d, J = 6.53 Hz, 6H), 1.75 (s, 3H), 2.40 (s, 3H), 3.38 (d, J = 5.90 Hz, 1H), 4.20-4.28 (m, 2H), 4.33-4.44 (m, 2H), 7.27-7.43 (dd, 1H), 7.62-7.76 (dd, 1H), 8.43-8.58 (bs, 1H). LCMS (ESI) m/z: 344 (M+1).

Example 124

3-(1-(Cyclopropylmethyl)-3-methylazepin-3-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Example 111. ¹ H-NMR (400 MHz, MethanoL-d ₄ ) ppm 0.46 (d, J = 4.02 Hz, 2H), 0.66-0.82 (m, 2H), 1.09 (d, J = 6.02 Hz, 1H), 1.76 (s, 3H), 2.37 (s, 3H), 3.19 (br. s., 2H), 4.19-4.40 (m, 2H), 4.54 (d, J = 9.16 Hz, 2H), 7.24 (br. s., 1H), 7.57 (br. s., 1H), 8.53 (br. s., 1H). LCMS (ESI) m/z: 356 (M+1).

Example 125

3-(1-(2-hydroxy-2-methylpropyl)-3-methylazepin-3-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This compound was prepared as described in Example 111. ¹ H-NMR (400 MHz, MethanoL-d ₄ ) ppm: 1.32 (s, 6H), 1.75 (s, 3H), 2.30-2.43 (m, 3H), 3.24 (s, 2H), 4.35 (d, J=9.91 Hz, 2H), 4.52 (d, J=9.29 Hz, 2H), 7.26 (d, J=8.03 Hz, 1H), 7.61 (d, J=11.04 Hz, 1H), 8.50 (br. s., 1H). LCMS (ESI) m/z: 374 (M+1).

Example 126

6-Fluoro-3-(1-isopropyl-4-methylpiperidin-4-yl)-2-methoxy-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

Example 126A

tert-Butyl 4-(1-cyano-2-(2-(2,6-dibromo-4-fluorophenyl)hydrazino)-2-oxoethyl)-4-methylpiperidine-1-carboxylate

Under nitrogen, a mixture of Example 105C (2.73 g, crude, 9.67 mmol), HATU (5.51 g, 0.26 mmol), Example 1D (3.29 g, 11.60 mmol), and triethylamine (2.84 g, 29.01 mmol) in DMF (20 mL) was stirred at 25°C for 10 hours. After completion of the reaction, the mixture was quenched with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with water (50 mL x 2) and brine (50 mL x 2), dried over sodium sulfate, filtered, and evaporated. The residue was purified by column chromatography to give the title compound (4.50 g, yield: 85%) as a yellow solid.

Example 126B

tert-Butyl 4-(5-amino-1-(2,6-dibromo-4-fluorophenyl)-3-hydroxy-1H-pyrazol-4-yl)-4-methylpiperidine-1-carboxylate

A mixture of Example 126A (4.50 g, 8.21 mmol) and potassium carbonate (2.27 g, 16.42 mmol) in ethanol (100 mL) was stirred at 80° C. for 15 hours. After the solvent was removed in vacuo, the residue was diluted with water (100 mL), the aqueous layer was extracted with ethyl acetate (100 mL×2), and the combined organic layers were washed with water (50 mL×2) and brine (50 mL×2), dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography to give the title compound (3.81 g, yield: 84%) as a yellow solid.

Example 126C

tert-Butyl 4-(5-amino-1-(2,6-dibromo-4-fluorophenyl)-3-methoxy-1H-pyrazol-4-yl)-4-methylpiperidine-1-carboxylate

A mixture of Example 126B (2.3 g, 3.65 mmol), iodomethane (517.80 mg, 3.65 mmol) and potassium carbonate (1.51 g, 10.94 mmol) in DMF (50 ml) was stirred at 25° C. for 15 hours. After the solvent was removed in vacuo, the residue was diluted with water (100 ml), the aqueous layer was extracted with ethyl acetate (100 ml×2), the combined organic layers were washed with water (50 ml×2), brine (50 ml×2), dried over sodium sulfate, filtered and evaporated, and the residue was purified by column chromatography to give the title compound (590 mg, yield: 28.76%) as a yellow solid.

Example 126D

tert-Butyl 4-(8-bromo-6-fluoro-2-methoxy-4H-benzo[4,5]imidazo[1,2-B]pyrazol-3-yl)-4-methylpiperidine-1-carboxylate

Under N2 protection, a mixture of Example 126C (680 mg, 1.21 mmol), cuprous iodide (69 mg, 0.36 mmol), N1,N2-dimethylethane-1,2-diamine (64 mg, 0.73 mmol), and potassium phosphate (770 mg, 3.63 mmol) in DMF (15 mL) was stirred at 70°C for 10 hours. After cooling to room temperature, the resulting mixture was filtered, the filtrate evaporated, and the residue purified by column chromatography to give the title compound (455 mg, 78% yield) as a white solid. LCMS (ESI) m/z: 481, 483 (M, M+2).

Example 126E

tert-Butyl 4-(8-cyano-6-fluoro-2-methoxy-4H-benzo[4,5]imidazo[1,2-B]pyrazol-3-yl)-4-methylpiperidine-1-carboxylate

Under nitrogen, a mixture of Example 126D (400 mg, 0.83 mmol), zinc cyanide (108 mg, 1.69 mmol), PD2(DBA)3 (152 mg, 0.16 mmol), DPPF (185 mg, 0.33 mmol), and Zn (108 mg, 1.66 mmol) in DMF (8 mL) was stirred at 120°C for 15 hours. After cooling to room temperature, the resulting mixture was filtered, the filtrate evaporated, and the residue purified by column chromatography to give the title compound (330 mg, 81% yield) as a yellow solid. LCMS (ESI) m/z: 428 (M+1).

Example 126F

tert-Butyl 4-(8-formylamino-6-fluoro-2-methoxy-4H-benzo[4,5]imidazo[1,2-B]pyrazol-3-yl)-4-methylpiperidine-1-carboxylate

To a mixed solution of Example 126E (200 mg, 0.47 mmol) and potassium carbonate (300 mg, 2.17 mmol) in DMSO (5 mL) at 0°C was added dropwise 30% H2O2 (5 mL). After stirring at 25°C for 15 hours, the mixture was diluted with water (50 mL), and the aqueous layer was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, filtered, and evaporated. The residue was purified by column chromatography to provide the title compound (195 mg, yield: 93%) as a white solid. LCMS (ESI) m/z: 446 (M+1).

Example 126G

6-Fluoro-2-methoxy-3-(4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

A solution of Example 126F (100 mg, 0.22 mmol) in a mixture of dichloromethane/trifluoroacetic acid (10 mL/3 mL) was stirred at 25° C. for 3 hours. The solvent was removed in vacuo to provide the title compound which was used directly in the next step without further purification.

Example 126H

6-Fluoro-3-(1-isopropyl-4-methylpiperidin-4-yl)-2-methoxy-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

A mixture of Example 126G (78 mg, crude oil, 0.22 mmol), sodium cyanoborocyanide (140 mg, 2.22 mmol) and acetone (70 mg, 1.2 mmol) in tetrahydrofuran/methanol (15 mL/10 mL) was stirred at 24° C. for 15 hours. The mixture was diluted with water (20 mL), the aqueous layer was extracted with ethyl acetate (30 mL×2), and the combined organic layers were washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by preparative HPLC to give the title compound (35 mg, 41% yield) as a white solid. ¹ H-NMR (400MHz, MethanoL-d ₄ ) δppm 1.27-1.52(m, 9H), 1.77-2.19(m, 2H), 2.69(br.s., 2H), 2.84-3.28(m, 2H), 3.39-3.55(m, 3H), 4.06(s, 3H), 7.31 (dd, J=8.03, 2.51Hz, 1H), 7.66 (dd, J=10.98, 2.45Hz, 1H), 8.55 (br.s., 1H). LCMS (ESI) m/z: 388 (M+1).

Example 127

2-Benzylmethoxy-6-fluoro-3-(1-isopropyl-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

Example 127A

A mixture of Example 126B (3.0 g, 5.48 mmol), Boc2O (10.0 g, 45.8 mmol) and DMAP (670 mg, 5.48 mmol) was stirred at 80° C. for 3 hours. After cooling to room temperature, the mixture was diluted with aqueous sodium bicarbonate solution (30 mL), the aqueous layer was extracted with dichloromethane (100 mL×3), and the combined organic layers were dried over sodium sulfate, filtered and evaporated to provide the title compound which was used directly in the next step without further purification (4.5 g crude product).

Example 127B

A mixture of Example 127A (4.5 g, 5.31 mmol) and potassium carbonate (1.46 g, 10.62 mmol) in methanol (40 mL) was stirred for 4 hours at 20° C. The mixture was filtered, the filtrate was evaporated, and the residue was purified by chromatography on silica gel to provide the title compound (3.1 g, yield: 80%) as a yellow solid.

Example 127C

A mixture of Example 127B (2.5 g, 3.35 mmol), potassium carbonate (925 mg, 6.7 mmol) and benzyl bromide (626 mg, 3.68 mmol) in methanol (30 mL) was stirred at 60° C. for 8 hours. The mixture was filtered, the filtrate was evaporated, and the residue was purified by chromatography to give the title compound (1.4 g crude) as a white solid.

Example 127D

3-(Benzyloxy)-1-(2,6-dibromo-4-fluorophenyl)-4-(4-methylpiperidin-4-yl)-1H-pyrazol-5-amine

A solution of Example 127C (1.4 g, 1.63 mmol) in 4 M hydrochloric acid/ethyl acetate (20 mL) was stirred at 10° C. for 3 hours. The solvent was removed in vacuo to provide the title compound (1.0 g, yield: 100%) which was used in the next step without further purification as a yellow solid.

Example 127E

tert-Butyl 4-(5-amino-3-(benzyloxy)-1-(2,6-dibromo-4-fluorophenyl)-1H-pyrazol-4-yl)-4-methylpiperidine-1-carboxylate

A mixture of Example 127D (1.0 g, 1.78 mmol), triethylamine (362 mg, 3.56 mmol) and Boc2O (776 mg, 3.56 mmol) in dichloromethane (15 mL) was stirred at 10° C. for 4 hours. The mixture was diluted with H2O (20 mL), the aqueous layer was extracted with dichloromethane (15 mL×2), the combined organic layers were washed with water, brine, dried over sodium sulfate, filtered and evaporated, and the residue was purified by column chromatography to give the title compound (1.0 g crude) as a white solid.

Example 127F

2-Benzylmethoxy-6-fluoro-3-(1-isopropyl-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

This example was prepared as described in Examples 126D-126H. ^1H NMR (400 MHz, DMSO-d ₆ ) 0.95 (d, J=6.5 Hz, 6H), 1.24 (s, 3H), 1.60-1.72 (m, 2H), 2.34 (br, s, 4H), 2.66-2.77 (m, 3H), 5.32 (s, 2H), 7.29-7.55 (m, 7H), 8.04 (s, 1H), 8.34 (br. s, 1H), 10.20 (s, 1H). LCMS (ESI) m/z: 464 (M+1).

Process F

Example 128

6-Fluoro-2-(piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

Example 128A

tert-Butyl 4-(2-cyanoacetyl)piperidine-1-carboxylate

To a solution of acetonitrile (5.06 g, 123.4 mmol) in anhydrous tetrahydrofuran (200 mL) at -78°C under a nitrogen atmosphere was added dropwise n-BuLi (39.5 mL, 98.6 mmol). After stirring at -78°C for 2 hours, 1-(tert-butyl)-4-methylpiperidine-1,4-dicarboxylate (20 g, 82.2 mmol) in tetrahydrofuran (100 mL) was added dropwise to the mixture. After the addition was complete, the mixture was warmed to 15°C and stirred for 16 hours before being quenched with saturated aqueous ammonium chloride (100 mL). The aqueous phase was extracted with ethyl acetate (100 mL x 2). The combined organic layers were dried over sodium sulfate, filtered, and evaporated. The residue was purified by column chromatography to provide the title compound (7.9 g, yield: 38.1%) as a yellow solid. LCMS (ESI) m/z: 253 (M+1).

Example 128B

tert-Butyl 4-(2-cyano-1-(2-(2,6-dibromo-4-fluorophenyl)hydrazono)ethyl)piperidine-1-carboxylate

A mixture of Example 128A (6.35 g, 25.16 mmol) and Example 1D (10 g, 35.2 mmol) in ethanol (80 mL) and HOAc (80 mL) was stirred at 85° C. for 16 hours. After cooling to room temperature, the mixture was evaporated to give the title compound which was used in the next step without further purification (15 g, crude).

Example 128C

tert-Butyl 4-(5-amino-1-(2,6-dibromo-4-fluorophenyl)-1H-pyrazol-3-yl)piperidine-1-carboxylate

A mixture of Example 128B (13 g, 25.1 mmol) and triethylamine (12.7 g, 125.5 mmol) in ethanol (100 mL) was heated to 80° C. for about 16 hours. After cooling to room temperature, the mixture was evaporated and the residue was purified by column chromatography to give the title compound (11 g, yield: 84.6%) as a yellow solid.

Implementation example 128D

tert-Butyl 4-(8-bromo-6-fluoro-4H-benzo[4,5]imidazo[1,2-B]pyrazol-2-yl)piperidine-1-carboxylate

Under nitrogen, a mixture of Example 128C (1.5 g, 2.9 mmol), cuprous iodide (166 mg, 0.87 mmol), potassium phosphate (1.8 g, 8.7 mmol), and N1,N2-dimethylethane-1,2-diamine (153 mg, 1.74 mmol) in DMF (8 mL) was stirred at 55°C for 18 hours. After cooling to room temperature, the mixture was diluted with water (20 mL), and the aqueous layer was extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate, filtered, and evaporated. The residue was purified by column chromatography to provide the title compound (350 mg, yield: 27.6%) as a yellow solid. LCMS (ESI) m/z: 437, 439 (M, M+2).

Example 128E

tert-Butyl 4-(8-carbamoyl-6-fluoro-4H-benzo[4,5]imidazo[1,2-B]pyrazol-2-yl)piperidine-1-carboxylate

Under nitrogen, a mixture of Example 128D (350 mg, 0.8 mmol), zinc cyanide (188 mg, 1.6 mmol), PD2(DBA)3 (110 mg, 0.12 mmol), DPPF (133 mg, 0.24 mmol), and zinc powder (104 mg, 1.6 mmol) in DMF (4 mL) was stirred at 120°C for 2 hours. After cooling to room temperature, the resulting mixture was filtered, the filtrate evaporated, and the residue purified by preparative TLC to give the title compound (50 mg, yield: 16.2%) as a yellow solid. LCMS (ESI) m/z: 402 (M+1).

Example 128F

6-Fluoro-2-(piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

A solution of Example 128E (50 mg, 0.125 mmol) in trifluoroacetic acid (1 mL) and dichloromethane (6 mL) was stirred at 20°C for 2 hours. The resulting mixture was evaporated, and the residue was purified by preparative HPLC to afford the title compound (23 mg, yield: 59.0%) as a white solid. ^1H -NMR (400 MHz, MethanoL-d ₄ ) ppm: 1.07-1.27 (m, 9H), 2.51 (d, J = 1.51 Hz, 2H), 2.76-2.97 (m, 2H), 3.34 (d, J = 3.26 Hz, 2H), 5.74 (br. s., 1H), 7.36-7.39 (m, 1H), 7.68-7.72 (m, 1H). LCMS (ESI) m/z: 302 (M+1).

Example 129

2-(1-ethylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide

A mixed solution of Example 128F (20 mg, 0.066 mmol), 40% acetaldehyde (0.2 ml), and sodium cyanoborocyanide (17 mg, 0.264 mmol) in methanol (5 mL) was stirred at 10°C for 16 hours. After completion of the reaction, the mixture was diluted with water (5 ml), and the aqueous layer was extracted with dichloromethane (20 ml x 2). The combined organic layers were evaporated, and the residue was purified by preparative HPLC to give the title compound (17.36 mg, yield: 78.9%) as a light yellow solid. ¹ H-NMR (400MHz, MethanoL-d ₄ )ppm1.38 (t, J=7.28Hz, 3H), 1.98-2.23 (m, 2H), 2.28-2.49 (m, 2H), 2.92-3.25 (m, 5H), 3.57 (d, J=11.54Hz, 2H), 5.83 (s, 1H), 7.29 (dd, J=8.28, 2.51Hz, 1H), 7.61 (dd, J=10.92, 2.51Hz, 1H), 8.60 (br.s., 1H). LCMS (ESI) m/z: 330 (M+1).

In vitro studies

Cellular PARylation analysis

HCC1937 cells were seeded into 96-well plates at 4×10 ⁴ cells/well and cultured overnight in a 37°C incubator. After treatment with the test compound for 30 minutes, the cells were treated with 1 mM hydrogen peroxide for 10 minutes. The cells were washed twice with 200 μL of pre-cooled PBS and fixed with 100 μL of pre-cooled methanol/acetone (7:3) in an ice bath for 30 minutes. After air drying, the cells were blocked with PBS-Tween-20 blocking buffer (0.05%) containing 5% skim milk powder for 30 minutes at room temperature. The cells were incubated with anti-PAR 10H antibody at a ratio of 1:100 in blocking buffer at room temperature for 1 hour, then washed three times with PBS-Tween-20, and then incubated in blocking buffer containing goat anti-mouse fluorescein-5(6)-isothiocyanate (FITC)-conjugated secondary antibody and 1 μg/mL DAPI at room temperature for 1 hour in the dark. After washing three times with PBS-Tween-20, the data were analyzed using a fluorescence microplate counter (Flexstation III, Molecular Device).

PARP enzyme test (according to the instructions of HT Universal PARP1 Colorimetric Assay Kit).

Histones were coated in 96-well plates and incubated overnight at 4°C. The plates were washed three times with 200 μL of PBST solution, blocked with blocking buffer, incubated at room temperature for 30 minutes, and washed three times with PBST solution. Test compounds were added to the plates, followed by 20 μL of diluted PARP1 (1 nM) or 20 μL of PARP2 (3 nM) solution and incubated for 1 or 2 hours. 50 μL of a 1:50 mixture of streptavidin-HRP was added to the plates and incubated at room temperature for 30 minutes. The plates were then washed three times with PBST buffer. 100 μL of HRP (chemiluminescent substrate A and substrate B (1:1)) was added to the plates. The plates were immediately read on a microplate reader (Envision, PerkinElmer).

Antiproliferative assay

MDA-MB-436 and MDA-MB-231 cells were seeded in 96-well plates at a density of 500 and 2000 cells per well, respectively, and cultured overnight. The culture medium was RPMI 1640 containing 10% (V/V) FBS and 1% (V/V) penicillin-streptomycin. After adding the test compound, the cells were treated for 8 days. Cell viability was measured using a CCK8 kit. The specific method was to add 10 μL of CCK8 reagent to each well and incubate at 37°C in a 5% CO2 incubator for 3 hours. After shaking for 10 minutes, the optical absorption value (OD value) was measured at 450 nm using a Flexstation III (Molecular Device).

For compound combination studies (combined with DNA-damaging drugs), the PF50 value is used to calculate drug synergy. PF50 = [IC50 of the test compound] / [IC50 of the compound at a fixed concentration of the DNA-damaging drug]. In this study, temozolomide (TMZ) was used as the DNA-damaging drug.

PARP-1 inhibition enzyme IC50 and cellular PARylation IC50 data for compounds of the present invention are provided below in Table I. Compounds with IC50 between 1 and 100 nM are designated as +++; compounds with IC50 between 101 and 1000 nM are designated as ++, and compounds with IC50 greater than 1000 nM are designated as +.

Table 1

Claims (21)

1. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof, in, D is selected from -C( _Rd1 )( _Rd2 )- or -N( _Rd4 )-; _Rd1 and _Rd2 are independently selected from H, F, Cl, Br, I, OH, CN, SH, or _NH2 , respectively. _R1 is selected from H, _C1-3 alkyl, _C1-3 alkoxy, benzyloxy, or _R101 is selected from H, methyl, ethyl, n-propyl, or isopropyl. _R3 is selected from H, F, Cl, Br, I, CN or methyl; _R2 is selected from H, CN, _-CH2N ( _R201 )( _R202 ), R ₂₀₁ and R ₂₀₂ are each independently selected from H, _C1-3 alkyl, _C1-3 alkyl acyl, _C3-6 cycloalkyl acyl, or _C3-6 cycloalkyl; R ₂₀₃ , R ₂₀₄ , R ₂₁₇ , and R ₂₁₈ are each independently selected from H, optionally substituted _C1-3 alkyl groups, cyclopropyl or cyclopropylmethylene, and the substituents are selected from F, Cl, Br, I, CN, OH, _NH2 , methyl or methoxy, and the number of substituents is 0, 1, 2 or 3. R ₂₁₉ is selected from ethyl or methyl; R ₂₀₅ and R ₂₀₆ are each independently selected from H or C _1-3 alkyl groups; R ₂₀₆ is also selected from F, Cl, Br, I, CN, OH or NH ₂ ; R ₂₀₇ is selected from H, optionally substituted _C1-3 alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclobutylmethylene, oxecyclobutyl or oxecyclobutylmethylene, and the substituent is selected from F, Cl, Br, I, CN, OH, _NH2 , methyl, trifluoromethyl, methoxy or methanesulfonyl, and the number of substituents is 0, 1, 2 or 3; R ₂₀₈ is selected from H, _C1-4 alkyl, cyclopropylmethylene, or cyclobutyl; R ₂₀₉ is selected from -N(R _d4 )-, O or S (＝O) ₂ ; R ₂₁₀ is selected from H, F, Cl, Br, I, CN, OH, NH ₂ , N,N-bis(C _1-3 alkyl)amino or C _1-3 alkylamino; R _211-213 are selected from H or C _1-4 alkoxycarbonyl, C _1-4 alkyl or CN groups optionally substituted with R ₂₁₅ ; R ₂₁₄ is selected from H, _C1-4 alkyl groups optionally substituted with R ₂₁₅ , 3-6 membered cycloalkyl groups, 3-6 membered cycloalkylmethylene groups, -S(=O) ₂ CH ₃ , R ₂₁₅ is selected from F, Cl, Br, I, CN, OH, NH ₂ , methyl, ethyl, methoxy, ethoxy, formyl, acetyl, methanesulfonyl, ethanesulfonyl, methoxycarbonyl, ethoxycarbonyl, dimethylamino, diethylamino, dimethylaminocarbonyl, or diethylaminocarbonyl. The number of R ₂₁₅ is 1, 2 or 3; Optionally, R ₂₁₂ and R ₂₁₃ together form a linker bond -CH _2- , -CH ₂ CH _2- , or -CH ₂ CH ₂ CH _2- ; T ₂₂ is selected from N or C (R ₂₂₄ ); R _220-224 are independently selected from H, F, Cl, Br, I, CN, OH, SH, NH ₂ , C _1-3 alkylamino, C _1-3 alkyl or R _d4 is selected from H or _RO3 ; _R03 is selected from _C1-10 alkyl groups; _R03 is optionally substituted with _R001 ; _R001 is selected from F, Cl, Br, I, OH, N( _CH3 ) ₂ , NH( _CH3 ), _NH2 , or methoxy. The number of R ₀₀₁ is independently selected from 0, 1, 2 or 3. 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the D is selected from -NH-, -N( _CH3 )-, -C(F) _2- , -C(H)(F)-, -C(H)(OH)-. 3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein _R1 is selected from H, methyl, methoxy, benzyloxy, ... _R3 is selected from H, F, and Cl. 4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein _R2 is selected from _-CH2N ( _R201 )( _R202 ), and _R201 and _R202 are independently selected from H or cyclopropionyl groups, respectively. 5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, _R2 is selected from 6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein _R2 is selected from [selection number missing]. R ₂₀₃ is selected from methyl, ethyl, n-propyl, isopropyl, -CH _2C (CH ₃ )(CH ₃ )(OH), cyclopropylmethylene. R ₂₀₄ is selected from methyl, ethyl, n-propyl, and isopropyl; R _217-219 are independently selected from ethyl and methyl, respectively. 7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein _R2 is selected from... 8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein _R2 is selected from [the group consisting of,] R ₂₀₅ is selected from H, methyl, ethyl, n-propyl, and isopropyl, and R ₂₀₆ is selected from H and OH. 9. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein _R2 is selected from [the group consisting of,]. _R2 is selected from 10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein, _R2 is selected from 11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein _R2 is selected from [the group consisting of,] R ₂₀₇ is selected from H, methyl, ethyl, n-propyl, isopropyl, -CH ₂ CF ₃ , -CH ₂ CH ₂ CF ₃ , -CH ₂ CH ₂ F, -CH ₂ CH ₂ S(＝O) ₂ CH ₃ , -CH ₂ CH ₂ CN, 12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein, _R2 is selected from 13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein _R2 is selected from [the group consisting of,] R ₂₀₈ is selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropylmethylene, and cyclobutyl. 14. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein _R2 is selected from... 15. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein _R2 is selected from the group consisting of , and _R209 is selected from the group consisting of . 16. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein _R2 is selected from [the group consisting of,] R ₂₁₀ is selected from dimethylamino, methylamino, and NH ₂ . 17. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein _R2 is selected from H, CN, methyl, ethyl, hydroxymethyl, or _{methoxycarbonyl} . R ₂₁₂ is selected from H, methyl, R ₂₁₃ is selected from H. R ₂₁₄ is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CH _2C (OH)(CH ₃ ) ₂ , -CH _2C (F ₎ (CH ₃ ) ₂ , _{-CH 2CH 2F} , -CH _2CF 3, -CH _2CH 2CF ₃ , -CH _{2CH 2NH 2} , -CH _{2CH 2OH ,} -CH _{2CH 2CN} , -CH _{2CH 2OCH 3} , -CH _{2CH 2CH 2OCH 3} , -CH _{2CH 2N} (CH ₃ ) ₂ , -S(＝O) _{2CH 3} , -CH _{2CH 2S} (＝O) _{2CH 3} , cyclopropyl, cyclopropylmethylene, 18. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein _R2 is selected from... 19. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein _R2 is selected from T, _R22 is selected from N or C ( _R224 ); and _R220-224 are each independently selected from _C1-3 alkylamino or _C1-3 alkyl. The _C1-3 alkylamino and _C1-3 alkyl groups are selected from methylaminomethylene. 20. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein _R2 is selected from... 21. A compound or a pharmaceutically acceptable salt thereof, selected from: 1) 6-Fluoro-3-(piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 2) 3-(1-ethylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 3) 6-Fluoro-3-(1-(2-fluoroethyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 4) 3-(1-Cyclopropylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 5) 3-(1-(cyclopropylmethyl)piperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 6) 6-Fluoro-3-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 7) 6-Fluoro-3-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 8) 3-(1-(cyclopropylformyl)piperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 9) 6-Fluoro-3-(1-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 10) 6-Fluoro-3-(1-isopropylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 11) 6-Fluoro-3-(1-(oxecyclobutan-3-yl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 12) 6-Fluoro-3-(1-propylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 13) 6-Fluoro-3-(1-(2-aminoethyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 14) 3-(1-(2-(dimethylamino)ethyl)piperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 15) 6-Fluoro-3-(1-(2-methoxyethyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 16) 6-Fluoro-3-(1-(2-hydroxyethyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 17) 3-(1-ethylpiperidin-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 18) 3-(1-ethylazacycloheptane-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 19) 6-Fluoro-3-(1-methylazacycloheptane-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 20) 6-Fluoro-3-(1-methylpyrrolidone-3-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 21) 3-(1-ethylpyrrolidone-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 22) 6-Fluoro-3-(1-isopropylpyrrolidone-3-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 23) 6-Fluoro-3-(pyrrolidone-2-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 24) 6-Fluoro-3-(1-methylpyrrolidone-2-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 25) 3-(1-ethylpyrrolidone-2-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 26) 3-(1-ethylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 27) 6-Fluoro-3-(1-propylpyrrolidone-2-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 28) 6-Fluoro-3-(3-methyl-3-azabicyclo[3.1.0]hexane-1-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 29) 3-(3-ethyl-3-azabicyclo[3.1.0]hexane-1-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 30) 3-(3-cyclobutyl-3-azabicyclo[3.1.0]hexane-1-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 31) 3-(3-cyclopropylmethylene-3-azabicyclo[3.1.0]hexane-1-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 32) 6-Fluoro-3-(3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 33) 3-(3-azabicyclo[3.1.0]hexane-6-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 34) 3-(3-ethyl-3-azabicyclo[3.1.0]hexane-6-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 35) 3-(8-ethyl-8-azabicyclo[3.2.1]oct-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 36) 6-Fluoro-3-(4-hydroxypyrrolidone-2-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 37) 3-Cyano-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 38) 3-Cyano-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 39) 3-Aminomethyl-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 40) 3-(cyclopropylcarbamomethyl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carbamoamide; 41) 6-Fluoro-3-(4-Fluorophenyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 42) 6-Fluoro-3-(2-Fluoro-4-((methylaminomethylene)phenyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 43) 6-Fluoro-3-(4-((methylamino)methyl)phenyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 44) 6-Fluoro-3-(2-Fluoro-5-((methylamino)methyl)phenyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 45) 6-Fluoro-3-(pyridin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazol-8-carboxamide; 46) 6-Fluoro-3-(4-(piperidin-3-yl)phenyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 47) 6-Fluoro-3-(tetrahydro-2H-pyran-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 48)3-(4-(dimethylamino)cyclohexyl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 49) 6-Fluoro-3-(4-methylpiperazin-1-carbonyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 50)3-(1-(cyclopropylmethyl)piperidin-4-yl)-4,4,6-trifluoro-4H-pyrazolo[1,5-a]indole-8-carboxamide; 51) 3-(1-ethylpiperidin-4-yl)-6-fluoro-4-hydroxy-4H-pyrazolo[1,5-a]indole-8-carboxamide; 52) 3-(1-ethylpiperidin-4-yl)-6-fluoro-4-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 53) 6-Fluoro-3-(4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 54) 3-(1-Ethyl-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 55)3-(1-Cyclopropyl-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 56) 6-Fluoro-3-(1-(2-hydroxy-2-methylpropyl)-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 57)3-(1-Cyclopropylmethylene-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 58)3-(1-(4,4-difluorocyclohexyl)-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 59) 6-Fluoro-3-(4-methyl-1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 60) 6-Fluoro-3-(1-(2-fluoroethyl)-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 61) 6-Fluoro-3-(4-methyl-1-(2,2,2-trifluoroethyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 62) 6-Fluoro-3-(4-methyl-1-(2,2,2-trifluoropropyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 63)3-(1-((1-cyanocyclopropyl)methyl)-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 64)3-(1-((1-cyanocyclobutyl)methyl)-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 65) 6-Fluoro-3-(4-methyl-1-(2-(methanesulfonyl)ethyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 66) 6-Fluoro-3-(4-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazol-8-carboxamide; 67)3-(1-((1-aminocyclopropyl)methyl)-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 68) 6-Fluoro-3-(4-methyl-1-(oxecyclobutane-3-ylmethyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 69) 6-Fluoro-3-(1-(2-methoxyethyl)-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 70)6-Fluoro-3-(1-((1-hydroxycyclopropyl)methyl)-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 71) 6-Fluoro-3-(4-methyl-1-((3-methyloxetane-3-yl)methyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 72) 6-Fluoro-3-(1-(3-methoxypropyl)-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 73) 6-Fluoro-3-(4-methyl-1-((1-(methanesulfonyl)cyclopropyl)methyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 74) 6-Fluoro-3-(4-methyl-1-(thiazolyl-2-ylmethyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 75) 6-Fluoro-3-(4-methyl-1-(methanesulfonyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 76) 6-Fluoro-3-(1-(3-fluorocyclobutyl)-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 77) 6-Fluoro-3-(4-methyl-1-(thiophen-2-ylmethyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 78)3-(1-((1-ethylpiperidin-4-yl)methyl)-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 79) 6-Fluoro-3-(4-methyl-1-((1-methylazacyclobutane-3-yl)methyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 80)2-((4-(8-carbamoyl-6-fluoro-4H-benzo[4,5]imidazo[1,2-B]pyrazol-3-yl)-4-methylpiperidin-1-yl)methyl)cyclopropanecarboxylic acid ethyl ester; 81)3-(1-((2-(dimethylaminomethyl)cyclopropyl)methyl)-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 82) 6-Fluoro-3-(1-Isobutyl-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide 83) 6-Fluoro-3-(4-methyl-1-((4-methylthiazolyl-5-yl)methyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 84) 6-Fluoro-3-(4-methyl-1-((1-methyl-1H-imidazol-2-yl)methyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 85)3-(1-((1,2-dimethyl-1H-imidazol-5-yl)methyl)-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 86)3-(1'-ethyl-4-methyl-[1,4'-bipiperidine]-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 87) 6-Fluoro-3-(4-methyl-1-((6-oxo-1,6-dihydropyridazin-3-yl)methyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 88)3-(1-(2-cyanoethyl)-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 89) 6-Chloro-3-(1-Ethyl-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 90)3-(1-ethyl-3-methylpyrrolidone-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 91)3-(1,3-dimethylpyrrolidone-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 92) 6-Fluoro-3-(1-Isopropyl-3-methylpyrrolidone-3-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 93)3-(1-(cyclopropylmethyl)-3-methylpyrrolidone-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 94) 6-Fluoro-3-(3-methyl-1-(oxecyclobutan-3-yl)pyrrolidine-3-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 95)6-Fluoro-3-(1-(2-fluoroethyl)-3-methylpyrrolidine-3-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 96)3-(1-((2,2-difluorocyclopropyl)methyl)-3-methylpyrrolidone-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 97) 6-Fluoro-3-(3-methyl-1-(2,2,2-trifluoroethyl)pyrrolidine-3-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 98) 6-Fluoro-3-(3-methyl-1-(2-(methanesulfonyl)ethyl)pyrrolidine-3-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 99) 6-Fluoro-3-(3-methyl-1-(3,3,3-trifluoropropyl)pyrrolidine-3-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 100)3-(1-((1-aminocyclopropyl)methyl)-3-methylpyrrolidone-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 101)3-(1-((1-cyanocyclobutyl)methyl)-3-methylpyrrolidone-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 102)3-(1-((1-cyanocyclopropyl)methyl)-3-methylpyrrolidone-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 103)3-(1-(2-cyanoisoyl)-3-methylpyrrolidine-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 104)3-(1-(cyclopropylmethyl)-3-methylpyrrolidone-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 105)6-Fluoro-3-(1-Isopropyl-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 106) 6-Fluoro-3-(4-methyl-1,1-dioxo-2H-thiaran-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 107)3-(1,4-ethylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 108)3-(4-cyano-1-(cyclopropylmethyl)piperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 109)3-(4-hydroxymethyl-1-(cyclopropylmethyl)piperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 110)4-(8-formamide-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazol-3-yl)-1-(cyclopropylmethyl)piperidine-4-carboxylic acid ethyl ester; 111)3-(1-(cyclopropylmethyl)-4-methylpiperidin-4-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 112)3-(1-ethyl-4-methylpiperidin-4-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 113)3-(1-isobutyl-4-methylpiperidin-4-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 114)3-(1-Isopropyl-4-methylpiperidin-4-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 115)3-(1,4-dimethylpiperidin-4-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 116)3-(1-(2-hydroxy-2-methylpropyl)-4-methylpiperidin-4-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 117)3-(1-ethyl-2,4-dimethylpiperidin-4-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 118)3-(1-ethyl-3-methylpyrrolidone-3-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 119)3-(1-isopropyl-3-methylpyrrolidone-3-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 120)3-(1-(cyclopropylmethyl)-3-methylpyrrolidone-3-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 121)3-(1,3-dimethylaza-3-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 122)3-(1-ethyl-3-methylaza-3-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 123)3-(1-isopropyl-3-methylaza-3-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 124)3-(1-(cyclopropylmethyl)-3-methylaza-3-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 125)3-(1-(2-hydroxy-2-methylpropyl)-3-methylaza-3-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 126)6-Fluoro-3-(1-Isopropyl-4-methylpiperidin-4-yl)-2-methoxy-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 127) 2-Benzylmethoxy-6-fluoro-3-(1-isopropyl-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 128)6-Fluoro-2-(piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; and 129)2-(1-Ethylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide.